role of toxicological analysis in the management of ...- simple signs: dizziness, transitory...
TRANSCRIPT
Role of toxicological analysis in the
management of poisonings with cardiotoxicants
Bruno Meacutegarbane
Reacuteanimation Meacutedicale et Toxicologique INSERM U705 Universiteacute Paris - Diderot
Hocircpital Lariboisiegravere Paris France
bull One among the first causes of hospital admission and death
bull Increasing incidence
bull In the USA 10th cause of exposures (37) but 4th cause of death (fatality rate 027)
Poisonings with cardiovascular agents
Poisoned patients
Cardiovascular failure
1554 60 (4 )
164 (11 ) 37 (22 )
January 1998 to October 2002 3922 patients
N Mortality rate
Lariboisiegravere Hospital ICU Paris France
Cardiotoxicants
ndash Cardiovascular pharmaceuticals
ndash Sodium-channel blockers (Class I)
ndash Beta-blockers (class II)
ndash Potassium channel blockers (sotalol) (class III)
ndash Calcium-channel antagonists (class IV)
ndash Cardioglycosides (class V)
ndash Non-cardiovascular pharmaceuticals
antipsychotics antidepressants antihistamines hellip
ndash Drugs cocaine amphetamines hellip
ndash Rural toxicants organophosphates pesticides hellip
ndash Industrial toxicants alumine phosphide hellip
ndash Household toxicants trichloroethylene hellip
ndash Plants digitalis aconit colchicine yew Taxus baccatahellip
ndash Over-the-counter laquo Best life raquo (sibutramine)
A larger entity than cardiovascular drugs
Definition of ldquosevere poisoningrdquo with cardiotoxicant requiring ICU admission
A poisoning should be considered as ldquosevererdquo if bull Life-threatening symptoms occur including hemodynamic instability cardiac arrhythmia or conduction disturbances coma seizures respiratory failure or alveolar hypoventilation bull The patient has been exposed to a large amount of toxicant requiring a close monitoring bull The patient is vulnerable (co-morbidities elderly or infants)
French Society of Critical Care Medicine Reacuteanimation 2006
Signal
measurement
Interpretation
- Diagnostic
- Prognostic
- Theacuterapeutical
Is toxicological
analysis useful
in cardiotoxicant
poisonings
Sampling
Bloodplasma
Urine
Gastric liquid
But also
Saliva
Sweat
Hair
Detection
Separation +
Detection
Quantification
Principle of a toxicological analysis
x
x x x
x
Urine Blood
Management of cardiotoxicant poisoning
bull Initial ABC assessment and resuscitation
bull History determination
bull Clinical examination ECG and laboratory features
bull Therapeutic indications
- Supportive treatments
- Gastrointestinal decontamination
- Elimination enhancement
- Antidotes
bull Toxicological analysis
Clinical approach and laboratory findings are more important
than toxicological analysis results for emergent decisions
2006
2012
Why does not the clinician need any toxicological analysis to manage his
patient with cardiotoxicant poisoning
ProCon debate
The prognostic value of the ingested dose
Example of ajmaline poisoning
Ingested tablets N Cardiac arrest
1 g 7 0
2 g 13 1
3 g 16 8
Delay for symptom occurrence 1 - 3 h All patients in cardiac arrest died
Conso F Press Med 1980
Acebutolol gt 15 g
Amitritptyline gt 2 g
Carbamazepine gt 10 g
Chloroquine gt 4 g
Clomipramine gt 2 g
Dextropropoxyphen gt 500 mg
Dosulepine gt 125 g
Flecainide gt 15 g
Maprotiline gt 3 g
Propranolol gt 2 g
Baud FJ Crit Care 2007
Doses resulting in severe cardiovascular failure
Simulated probability over time for having an epinephrine infusion rate gt3 mgh
Meacutegarbane B Clin Tox 2011
The prognostic value of the ingested dose Example of chloroquine poisoning
Assessment of patientrsquos low risk if none present in the ED
- Systolic pressure lt100 mm Hg - Seizures - Unresponsiveness to verbal stimuli - Need for intubation - Any rhythm except sinus - Second- or third-degree atrioventricular block - QRS ge 012 s - PaO2 ge45 mmHg
Among the 151 low-risk patients none developed a high-risk condition after admission and none required ICU intervention These predictive criteria eliminated over 50 ICU days without compromising quality of care
Excessive admission in the ICU may also result in non-useful expenses and limited bed availability
Predicting the clinical course in intentional drug overdose in the emergency room
Brett AS Arch Intern Med 1987
Echocardiography coupled with Doppler allows a direct visualization of the heart contractility and aspects (ventricle dilatation myocardium thickness valve diseases) However it remains operator-dependent
Echocardiography
Hypovolemia or vasoplegia Cardiogenic shock
Echocardiography aspects
Severe dysrhythmia
- VO2 110 mLminm2
- SaO2 95
- Hb 11 gdl
40
90
SvO2 ()
1
Cardiac index (Lminm2)
2 3
57
70
5 6 7
80
83
SvO2 versus cardiac index relationships
SvO2 = SaO2 - VO2
IC x Hb x 134
Manini AF ClinTox 2010
- Despite of absence of specificity he serum lactate concentration had an excellent prognostic utility to predict drug-overdose fatality - The optimal lactate cut-point was 30 mmolL (84 sensitivity 75 specificity) which conferred a 158-fold increase in odds of fatality (p lt 0001)
Serum lactate is an excellent prognosticator
ROC-AUC 087 (95 CI 081ndash094)
Lactate is a marker of all types of SHOCK
1048707 A marker of inadequate perfusion or cellular O2 consumption
1048707 A marker of inadequate resuscitation and management
1048707 A predictor of patient bad outcome and development of organ
dysfunction
Beta-blocker poisonings Prognostic value of lactate concentration on admission
0
3
6
9
12
15
18
21
24
27
30
Survivors Fatalities
plt 00008S
eru
m l
acta
te c
on
cen
trati
on
s (
mm
ol
L)
0
3
6
9
12
15
18
21
24
27
30
On admissionvalues
plt 00001
Peakvalues
Seru
m l
acta
te c
on
cen
trati
on
s (
mm
ol
L)
The ROC-AUC of initial lactate for predicting mortality was 084 (074-094)
The cutoff point maximizing the sum of sensitivity and specificity was 27 mmolL
For the 30 mmolL selected lactate cutoff point 55 sensitivity 80 specificity
Meacutegarbane B Clin Tox 2010
Boehnert MT N Engl J Med 1985
Poisonings with tricyclic antidepressants Prognostic value of QRS to predict seizures and arrhythmias
Serum glucose as biomarker in calcium channel blocker poisonings
Levine M Crit Care Med 2007
Initial glucose level Peak glucose level
Increase in blood glucose +71 vs 0 p=00067
Serum potassium as biomarker in digitalis poisoning
Female
Male
lt 55
gt 55
lt 55
gt 55
Yes
No
Yes
No
Yes
No
Yes
No
K + gt45
Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No
Death rate
17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23
AV block Age
Dally S Press Med 1981
0 8 16 24 32 40 48 56
0
40
80
120
160
200
240
280
Plasma Lactate (mmolL)
Blo
od
Cyan
ide (
microm
ol
l)
Lactate as biomarker in cyanide poisoning
Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002
Chloroquine poisoning prognosis assessment
Supposed
ingested dose
Systolic BP QRS
duration
Severe gt 4 g or lt 100 mmHg or gt 010 s
Moderate 2 - 4 g and
gt 100 mmHg and
lt 010 s
Mild
lt 2 g and
gt 100 mmHg and
lt 010 s
Clemessy JL et al Crit Care Med 1996
Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg
Intubation and mechanical ventilation
Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h
Riou B N Engl J Med 1988
Macrocirculation level
- Measurement of blood pressure and cardiac index Microcirculation level
- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain
- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)
Hemodynamic monitoring of cardiotoxicant poisonings
Poisonings with tricyclic antidepressants Value of serum concentrations
Boehnert MT N Engl J Med 1985
Prognostic value of serum theophylline concentration
Sessler CN Am J Med 1990
Why does the clinician need toxicological analysis to manage his
patient with cardiotoxicant poisoning
ProCon debate
- Positive diagnosis assessment to confirm a toxic hypothesis
- Differential diagnosis to exclude a toxic hypothesis
- Prognosis evaluation
- Help for treatment indications monitoring and re-evaluation
- Retrospective evaluation medico-legal issue or scientific studies
What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings
t
Severity C blood
t
Severity C blood
Confirm severity Supportive treatments
Prognostic factors Antidotes
Interest of analysis according to drug effects
Injury-inducing drugs
Functional drugs
Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues
Prerequisite availability of toxicological analysis
- Complexity and requirements of the assays
- Dialogue between biologists and clinicians
Importance of conservative plasma and urine sampling (initial and repetitive)
Expert opinion on appropriateness of disposal according to availability of drug screening
Fabbri A Emerg Med J 2003
Does a comprehensive drug screening add to decision making for poisonings in the ED
improve agreement on patient disposal Save potentially hospital resources
Meprobamate poisonings Is serum concentration useful to indicate the
mechanism of shock
Charron C Intensive Care Med 2005
Dose-dependent hypotension with narrowed QRS
- hypovolemia
- vasoplegia if concentrations le 150 mgl
- cardiogenic if concentrations gt 150 mgl
Plasma chloroquine concentration le 12 M No death
12-25 microM death rate 2
gt 25 microM death rate 22
gt 50 microM death rate 60
Chloroquine poisoning In-hospital prognosis assessment using
blood concentrations
Clemessy JL Crit Care Med 1996
TKTD using blood concentrations TKTD using plasma concentrations
Chloroquine poisoning blood vs plasma concentrations
0 25 50 75 100 125 15000
05
10
15
20
25
30
35
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 096
0 10 20 30 40 5000
05
10
15
20
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 091
0 1 2 3 4 5 6 7 8 900
05
10
15
20
Plasma chloroquine concentration (micromolL)
Ep
inep
hri
ne
infu
sio
n r
ate
(mg
h)
0 5 10 15 20 250
1
2
3
4
Plasma chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh)
R2 = 005
R2 = 017
Patient 1
Patient 2
PKPD population modeling in chloroquine poisonings
Meacutegarbane B Clin Tox2010
Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings
Relationship Between PlasmaFlecainide Concentration and
Outcome
Survivors Fatalities
0
1
2
3
4
5
6
7
8
9
10
Outcome of Acute Poisonings
Pla
sm
a F
lecain
ide
Co
ncen
trati
on
s (
mg
L)
Meacutegarbane B Clin Tox 2007
Meacutegarbane B BCPT 2010
Verapamil poisonings
Flecainide poisonings
Meacutegarbane B Clin Tox 2002 (abstract)
0
5
10
15
20
25P
red
icte
d c
on
cen
trati
on
s (n
gm
l)
0
10
0
20
0
30
0
40
0
Time since ingestion (hours)
Predicted concentration profiles
Non suvivors C(t) = 242 exp (-0003t)
Survivors C(t) = 177 exp (-0019t)
Cut-off C(t) = 207 exp (-0011t)
0
20
40
60
80
Co
lch
icin
e p
lasm
a c
on
cen
tra
tion
on
ad
mis
sio
n(n
gm
l)
Alive patients (N = 18)
Dead patients(N = 5)
Colchicine poisonings prognostic value of the time-course of serum concentrations
Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments
Q = body load of glycoside to neutralize
Estimation using ingested amount of digitalis
Estimation using serum glycoside concentration
Q = Weight
(kg)
volume of distribution
digoxin 56 lkg
digitoxin 056 lkg
Serum glycoside concentration
(ngml) x x
Q = x Ingested amount (mg) digoxin bioavailability (60 )
digitoxin bioavailability (100 ) or
One vial of digibind (40 mg) neutralizes 06 mg of digoxin
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
bull One among the first causes of hospital admission and death
bull Increasing incidence
bull In the USA 10th cause of exposures (37) but 4th cause of death (fatality rate 027)
Poisonings with cardiovascular agents
Poisoned patients
Cardiovascular failure
1554 60 (4 )
164 (11 ) 37 (22 )
January 1998 to October 2002 3922 patients
N Mortality rate
Lariboisiegravere Hospital ICU Paris France
Cardiotoxicants
ndash Cardiovascular pharmaceuticals
ndash Sodium-channel blockers (Class I)
ndash Beta-blockers (class II)
ndash Potassium channel blockers (sotalol) (class III)
ndash Calcium-channel antagonists (class IV)
ndash Cardioglycosides (class V)
ndash Non-cardiovascular pharmaceuticals
antipsychotics antidepressants antihistamines hellip
ndash Drugs cocaine amphetamines hellip
ndash Rural toxicants organophosphates pesticides hellip
ndash Industrial toxicants alumine phosphide hellip
ndash Household toxicants trichloroethylene hellip
ndash Plants digitalis aconit colchicine yew Taxus baccatahellip
ndash Over-the-counter laquo Best life raquo (sibutramine)
A larger entity than cardiovascular drugs
Definition of ldquosevere poisoningrdquo with cardiotoxicant requiring ICU admission
A poisoning should be considered as ldquosevererdquo if bull Life-threatening symptoms occur including hemodynamic instability cardiac arrhythmia or conduction disturbances coma seizures respiratory failure or alveolar hypoventilation bull The patient has been exposed to a large amount of toxicant requiring a close monitoring bull The patient is vulnerable (co-morbidities elderly or infants)
French Society of Critical Care Medicine Reacuteanimation 2006
Signal
measurement
Interpretation
- Diagnostic
- Prognostic
- Theacuterapeutical
Is toxicological
analysis useful
in cardiotoxicant
poisonings
Sampling
Bloodplasma
Urine
Gastric liquid
But also
Saliva
Sweat
Hair
Detection
Separation +
Detection
Quantification
Principle of a toxicological analysis
x
x x x
x
Urine Blood
Management of cardiotoxicant poisoning
bull Initial ABC assessment and resuscitation
bull History determination
bull Clinical examination ECG and laboratory features
bull Therapeutic indications
- Supportive treatments
- Gastrointestinal decontamination
- Elimination enhancement
- Antidotes
bull Toxicological analysis
Clinical approach and laboratory findings are more important
than toxicological analysis results for emergent decisions
2006
2012
Why does not the clinician need any toxicological analysis to manage his
patient with cardiotoxicant poisoning
ProCon debate
The prognostic value of the ingested dose
Example of ajmaline poisoning
Ingested tablets N Cardiac arrest
1 g 7 0
2 g 13 1
3 g 16 8
Delay for symptom occurrence 1 - 3 h All patients in cardiac arrest died
Conso F Press Med 1980
Acebutolol gt 15 g
Amitritptyline gt 2 g
Carbamazepine gt 10 g
Chloroquine gt 4 g
Clomipramine gt 2 g
Dextropropoxyphen gt 500 mg
Dosulepine gt 125 g
Flecainide gt 15 g
Maprotiline gt 3 g
Propranolol gt 2 g
Baud FJ Crit Care 2007
Doses resulting in severe cardiovascular failure
Simulated probability over time for having an epinephrine infusion rate gt3 mgh
Meacutegarbane B Clin Tox 2011
The prognostic value of the ingested dose Example of chloroquine poisoning
Assessment of patientrsquos low risk if none present in the ED
- Systolic pressure lt100 mm Hg - Seizures - Unresponsiveness to verbal stimuli - Need for intubation - Any rhythm except sinus - Second- or third-degree atrioventricular block - QRS ge 012 s - PaO2 ge45 mmHg
Among the 151 low-risk patients none developed a high-risk condition after admission and none required ICU intervention These predictive criteria eliminated over 50 ICU days without compromising quality of care
Excessive admission in the ICU may also result in non-useful expenses and limited bed availability
Predicting the clinical course in intentional drug overdose in the emergency room
Brett AS Arch Intern Med 1987
Echocardiography coupled with Doppler allows a direct visualization of the heart contractility and aspects (ventricle dilatation myocardium thickness valve diseases) However it remains operator-dependent
Echocardiography
Hypovolemia or vasoplegia Cardiogenic shock
Echocardiography aspects
Severe dysrhythmia
- VO2 110 mLminm2
- SaO2 95
- Hb 11 gdl
40
90
SvO2 ()
1
Cardiac index (Lminm2)
2 3
57
70
5 6 7
80
83
SvO2 versus cardiac index relationships
SvO2 = SaO2 - VO2
IC x Hb x 134
Manini AF ClinTox 2010
- Despite of absence of specificity he serum lactate concentration had an excellent prognostic utility to predict drug-overdose fatality - The optimal lactate cut-point was 30 mmolL (84 sensitivity 75 specificity) which conferred a 158-fold increase in odds of fatality (p lt 0001)
Serum lactate is an excellent prognosticator
ROC-AUC 087 (95 CI 081ndash094)
Lactate is a marker of all types of SHOCK
1048707 A marker of inadequate perfusion or cellular O2 consumption
1048707 A marker of inadequate resuscitation and management
1048707 A predictor of patient bad outcome and development of organ
dysfunction
Beta-blocker poisonings Prognostic value of lactate concentration on admission
0
3
6
9
12
15
18
21
24
27
30
Survivors Fatalities
plt 00008S
eru
m l
acta
te c
on
cen
trati
on
s (
mm
ol
L)
0
3
6
9
12
15
18
21
24
27
30
On admissionvalues
plt 00001
Peakvalues
Seru
m l
acta
te c
on
cen
trati
on
s (
mm
ol
L)
The ROC-AUC of initial lactate for predicting mortality was 084 (074-094)
The cutoff point maximizing the sum of sensitivity and specificity was 27 mmolL
For the 30 mmolL selected lactate cutoff point 55 sensitivity 80 specificity
Meacutegarbane B Clin Tox 2010
Boehnert MT N Engl J Med 1985
Poisonings with tricyclic antidepressants Prognostic value of QRS to predict seizures and arrhythmias
Serum glucose as biomarker in calcium channel blocker poisonings
Levine M Crit Care Med 2007
Initial glucose level Peak glucose level
Increase in blood glucose +71 vs 0 p=00067
Serum potassium as biomarker in digitalis poisoning
Female
Male
lt 55
gt 55
lt 55
gt 55
Yes
No
Yes
No
Yes
No
Yes
No
K + gt45
Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No
Death rate
17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23
AV block Age
Dally S Press Med 1981
0 8 16 24 32 40 48 56
0
40
80
120
160
200
240
280
Plasma Lactate (mmolL)
Blo
od
Cyan
ide (
microm
ol
l)
Lactate as biomarker in cyanide poisoning
Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002
Chloroquine poisoning prognosis assessment
Supposed
ingested dose
Systolic BP QRS
duration
Severe gt 4 g or lt 100 mmHg or gt 010 s
Moderate 2 - 4 g and
gt 100 mmHg and
lt 010 s
Mild
lt 2 g and
gt 100 mmHg and
lt 010 s
Clemessy JL et al Crit Care Med 1996
Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg
Intubation and mechanical ventilation
Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h
Riou B N Engl J Med 1988
Macrocirculation level
- Measurement of blood pressure and cardiac index Microcirculation level
- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain
- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)
Hemodynamic monitoring of cardiotoxicant poisonings
Poisonings with tricyclic antidepressants Value of serum concentrations
Boehnert MT N Engl J Med 1985
Prognostic value of serum theophylline concentration
Sessler CN Am J Med 1990
Why does the clinician need toxicological analysis to manage his
patient with cardiotoxicant poisoning
ProCon debate
- Positive diagnosis assessment to confirm a toxic hypothesis
- Differential diagnosis to exclude a toxic hypothesis
- Prognosis evaluation
- Help for treatment indications monitoring and re-evaluation
- Retrospective evaluation medico-legal issue or scientific studies
What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings
t
Severity C blood
t
Severity C blood
Confirm severity Supportive treatments
Prognostic factors Antidotes
Interest of analysis according to drug effects
Injury-inducing drugs
Functional drugs
Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues
Prerequisite availability of toxicological analysis
- Complexity and requirements of the assays
- Dialogue between biologists and clinicians
Importance of conservative plasma and urine sampling (initial and repetitive)
Expert opinion on appropriateness of disposal according to availability of drug screening
Fabbri A Emerg Med J 2003
Does a comprehensive drug screening add to decision making for poisonings in the ED
improve agreement on patient disposal Save potentially hospital resources
Meprobamate poisonings Is serum concentration useful to indicate the
mechanism of shock
Charron C Intensive Care Med 2005
Dose-dependent hypotension with narrowed QRS
- hypovolemia
- vasoplegia if concentrations le 150 mgl
- cardiogenic if concentrations gt 150 mgl
Plasma chloroquine concentration le 12 M No death
12-25 microM death rate 2
gt 25 microM death rate 22
gt 50 microM death rate 60
Chloroquine poisoning In-hospital prognosis assessment using
blood concentrations
Clemessy JL Crit Care Med 1996
TKTD using blood concentrations TKTD using plasma concentrations
Chloroquine poisoning blood vs plasma concentrations
0 25 50 75 100 125 15000
05
10
15
20
25
30
35
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 096
0 10 20 30 40 5000
05
10
15
20
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 091
0 1 2 3 4 5 6 7 8 900
05
10
15
20
Plasma chloroquine concentration (micromolL)
Ep
inep
hri
ne
infu
sio
n r
ate
(mg
h)
0 5 10 15 20 250
1
2
3
4
Plasma chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh)
R2 = 005
R2 = 017
Patient 1
Patient 2
PKPD population modeling in chloroquine poisonings
Meacutegarbane B Clin Tox2010
Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings
Relationship Between PlasmaFlecainide Concentration and
Outcome
Survivors Fatalities
0
1
2
3
4
5
6
7
8
9
10
Outcome of Acute Poisonings
Pla
sm
a F
lecain
ide
Co
ncen
trati
on
s (
mg
L)
Meacutegarbane B Clin Tox 2007
Meacutegarbane B BCPT 2010
Verapamil poisonings
Flecainide poisonings
Meacutegarbane B Clin Tox 2002 (abstract)
0
5
10
15
20
25P
red
icte
d c
on
cen
trati
on
s (n
gm
l)
0
10
0
20
0
30
0
40
0
Time since ingestion (hours)
Predicted concentration profiles
Non suvivors C(t) = 242 exp (-0003t)
Survivors C(t) = 177 exp (-0019t)
Cut-off C(t) = 207 exp (-0011t)
0
20
40
60
80
Co
lch
icin
e p
lasm
a c
on
cen
tra
tion
on
ad
mis
sio
n(n
gm
l)
Alive patients (N = 18)
Dead patients(N = 5)
Colchicine poisonings prognostic value of the time-course of serum concentrations
Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments
Q = body load of glycoside to neutralize
Estimation using ingested amount of digitalis
Estimation using serum glycoside concentration
Q = Weight
(kg)
volume of distribution
digoxin 56 lkg
digitoxin 056 lkg
Serum glycoside concentration
(ngml) x x
Q = x Ingested amount (mg) digoxin bioavailability (60 )
digitoxin bioavailability (100 ) or
One vial of digibind (40 mg) neutralizes 06 mg of digoxin
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
Cardiotoxicants
ndash Cardiovascular pharmaceuticals
ndash Sodium-channel blockers (Class I)
ndash Beta-blockers (class II)
ndash Potassium channel blockers (sotalol) (class III)
ndash Calcium-channel antagonists (class IV)
ndash Cardioglycosides (class V)
ndash Non-cardiovascular pharmaceuticals
antipsychotics antidepressants antihistamines hellip
ndash Drugs cocaine amphetamines hellip
ndash Rural toxicants organophosphates pesticides hellip
ndash Industrial toxicants alumine phosphide hellip
ndash Household toxicants trichloroethylene hellip
ndash Plants digitalis aconit colchicine yew Taxus baccatahellip
ndash Over-the-counter laquo Best life raquo (sibutramine)
A larger entity than cardiovascular drugs
Definition of ldquosevere poisoningrdquo with cardiotoxicant requiring ICU admission
A poisoning should be considered as ldquosevererdquo if bull Life-threatening symptoms occur including hemodynamic instability cardiac arrhythmia or conduction disturbances coma seizures respiratory failure or alveolar hypoventilation bull The patient has been exposed to a large amount of toxicant requiring a close monitoring bull The patient is vulnerable (co-morbidities elderly or infants)
French Society of Critical Care Medicine Reacuteanimation 2006
Signal
measurement
Interpretation
- Diagnostic
- Prognostic
- Theacuterapeutical
Is toxicological
analysis useful
in cardiotoxicant
poisonings
Sampling
Bloodplasma
Urine
Gastric liquid
But also
Saliva
Sweat
Hair
Detection
Separation +
Detection
Quantification
Principle of a toxicological analysis
x
x x x
x
Urine Blood
Management of cardiotoxicant poisoning
bull Initial ABC assessment and resuscitation
bull History determination
bull Clinical examination ECG and laboratory features
bull Therapeutic indications
- Supportive treatments
- Gastrointestinal decontamination
- Elimination enhancement
- Antidotes
bull Toxicological analysis
Clinical approach and laboratory findings are more important
than toxicological analysis results for emergent decisions
2006
2012
Why does not the clinician need any toxicological analysis to manage his
patient with cardiotoxicant poisoning
ProCon debate
The prognostic value of the ingested dose
Example of ajmaline poisoning
Ingested tablets N Cardiac arrest
1 g 7 0
2 g 13 1
3 g 16 8
Delay for symptom occurrence 1 - 3 h All patients in cardiac arrest died
Conso F Press Med 1980
Acebutolol gt 15 g
Amitritptyline gt 2 g
Carbamazepine gt 10 g
Chloroquine gt 4 g
Clomipramine gt 2 g
Dextropropoxyphen gt 500 mg
Dosulepine gt 125 g
Flecainide gt 15 g
Maprotiline gt 3 g
Propranolol gt 2 g
Baud FJ Crit Care 2007
Doses resulting in severe cardiovascular failure
Simulated probability over time for having an epinephrine infusion rate gt3 mgh
Meacutegarbane B Clin Tox 2011
The prognostic value of the ingested dose Example of chloroquine poisoning
Assessment of patientrsquos low risk if none present in the ED
- Systolic pressure lt100 mm Hg - Seizures - Unresponsiveness to verbal stimuli - Need for intubation - Any rhythm except sinus - Second- or third-degree atrioventricular block - QRS ge 012 s - PaO2 ge45 mmHg
Among the 151 low-risk patients none developed a high-risk condition after admission and none required ICU intervention These predictive criteria eliminated over 50 ICU days without compromising quality of care
Excessive admission in the ICU may also result in non-useful expenses and limited bed availability
Predicting the clinical course in intentional drug overdose in the emergency room
Brett AS Arch Intern Med 1987
Echocardiography coupled with Doppler allows a direct visualization of the heart contractility and aspects (ventricle dilatation myocardium thickness valve diseases) However it remains operator-dependent
Echocardiography
Hypovolemia or vasoplegia Cardiogenic shock
Echocardiography aspects
Severe dysrhythmia
- VO2 110 mLminm2
- SaO2 95
- Hb 11 gdl
40
90
SvO2 ()
1
Cardiac index (Lminm2)
2 3
57
70
5 6 7
80
83
SvO2 versus cardiac index relationships
SvO2 = SaO2 - VO2
IC x Hb x 134
Manini AF ClinTox 2010
- Despite of absence of specificity he serum lactate concentration had an excellent prognostic utility to predict drug-overdose fatality - The optimal lactate cut-point was 30 mmolL (84 sensitivity 75 specificity) which conferred a 158-fold increase in odds of fatality (p lt 0001)
Serum lactate is an excellent prognosticator
ROC-AUC 087 (95 CI 081ndash094)
Lactate is a marker of all types of SHOCK
1048707 A marker of inadequate perfusion or cellular O2 consumption
1048707 A marker of inadequate resuscitation and management
1048707 A predictor of patient bad outcome and development of organ
dysfunction
Beta-blocker poisonings Prognostic value of lactate concentration on admission
0
3
6
9
12
15
18
21
24
27
30
Survivors Fatalities
plt 00008S
eru
m l
acta
te c
on
cen
trati
on
s (
mm
ol
L)
0
3
6
9
12
15
18
21
24
27
30
On admissionvalues
plt 00001
Peakvalues
Seru
m l
acta
te c
on
cen
trati
on
s (
mm
ol
L)
The ROC-AUC of initial lactate for predicting mortality was 084 (074-094)
The cutoff point maximizing the sum of sensitivity and specificity was 27 mmolL
For the 30 mmolL selected lactate cutoff point 55 sensitivity 80 specificity
Meacutegarbane B Clin Tox 2010
Boehnert MT N Engl J Med 1985
Poisonings with tricyclic antidepressants Prognostic value of QRS to predict seizures and arrhythmias
Serum glucose as biomarker in calcium channel blocker poisonings
Levine M Crit Care Med 2007
Initial glucose level Peak glucose level
Increase in blood glucose +71 vs 0 p=00067
Serum potassium as biomarker in digitalis poisoning
Female
Male
lt 55
gt 55
lt 55
gt 55
Yes
No
Yes
No
Yes
No
Yes
No
K + gt45
Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No
Death rate
17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23
AV block Age
Dally S Press Med 1981
0 8 16 24 32 40 48 56
0
40
80
120
160
200
240
280
Plasma Lactate (mmolL)
Blo
od
Cyan
ide (
microm
ol
l)
Lactate as biomarker in cyanide poisoning
Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002
Chloroquine poisoning prognosis assessment
Supposed
ingested dose
Systolic BP QRS
duration
Severe gt 4 g or lt 100 mmHg or gt 010 s
Moderate 2 - 4 g and
gt 100 mmHg and
lt 010 s
Mild
lt 2 g and
gt 100 mmHg and
lt 010 s
Clemessy JL et al Crit Care Med 1996
Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg
Intubation and mechanical ventilation
Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h
Riou B N Engl J Med 1988
Macrocirculation level
- Measurement of blood pressure and cardiac index Microcirculation level
- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain
- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)
Hemodynamic monitoring of cardiotoxicant poisonings
Poisonings with tricyclic antidepressants Value of serum concentrations
Boehnert MT N Engl J Med 1985
Prognostic value of serum theophylline concentration
Sessler CN Am J Med 1990
Why does the clinician need toxicological analysis to manage his
patient with cardiotoxicant poisoning
ProCon debate
- Positive diagnosis assessment to confirm a toxic hypothesis
- Differential diagnosis to exclude a toxic hypothesis
- Prognosis evaluation
- Help for treatment indications monitoring and re-evaluation
- Retrospective evaluation medico-legal issue or scientific studies
What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings
t
Severity C blood
t
Severity C blood
Confirm severity Supportive treatments
Prognostic factors Antidotes
Interest of analysis according to drug effects
Injury-inducing drugs
Functional drugs
Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues
Prerequisite availability of toxicological analysis
- Complexity and requirements of the assays
- Dialogue between biologists and clinicians
Importance of conservative plasma and urine sampling (initial and repetitive)
Expert opinion on appropriateness of disposal according to availability of drug screening
Fabbri A Emerg Med J 2003
Does a comprehensive drug screening add to decision making for poisonings in the ED
improve agreement on patient disposal Save potentially hospital resources
Meprobamate poisonings Is serum concentration useful to indicate the
mechanism of shock
Charron C Intensive Care Med 2005
Dose-dependent hypotension with narrowed QRS
- hypovolemia
- vasoplegia if concentrations le 150 mgl
- cardiogenic if concentrations gt 150 mgl
Plasma chloroquine concentration le 12 M No death
12-25 microM death rate 2
gt 25 microM death rate 22
gt 50 microM death rate 60
Chloroquine poisoning In-hospital prognosis assessment using
blood concentrations
Clemessy JL Crit Care Med 1996
TKTD using blood concentrations TKTD using plasma concentrations
Chloroquine poisoning blood vs plasma concentrations
0 25 50 75 100 125 15000
05
10
15
20
25
30
35
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 096
0 10 20 30 40 5000
05
10
15
20
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 091
0 1 2 3 4 5 6 7 8 900
05
10
15
20
Plasma chloroquine concentration (micromolL)
Ep
inep
hri
ne
infu
sio
n r
ate
(mg
h)
0 5 10 15 20 250
1
2
3
4
Plasma chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh)
R2 = 005
R2 = 017
Patient 1
Patient 2
PKPD population modeling in chloroquine poisonings
Meacutegarbane B Clin Tox2010
Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings
Relationship Between PlasmaFlecainide Concentration and
Outcome
Survivors Fatalities
0
1
2
3
4
5
6
7
8
9
10
Outcome of Acute Poisonings
Pla
sm
a F
lecain
ide
Co
ncen
trati
on
s (
mg
L)
Meacutegarbane B Clin Tox 2007
Meacutegarbane B BCPT 2010
Verapamil poisonings
Flecainide poisonings
Meacutegarbane B Clin Tox 2002 (abstract)
0
5
10
15
20
25P
red
icte
d c
on
cen
trati
on
s (n
gm
l)
0
10
0
20
0
30
0
40
0
Time since ingestion (hours)
Predicted concentration profiles
Non suvivors C(t) = 242 exp (-0003t)
Survivors C(t) = 177 exp (-0019t)
Cut-off C(t) = 207 exp (-0011t)
0
20
40
60
80
Co
lch
icin
e p
lasm
a c
on
cen
tra
tion
on
ad
mis
sio
n(n
gm
l)
Alive patients (N = 18)
Dead patients(N = 5)
Colchicine poisonings prognostic value of the time-course of serum concentrations
Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments
Q = body load of glycoside to neutralize
Estimation using ingested amount of digitalis
Estimation using serum glycoside concentration
Q = Weight
(kg)
volume of distribution
digoxin 56 lkg
digitoxin 056 lkg
Serum glycoside concentration
(ngml) x x
Q = x Ingested amount (mg) digoxin bioavailability (60 )
digitoxin bioavailability (100 ) or
One vial of digibind (40 mg) neutralizes 06 mg of digoxin
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
Definition of ldquosevere poisoningrdquo with cardiotoxicant requiring ICU admission
A poisoning should be considered as ldquosevererdquo if bull Life-threatening symptoms occur including hemodynamic instability cardiac arrhythmia or conduction disturbances coma seizures respiratory failure or alveolar hypoventilation bull The patient has been exposed to a large amount of toxicant requiring a close monitoring bull The patient is vulnerable (co-morbidities elderly or infants)
French Society of Critical Care Medicine Reacuteanimation 2006
Signal
measurement
Interpretation
- Diagnostic
- Prognostic
- Theacuterapeutical
Is toxicological
analysis useful
in cardiotoxicant
poisonings
Sampling
Bloodplasma
Urine
Gastric liquid
But also
Saliva
Sweat
Hair
Detection
Separation +
Detection
Quantification
Principle of a toxicological analysis
x
x x x
x
Urine Blood
Management of cardiotoxicant poisoning
bull Initial ABC assessment and resuscitation
bull History determination
bull Clinical examination ECG and laboratory features
bull Therapeutic indications
- Supportive treatments
- Gastrointestinal decontamination
- Elimination enhancement
- Antidotes
bull Toxicological analysis
Clinical approach and laboratory findings are more important
than toxicological analysis results for emergent decisions
2006
2012
Why does not the clinician need any toxicological analysis to manage his
patient with cardiotoxicant poisoning
ProCon debate
The prognostic value of the ingested dose
Example of ajmaline poisoning
Ingested tablets N Cardiac arrest
1 g 7 0
2 g 13 1
3 g 16 8
Delay for symptom occurrence 1 - 3 h All patients in cardiac arrest died
Conso F Press Med 1980
Acebutolol gt 15 g
Amitritptyline gt 2 g
Carbamazepine gt 10 g
Chloroquine gt 4 g
Clomipramine gt 2 g
Dextropropoxyphen gt 500 mg
Dosulepine gt 125 g
Flecainide gt 15 g
Maprotiline gt 3 g
Propranolol gt 2 g
Baud FJ Crit Care 2007
Doses resulting in severe cardiovascular failure
Simulated probability over time for having an epinephrine infusion rate gt3 mgh
Meacutegarbane B Clin Tox 2011
The prognostic value of the ingested dose Example of chloroquine poisoning
Assessment of patientrsquos low risk if none present in the ED
- Systolic pressure lt100 mm Hg - Seizures - Unresponsiveness to verbal stimuli - Need for intubation - Any rhythm except sinus - Second- or third-degree atrioventricular block - QRS ge 012 s - PaO2 ge45 mmHg
Among the 151 low-risk patients none developed a high-risk condition after admission and none required ICU intervention These predictive criteria eliminated over 50 ICU days without compromising quality of care
Excessive admission in the ICU may also result in non-useful expenses and limited bed availability
Predicting the clinical course in intentional drug overdose in the emergency room
Brett AS Arch Intern Med 1987
Echocardiography coupled with Doppler allows a direct visualization of the heart contractility and aspects (ventricle dilatation myocardium thickness valve diseases) However it remains operator-dependent
Echocardiography
Hypovolemia or vasoplegia Cardiogenic shock
Echocardiography aspects
Severe dysrhythmia
- VO2 110 mLminm2
- SaO2 95
- Hb 11 gdl
40
90
SvO2 ()
1
Cardiac index (Lminm2)
2 3
57
70
5 6 7
80
83
SvO2 versus cardiac index relationships
SvO2 = SaO2 - VO2
IC x Hb x 134
Manini AF ClinTox 2010
- Despite of absence of specificity he serum lactate concentration had an excellent prognostic utility to predict drug-overdose fatality - The optimal lactate cut-point was 30 mmolL (84 sensitivity 75 specificity) which conferred a 158-fold increase in odds of fatality (p lt 0001)
Serum lactate is an excellent prognosticator
ROC-AUC 087 (95 CI 081ndash094)
Lactate is a marker of all types of SHOCK
1048707 A marker of inadequate perfusion or cellular O2 consumption
1048707 A marker of inadequate resuscitation and management
1048707 A predictor of patient bad outcome and development of organ
dysfunction
Beta-blocker poisonings Prognostic value of lactate concentration on admission
0
3
6
9
12
15
18
21
24
27
30
Survivors Fatalities
plt 00008S
eru
m l
acta
te c
on
cen
trati
on
s (
mm
ol
L)
0
3
6
9
12
15
18
21
24
27
30
On admissionvalues
plt 00001
Peakvalues
Seru
m l
acta
te c
on
cen
trati
on
s (
mm
ol
L)
The ROC-AUC of initial lactate for predicting mortality was 084 (074-094)
The cutoff point maximizing the sum of sensitivity and specificity was 27 mmolL
For the 30 mmolL selected lactate cutoff point 55 sensitivity 80 specificity
Meacutegarbane B Clin Tox 2010
Boehnert MT N Engl J Med 1985
Poisonings with tricyclic antidepressants Prognostic value of QRS to predict seizures and arrhythmias
Serum glucose as biomarker in calcium channel blocker poisonings
Levine M Crit Care Med 2007
Initial glucose level Peak glucose level
Increase in blood glucose +71 vs 0 p=00067
Serum potassium as biomarker in digitalis poisoning
Female
Male
lt 55
gt 55
lt 55
gt 55
Yes
No
Yes
No
Yes
No
Yes
No
K + gt45
Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No
Death rate
17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23
AV block Age
Dally S Press Med 1981
0 8 16 24 32 40 48 56
0
40
80
120
160
200
240
280
Plasma Lactate (mmolL)
Blo
od
Cyan
ide (
microm
ol
l)
Lactate as biomarker in cyanide poisoning
Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002
Chloroquine poisoning prognosis assessment
Supposed
ingested dose
Systolic BP QRS
duration
Severe gt 4 g or lt 100 mmHg or gt 010 s
Moderate 2 - 4 g and
gt 100 mmHg and
lt 010 s
Mild
lt 2 g and
gt 100 mmHg and
lt 010 s
Clemessy JL et al Crit Care Med 1996
Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg
Intubation and mechanical ventilation
Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h
Riou B N Engl J Med 1988
Macrocirculation level
- Measurement of blood pressure and cardiac index Microcirculation level
- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain
- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)
Hemodynamic monitoring of cardiotoxicant poisonings
Poisonings with tricyclic antidepressants Value of serum concentrations
Boehnert MT N Engl J Med 1985
Prognostic value of serum theophylline concentration
Sessler CN Am J Med 1990
Why does the clinician need toxicological analysis to manage his
patient with cardiotoxicant poisoning
ProCon debate
- Positive diagnosis assessment to confirm a toxic hypothesis
- Differential diagnosis to exclude a toxic hypothesis
- Prognosis evaluation
- Help for treatment indications monitoring and re-evaluation
- Retrospective evaluation medico-legal issue or scientific studies
What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings
t
Severity C blood
t
Severity C blood
Confirm severity Supportive treatments
Prognostic factors Antidotes
Interest of analysis according to drug effects
Injury-inducing drugs
Functional drugs
Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues
Prerequisite availability of toxicological analysis
- Complexity and requirements of the assays
- Dialogue between biologists and clinicians
Importance of conservative plasma and urine sampling (initial and repetitive)
Expert opinion on appropriateness of disposal according to availability of drug screening
Fabbri A Emerg Med J 2003
Does a comprehensive drug screening add to decision making for poisonings in the ED
improve agreement on patient disposal Save potentially hospital resources
Meprobamate poisonings Is serum concentration useful to indicate the
mechanism of shock
Charron C Intensive Care Med 2005
Dose-dependent hypotension with narrowed QRS
- hypovolemia
- vasoplegia if concentrations le 150 mgl
- cardiogenic if concentrations gt 150 mgl
Plasma chloroquine concentration le 12 M No death
12-25 microM death rate 2
gt 25 microM death rate 22
gt 50 microM death rate 60
Chloroquine poisoning In-hospital prognosis assessment using
blood concentrations
Clemessy JL Crit Care Med 1996
TKTD using blood concentrations TKTD using plasma concentrations
Chloroquine poisoning blood vs plasma concentrations
0 25 50 75 100 125 15000
05
10
15
20
25
30
35
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 096
0 10 20 30 40 5000
05
10
15
20
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 091
0 1 2 3 4 5 6 7 8 900
05
10
15
20
Plasma chloroquine concentration (micromolL)
Ep
inep
hri
ne
infu
sio
n r
ate
(mg
h)
0 5 10 15 20 250
1
2
3
4
Plasma chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh)
R2 = 005
R2 = 017
Patient 1
Patient 2
PKPD population modeling in chloroquine poisonings
Meacutegarbane B Clin Tox2010
Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings
Relationship Between PlasmaFlecainide Concentration and
Outcome
Survivors Fatalities
0
1
2
3
4
5
6
7
8
9
10
Outcome of Acute Poisonings
Pla
sm
a F
lecain
ide
Co
ncen
trati
on
s (
mg
L)
Meacutegarbane B Clin Tox 2007
Meacutegarbane B BCPT 2010
Verapamil poisonings
Flecainide poisonings
Meacutegarbane B Clin Tox 2002 (abstract)
0
5
10
15
20
25P
red
icte
d c
on
cen
trati
on
s (n
gm
l)
0
10
0
20
0
30
0
40
0
Time since ingestion (hours)
Predicted concentration profiles
Non suvivors C(t) = 242 exp (-0003t)
Survivors C(t) = 177 exp (-0019t)
Cut-off C(t) = 207 exp (-0011t)
0
20
40
60
80
Co
lch
icin
e p
lasm
a c
on
cen
tra
tion
on
ad
mis
sio
n(n
gm
l)
Alive patients (N = 18)
Dead patients(N = 5)
Colchicine poisonings prognostic value of the time-course of serum concentrations
Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments
Q = body load of glycoside to neutralize
Estimation using ingested amount of digitalis
Estimation using serum glycoside concentration
Q = Weight
(kg)
volume of distribution
digoxin 56 lkg
digitoxin 056 lkg
Serum glycoside concentration
(ngml) x x
Q = x Ingested amount (mg) digoxin bioavailability (60 )
digitoxin bioavailability (100 ) or
One vial of digibind (40 mg) neutralizes 06 mg of digoxin
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
Signal
measurement
Interpretation
- Diagnostic
- Prognostic
- Theacuterapeutical
Is toxicological
analysis useful
in cardiotoxicant
poisonings
Sampling
Bloodplasma
Urine
Gastric liquid
But also
Saliva
Sweat
Hair
Detection
Separation +
Detection
Quantification
Principle of a toxicological analysis
x
x x x
x
Urine Blood
Management of cardiotoxicant poisoning
bull Initial ABC assessment and resuscitation
bull History determination
bull Clinical examination ECG and laboratory features
bull Therapeutic indications
- Supportive treatments
- Gastrointestinal decontamination
- Elimination enhancement
- Antidotes
bull Toxicological analysis
Clinical approach and laboratory findings are more important
than toxicological analysis results for emergent decisions
2006
2012
Why does not the clinician need any toxicological analysis to manage his
patient with cardiotoxicant poisoning
ProCon debate
The prognostic value of the ingested dose
Example of ajmaline poisoning
Ingested tablets N Cardiac arrest
1 g 7 0
2 g 13 1
3 g 16 8
Delay for symptom occurrence 1 - 3 h All patients in cardiac arrest died
Conso F Press Med 1980
Acebutolol gt 15 g
Amitritptyline gt 2 g
Carbamazepine gt 10 g
Chloroquine gt 4 g
Clomipramine gt 2 g
Dextropropoxyphen gt 500 mg
Dosulepine gt 125 g
Flecainide gt 15 g
Maprotiline gt 3 g
Propranolol gt 2 g
Baud FJ Crit Care 2007
Doses resulting in severe cardiovascular failure
Simulated probability over time for having an epinephrine infusion rate gt3 mgh
Meacutegarbane B Clin Tox 2011
The prognostic value of the ingested dose Example of chloroquine poisoning
Assessment of patientrsquos low risk if none present in the ED
- Systolic pressure lt100 mm Hg - Seizures - Unresponsiveness to verbal stimuli - Need for intubation - Any rhythm except sinus - Second- or third-degree atrioventricular block - QRS ge 012 s - PaO2 ge45 mmHg
Among the 151 low-risk patients none developed a high-risk condition after admission and none required ICU intervention These predictive criteria eliminated over 50 ICU days without compromising quality of care
Excessive admission in the ICU may also result in non-useful expenses and limited bed availability
Predicting the clinical course in intentional drug overdose in the emergency room
Brett AS Arch Intern Med 1987
Echocardiography coupled with Doppler allows a direct visualization of the heart contractility and aspects (ventricle dilatation myocardium thickness valve diseases) However it remains operator-dependent
Echocardiography
Hypovolemia or vasoplegia Cardiogenic shock
Echocardiography aspects
Severe dysrhythmia
- VO2 110 mLminm2
- SaO2 95
- Hb 11 gdl
40
90
SvO2 ()
1
Cardiac index (Lminm2)
2 3
57
70
5 6 7
80
83
SvO2 versus cardiac index relationships
SvO2 = SaO2 - VO2
IC x Hb x 134
Manini AF ClinTox 2010
- Despite of absence of specificity he serum lactate concentration had an excellent prognostic utility to predict drug-overdose fatality - The optimal lactate cut-point was 30 mmolL (84 sensitivity 75 specificity) which conferred a 158-fold increase in odds of fatality (p lt 0001)
Serum lactate is an excellent prognosticator
ROC-AUC 087 (95 CI 081ndash094)
Lactate is a marker of all types of SHOCK
1048707 A marker of inadequate perfusion or cellular O2 consumption
1048707 A marker of inadequate resuscitation and management
1048707 A predictor of patient bad outcome and development of organ
dysfunction
Beta-blocker poisonings Prognostic value of lactate concentration on admission
0
3
6
9
12
15
18
21
24
27
30
Survivors Fatalities
plt 00008S
eru
m l
acta
te c
on
cen
trati
on
s (
mm
ol
L)
0
3
6
9
12
15
18
21
24
27
30
On admissionvalues
plt 00001
Peakvalues
Seru
m l
acta
te c
on
cen
trati
on
s (
mm
ol
L)
The ROC-AUC of initial lactate for predicting mortality was 084 (074-094)
The cutoff point maximizing the sum of sensitivity and specificity was 27 mmolL
For the 30 mmolL selected lactate cutoff point 55 sensitivity 80 specificity
Meacutegarbane B Clin Tox 2010
Boehnert MT N Engl J Med 1985
Poisonings with tricyclic antidepressants Prognostic value of QRS to predict seizures and arrhythmias
Serum glucose as biomarker in calcium channel blocker poisonings
Levine M Crit Care Med 2007
Initial glucose level Peak glucose level
Increase in blood glucose +71 vs 0 p=00067
Serum potassium as biomarker in digitalis poisoning
Female
Male
lt 55
gt 55
lt 55
gt 55
Yes
No
Yes
No
Yes
No
Yes
No
K + gt45
Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No
Death rate
17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23
AV block Age
Dally S Press Med 1981
0 8 16 24 32 40 48 56
0
40
80
120
160
200
240
280
Plasma Lactate (mmolL)
Blo
od
Cyan
ide (
microm
ol
l)
Lactate as biomarker in cyanide poisoning
Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002
Chloroquine poisoning prognosis assessment
Supposed
ingested dose
Systolic BP QRS
duration
Severe gt 4 g or lt 100 mmHg or gt 010 s
Moderate 2 - 4 g and
gt 100 mmHg and
lt 010 s
Mild
lt 2 g and
gt 100 mmHg and
lt 010 s
Clemessy JL et al Crit Care Med 1996
Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg
Intubation and mechanical ventilation
Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h
Riou B N Engl J Med 1988
Macrocirculation level
- Measurement of blood pressure and cardiac index Microcirculation level
- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain
- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)
Hemodynamic monitoring of cardiotoxicant poisonings
Poisonings with tricyclic antidepressants Value of serum concentrations
Boehnert MT N Engl J Med 1985
Prognostic value of serum theophylline concentration
Sessler CN Am J Med 1990
Why does the clinician need toxicological analysis to manage his
patient with cardiotoxicant poisoning
ProCon debate
- Positive diagnosis assessment to confirm a toxic hypothesis
- Differential diagnosis to exclude a toxic hypothesis
- Prognosis evaluation
- Help for treatment indications monitoring and re-evaluation
- Retrospective evaluation medico-legal issue or scientific studies
What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings
t
Severity C blood
t
Severity C blood
Confirm severity Supportive treatments
Prognostic factors Antidotes
Interest of analysis according to drug effects
Injury-inducing drugs
Functional drugs
Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues
Prerequisite availability of toxicological analysis
- Complexity and requirements of the assays
- Dialogue between biologists and clinicians
Importance of conservative plasma and urine sampling (initial and repetitive)
Expert opinion on appropriateness of disposal according to availability of drug screening
Fabbri A Emerg Med J 2003
Does a comprehensive drug screening add to decision making for poisonings in the ED
improve agreement on patient disposal Save potentially hospital resources
Meprobamate poisonings Is serum concentration useful to indicate the
mechanism of shock
Charron C Intensive Care Med 2005
Dose-dependent hypotension with narrowed QRS
- hypovolemia
- vasoplegia if concentrations le 150 mgl
- cardiogenic if concentrations gt 150 mgl
Plasma chloroquine concentration le 12 M No death
12-25 microM death rate 2
gt 25 microM death rate 22
gt 50 microM death rate 60
Chloroquine poisoning In-hospital prognosis assessment using
blood concentrations
Clemessy JL Crit Care Med 1996
TKTD using blood concentrations TKTD using plasma concentrations
Chloroquine poisoning blood vs plasma concentrations
0 25 50 75 100 125 15000
05
10
15
20
25
30
35
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 096
0 10 20 30 40 5000
05
10
15
20
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 091
0 1 2 3 4 5 6 7 8 900
05
10
15
20
Plasma chloroquine concentration (micromolL)
Ep
inep
hri
ne
infu
sio
n r
ate
(mg
h)
0 5 10 15 20 250
1
2
3
4
Plasma chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh)
R2 = 005
R2 = 017
Patient 1
Patient 2
PKPD population modeling in chloroquine poisonings
Meacutegarbane B Clin Tox2010
Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings
Relationship Between PlasmaFlecainide Concentration and
Outcome
Survivors Fatalities
0
1
2
3
4
5
6
7
8
9
10
Outcome of Acute Poisonings
Pla
sm
a F
lecain
ide
Co
ncen
trati
on
s (
mg
L)
Meacutegarbane B Clin Tox 2007
Meacutegarbane B BCPT 2010
Verapamil poisonings
Flecainide poisonings
Meacutegarbane B Clin Tox 2002 (abstract)
0
5
10
15
20
25P
red
icte
d c
on
cen
trati
on
s (n
gm
l)
0
10
0
20
0
30
0
40
0
Time since ingestion (hours)
Predicted concentration profiles
Non suvivors C(t) = 242 exp (-0003t)
Survivors C(t) = 177 exp (-0019t)
Cut-off C(t) = 207 exp (-0011t)
0
20
40
60
80
Co
lch
icin
e p
lasm
a c
on
cen
tra
tion
on
ad
mis
sio
n(n
gm
l)
Alive patients (N = 18)
Dead patients(N = 5)
Colchicine poisonings prognostic value of the time-course of serum concentrations
Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments
Q = body load of glycoside to neutralize
Estimation using ingested amount of digitalis
Estimation using serum glycoside concentration
Q = Weight
(kg)
volume of distribution
digoxin 56 lkg
digitoxin 056 lkg
Serum glycoside concentration
(ngml) x x
Q = x Ingested amount (mg) digoxin bioavailability (60 )
digitoxin bioavailability (100 ) or
One vial of digibind (40 mg) neutralizes 06 mg of digoxin
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
Management of cardiotoxicant poisoning
bull Initial ABC assessment and resuscitation
bull History determination
bull Clinical examination ECG and laboratory features
bull Therapeutic indications
- Supportive treatments
- Gastrointestinal decontamination
- Elimination enhancement
- Antidotes
bull Toxicological analysis
Clinical approach and laboratory findings are more important
than toxicological analysis results for emergent decisions
2006
2012
Why does not the clinician need any toxicological analysis to manage his
patient with cardiotoxicant poisoning
ProCon debate
The prognostic value of the ingested dose
Example of ajmaline poisoning
Ingested tablets N Cardiac arrest
1 g 7 0
2 g 13 1
3 g 16 8
Delay for symptom occurrence 1 - 3 h All patients in cardiac arrest died
Conso F Press Med 1980
Acebutolol gt 15 g
Amitritptyline gt 2 g
Carbamazepine gt 10 g
Chloroquine gt 4 g
Clomipramine gt 2 g
Dextropropoxyphen gt 500 mg
Dosulepine gt 125 g
Flecainide gt 15 g
Maprotiline gt 3 g
Propranolol gt 2 g
Baud FJ Crit Care 2007
Doses resulting in severe cardiovascular failure
Simulated probability over time for having an epinephrine infusion rate gt3 mgh
Meacutegarbane B Clin Tox 2011
The prognostic value of the ingested dose Example of chloroquine poisoning
Assessment of patientrsquos low risk if none present in the ED
- Systolic pressure lt100 mm Hg - Seizures - Unresponsiveness to verbal stimuli - Need for intubation - Any rhythm except sinus - Second- or third-degree atrioventricular block - QRS ge 012 s - PaO2 ge45 mmHg
Among the 151 low-risk patients none developed a high-risk condition after admission and none required ICU intervention These predictive criteria eliminated over 50 ICU days without compromising quality of care
Excessive admission in the ICU may also result in non-useful expenses and limited bed availability
Predicting the clinical course in intentional drug overdose in the emergency room
Brett AS Arch Intern Med 1987
Echocardiography coupled with Doppler allows a direct visualization of the heart contractility and aspects (ventricle dilatation myocardium thickness valve diseases) However it remains operator-dependent
Echocardiography
Hypovolemia or vasoplegia Cardiogenic shock
Echocardiography aspects
Severe dysrhythmia
- VO2 110 mLminm2
- SaO2 95
- Hb 11 gdl
40
90
SvO2 ()
1
Cardiac index (Lminm2)
2 3
57
70
5 6 7
80
83
SvO2 versus cardiac index relationships
SvO2 = SaO2 - VO2
IC x Hb x 134
Manini AF ClinTox 2010
- Despite of absence of specificity he serum lactate concentration had an excellent prognostic utility to predict drug-overdose fatality - The optimal lactate cut-point was 30 mmolL (84 sensitivity 75 specificity) which conferred a 158-fold increase in odds of fatality (p lt 0001)
Serum lactate is an excellent prognosticator
ROC-AUC 087 (95 CI 081ndash094)
Lactate is a marker of all types of SHOCK
1048707 A marker of inadequate perfusion or cellular O2 consumption
1048707 A marker of inadequate resuscitation and management
1048707 A predictor of patient bad outcome and development of organ
dysfunction
Beta-blocker poisonings Prognostic value of lactate concentration on admission
0
3
6
9
12
15
18
21
24
27
30
Survivors Fatalities
plt 00008S
eru
m l
acta
te c
on
cen
trati
on
s (
mm
ol
L)
0
3
6
9
12
15
18
21
24
27
30
On admissionvalues
plt 00001
Peakvalues
Seru
m l
acta
te c
on
cen
trati
on
s (
mm
ol
L)
The ROC-AUC of initial lactate for predicting mortality was 084 (074-094)
The cutoff point maximizing the sum of sensitivity and specificity was 27 mmolL
For the 30 mmolL selected lactate cutoff point 55 sensitivity 80 specificity
Meacutegarbane B Clin Tox 2010
Boehnert MT N Engl J Med 1985
Poisonings with tricyclic antidepressants Prognostic value of QRS to predict seizures and arrhythmias
Serum glucose as biomarker in calcium channel blocker poisonings
Levine M Crit Care Med 2007
Initial glucose level Peak glucose level
Increase in blood glucose +71 vs 0 p=00067
Serum potassium as biomarker in digitalis poisoning
Female
Male
lt 55
gt 55
lt 55
gt 55
Yes
No
Yes
No
Yes
No
Yes
No
K + gt45
Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No
Death rate
17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23
AV block Age
Dally S Press Med 1981
0 8 16 24 32 40 48 56
0
40
80
120
160
200
240
280
Plasma Lactate (mmolL)
Blo
od
Cyan
ide (
microm
ol
l)
Lactate as biomarker in cyanide poisoning
Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002
Chloroquine poisoning prognosis assessment
Supposed
ingested dose
Systolic BP QRS
duration
Severe gt 4 g or lt 100 mmHg or gt 010 s
Moderate 2 - 4 g and
gt 100 mmHg and
lt 010 s
Mild
lt 2 g and
gt 100 mmHg and
lt 010 s
Clemessy JL et al Crit Care Med 1996
Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg
Intubation and mechanical ventilation
Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h
Riou B N Engl J Med 1988
Macrocirculation level
- Measurement of blood pressure and cardiac index Microcirculation level
- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain
- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)
Hemodynamic monitoring of cardiotoxicant poisonings
Poisonings with tricyclic antidepressants Value of serum concentrations
Boehnert MT N Engl J Med 1985
Prognostic value of serum theophylline concentration
Sessler CN Am J Med 1990
Why does the clinician need toxicological analysis to manage his
patient with cardiotoxicant poisoning
ProCon debate
- Positive diagnosis assessment to confirm a toxic hypothesis
- Differential diagnosis to exclude a toxic hypothesis
- Prognosis evaluation
- Help for treatment indications monitoring and re-evaluation
- Retrospective evaluation medico-legal issue or scientific studies
What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings
t
Severity C blood
t
Severity C blood
Confirm severity Supportive treatments
Prognostic factors Antidotes
Interest of analysis according to drug effects
Injury-inducing drugs
Functional drugs
Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues
Prerequisite availability of toxicological analysis
- Complexity and requirements of the assays
- Dialogue between biologists and clinicians
Importance of conservative plasma and urine sampling (initial and repetitive)
Expert opinion on appropriateness of disposal according to availability of drug screening
Fabbri A Emerg Med J 2003
Does a comprehensive drug screening add to decision making for poisonings in the ED
improve agreement on patient disposal Save potentially hospital resources
Meprobamate poisonings Is serum concentration useful to indicate the
mechanism of shock
Charron C Intensive Care Med 2005
Dose-dependent hypotension with narrowed QRS
- hypovolemia
- vasoplegia if concentrations le 150 mgl
- cardiogenic if concentrations gt 150 mgl
Plasma chloroquine concentration le 12 M No death
12-25 microM death rate 2
gt 25 microM death rate 22
gt 50 microM death rate 60
Chloroquine poisoning In-hospital prognosis assessment using
blood concentrations
Clemessy JL Crit Care Med 1996
TKTD using blood concentrations TKTD using plasma concentrations
Chloroquine poisoning blood vs plasma concentrations
0 25 50 75 100 125 15000
05
10
15
20
25
30
35
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 096
0 10 20 30 40 5000
05
10
15
20
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 091
0 1 2 3 4 5 6 7 8 900
05
10
15
20
Plasma chloroquine concentration (micromolL)
Ep
inep
hri
ne
infu
sio
n r
ate
(mg
h)
0 5 10 15 20 250
1
2
3
4
Plasma chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh)
R2 = 005
R2 = 017
Patient 1
Patient 2
PKPD population modeling in chloroquine poisonings
Meacutegarbane B Clin Tox2010
Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings
Relationship Between PlasmaFlecainide Concentration and
Outcome
Survivors Fatalities
0
1
2
3
4
5
6
7
8
9
10
Outcome of Acute Poisonings
Pla
sm
a F
lecain
ide
Co
ncen
trati
on
s (
mg
L)
Meacutegarbane B Clin Tox 2007
Meacutegarbane B BCPT 2010
Verapamil poisonings
Flecainide poisonings
Meacutegarbane B Clin Tox 2002 (abstract)
0
5
10
15
20
25P
red
icte
d c
on
cen
trati
on
s (n
gm
l)
0
10
0
20
0
30
0
40
0
Time since ingestion (hours)
Predicted concentration profiles
Non suvivors C(t) = 242 exp (-0003t)
Survivors C(t) = 177 exp (-0019t)
Cut-off C(t) = 207 exp (-0011t)
0
20
40
60
80
Co
lch
icin
e p
lasm
a c
on
cen
tra
tion
on
ad
mis
sio
n(n
gm
l)
Alive patients (N = 18)
Dead patients(N = 5)
Colchicine poisonings prognostic value of the time-course of serum concentrations
Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments
Q = body load of glycoside to neutralize
Estimation using ingested amount of digitalis
Estimation using serum glycoside concentration
Q = Weight
(kg)
volume of distribution
digoxin 56 lkg
digitoxin 056 lkg
Serum glycoside concentration
(ngml) x x
Q = x Ingested amount (mg) digoxin bioavailability (60 )
digitoxin bioavailability (100 ) or
One vial of digibind (40 mg) neutralizes 06 mg of digoxin
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
Why does not the clinician need any toxicological analysis to manage his
patient with cardiotoxicant poisoning
ProCon debate
The prognostic value of the ingested dose
Example of ajmaline poisoning
Ingested tablets N Cardiac arrest
1 g 7 0
2 g 13 1
3 g 16 8
Delay for symptom occurrence 1 - 3 h All patients in cardiac arrest died
Conso F Press Med 1980
Acebutolol gt 15 g
Amitritptyline gt 2 g
Carbamazepine gt 10 g
Chloroquine gt 4 g
Clomipramine gt 2 g
Dextropropoxyphen gt 500 mg
Dosulepine gt 125 g
Flecainide gt 15 g
Maprotiline gt 3 g
Propranolol gt 2 g
Baud FJ Crit Care 2007
Doses resulting in severe cardiovascular failure
Simulated probability over time for having an epinephrine infusion rate gt3 mgh
Meacutegarbane B Clin Tox 2011
The prognostic value of the ingested dose Example of chloroquine poisoning
Assessment of patientrsquos low risk if none present in the ED
- Systolic pressure lt100 mm Hg - Seizures - Unresponsiveness to verbal stimuli - Need for intubation - Any rhythm except sinus - Second- or third-degree atrioventricular block - QRS ge 012 s - PaO2 ge45 mmHg
Among the 151 low-risk patients none developed a high-risk condition after admission and none required ICU intervention These predictive criteria eliminated over 50 ICU days without compromising quality of care
Excessive admission in the ICU may also result in non-useful expenses and limited bed availability
Predicting the clinical course in intentional drug overdose in the emergency room
Brett AS Arch Intern Med 1987
Echocardiography coupled with Doppler allows a direct visualization of the heart contractility and aspects (ventricle dilatation myocardium thickness valve diseases) However it remains operator-dependent
Echocardiography
Hypovolemia or vasoplegia Cardiogenic shock
Echocardiography aspects
Severe dysrhythmia
- VO2 110 mLminm2
- SaO2 95
- Hb 11 gdl
40
90
SvO2 ()
1
Cardiac index (Lminm2)
2 3
57
70
5 6 7
80
83
SvO2 versus cardiac index relationships
SvO2 = SaO2 - VO2
IC x Hb x 134
Manini AF ClinTox 2010
- Despite of absence of specificity he serum lactate concentration had an excellent prognostic utility to predict drug-overdose fatality - The optimal lactate cut-point was 30 mmolL (84 sensitivity 75 specificity) which conferred a 158-fold increase in odds of fatality (p lt 0001)
Serum lactate is an excellent prognosticator
ROC-AUC 087 (95 CI 081ndash094)
Lactate is a marker of all types of SHOCK
1048707 A marker of inadequate perfusion or cellular O2 consumption
1048707 A marker of inadequate resuscitation and management
1048707 A predictor of patient bad outcome and development of organ
dysfunction
Beta-blocker poisonings Prognostic value of lactate concentration on admission
0
3
6
9
12
15
18
21
24
27
30
Survivors Fatalities
plt 00008S
eru
m l
acta
te c
on
cen
trati
on
s (
mm
ol
L)
0
3
6
9
12
15
18
21
24
27
30
On admissionvalues
plt 00001
Peakvalues
Seru
m l
acta
te c
on
cen
trati
on
s (
mm
ol
L)
The ROC-AUC of initial lactate for predicting mortality was 084 (074-094)
The cutoff point maximizing the sum of sensitivity and specificity was 27 mmolL
For the 30 mmolL selected lactate cutoff point 55 sensitivity 80 specificity
Meacutegarbane B Clin Tox 2010
Boehnert MT N Engl J Med 1985
Poisonings with tricyclic antidepressants Prognostic value of QRS to predict seizures and arrhythmias
Serum glucose as biomarker in calcium channel blocker poisonings
Levine M Crit Care Med 2007
Initial glucose level Peak glucose level
Increase in blood glucose +71 vs 0 p=00067
Serum potassium as biomarker in digitalis poisoning
Female
Male
lt 55
gt 55
lt 55
gt 55
Yes
No
Yes
No
Yes
No
Yes
No
K + gt45
Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No
Death rate
17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23
AV block Age
Dally S Press Med 1981
0 8 16 24 32 40 48 56
0
40
80
120
160
200
240
280
Plasma Lactate (mmolL)
Blo
od
Cyan
ide (
microm
ol
l)
Lactate as biomarker in cyanide poisoning
Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002
Chloroquine poisoning prognosis assessment
Supposed
ingested dose
Systolic BP QRS
duration
Severe gt 4 g or lt 100 mmHg or gt 010 s
Moderate 2 - 4 g and
gt 100 mmHg and
lt 010 s
Mild
lt 2 g and
gt 100 mmHg and
lt 010 s
Clemessy JL et al Crit Care Med 1996
Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg
Intubation and mechanical ventilation
Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h
Riou B N Engl J Med 1988
Macrocirculation level
- Measurement of blood pressure and cardiac index Microcirculation level
- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain
- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)
Hemodynamic monitoring of cardiotoxicant poisonings
Poisonings with tricyclic antidepressants Value of serum concentrations
Boehnert MT N Engl J Med 1985
Prognostic value of serum theophylline concentration
Sessler CN Am J Med 1990
Why does the clinician need toxicological analysis to manage his
patient with cardiotoxicant poisoning
ProCon debate
- Positive diagnosis assessment to confirm a toxic hypothesis
- Differential diagnosis to exclude a toxic hypothesis
- Prognosis evaluation
- Help for treatment indications monitoring and re-evaluation
- Retrospective evaluation medico-legal issue or scientific studies
What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings
t
Severity C blood
t
Severity C blood
Confirm severity Supportive treatments
Prognostic factors Antidotes
Interest of analysis according to drug effects
Injury-inducing drugs
Functional drugs
Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues
Prerequisite availability of toxicological analysis
- Complexity and requirements of the assays
- Dialogue between biologists and clinicians
Importance of conservative plasma and urine sampling (initial and repetitive)
Expert opinion on appropriateness of disposal according to availability of drug screening
Fabbri A Emerg Med J 2003
Does a comprehensive drug screening add to decision making for poisonings in the ED
improve agreement on patient disposal Save potentially hospital resources
Meprobamate poisonings Is serum concentration useful to indicate the
mechanism of shock
Charron C Intensive Care Med 2005
Dose-dependent hypotension with narrowed QRS
- hypovolemia
- vasoplegia if concentrations le 150 mgl
- cardiogenic if concentrations gt 150 mgl
Plasma chloroquine concentration le 12 M No death
12-25 microM death rate 2
gt 25 microM death rate 22
gt 50 microM death rate 60
Chloroquine poisoning In-hospital prognosis assessment using
blood concentrations
Clemessy JL Crit Care Med 1996
TKTD using blood concentrations TKTD using plasma concentrations
Chloroquine poisoning blood vs plasma concentrations
0 25 50 75 100 125 15000
05
10
15
20
25
30
35
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 096
0 10 20 30 40 5000
05
10
15
20
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 091
0 1 2 3 4 5 6 7 8 900
05
10
15
20
Plasma chloroquine concentration (micromolL)
Ep
inep
hri
ne
infu
sio
n r
ate
(mg
h)
0 5 10 15 20 250
1
2
3
4
Plasma chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh)
R2 = 005
R2 = 017
Patient 1
Patient 2
PKPD population modeling in chloroquine poisonings
Meacutegarbane B Clin Tox2010
Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings
Relationship Between PlasmaFlecainide Concentration and
Outcome
Survivors Fatalities
0
1
2
3
4
5
6
7
8
9
10
Outcome of Acute Poisonings
Pla
sm
a F
lecain
ide
Co
ncen
trati
on
s (
mg
L)
Meacutegarbane B Clin Tox 2007
Meacutegarbane B BCPT 2010
Verapamil poisonings
Flecainide poisonings
Meacutegarbane B Clin Tox 2002 (abstract)
0
5
10
15
20
25P
red
icte
d c
on
cen
trati
on
s (n
gm
l)
0
10
0
20
0
30
0
40
0
Time since ingestion (hours)
Predicted concentration profiles
Non suvivors C(t) = 242 exp (-0003t)
Survivors C(t) = 177 exp (-0019t)
Cut-off C(t) = 207 exp (-0011t)
0
20
40
60
80
Co
lch
icin
e p
lasm
a c
on
cen
tra
tion
on
ad
mis
sio
n(n
gm
l)
Alive patients (N = 18)
Dead patients(N = 5)
Colchicine poisonings prognostic value of the time-course of serum concentrations
Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments
Q = body load of glycoside to neutralize
Estimation using ingested amount of digitalis
Estimation using serum glycoside concentration
Q = Weight
(kg)
volume of distribution
digoxin 56 lkg
digitoxin 056 lkg
Serum glycoside concentration
(ngml) x x
Q = x Ingested amount (mg) digoxin bioavailability (60 )
digitoxin bioavailability (100 ) or
One vial of digibind (40 mg) neutralizes 06 mg of digoxin
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
The prognostic value of the ingested dose
Example of ajmaline poisoning
Ingested tablets N Cardiac arrest
1 g 7 0
2 g 13 1
3 g 16 8
Delay for symptom occurrence 1 - 3 h All patients in cardiac arrest died
Conso F Press Med 1980
Acebutolol gt 15 g
Amitritptyline gt 2 g
Carbamazepine gt 10 g
Chloroquine gt 4 g
Clomipramine gt 2 g
Dextropropoxyphen gt 500 mg
Dosulepine gt 125 g
Flecainide gt 15 g
Maprotiline gt 3 g
Propranolol gt 2 g
Baud FJ Crit Care 2007
Doses resulting in severe cardiovascular failure
Simulated probability over time for having an epinephrine infusion rate gt3 mgh
Meacutegarbane B Clin Tox 2011
The prognostic value of the ingested dose Example of chloroquine poisoning
Assessment of patientrsquos low risk if none present in the ED
- Systolic pressure lt100 mm Hg - Seizures - Unresponsiveness to verbal stimuli - Need for intubation - Any rhythm except sinus - Second- or third-degree atrioventricular block - QRS ge 012 s - PaO2 ge45 mmHg
Among the 151 low-risk patients none developed a high-risk condition after admission and none required ICU intervention These predictive criteria eliminated over 50 ICU days without compromising quality of care
Excessive admission in the ICU may also result in non-useful expenses and limited bed availability
Predicting the clinical course in intentional drug overdose in the emergency room
Brett AS Arch Intern Med 1987
Echocardiography coupled with Doppler allows a direct visualization of the heart contractility and aspects (ventricle dilatation myocardium thickness valve diseases) However it remains operator-dependent
Echocardiography
Hypovolemia or vasoplegia Cardiogenic shock
Echocardiography aspects
Severe dysrhythmia
- VO2 110 mLminm2
- SaO2 95
- Hb 11 gdl
40
90
SvO2 ()
1
Cardiac index (Lminm2)
2 3
57
70
5 6 7
80
83
SvO2 versus cardiac index relationships
SvO2 = SaO2 - VO2
IC x Hb x 134
Manini AF ClinTox 2010
- Despite of absence of specificity he serum lactate concentration had an excellent prognostic utility to predict drug-overdose fatality - The optimal lactate cut-point was 30 mmolL (84 sensitivity 75 specificity) which conferred a 158-fold increase in odds of fatality (p lt 0001)
Serum lactate is an excellent prognosticator
ROC-AUC 087 (95 CI 081ndash094)
Lactate is a marker of all types of SHOCK
1048707 A marker of inadequate perfusion or cellular O2 consumption
1048707 A marker of inadequate resuscitation and management
1048707 A predictor of patient bad outcome and development of organ
dysfunction
Beta-blocker poisonings Prognostic value of lactate concentration on admission
0
3
6
9
12
15
18
21
24
27
30
Survivors Fatalities
plt 00008S
eru
m l
acta
te c
on
cen
trati
on
s (
mm
ol
L)
0
3
6
9
12
15
18
21
24
27
30
On admissionvalues
plt 00001
Peakvalues
Seru
m l
acta
te c
on
cen
trati
on
s (
mm
ol
L)
The ROC-AUC of initial lactate for predicting mortality was 084 (074-094)
The cutoff point maximizing the sum of sensitivity and specificity was 27 mmolL
For the 30 mmolL selected lactate cutoff point 55 sensitivity 80 specificity
Meacutegarbane B Clin Tox 2010
Boehnert MT N Engl J Med 1985
Poisonings with tricyclic antidepressants Prognostic value of QRS to predict seizures and arrhythmias
Serum glucose as biomarker in calcium channel blocker poisonings
Levine M Crit Care Med 2007
Initial glucose level Peak glucose level
Increase in blood glucose +71 vs 0 p=00067
Serum potassium as biomarker in digitalis poisoning
Female
Male
lt 55
gt 55
lt 55
gt 55
Yes
No
Yes
No
Yes
No
Yes
No
K + gt45
Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No
Death rate
17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23
AV block Age
Dally S Press Med 1981
0 8 16 24 32 40 48 56
0
40
80
120
160
200
240
280
Plasma Lactate (mmolL)
Blo
od
Cyan
ide (
microm
ol
l)
Lactate as biomarker in cyanide poisoning
Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002
Chloroquine poisoning prognosis assessment
Supposed
ingested dose
Systolic BP QRS
duration
Severe gt 4 g or lt 100 mmHg or gt 010 s
Moderate 2 - 4 g and
gt 100 mmHg and
lt 010 s
Mild
lt 2 g and
gt 100 mmHg and
lt 010 s
Clemessy JL et al Crit Care Med 1996
Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg
Intubation and mechanical ventilation
Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h
Riou B N Engl J Med 1988
Macrocirculation level
- Measurement of blood pressure and cardiac index Microcirculation level
- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain
- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)
Hemodynamic monitoring of cardiotoxicant poisonings
Poisonings with tricyclic antidepressants Value of serum concentrations
Boehnert MT N Engl J Med 1985
Prognostic value of serum theophylline concentration
Sessler CN Am J Med 1990
Why does the clinician need toxicological analysis to manage his
patient with cardiotoxicant poisoning
ProCon debate
- Positive diagnosis assessment to confirm a toxic hypothesis
- Differential diagnosis to exclude a toxic hypothesis
- Prognosis evaluation
- Help for treatment indications monitoring and re-evaluation
- Retrospective evaluation medico-legal issue or scientific studies
What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings
t
Severity C blood
t
Severity C blood
Confirm severity Supportive treatments
Prognostic factors Antidotes
Interest of analysis according to drug effects
Injury-inducing drugs
Functional drugs
Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues
Prerequisite availability of toxicological analysis
- Complexity and requirements of the assays
- Dialogue between biologists and clinicians
Importance of conservative plasma and urine sampling (initial and repetitive)
Expert opinion on appropriateness of disposal according to availability of drug screening
Fabbri A Emerg Med J 2003
Does a comprehensive drug screening add to decision making for poisonings in the ED
improve agreement on patient disposal Save potentially hospital resources
Meprobamate poisonings Is serum concentration useful to indicate the
mechanism of shock
Charron C Intensive Care Med 2005
Dose-dependent hypotension with narrowed QRS
- hypovolemia
- vasoplegia if concentrations le 150 mgl
- cardiogenic if concentrations gt 150 mgl
Plasma chloroquine concentration le 12 M No death
12-25 microM death rate 2
gt 25 microM death rate 22
gt 50 microM death rate 60
Chloroquine poisoning In-hospital prognosis assessment using
blood concentrations
Clemessy JL Crit Care Med 1996
TKTD using blood concentrations TKTD using plasma concentrations
Chloroquine poisoning blood vs plasma concentrations
0 25 50 75 100 125 15000
05
10
15
20
25
30
35
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 096
0 10 20 30 40 5000
05
10
15
20
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 091
0 1 2 3 4 5 6 7 8 900
05
10
15
20
Plasma chloroquine concentration (micromolL)
Ep
inep
hri
ne
infu
sio
n r
ate
(mg
h)
0 5 10 15 20 250
1
2
3
4
Plasma chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh)
R2 = 005
R2 = 017
Patient 1
Patient 2
PKPD population modeling in chloroquine poisonings
Meacutegarbane B Clin Tox2010
Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings
Relationship Between PlasmaFlecainide Concentration and
Outcome
Survivors Fatalities
0
1
2
3
4
5
6
7
8
9
10
Outcome of Acute Poisonings
Pla
sm
a F
lecain
ide
Co
ncen
trati
on
s (
mg
L)
Meacutegarbane B Clin Tox 2007
Meacutegarbane B BCPT 2010
Verapamil poisonings
Flecainide poisonings
Meacutegarbane B Clin Tox 2002 (abstract)
0
5
10
15
20
25P
red
icte
d c
on
cen
trati
on
s (n
gm
l)
0
10
0
20
0
30
0
40
0
Time since ingestion (hours)
Predicted concentration profiles
Non suvivors C(t) = 242 exp (-0003t)
Survivors C(t) = 177 exp (-0019t)
Cut-off C(t) = 207 exp (-0011t)
0
20
40
60
80
Co
lch
icin
e p
lasm
a c
on
cen
tra
tion
on
ad
mis
sio
n(n
gm
l)
Alive patients (N = 18)
Dead patients(N = 5)
Colchicine poisonings prognostic value of the time-course of serum concentrations
Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments
Q = body load of glycoside to neutralize
Estimation using ingested amount of digitalis
Estimation using serum glycoside concentration
Q = Weight
(kg)
volume of distribution
digoxin 56 lkg
digitoxin 056 lkg
Serum glycoside concentration
(ngml) x x
Q = x Ingested amount (mg) digoxin bioavailability (60 )
digitoxin bioavailability (100 ) or
One vial of digibind (40 mg) neutralizes 06 mg of digoxin
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
Acebutolol gt 15 g
Amitritptyline gt 2 g
Carbamazepine gt 10 g
Chloroquine gt 4 g
Clomipramine gt 2 g
Dextropropoxyphen gt 500 mg
Dosulepine gt 125 g
Flecainide gt 15 g
Maprotiline gt 3 g
Propranolol gt 2 g
Baud FJ Crit Care 2007
Doses resulting in severe cardiovascular failure
Simulated probability over time for having an epinephrine infusion rate gt3 mgh
Meacutegarbane B Clin Tox 2011
The prognostic value of the ingested dose Example of chloroquine poisoning
Assessment of patientrsquos low risk if none present in the ED
- Systolic pressure lt100 mm Hg - Seizures - Unresponsiveness to verbal stimuli - Need for intubation - Any rhythm except sinus - Second- or third-degree atrioventricular block - QRS ge 012 s - PaO2 ge45 mmHg
Among the 151 low-risk patients none developed a high-risk condition after admission and none required ICU intervention These predictive criteria eliminated over 50 ICU days without compromising quality of care
Excessive admission in the ICU may also result in non-useful expenses and limited bed availability
Predicting the clinical course in intentional drug overdose in the emergency room
Brett AS Arch Intern Med 1987
Echocardiography coupled with Doppler allows a direct visualization of the heart contractility and aspects (ventricle dilatation myocardium thickness valve diseases) However it remains operator-dependent
Echocardiography
Hypovolemia or vasoplegia Cardiogenic shock
Echocardiography aspects
Severe dysrhythmia
- VO2 110 mLminm2
- SaO2 95
- Hb 11 gdl
40
90
SvO2 ()
1
Cardiac index (Lminm2)
2 3
57
70
5 6 7
80
83
SvO2 versus cardiac index relationships
SvO2 = SaO2 - VO2
IC x Hb x 134
Manini AF ClinTox 2010
- Despite of absence of specificity he serum lactate concentration had an excellent prognostic utility to predict drug-overdose fatality - The optimal lactate cut-point was 30 mmolL (84 sensitivity 75 specificity) which conferred a 158-fold increase in odds of fatality (p lt 0001)
Serum lactate is an excellent prognosticator
ROC-AUC 087 (95 CI 081ndash094)
Lactate is a marker of all types of SHOCK
1048707 A marker of inadequate perfusion or cellular O2 consumption
1048707 A marker of inadequate resuscitation and management
1048707 A predictor of patient bad outcome and development of organ
dysfunction
Beta-blocker poisonings Prognostic value of lactate concentration on admission
0
3
6
9
12
15
18
21
24
27
30
Survivors Fatalities
plt 00008S
eru
m l
acta
te c
on
cen
trati
on
s (
mm
ol
L)
0
3
6
9
12
15
18
21
24
27
30
On admissionvalues
plt 00001
Peakvalues
Seru
m l
acta
te c
on
cen
trati
on
s (
mm
ol
L)
The ROC-AUC of initial lactate for predicting mortality was 084 (074-094)
The cutoff point maximizing the sum of sensitivity and specificity was 27 mmolL
For the 30 mmolL selected lactate cutoff point 55 sensitivity 80 specificity
Meacutegarbane B Clin Tox 2010
Boehnert MT N Engl J Med 1985
Poisonings with tricyclic antidepressants Prognostic value of QRS to predict seizures and arrhythmias
Serum glucose as biomarker in calcium channel blocker poisonings
Levine M Crit Care Med 2007
Initial glucose level Peak glucose level
Increase in blood glucose +71 vs 0 p=00067
Serum potassium as biomarker in digitalis poisoning
Female
Male
lt 55
gt 55
lt 55
gt 55
Yes
No
Yes
No
Yes
No
Yes
No
K + gt45
Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No
Death rate
17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23
AV block Age
Dally S Press Med 1981
0 8 16 24 32 40 48 56
0
40
80
120
160
200
240
280
Plasma Lactate (mmolL)
Blo
od
Cyan
ide (
microm
ol
l)
Lactate as biomarker in cyanide poisoning
Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002
Chloroquine poisoning prognosis assessment
Supposed
ingested dose
Systolic BP QRS
duration
Severe gt 4 g or lt 100 mmHg or gt 010 s
Moderate 2 - 4 g and
gt 100 mmHg and
lt 010 s
Mild
lt 2 g and
gt 100 mmHg and
lt 010 s
Clemessy JL et al Crit Care Med 1996
Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg
Intubation and mechanical ventilation
Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h
Riou B N Engl J Med 1988
Macrocirculation level
- Measurement of blood pressure and cardiac index Microcirculation level
- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain
- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)
Hemodynamic monitoring of cardiotoxicant poisonings
Poisonings with tricyclic antidepressants Value of serum concentrations
Boehnert MT N Engl J Med 1985
Prognostic value of serum theophylline concentration
Sessler CN Am J Med 1990
Why does the clinician need toxicological analysis to manage his
patient with cardiotoxicant poisoning
ProCon debate
- Positive diagnosis assessment to confirm a toxic hypothesis
- Differential diagnosis to exclude a toxic hypothesis
- Prognosis evaluation
- Help for treatment indications monitoring and re-evaluation
- Retrospective evaluation medico-legal issue or scientific studies
What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings
t
Severity C blood
t
Severity C blood
Confirm severity Supportive treatments
Prognostic factors Antidotes
Interest of analysis according to drug effects
Injury-inducing drugs
Functional drugs
Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues
Prerequisite availability of toxicological analysis
- Complexity and requirements of the assays
- Dialogue between biologists and clinicians
Importance of conservative plasma and urine sampling (initial and repetitive)
Expert opinion on appropriateness of disposal according to availability of drug screening
Fabbri A Emerg Med J 2003
Does a comprehensive drug screening add to decision making for poisonings in the ED
improve agreement on patient disposal Save potentially hospital resources
Meprobamate poisonings Is serum concentration useful to indicate the
mechanism of shock
Charron C Intensive Care Med 2005
Dose-dependent hypotension with narrowed QRS
- hypovolemia
- vasoplegia if concentrations le 150 mgl
- cardiogenic if concentrations gt 150 mgl
Plasma chloroquine concentration le 12 M No death
12-25 microM death rate 2
gt 25 microM death rate 22
gt 50 microM death rate 60
Chloroquine poisoning In-hospital prognosis assessment using
blood concentrations
Clemessy JL Crit Care Med 1996
TKTD using blood concentrations TKTD using plasma concentrations
Chloroquine poisoning blood vs plasma concentrations
0 25 50 75 100 125 15000
05
10
15
20
25
30
35
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 096
0 10 20 30 40 5000
05
10
15
20
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 091
0 1 2 3 4 5 6 7 8 900
05
10
15
20
Plasma chloroquine concentration (micromolL)
Ep
inep
hri
ne
infu
sio
n r
ate
(mg
h)
0 5 10 15 20 250
1
2
3
4
Plasma chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh)
R2 = 005
R2 = 017
Patient 1
Patient 2
PKPD population modeling in chloroquine poisonings
Meacutegarbane B Clin Tox2010
Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings
Relationship Between PlasmaFlecainide Concentration and
Outcome
Survivors Fatalities
0
1
2
3
4
5
6
7
8
9
10
Outcome of Acute Poisonings
Pla
sm
a F
lecain
ide
Co
ncen
trati
on
s (
mg
L)
Meacutegarbane B Clin Tox 2007
Meacutegarbane B BCPT 2010
Verapamil poisonings
Flecainide poisonings
Meacutegarbane B Clin Tox 2002 (abstract)
0
5
10
15
20
25P
red
icte
d c
on
cen
trati
on
s (n
gm
l)
0
10
0
20
0
30
0
40
0
Time since ingestion (hours)
Predicted concentration profiles
Non suvivors C(t) = 242 exp (-0003t)
Survivors C(t) = 177 exp (-0019t)
Cut-off C(t) = 207 exp (-0011t)
0
20
40
60
80
Co
lch
icin
e p
lasm
a c
on
cen
tra
tion
on
ad
mis
sio
n(n
gm
l)
Alive patients (N = 18)
Dead patients(N = 5)
Colchicine poisonings prognostic value of the time-course of serum concentrations
Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments
Q = body load of glycoside to neutralize
Estimation using ingested amount of digitalis
Estimation using serum glycoside concentration
Q = Weight
(kg)
volume of distribution
digoxin 56 lkg
digitoxin 056 lkg
Serum glycoside concentration
(ngml) x x
Q = x Ingested amount (mg) digoxin bioavailability (60 )
digitoxin bioavailability (100 ) or
One vial of digibind (40 mg) neutralizes 06 mg of digoxin
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
Simulated probability over time for having an epinephrine infusion rate gt3 mgh
Meacutegarbane B Clin Tox 2011
The prognostic value of the ingested dose Example of chloroquine poisoning
Assessment of patientrsquos low risk if none present in the ED
- Systolic pressure lt100 mm Hg - Seizures - Unresponsiveness to verbal stimuli - Need for intubation - Any rhythm except sinus - Second- or third-degree atrioventricular block - QRS ge 012 s - PaO2 ge45 mmHg
Among the 151 low-risk patients none developed a high-risk condition after admission and none required ICU intervention These predictive criteria eliminated over 50 ICU days without compromising quality of care
Excessive admission in the ICU may also result in non-useful expenses and limited bed availability
Predicting the clinical course in intentional drug overdose in the emergency room
Brett AS Arch Intern Med 1987
Echocardiography coupled with Doppler allows a direct visualization of the heart contractility and aspects (ventricle dilatation myocardium thickness valve diseases) However it remains operator-dependent
Echocardiography
Hypovolemia or vasoplegia Cardiogenic shock
Echocardiography aspects
Severe dysrhythmia
- VO2 110 mLminm2
- SaO2 95
- Hb 11 gdl
40
90
SvO2 ()
1
Cardiac index (Lminm2)
2 3
57
70
5 6 7
80
83
SvO2 versus cardiac index relationships
SvO2 = SaO2 - VO2
IC x Hb x 134
Manini AF ClinTox 2010
- Despite of absence of specificity he serum lactate concentration had an excellent prognostic utility to predict drug-overdose fatality - The optimal lactate cut-point was 30 mmolL (84 sensitivity 75 specificity) which conferred a 158-fold increase in odds of fatality (p lt 0001)
Serum lactate is an excellent prognosticator
ROC-AUC 087 (95 CI 081ndash094)
Lactate is a marker of all types of SHOCK
1048707 A marker of inadequate perfusion or cellular O2 consumption
1048707 A marker of inadequate resuscitation and management
1048707 A predictor of patient bad outcome and development of organ
dysfunction
Beta-blocker poisonings Prognostic value of lactate concentration on admission
0
3
6
9
12
15
18
21
24
27
30
Survivors Fatalities
plt 00008S
eru
m l
acta
te c
on
cen
trati
on
s (
mm
ol
L)
0
3
6
9
12
15
18
21
24
27
30
On admissionvalues
plt 00001
Peakvalues
Seru
m l
acta
te c
on
cen
trati
on
s (
mm
ol
L)
The ROC-AUC of initial lactate for predicting mortality was 084 (074-094)
The cutoff point maximizing the sum of sensitivity and specificity was 27 mmolL
For the 30 mmolL selected lactate cutoff point 55 sensitivity 80 specificity
Meacutegarbane B Clin Tox 2010
Boehnert MT N Engl J Med 1985
Poisonings with tricyclic antidepressants Prognostic value of QRS to predict seizures and arrhythmias
Serum glucose as biomarker in calcium channel blocker poisonings
Levine M Crit Care Med 2007
Initial glucose level Peak glucose level
Increase in blood glucose +71 vs 0 p=00067
Serum potassium as biomarker in digitalis poisoning
Female
Male
lt 55
gt 55
lt 55
gt 55
Yes
No
Yes
No
Yes
No
Yes
No
K + gt45
Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No
Death rate
17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23
AV block Age
Dally S Press Med 1981
0 8 16 24 32 40 48 56
0
40
80
120
160
200
240
280
Plasma Lactate (mmolL)
Blo
od
Cyan
ide (
microm
ol
l)
Lactate as biomarker in cyanide poisoning
Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002
Chloroquine poisoning prognosis assessment
Supposed
ingested dose
Systolic BP QRS
duration
Severe gt 4 g or lt 100 mmHg or gt 010 s
Moderate 2 - 4 g and
gt 100 mmHg and
lt 010 s
Mild
lt 2 g and
gt 100 mmHg and
lt 010 s
Clemessy JL et al Crit Care Med 1996
Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg
Intubation and mechanical ventilation
Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h
Riou B N Engl J Med 1988
Macrocirculation level
- Measurement of blood pressure and cardiac index Microcirculation level
- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain
- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)
Hemodynamic monitoring of cardiotoxicant poisonings
Poisonings with tricyclic antidepressants Value of serum concentrations
Boehnert MT N Engl J Med 1985
Prognostic value of serum theophylline concentration
Sessler CN Am J Med 1990
Why does the clinician need toxicological analysis to manage his
patient with cardiotoxicant poisoning
ProCon debate
- Positive diagnosis assessment to confirm a toxic hypothesis
- Differential diagnosis to exclude a toxic hypothesis
- Prognosis evaluation
- Help for treatment indications monitoring and re-evaluation
- Retrospective evaluation medico-legal issue or scientific studies
What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings
t
Severity C blood
t
Severity C blood
Confirm severity Supportive treatments
Prognostic factors Antidotes
Interest of analysis according to drug effects
Injury-inducing drugs
Functional drugs
Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues
Prerequisite availability of toxicological analysis
- Complexity and requirements of the assays
- Dialogue between biologists and clinicians
Importance of conservative plasma and urine sampling (initial and repetitive)
Expert opinion on appropriateness of disposal according to availability of drug screening
Fabbri A Emerg Med J 2003
Does a comprehensive drug screening add to decision making for poisonings in the ED
improve agreement on patient disposal Save potentially hospital resources
Meprobamate poisonings Is serum concentration useful to indicate the
mechanism of shock
Charron C Intensive Care Med 2005
Dose-dependent hypotension with narrowed QRS
- hypovolemia
- vasoplegia if concentrations le 150 mgl
- cardiogenic if concentrations gt 150 mgl
Plasma chloroquine concentration le 12 M No death
12-25 microM death rate 2
gt 25 microM death rate 22
gt 50 microM death rate 60
Chloroquine poisoning In-hospital prognosis assessment using
blood concentrations
Clemessy JL Crit Care Med 1996
TKTD using blood concentrations TKTD using plasma concentrations
Chloroquine poisoning blood vs plasma concentrations
0 25 50 75 100 125 15000
05
10
15
20
25
30
35
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 096
0 10 20 30 40 5000
05
10
15
20
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 091
0 1 2 3 4 5 6 7 8 900
05
10
15
20
Plasma chloroquine concentration (micromolL)
Ep
inep
hri
ne
infu
sio
n r
ate
(mg
h)
0 5 10 15 20 250
1
2
3
4
Plasma chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh)
R2 = 005
R2 = 017
Patient 1
Patient 2
PKPD population modeling in chloroquine poisonings
Meacutegarbane B Clin Tox2010
Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings
Relationship Between PlasmaFlecainide Concentration and
Outcome
Survivors Fatalities
0
1
2
3
4
5
6
7
8
9
10
Outcome of Acute Poisonings
Pla
sm
a F
lecain
ide
Co
ncen
trati
on
s (
mg
L)
Meacutegarbane B Clin Tox 2007
Meacutegarbane B BCPT 2010
Verapamil poisonings
Flecainide poisonings
Meacutegarbane B Clin Tox 2002 (abstract)
0
5
10
15
20
25P
red
icte
d c
on
cen
trati
on
s (n
gm
l)
0
10
0
20
0
30
0
40
0
Time since ingestion (hours)
Predicted concentration profiles
Non suvivors C(t) = 242 exp (-0003t)
Survivors C(t) = 177 exp (-0019t)
Cut-off C(t) = 207 exp (-0011t)
0
20
40
60
80
Co
lch
icin
e p
lasm
a c
on
cen
tra
tion
on
ad
mis
sio
n(n
gm
l)
Alive patients (N = 18)
Dead patients(N = 5)
Colchicine poisonings prognostic value of the time-course of serum concentrations
Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments
Q = body load of glycoside to neutralize
Estimation using ingested amount of digitalis
Estimation using serum glycoside concentration
Q = Weight
(kg)
volume of distribution
digoxin 56 lkg
digitoxin 056 lkg
Serum glycoside concentration
(ngml) x x
Q = x Ingested amount (mg) digoxin bioavailability (60 )
digitoxin bioavailability (100 ) or
One vial of digibind (40 mg) neutralizes 06 mg of digoxin
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
Assessment of patientrsquos low risk if none present in the ED
- Systolic pressure lt100 mm Hg - Seizures - Unresponsiveness to verbal stimuli - Need for intubation - Any rhythm except sinus - Second- or third-degree atrioventricular block - QRS ge 012 s - PaO2 ge45 mmHg
Among the 151 low-risk patients none developed a high-risk condition after admission and none required ICU intervention These predictive criteria eliminated over 50 ICU days without compromising quality of care
Excessive admission in the ICU may also result in non-useful expenses and limited bed availability
Predicting the clinical course in intentional drug overdose in the emergency room
Brett AS Arch Intern Med 1987
Echocardiography coupled with Doppler allows a direct visualization of the heart contractility and aspects (ventricle dilatation myocardium thickness valve diseases) However it remains operator-dependent
Echocardiography
Hypovolemia or vasoplegia Cardiogenic shock
Echocardiography aspects
Severe dysrhythmia
- VO2 110 mLminm2
- SaO2 95
- Hb 11 gdl
40
90
SvO2 ()
1
Cardiac index (Lminm2)
2 3
57
70
5 6 7
80
83
SvO2 versus cardiac index relationships
SvO2 = SaO2 - VO2
IC x Hb x 134
Manini AF ClinTox 2010
- Despite of absence of specificity he serum lactate concentration had an excellent prognostic utility to predict drug-overdose fatality - The optimal lactate cut-point was 30 mmolL (84 sensitivity 75 specificity) which conferred a 158-fold increase in odds of fatality (p lt 0001)
Serum lactate is an excellent prognosticator
ROC-AUC 087 (95 CI 081ndash094)
Lactate is a marker of all types of SHOCK
1048707 A marker of inadequate perfusion or cellular O2 consumption
1048707 A marker of inadequate resuscitation and management
1048707 A predictor of patient bad outcome and development of organ
dysfunction
Beta-blocker poisonings Prognostic value of lactate concentration on admission
0
3
6
9
12
15
18
21
24
27
30
Survivors Fatalities
plt 00008S
eru
m l
acta
te c
on
cen
trati
on
s (
mm
ol
L)
0
3
6
9
12
15
18
21
24
27
30
On admissionvalues
plt 00001
Peakvalues
Seru
m l
acta
te c
on
cen
trati
on
s (
mm
ol
L)
The ROC-AUC of initial lactate for predicting mortality was 084 (074-094)
The cutoff point maximizing the sum of sensitivity and specificity was 27 mmolL
For the 30 mmolL selected lactate cutoff point 55 sensitivity 80 specificity
Meacutegarbane B Clin Tox 2010
Boehnert MT N Engl J Med 1985
Poisonings with tricyclic antidepressants Prognostic value of QRS to predict seizures and arrhythmias
Serum glucose as biomarker in calcium channel blocker poisonings
Levine M Crit Care Med 2007
Initial glucose level Peak glucose level
Increase in blood glucose +71 vs 0 p=00067
Serum potassium as biomarker in digitalis poisoning
Female
Male
lt 55
gt 55
lt 55
gt 55
Yes
No
Yes
No
Yes
No
Yes
No
K + gt45
Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No
Death rate
17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23
AV block Age
Dally S Press Med 1981
0 8 16 24 32 40 48 56
0
40
80
120
160
200
240
280
Plasma Lactate (mmolL)
Blo
od
Cyan
ide (
microm
ol
l)
Lactate as biomarker in cyanide poisoning
Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002
Chloroquine poisoning prognosis assessment
Supposed
ingested dose
Systolic BP QRS
duration
Severe gt 4 g or lt 100 mmHg or gt 010 s
Moderate 2 - 4 g and
gt 100 mmHg and
lt 010 s
Mild
lt 2 g and
gt 100 mmHg and
lt 010 s
Clemessy JL et al Crit Care Med 1996
Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg
Intubation and mechanical ventilation
Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h
Riou B N Engl J Med 1988
Macrocirculation level
- Measurement of blood pressure and cardiac index Microcirculation level
- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain
- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)
Hemodynamic monitoring of cardiotoxicant poisonings
Poisonings with tricyclic antidepressants Value of serum concentrations
Boehnert MT N Engl J Med 1985
Prognostic value of serum theophylline concentration
Sessler CN Am J Med 1990
Why does the clinician need toxicological analysis to manage his
patient with cardiotoxicant poisoning
ProCon debate
- Positive diagnosis assessment to confirm a toxic hypothesis
- Differential diagnosis to exclude a toxic hypothesis
- Prognosis evaluation
- Help for treatment indications monitoring and re-evaluation
- Retrospective evaluation medico-legal issue or scientific studies
What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings
t
Severity C blood
t
Severity C blood
Confirm severity Supportive treatments
Prognostic factors Antidotes
Interest of analysis according to drug effects
Injury-inducing drugs
Functional drugs
Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues
Prerequisite availability of toxicological analysis
- Complexity and requirements of the assays
- Dialogue between biologists and clinicians
Importance of conservative plasma and urine sampling (initial and repetitive)
Expert opinion on appropriateness of disposal according to availability of drug screening
Fabbri A Emerg Med J 2003
Does a comprehensive drug screening add to decision making for poisonings in the ED
improve agreement on patient disposal Save potentially hospital resources
Meprobamate poisonings Is serum concentration useful to indicate the
mechanism of shock
Charron C Intensive Care Med 2005
Dose-dependent hypotension with narrowed QRS
- hypovolemia
- vasoplegia if concentrations le 150 mgl
- cardiogenic if concentrations gt 150 mgl
Plasma chloroquine concentration le 12 M No death
12-25 microM death rate 2
gt 25 microM death rate 22
gt 50 microM death rate 60
Chloroquine poisoning In-hospital prognosis assessment using
blood concentrations
Clemessy JL Crit Care Med 1996
TKTD using blood concentrations TKTD using plasma concentrations
Chloroquine poisoning blood vs plasma concentrations
0 25 50 75 100 125 15000
05
10
15
20
25
30
35
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 096
0 10 20 30 40 5000
05
10
15
20
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 091
0 1 2 3 4 5 6 7 8 900
05
10
15
20
Plasma chloroquine concentration (micromolL)
Ep
inep
hri
ne
infu
sio
n r
ate
(mg
h)
0 5 10 15 20 250
1
2
3
4
Plasma chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh)
R2 = 005
R2 = 017
Patient 1
Patient 2
PKPD population modeling in chloroquine poisonings
Meacutegarbane B Clin Tox2010
Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings
Relationship Between PlasmaFlecainide Concentration and
Outcome
Survivors Fatalities
0
1
2
3
4
5
6
7
8
9
10
Outcome of Acute Poisonings
Pla
sm
a F
lecain
ide
Co
ncen
trati
on
s (
mg
L)
Meacutegarbane B Clin Tox 2007
Meacutegarbane B BCPT 2010
Verapamil poisonings
Flecainide poisonings
Meacutegarbane B Clin Tox 2002 (abstract)
0
5
10
15
20
25P
red
icte
d c
on
cen
trati
on
s (n
gm
l)
0
10
0
20
0
30
0
40
0
Time since ingestion (hours)
Predicted concentration profiles
Non suvivors C(t) = 242 exp (-0003t)
Survivors C(t) = 177 exp (-0019t)
Cut-off C(t) = 207 exp (-0011t)
0
20
40
60
80
Co
lch
icin
e p
lasm
a c
on
cen
tra
tion
on
ad
mis
sio
n(n
gm
l)
Alive patients (N = 18)
Dead patients(N = 5)
Colchicine poisonings prognostic value of the time-course of serum concentrations
Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments
Q = body load of glycoside to neutralize
Estimation using ingested amount of digitalis
Estimation using serum glycoside concentration
Q = Weight
(kg)
volume of distribution
digoxin 56 lkg
digitoxin 056 lkg
Serum glycoside concentration
(ngml) x x
Q = x Ingested amount (mg) digoxin bioavailability (60 )
digitoxin bioavailability (100 ) or
One vial of digibind (40 mg) neutralizes 06 mg of digoxin
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
Echocardiography coupled with Doppler allows a direct visualization of the heart contractility and aspects (ventricle dilatation myocardium thickness valve diseases) However it remains operator-dependent
Echocardiography
Hypovolemia or vasoplegia Cardiogenic shock
Echocardiography aspects
Severe dysrhythmia
- VO2 110 mLminm2
- SaO2 95
- Hb 11 gdl
40
90
SvO2 ()
1
Cardiac index (Lminm2)
2 3
57
70
5 6 7
80
83
SvO2 versus cardiac index relationships
SvO2 = SaO2 - VO2
IC x Hb x 134
Manini AF ClinTox 2010
- Despite of absence of specificity he serum lactate concentration had an excellent prognostic utility to predict drug-overdose fatality - The optimal lactate cut-point was 30 mmolL (84 sensitivity 75 specificity) which conferred a 158-fold increase in odds of fatality (p lt 0001)
Serum lactate is an excellent prognosticator
ROC-AUC 087 (95 CI 081ndash094)
Lactate is a marker of all types of SHOCK
1048707 A marker of inadequate perfusion or cellular O2 consumption
1048707 A marker of inadequate resuscitation and management
1048707 A predictor of patient bad outcome and development of organ
dysfunction
Beta-blocker poisonings Prognostic value of lactate concentration on admission
0
3
6
9
12
15
18
21
24
27
30
Survivors Fatalities
plt 00008S
eru
m l
acta
te c
on
cen
trati
on
s (
mm
ol
L)
0
3
6
9
12
15
18
21
24
27
30
On admissionvalues
plt 00001
Peakvalues
Seru
m l
acta
te c
on
cen
trati
on
s (
mm
ol
L)
The ROC-AUC of initial lactate for predicting mortality was 084 (074-094)
The cutoff point maximizing the sum of sensitivity and specificity was 27 mmolL
For the 30 mmolL selected lactate cutoff point 55 sensitivity 80 specificity
Meacutegarbane B Clin Tox 2010
Boehnert MT N Engl J Med 1985
Poisonings with tricyclic antidepressants Prognostic value of QRS to predict seizures and arrhythmias
Serum glucose as biomarker in calcium channel blocker poisonings
Levine M Crit Care Med 2007
Initial glucose level Peak glucose level
Increase in blood glucose +71 vs 0 p=00067
Serum potassium as biomarker in digitalis poisoning
Female
Male
lt 55
gt 55
lt 55
gt 55
Yes
No
Yes
No
Yes
No
Yes
No
K + gt45
Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No
Death rate
17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23
AV block Age
Dally S Press Med 1981
0 8 16 24 32 40 48 56
0
40
80
120
160
200
240
280
Plasma Lactate (mmolL)
Blo
od
Cyan
ide (
microm
ol
l)
Lactate as biomarker in cyanide poisoning
Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002
Chloroquine poisoning prognosis assessment
Supposed
ingested dose
Systolic BP QRS
duration
Severe gt 4 g or lt 100 mmHg or gt 010 s
Moderate 2 - 4 g and
gt 100 mmHg and
lt 010 s
Mild
lt 2 g and
gt 100 mmHg and
lt 010 s
Clemessy JL et al Crit Care Med 1996
Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg
Intubation and mechanical ventilation
Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h
Riou B N Engl J Med 1988
Macrocirculation level
- Measurement of blood pressure and cardiac index Microcirculation level
- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain
- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)
Hemodynamic monitoring of cardiotoxicant poisonings
Poisonings with tricyclic antidepressants Value of serum concentrations
Boehnert MT N Engl J Med 1985
Prognostic value of serum theophylline concentration
Sessler CN Am J Med 1990
Why does the clinician need toxicological analysis to manage his
patient with cardiotoxicant poisoning
ProCon debate
- Positive diagnosis assessment to confirm a toxic hypothesis
- Differential diagnosis to exclude a toxic hypothesis
- Prognosis evaluation
- Help for treatment indications monitoring and re-evaluation
- Retrospective evaluation medico-legal issue or scientific studies
What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings
t
Severity C blood
t
Severity C blood
Confirm severity Supportive treatments
Prognostic factors Antidotes
Interest of analysis according to drug effects
Injury-inducing drugs
Functional drugs
Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues
Prerequisite availability of toxicological analysis
- Complexity and requirements of the assays
- Dialogue between biologists and clinicians
Importance of conservative plasma and urine sampling (initial and repetitive)
Expert opinion on appropriateness of disposal according to availability of drug screening
Fabbri A Emerg Med J 2003
Does a comprehensive drug screening add to decision making for poisonings in the ED
improve agreement on patient disposal Save potentially hospital resources
Meprobamate poisonings Is serum concentration useful to indicate the
mechanism of shock
Charron C Intensive Care Med 2005
Dose-dependent hypotension with narrowed QRS
- hypovolemia
- vasoplegia if concentrations le 150 mgl
- cardiogenic if concentrations gt 150 mgl
Plasma chloroquine concentration le 12 M No death
12-25 microM death rate 2
gt 25 microM death rate 22
gt 50 microM death rate 60
Chloroquine poisoning In-hospital prognosis assessment using
blood concentrations
Clemessy JL Crit Care Med 1996
TKTD using blood concentrations TKTD using plasma concentrations
Chloroquine poisoning blood vs plasma concentrations
0 25 50 75 100 125 15000
05
10
15
20
25
30
35
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 096
0 10 20 30 40 5000
05
10
15
20
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 091
0 1 2 3 4 5 6 7 8 900
05
10
15
20
Plasma chloroquine concentration (micromolL)
Ep
inep
hri
ne
infu
sio
n r
ate
(mg
h)
0 5 10 15 20 250
1
2
3
4
Plasma chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh)
R2 = 005
R2 = 017
Patient 1
Patient 2
PKPD population modeling in chloroquine poisonings
Meacutegarbane B Clin Tox2010
Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings
Relationship Between PlasmaFlecainide Concentration and
Outcome
Survivors Fatalities
0
1
2
3
4
5
6
7
8
9
10
Outcome of Acute Poisonings
Pla
sm
a F
lecain
ide
Co
ncen
trati
on
s (
mg
L)
Meacutegarbane B Clin Tox 2007
Meacutegarbane B BCPT 2010
Verapamil poisonings
Flecainide poisonings
Meacutegarbane B Clin Tox 2002 (abstract)
0
5
10
15
20
25P
red
icte
d c
on
cen
trati
on
s (n
gm
l)
0
10
0
20
0
30
0
40
0
Time since ingestion (hours)
Predicted concentration profiles
Non suvivors C(t) = 242 exp (-0003t)
Survivors C(t) = 177 exp (-0019t)
Cut-off C(t) = 207 exp (-0011t)
0
20
40
60
80
Co
lch
icin
e p
lasm
a c
on
cen
tra
tion
on
ad
mis
sio
n(n
gm
l)
Alive patients (N = 18)
Dead patients(N = 5)
Colchicine poisonings prognostic value of the time-course of serum concentrations
Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments
Q = body load of glycoside to neutralize
Estimation using ingested amount of digitalis
Estimation using serum glycoside concentration
Q = Weight
(kg)
volume of distribution
digoxin 56 lkg
digitoxin 056 lkg
Serum glycoside concentration
(ngml) x x
Q = x Ingested amount (mg) digoxin bioavailability (60 )
digitoxin bioavailability (100 ) or
One vial of digibind (40 mg) neutralizes 06 mg of digoxin
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
- VO2 110 mLminm2
- SaO2 95
- Hb 11 gdl
40
90
SvO2 ()
1
Cardiac index (Lminm2)
2 3
57
70
5 6 7
80
83
SvO2 versus cardiac index relationships
SvO2 = SaO2 - VO2
IC x Hb x 134
Manini AF ClinTox 2010
- Despite of absence of specificity he serum lactate concentration had an excellent prognostic utility to predict drug-overdose fatality - The optimal lactate cut-point was 30 mmolL (84 sensitivity 75 specificity) which conferred a 158-fold increase in odds of fatality (p lt 0001)
Serum lactate is an excellent prognosticator
ROC-AUC 087 (95 CI 081ndash094)
Lactate is a marker of all types of SHOCK
1048707 A marker of inadequate perfusion or cellular O2 consumption
1048707 A marker of inadequate resuscitation and management
1048707 A predictor of patient bad outcome and development of organ
dysfunction
Beta-blocker poisonings Prognostic value of lactate concentration on admission
0
3
6
9
12
15
18
21
24
27
30
Survivors Fatalities
plt 00008S
eru
m l
acta
te c
on
cen
trati
on
s (
mm
ol
L)
0
3
6
9
12
15
18
21
24
27
30
On admissionvalues
plt 00001
Peakvalues
Seru
m l
acta
te c
on
cen
trati
on
s (
mm
ol
L)
The ROC-AUC of initial lactate for predicting mortality was 084 (074-094)
The cutoff point maximizing the sum of sensitivity and specificity was 27 mmolL
For the 30 mmolL selected lactate cutoff point 55 sensitivity 80 specificity
Meacutegarbane B Clin Tox 2010
Boehnert MT N Engl J Med 1985
Poisonings with tricyclic antidepressants Prognostic value of QRS to predict seizures and arrhythmias
Serum glucose as biomarker in calcium channel blocker poisonings
Levine M Crit Care Med 2007
Initial glucose level Peak glucose level
Increase in blood glucose +71 vs 0 p=00067
Serum potassium as biomarker in digitalis poisoning
Female
Male
lt 55
gt 55
lt 55
gt 55
Yes
No
Yes
No
Yes
No
Yes
No
K + gt45
Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No
Death rate
17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23
AV block Age
Dally S Press Med 1981
0 8 16 24 32 40 48 56
0
40
80
120
160
200
240
280
Plasma Lactate (mmolL)
Blo
od
Cyan
ide (
microm
ol
l)
Lactate as biomarker in cyanide poisoning
Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002
Chloroquine poisoning prognosis assessment
Supposed
ingested dose
Systolic BP QRS
duration
Severe gt 4 g or lt 100 mmHg or gt 010 s
Moderate 2 - 4 g and
gt 100 mmHg and
lt 010 s
Mild
lt 2 g and
gt 100 mmHg and
lt 010 s
Clemessy JL et al Crit Care Med 1996
Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg
Intubation and mechanical ventilation
Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h
Riou B N Engl J Med 1988
Macrocirculation level
- Measurement of blood pressure and cardiac index Microcirculation level
- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain
- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)
Hemodynamic monitoring of cardiotoxicant poisonings
Poisonings with tricyclic antidepressants Value of serum concentrations
Boehnert MT N Engl J Med 1985
Prognostic value of serum theophylline concentration
Sessler CN Am J Med 1990
Why does the clinician need toxicological analysis to manage his
patient with cardiotoxicant poisoning
ProCon debate
- Positive diagnosis assessment to confirm a toxic hypothesis
- Differential diagnosis to exclude a toxic hypothesis
- Prognosis evaluation
- Help for treatment indications monitoring and re-evaluation
- Retrospective evaluation medico-legal issue or scientific studies
What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings
t
Severity C blood
t
Severity C blood
Confirm severity Supportive treatments
Prognostic factors Antidotes
Interest of analysis according to drug effects
Injury-inducing drugs
Functional drugs
Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues
Prerequisite availability of toxicological analysis
- Complexity and requirements of the assays
- Dialogue between biologists and clinicians
Importance of conservative plasma and urine sampling (initial and repetitive)
Expert opinion on appropriateness of disposal according to availability of drug screening
Fabbri A Emerg Med J 2003
Does a comprehensive drug screening add to decision making for poisonings in the ED
improve agreement on patient disposal Save potentially hospital resources
Meprobamate poisonings Is serum concentration useful to indicate the
mechanism of shock
Charron C Intensive Care Med 2005
Dose-dependent hypotension with narrowed QRS
- hypovolemia
- vasoplegia if concentrations le 150 mgl
- cardiogenic if concentrations gt 150 mgl
Plasma chloroquine concentration le 12 M No death
12-25 microM death rate 2
gt 25 microM death rate 22
gt 50 microM death rate 60
Chloroquine poisoning In-hospital prognosis assessment using
blood concentrations
Clemessy JL Crit Care Med 1996
TKTD using blood concentrations TKTD using plasma concentrations
Chloroquine poisoning blood vs plasma concentrations
0 25 50 75 100 125 15000
05
10
15
20
25
30
35
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 096
0 10 20 30 40 5000
05
10
15
20
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 091
0 1 2 3 4 5 6 7 8 900
05
10
15
20
Plasma chloroquine concentration (micromolL)
Ep
inep
hri
ne
infu
sio
n r
ate
(mg
h)
0 5 10 15 20 250
1
2
3
4
Plasma chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh)
R2 = 005
R2 = 017
Patient 1
Patient 2
PKPD population modeling in chloroquine poisonings
Meacutegarbane B Clin Tox2010
Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings
Relationship Between PlasmaFlecainide Concentration and
Outcome
Survivors Fatalities
0
1
2
3
4
5
6
7
8
9
10
Outcome of Acute Poisonings
Pla
sm
a F
lecain
ide
Co
ncen
trati
on
s (
mg
L)
Meacutegarbane B Clin Tox 2007
Meacutegarbane B BCPT 2010
Verapamil poisonings
Flecainide poisonings
Meacutegarbane B Clin Tox 2002 (abstract)
0
5
10
15
20
25P
red
icte
d c
on
cen
trati
on
s (n
gm
l)
0
10
0
20
0
30
0
40
0
Time since ingestion (hours)
Predicted concentration profiles
Non suvivors C(t) = 242 exp (-0003t)
Survivors C(t) = 177 exp (-0019t)
Cut-off C(t) = 207 exp (-0011t)
0
20
40
60
80
Co
lch
icin
e p
lasm
a c
on
cen
tra
tion
on
ad
mis
sio
n(n
gm
l)
Alive patients (N = 18)
Dead patients(N = 5)
Colchicine poisonings prognostic value of the time-course of serum concentrations
Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments
Q = body load of glycoside to neutralize
Estimation using ingested amount of digitalis
Estimation using serum glycoside concentration
Q = Weight
(kg)
volume of distribution
digoxin 56 lkg
digitoxin 056 lkg
Serum glycoside concentration
(ngml) x x
Q = x Ingested amount (mg) digoxin bioavailability (60 )
digitoxin bioavailability (100 ) or
One vial of digibind (40 mg) neutralizes 06 mg of digoxin
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
Manini AF ClinTox 2010
- Despite of absence of specificity he serum lactate concentration had an excellent prognostic utility to predict drug-overdose fatality - The optimal lactate cut-point was 30 mmolL (84 sensitivity 75 specificity) which conferred a 158-fold increase in odds of fatality (p lt 0001)
Serum lactate is an excellent prognosticator
ROC-AUC 087 (95 CI 081ndash094)
Lactate is a marker of all types of SHOCK
1048707 A marker of inadequate perfusion or cellular O2 consumption
1048707 A marker of inadequate resuscitation and management
1048707 A predictor of patient bad outcome and development of organ
dysfunction
Beta-blocker poisonings Prognostic value of lactate concentration on admission
0
3
6
9
12
15
18
21
24
27
30
Survivors Fatalities
plt 00008S
eru
m l
acta
te c
on
cen
trati
on
s (
mm
ol
L)
0
3
6
9
12
15
18
21
24
27
30
On admissionvalues
plt 00001
Peakvalues
Seru
m l
acta
te c
on
cen
trati
on
s (
mm
ol
L)
The ROC-AUC of initial lactate for predicting mortality was 084 (074-094)
The cutoff point maximizing the sum of sensitivity and specificity was 27 mmolL
For the 30 mmolL selected lactate cutoff point 55 sensitivity 80 specificity
Meacutegarbane B Clin Tox 2010
Boehnert MT N Engl J Med 1985
Poisonings with tricyclic antidepressants Prognostic value of QRS to predict seizures and arrhythmias
Serum glucose as biomarker in calcium channel blocker poisonings
Levine M Crit Care Med 2007
Initial glucose level Peak glucose level
Increase in blood glucose +71 vs 0 p=00067
Serum potassium as biomarker in digitalis poisoning
Female
Male
lt 55
gt 55
lt 55
gt 55
Yes
No
Yes
No
Yes
No
Yes
No
K + gt45
Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No
Death rate
17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23
AV block Age
Dally S Press Med 1981
0 8 16 24 32 40 48 56
0
40
80
120
160
200
240
280
Plasma Lactate (mmolL)
Blo
od
Cyan
ide (
microm
ol
l)
Lactate as biomarker in cyanide poisoning
Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002
Chloroquine poisoning prognosis assessment
Supposed
ingested dose
Systolic BP QRS
duration
Severe gt 4 g or lt 100 mmHg or gt 010 s
Moderate 2 - 4 g and
gt 100 mmHg and
lt 010 s
Mild
lt 2 g and
gt 100 mmHg and
lt 010 s
Clemessy JL et al Crit Care Med 1996
Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg
Intubation and mechanical ventilation
Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h
Riou B N Engl J Med 1988
Macrocirculation level
- Measurement of blood pressure and cardiac index Microcirculation level
- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain
- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)
Hemodynamic monitoring of cardiotoxicant poisonings
Poisonings with tricyclic antidepressants Value of serum concentrations
Boehnert MT N Engl J Med 1985
Prognostic value of serum theophylline concentration
Sessler CN Am J Med 1990
Why does the clinician need toxicological analysis to manage his
patient with cardiotoxicant poisoning
ProCon debate
- Positive diagnosis assessment to confirm a toxic hypothesis
- Differential diagnosis to exclude a toxic hypothesis
- Prognosis evaluation
- Help for treatment indications monitoring and re-evaluation
- Retrospective evaluation medico-legal issue or scientific studies
What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings
t
Severity C blood
t
Severity C blood
Confirm severity Supportive treatments
Prognostic factors Antidotes
Interest of analysis according to drug effects
Injury-inducing drugs
Functional drugs
Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues
Prerequisite availability of toxicological analysis
- Complexity and requirements of the assays
- Dialogue between biologists and clinicians
Importance of conservative plasma and urine sampling (initial and repetitive)
Expert opinion on appropriateness of disposal according to availability of drug screening
Fabbri A Emerg Med J 2003
Does a comprehensive drug screening add to decision making for poisonings in the ED
improve agreement on patient disposal Save potentially hospital resources
Meprobamate poisonings Is serum concentration useful to indicate the
mechanism of shock
Charron C Intensive Care Med 2005
Dose-dependent hypotension with narrowed QRS
- hypovolemia
- vasoplegia if concentrations le 150 mgl
- cardiogenic if concentrations gt 150 mgl
Plasma chloroquine concentration le 12 M No death
12-25 microM death rate 2
gt 25 microM death rate 22
gt 50 microM death rate 60
Chloroquine poisoning In-hospital prognosis assessment using
blood concentrations
Clemessy JL Crit Care Med 1996
TKTD using blood concentrations TKTD using plasma concentrations
Chloroquine poisoning blood vs plasma concentrations
0 25 50 75 100 125 15000
05
10
15
20
25
30
35
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 096
0 10 20 30 40 5000
05
10
15
20
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 091
0 1 2 3 4 5 6 7 8 900
05
10
15
20
Plasma chloroquine concentration (micromolL)
Ep
inep
hri
ne
infu
sio
n r
ate
(mg
h)
0 5 10 15 20 250
1
2
3
4
Plasma chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh)
R2 = 005
R2 = 017
Patient 1
Patient 2
PKPD population modeling in chloroquine poisonings
Meacutegarbane B Clin Tox2010
Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings
Relationship Between PlasmaFlecainide Concentration and
Outcome
Survivors Fatalities
0
1
2
3
4
5
6
7
8
9
10
Outcome of Acute Poisonings
Pla
sm
a F
lecain
ide
Co
ncen
trati
on
s (
mg
L)
Meacutegarbane B Clin Tox 2007
Meacutegarbane B BCPT 2010
Verapamil poisonings
Flecainide poisonings
Meacutegarbane B Clin Tox 2002 (abstract)
0
5
10
15
20
25P
red
icte
d c
on
cen
trati
on
s (n
gm
l)
0
10
0
20
0
30
0
40
0
Time since ingestion (hours)
Predicted concentration profiles
Non suvivors C(t) = 242 exp (-0003t)
Survivors C(t) = 177 exp (-0019t)
Cut-off C(t) = 207 exp (-0011t)
0
20
40
60
80
Co
lch
icin
e p
lasm
a c
on
cen
tra
tion
on
ad
mis
sio
n(n
gm
l)
Alive patients (N = 18)
Dead patients(N = 5)
Colchicine poisonings prognostic value of the time-course of serum concentrations
Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments
Q = body load of glycoside to neutralize
Estimation using ingested amount of digitalis
Estimation using serum glycoside concentration
Q = Weight
(kg)
volume of distribution
digoxin 56 lkg
digitoxin 056 lkg
Serum glycoside concentration
(ngml) x x
Q = x Ingested amount (mg) digoxin bioavailability (60 )
digitoxin bioavailability (100 ) or
One vial of digibind (40 mg) neutralizes 06 mg of digoxin
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
Beta-blocker poisonings Prognostic value of lactate concentration on admission
0
3
6
9
12
15
18
21
24
27
30
Survivors Fatalities
plt 00008S
eru
m l
acta
te c
on
cen
trati
on
s (
mm
ol
L)
0
3
6
9
12
15
18
21
24
27
30
On admissionvalues
plt 00001
Peakvalues
Seru
m l
acta
te c
on
cen
trati
on
s (
mm
ol
L)
The ROC-AUC of initial lactate for predicting mortality was 084 (074-094)
The cutoff point maximizing the sum of sensitivity and specificity was 27 mmolL
For the 30 mmolL selected lactate cutoff point 55 sensitivity 80 specificity
Meacutegarbane B Clin Tox 2010
Boehnert MT N Engl J Med 1985
Poisonings with tricyclic antidepressants Prognostic value of QRS to predict seizures and arrhythmias
Serum glucose as biomarker in calcium channel blocker poisonings
Levine M Crit Care Med 2007
Initial glucose level Peak glucose level
Increase in blood glucose +71 vs 0 p=00067
Serum potassium as biomarker in digitalis poisoning
Female
Male
lt 55
gt 55
lt 55
gt 55
Yes
No
Yes
No
Yes
No
Yes
No
K + gt45
Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No
Death rate
17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23
AV block Age
Dally S Press Med 1981
0 8 16 24 32 40 48 56
0
40
80
120
160
200
240
280
Plasma Lactate (mmolL)
Blo
od
Cyan
ide (
microm
ol
l)
Lactate as biomarker in cyanide poisoning
Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002
Chloroquine poisoning prognosis assessment
Supposed
ingested dose
Systolic BP QRS
duration
Severe gt 4 g or lt 100 mmHg or gt 010 s
Moderate 2 - 4 g and
gt 100 mmHg and
lt 010 s
Mild
lt 2 g and
gt 100 mmHg and
lt 010 s
Clemessy JL et al Crit Care Med 1996
Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg
Intubation and mechanical ventilation
Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h
Riou B N Engl J Med 1988
Macrocirculation level
- Measurement of blood pressure and cardiac index Microcirculation level
- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain
- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)
Hemodynamic monitoring of cardiotoxicant poisonings
Poisonings with tricyclic antidepressants Value of serum concentrations
Boehnert MT N Engl J Med 1985
Prognostic value of serum theophylline concentration
Sessler CN Am J Med 1990
Why does the clinician need toxicological analysis to manage his
patient with cardiotoxicant poisoning
ProCon debate
- Positive diagnosis assessment to confirm a toxic hypothesis
- Differential diagnosis to exclude a toxic hypothesis
- Prognosis evaluation
- Help for treatment indications monitoring and re-evaluation
- Retrospective evaluation medico-legal issue or scientific studies
What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings
t
Severity C blood
t
Severity C blood
Confirm severity Supportive treatments
Prognostic factors Antidotes
Interest of analysis according to drug effects
Injury-inducing drugs
Functional drugs
Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues
Prerequisite availability of toxicological analysis
- Complexity and requirements of the assays
- Dialogue between biologists and clinicians
Importance of conservative plasma and urine sampling (initial and repetitive)
Expert opinion on appropriateness of disposal according to availability of drug screening
Fabbri A Emerg Med J 2003
Does a comprehensive drug screening add to decision making for poisonings in the ED
improve agreement on patient disposal Save potentially hospital resources
Meprobamate poisonings Is serum concentration useful to indicate the
mechanism of shock
Charron C Intensive Care Med 2005
Dose-dependent hypotension with narrowed QRS
- hypovolemia
- vasoplegia if concentrations le 150 mgl
- cardiogenic if concentrations gt 150 mgl
Plasma chloroquine concentration le 12 M No death
12-25 microM death rate 2
gt 25 microM death rate 22
gt 50 microM death rate 60
Chloroquine poisoning In-hospital prognosis assessment using
blood concentrations
Clemessy JL Crit Care Med 1996
TKTD using blood concentrations TKTD using plasma concentrations
Chloroquine poisoning blood vs plasma concentrations
0 25 50 75 100 125 15000
05
10
15
20
25
30
35
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 096
0 10 20 30 40 5000
05
10
15
20
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 091
0 1 2 3 4 5 6 7 8 900
05
10
15
20
Plasma chloroquine concentration (micromolL)
Ep
inep
hri
ne
infu
sio
n r
ate
(mg
h)
0 5 10 15 20 250
1
2
3
4
Plasma chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh)
R2 = 005
R2 = 017
Patient 1
Patient 2
PKPD population modeling in chloroquine poisonings
Meacutegarbane B Clin Tox2010
Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings
Relationship Between PlasmaFlecainide Concentration and
Outcome
Survivors Fatalities
0
1
2
3
4
5
6
7
8
9
10
Outcome of Acute Poisonings
Pla
sm
a F
lecain
ide
Co
ncen
trati
on
s (
mg
L)
Meacutegarbane B Clin Tox 2007
Meacutegarbane B BCPT 2010
Verapamil poisonings
Flecainide poisonings
Meacutegarbane B Clin Tox 2002 (abstract)
0
5
10
15
20
25P
red
icte
d c
on
cen
trati
on
s (n
gm
l)
0
10
0
20
0
30
0
40
0
Time since ingestion (hours)
Predicted concentration profiles
Non suvivors C(t) = 242 exp (-0003t)
Survivors C(t) = 177 exp (-0019t)
Cut-off C(t) = 207 exp (-0011t)
0
20
40
60
80
Co
lch
icin
e p
lasm
a c
on
cen
tra
tion
on
ad
mis
sio
n(n
gm
l)
Alive patients (N = 18)
Dead patients(N = 5)
Colchicine poisonings prognostic value of the time-course of serum concentrations
Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments
Q = body load of glycoside to neutralize
Estimation using ingested amount of digitalis
Estimation using serum glycoside concentration
Q = Weight
(kg)
volume of distribution
digoxin 56 lkg
digitoxin 056 lkg
Serum glycoside concentration
(ngml) x x
Q = x Ingested amount (mg) digoxin bioavailability (60 )
digitoxin bioavailability (100 ) or
One vial of digibind (40 mg) neutralizes 06 mg of digoxin
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
Boehnert MT N Engl J Med 1985
Poisonings with tricyclic antidepressants Prognostic value of QRS to predict seizures and arrhythmias
Serum glucose as biomarker in calcium channel blocker poisonings
Levine M Crit Care Med 2007
Initial glucose level Peak glucose level
Increase in blood glucose +71 vs 0 p=00067
Serum potassium as biomarker in digitalis poisoning
Female
Male
lt 55
gt 55
lt 55
gt 55
Yes
No
Yes
No
Yes
No
Yes
No
K + gt45
Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No
Death rate
17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23
AV block Age
Dally S Press Med 1981
0 8 16 24 32 40 48 56
0
40
80
120
160
200
240
280
Plasma Lactate (mmolL)
Blo
od
Cyan
ide (
microm
ol
l)
Lactate as biomarker in cyanide poisoning
Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002
Chloroquine poisoning prognosis assessment
Supposed
ingested dose
Systolic BP QRS
duration
Severe gt 4 g or lt 100 mmHg or gt 010 s
Moderate 2 - 4 g and
gt 100 mmHg and
lt 010 s
Mild
lt 2 g and
gt 100 mmHg and
lt 010 s
Clemessy JL et al Crit Care Med 1996
Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg
Intubation and mechanical ventilation
Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h
Riou B N Engl J Med 1988
Macrocirculation level
- Measurement of blood pressure and cardiac index Microcirculation level
- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain
- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)
Hemodynamic monitoring of cardiotoxicant poisonings
Poisonings with tricyclic antidepressants Value of serum concentrations
Boehnert MT N Engl J Med 1985
Prognostic value of serum theophylline concentration
Sessler CN Am J Med 1990
Why does the clinician need toxicological analysis to manage his
patient with cardiotoxicant poisoning
ProCon debate
- Positive diagnosis assessment to confirm a toxic hypothesis
- Differential diagnosis to exclude a toxic hypothesis
- Prognosis evaluation
- Help for treatment indications monitoring and re-evaluation
- Retrospective evaluation medico-legal issue or scientific studies
What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings
t
Severity C blood
t
Severity C blood
Confirm severity Supportive treatments
Prognostic factors Antidotes
Interest of analysis according to drug effects
Injury-inducing drugs
Functional drugs
Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues
Prerequisite availability of toxicological analysis
- Complexity and requirements of the assays
- Dialogue between biologists and clinicians
Importance of conservative plasma and urine sampling (initial and repetitive)
Expert opinion on appropriateness of disposal according to availability of drug screening
Fabbri A Emerg Med J 2003
Does a comprehensive drug screening add to decision making for poisonings in the ED
improve agreement on patient disposal Save potentially hospital resources
Meprobamate poisonings Is serum concentration useful to indicate the
mechanism of shock
Charron C Intensive Care Med 2005
Dose-dependent hypotension with narrowed QRS
- hypovolemia
- vasoplegia if concentrations le 150 mgl
- cardiogenic if concentrations gt 150 mgl
Plasma chloroquine concentration le 12 M No death
12-25 microM death rate 2
gt 25 microM death rate 22
gt 50 microM death rate 60
Chloroquine poisoning In-hospital prognosis assessment using
blood concentrations
Clemessy JL Crit Care Med 1996
TKTD using blood concentrations TKTD using plasma concentrations
Chloroquine poisoning blood vs plasma concentrations
0 25 50 75 100 125 15000
05
10
15
20
25
30
35
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 096
0 10 20 30 40 5000
05
10
15
20
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 091
0 1 2 3 4 5 6 7 8 900
05
10
15
20
Plasma chloroquine concentration (micromolL)
Ep
inep
hri
ne
infu
sio
n r
ate
(mg
h)
0 5 10 15 20 250
1
2
3
4
Plasma chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh)
R2 = 005
R2 = 017
Patient 1
Patient 2
PKPD population modeling in chloroquine poisonings
Meacutegarbane B Clin Tox2010
Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings
Relationship Between PlasmaFlecainide Concentration and
Outcome
Survivors Fatalities
0
1
2
3
4
5
6
7
8
9
10
Outcome of Acute Poisonings
Pla
sm
a F
lecain
ide
Co
ncen
trati
on
s (
mg
L)
Meacutegarbane B Clin Tox 2007
Meacutegarbane B BCPT 2010
Verapamil poisonings
Flecainide poisonings
Meacutegarbane B Clin Tox 2002 (abstract)
0
5
10
15
20
25P
red
icte
d c
on
cen
trati
on
s (n
gm
l)
0
10
0
20
0
30
0
40
0
Time since ingestion (hours)
Predicted concentration profiles
Non suvivors C(t) = 242 exp (-0003t)
Survivors C(t) = 177 exp (-0019t)
Cut-off C(t) = 207 exp (-0011t)
0
20
40
60
80
Co
lch
icin
e p
lasm
a c
on
cen
tra
tion
on
ad
mis
sio
n(n
gm
l)
Alive patients (N = 18)
Dead patients(N = 5)
Colchicine poisonings prognostic value of the time-course of serum concentrations
Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments
Q = body load of glycoside to neutralize
Estimation using ingested amount of digitalis
Estimation using serum glycoside concentration
Q = Weight
(kg)
volume of distribution
digoxin 56 lkg
digitoxin 056 lkg
Serum glycoside concentration
(ngml) x x
Q = x Ingested amount (mg) digoxin bioavailability (60 )
digitoxin bioavailability (100 ) or
One vial of digibind (40 mg) neutralizes 06 mg of digoxin
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
Serum glucose as biomarker in calcium channel blocker poisonings
Levine M Crit Care Med 2007
Initial glucose level Peak glucose level
Increase in blood glucose +71 vs 0 p=00067
Serum potassium as biomarker in digitalis poisoning
Female
Male
lt 55
gt 55
lt 55
gt 55
Yes
No
Yes
No
Yes
No
Yes
No
K + gt45
Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No
Death rate
17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23
AV block Age
Dally S Press Med 1981
0 8 16 24 32 40 48 56
0
40
80
120
160
200
240
280
Plasma Lactate (mmolL)
Blo
od
Cyan
ide (
microm
ol
l)
Lactate as biomarker in cyanide poisoning
Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002
Chloroquine poisoning prognosis assessment
Supposed
ingested dose
Systolic BP QRS
duration
Severe gt 4 g or lt 100 mmHg or gt 010 s
Moderate 2 - 4 g and
gt 100 mmHg and
lt 010 s
Mild
lt 2 g and
gt 100 mmHg and
lt 010 s
Clemessy JL et al Crit Care Med 1996
Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg
Intubation and mechanical ventilation
Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h
Riou B N Engl J Med 1988
Macrocirculation level
- Measurement of blood pressure and cardiac index Microcirculation level
- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain
- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)
Hemodynamic monitoring of cardiotoxicant poisonings
Poisonings with tricyclic antidepressants Value of serum concentrations
Boehnert MT N Engl J Med 1985
Prognostic value of serum theophylline concentration
Sessler CN Am J Med 1990
Why does the clinician need toxicological analysis to manage his
patient with cardiotoxicant poisoning
ProCon debate
- Positive diagnosis assessment to confirm a toxic hypothesis
- Differential diagnosis to exclude a toxic hypothesis
- Prognosis evaluation
- Help for treatment indications monitoring and re-evaluation
- Retrospective evaluation medico-legal issue or scientific studies
What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings
t
Severity C blood
t
Severity C blood
Confirm severity Supportive treatments
Prognostic factors Antidotes
Interest of analysis according to drug effects
Injury-inducing drugs
Functional drugs
Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues
Prerequisite availability of toxicological analysis
- Complexity and requirements of the assays
- Dialogue between biologists and clinicians
Importance of conservative plasma and urine sampling (initial and repetitive)
Expert opinion on appropriateness of disposal according to availability of drug screening
Fabbri A Emerg Med J 2003
Does a comprehensive drug screening add to decision making for poisonings in the ED
improve agreement on patient disposal Save potentially hospital resources
Meprobamate poisonings Is serum concentration useful to indicate the
mechanism of shock
Charron C Intensive Care Med 2005
Dose-dependent hypotension with narrowed QRS
- hypovolemia
- vasoplegia if concentrations le 150 mgl
- cardiogenic if concentrations gt 150 mgl
Plasma chloroquine concentration le 12 M No death
12-25 microM death rate 2
gt 25 microM death rate 22
gt 50 microM death rate 60
Chloroquine poisoning In-hospital prognosis assessment using
blood concentrations
Clemessy JL Crit Care Med 1996
TKTD using blood concentrations TKTD using plasma concentrations
Chloroquine poisoning blood vs plasma concentrations
0 25 50 75 100 125 15000
05
10
15
20
25
30
35
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 096
0 10 20 30 40 5000
05
10
15
20
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 091
0 1 2 3 4 5 6 7 8 900
05
10
15
20
Plasma chloroquine concentration (micromolL)
Ep
inep
hri
ne
infu
sio
n r
ate
(mg
h)
0 5 10 15 20 250
1
2
3
4
Plasma chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh)
R2 = 005
R2 = 017
Patient 1
Patient 2
PKPD population modeling in chloroquine poisonings
Meacutegarbane B Clin Tox2010
Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings
Relationship Between PlasmaFlecainide Concentration and
Outcome
Survivors Fatalities
0
1
2
3
4
5
6
7
8
9
10
Outcome of Acute Poisonings
Pla
sm
a F
lecain
ide
Co
ncen
trati
on
s (
mg
L)
Meacutegarbane B Clin Tox 2007
Meacutegarbane B BCPT 2010
Verapamil poisonings
Flecainide poisonings
Meacutegarbane B Clin Tox 2002 (abstract)
0
5
10
15
20
25P
red
icte
d c
on
cen
trati
on
s (n
gm
l)
0
10
0
20
0
30
0
40
0
Time since ingestion (hours)
Predicted concentration profiles
Non suvivors C(t) = 242 exp (-0003t)
Survivors C(t) = 177 exp (-0019t)
Cut-off C(t) = 207 exp (-0011t)
0
20
40
60
80
Co
lch
icin
e p
lasm
a c
on
cen
tra
tion
on
ad
mis
sio
n(n
gm
l)
Alive patients (N = 18)
Dead patients(N = 5)
Colchicine poisonings prognostic value of the time-course of serum concentrations
Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments
Q = body load of glycoside to neutralize
Estimation using ingested amount of digitalis
Estimation using serum glycoside concentration
Q = Weight
(kg)
volume of distribution
digoxin 56 lkg
digitoxin 056 lkg
Serum glycoside concentration
(ngml) x x
Q = x Ingested amount (mg) digoxin bioavailability (60 )
digitoxin bioavailability (100 ) or
One vial of digibind (40 mg) neutralizes 06 mg of digoxin
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
Serum potassium as biomarker in digitalis poisoning
Female
Male
lt 55
gt 55
lt 55
gt 55
Yes
No
Yes
No
Yes
No
Yes
No
K + gt45
Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No
Death rate
17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23
AV block Age
Dally S Press Med 1981
0 8 16 24 32 40 48 56
0
40
80
120
160
200
240
280
Plasma Lactate (mmolL)
Blo
od
Cyan
ide (
microm
ol
l)
Lactate as biomarker in cyanide poisoning
Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002
Chloroquine poisoning prognosis assessment
Supposed
ingested dose
Systolic BP QRS
duration
Severe gt 4 g or lt 100 mmHg or gt 010 s
Moderate 2 - 4 g and
gt 100 mmHg and
lt 010 s
Mild
lt 2 g and
gt 100 mmHg and
lt 010 s
Clemessy JL et al Crit Care Med 1996
Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg
Intubation and mechanical ventilation
Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h
Riou B N Engl J Med 1988
Macrocirculation level
- Measurement of blood pressure and cardiac index Microcirculation level
- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain
- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)
Hemodynamic monitoring of cardiotoxicant poisonings
Poisonings with tricyclic antidepressants Value of serum concentrations
Boehnert MT N Engl J Med 1985
Prognostic value of serum theophylline concentration
Sessler CN Am J Med 1990
Why does the clinician need toxicological analysis to manage his
patient with cardiotoxicant poisoning
ProCon debate
- Positive diagnosis assessment to confirm a toxic hypothesis
- Differential diagnosis to exclude a toxic hypothesis
- Prognosis evaluation
- Help for treatment indications monitoring and re-evaluation
- Retrospective evaluation medico-legal issue or scientific studies
What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings
t
Severity C blood
t
Severity C blood
Confirm severity Supportive treatments
Prognostic factors Antidotes
Interest of analysis according to drug effects
Injury-inducing drugs
Functional drugs
Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues
Prerequisite availability of toxicological analysis
- Complexity and requirements of the assays
- Dialogue between biologists and clinicians
Importance of conservative plasma and urine sampling (initial and repetitive)
Expert opinion on appropriateness of disposal according to availability of drug screening
Fabbri A Emerg Med J 2003
Does a comprehensive drug screening add to decision making for poisonings in the ED
improve agreement on patient disposal Save potentially hospital resources
Meprobamate poisonings Is serum concentration useful to indicate the
mechanism of shock
Charron C Intensive Care Med 2005
Dose-dependent hypotension with narrowed QRS
- hypovolemia
- vasoplegia if concentrations le 150 mgl
- cardiogenic if concentrations gt 150 mgl
Plasma chloroquine concentration le 12 M No death
12-25 microM death rate 2
gt 25 microM death rate 22
gt 50 microM death rate 60
Chloroquine poisoning In-hospital prognosis assessment using
blood concentrations
Clemessy JL Crit Care Med 1996
TKTD using blood concentrations TKTD using plasma concentrations
Chloroquine poisoning blood vs plasma concentrations
0 25 50 75 100 125 15000
05
10
15
20
25
30
35
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 096
0 10 20 30 40 5000
05
10
15
20
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 091
0 1 2 3 4 5 6 7 8 900
05
10
15
20
Plasma chloroquine concentration (micromolL)
Ep
inep
hri
ne
infu
sio
n r
ate
(mg
h)
0 5 10 15 20 250
1
2
3
4
Plasma chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh)
R2 = 005
R2 = 017
Patient 1
Patient 2
PKPD population modeling in chloroquine poisonings
Meacutegarbane B Clin Tox2010
Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings
Relationship Between PlasmaFlecainide Concentration and
Outcome
Survivors Fatalities
0
1
2
3
4
5
6
7
8
9
10
Outcome of Acute Poisonings
Pla
sm
a F
lecain
ide
Co
ncen
trati
on
s (
mg
L)
Meacutegarbane B Clin Tox 2007
Meacutegarbane B BCPT 2010
Verapamil poisonings
Flecainide poisonings
Meacutegarbane B Clin Tox 2002 (abstract)
0
5
10
15
20
25P
red
icte
d c
on
cen
trati
on
s (n
gm
l)
0
10
0
20
0
30
0
40
0
Time since ingestion (hours)
Predicted concentration profiles
Non suvivors C(t) = 242 exp (-0003t)
Survivors C(t) = 177 exp (-0019t)
Cut-off C(t) = 207 exp (-0011t)
0
20
40
60
80
Co
lch
icin
e p
lasm
a c
on
cen
tra
tion
on
ad
mis
sio
n(n
gm
l)
Alive patients (N = 18)
Dead patients(N = 5)
Colchicine poisonings prognostic value of the time-course of serum concentrations
Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments
Q = body load of glycoside to neutralize
Estimation using ingested amount of digitalis
Estimation using serum glycoside concentration
Q = Weight
(kg)
volume of distribution
digoxin 56 lkg
digitoxin 056 lkg
Serum glycoside concentration
(ngml) x x
Q = x Ingested amount (mg) digoxin bioavailability (60 )
digitoxin bioavailability (100 ) or
One vial of digibind (40 mg) neutralizes 06 mg of digoxin
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
0 8 16 24 32 40 48 56
0
40
80
120
160
200
240
280
Plasma Lactate (mmolL)
Blo
od
Cyan
ide (
microm
ol
l)
Lactate as biomarker in cyanide poisoning
Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002
Chloroquine poisoning prognosis assessment
Supposed
ingested dose
Systolic BP QRS
duration
Severe gt 4 g or lt 100 mmHg or gt 010 s
Moderate 2 - 4 g and
gt 100 mmHg and
lt 010 s
Mild
lt 2 g and
gt 100 mmHg and
lt 010 s
Clemessy JL et al Crit Care Med 1996
Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg
Intubation and mechanical ventilation
Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h
Riou B N Engl J Med 1988
Macrocirculation level
- Measurement of blood pressure and cardiac index Microcirculation level
- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain
- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)
Hemodynamic monitoring of cardiotoxicant poisonings
Poisonings with tricyclic antidepressants Value of serum concentrations
Boehnert MT N Engl J Med 1985
Prognostic value of serum theophylline concentration
Sessler CN Am J Med 1990
Why does the clinician need toxicological analysis to manage his
patient with cardiotoxicant poisoning
ProCon debate
- Positive diagnosis assessment to confirm a toxic hypothesis
- Differential diagnosis to exclude a toxic hypothesis
- Prognosis evaluation
- Help for treatment indications monitoring and re-evaluation
- Retrospective evaluation medico-legal issue or scientific studies
What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings
t
Severity C blood
t
Severity C blood
Confirm severity Supportive treatments
Prognostic factors Antidotes
Interest of analysis according to drug effects
Injury-inducing drugs
Functional drugs
Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues
Prerequisite availability of toxicological analysis
- Complexity and requirements of the assays
- Dialogue between biologists and clinicians
Importance of conservative plasma and urine sampling (initial and repetitive)
Expert opinion on appropriateness of disposal according to availability of drug screening
Fabbri A Emerg Med J 2003
Does a comprehensive drug screening add to decision making for poisonings in the ED
improve agreement on patient disposal Save potentially hospital resources
Meprobamate poisonings Is serum concentration useful to indicate the
mechanism of shock
Charron C Intensive Care Med 2005
Dose-dependent hypotension with narrowed QRS
- hypovolemia
- vasoplegia if concentrations le 150 mgl
- cardiogenic if concentrations gt 150 mgl
Plasma chloroquine concentration le 12 M No death
12-25 microM death rate 2
gt 25 microM death rate 22
gt 50 microM death rate 60
Chloroquine poisoning In-hospital prognosis assessment using
blood concentrations
Clemessy JL Crit Care Med 1996
TKTD using blood concentrations TKTD using plasma concentrations
Chloroquine poisoning blood vs plasma concentrations
0 25 50 75 100 125 15000
05
10
15
20
25
30
35
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 096
0 10 20 30 40 5000
05
10
15
20
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 091
0 1 2 3 4 5 6 7 8 900
05
10
15
20
Plasma chloroquine concentration (micromolL)
Ep
inep
hri
ne
infu
sio
n r
ate
(mg
h)
0 5 10 15 20 250
1
2
3
4
Plasma chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh)
R2 = 005
R2 = 017
Patient 1
Patient 2
PKPD population modeling in chloroquine poisonings
Meacutegarbane B Clin Tox2010
Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings
Relationship Between PlasmaFlecainide Concentration and
Outcome
Survivors Fatalities
0
1
2
3
4
5
6
7
8
9
10
Outcome of Acute Poisonings
Pla
sm
a F
lecain
ide
Co
ncen
trati
on
s (
mg
L)
Meacutegarbane B Clin Tox 2007
Meacutegarbane B BCPT 2010
Verapamil poisonings
Flecainide poisonings
Meacutegarbane B Clin Tox 2002 (abstract)
0
5
10
15
20
25P
red
icte
d c
on
cen
trati
on
s (n
gm
l)
0
10
0
20
0
30
0
40
0
Time since ingestion (hours)
Predicted concentration profiles
Non suvivors C(t) = 242 exp (-0003t)
Survivors C(t) = 177 exp (-0019t)
Cut-off C(t) = 207 exp (-0011t)
0
20
40
60
80
Co
lch
icin
e p
lasm
a c
on
cen
tra
tion
on
ad
mis
sio
n(n
gm
l)
Alive patients (N = 18)
Dead patients(N = 5)
Colchicine poisonings prognostic value of the time-course of serum concentrations
Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments
Q = body load of glycoside to neutralize
Estimation using ingested amount of digitalis
Estimation using serum glycoside concentration
Q = Weight
(kg)
volume of distribution
digoxin 56 lkg
digitoxin 056 lkg
Serum glycoside concentration
(ngml) x x
Q = x Ingested amount (mg) digoxin bioavailability (60 )
digitoxin bioavailability (100 ) or
One vial of digibind (40 mg) neutralizes 06 mg of digoxin
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
Chloroquine poisoning prognosis assessment
Supposed
ingested dose
Systolic BP QRS
duration
Severe gt 4 g or lt 100 mmHg or gt 010 s
Moderate 2 - 4 g and
gt 100 mmHg and
lt 010 s
Mild
lt 2 g and
gt 100 mmHg and
lt 010 s
Clemessy JL et al Crit Care Med 1996
Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg
Intubation and mechanical ventilation
Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h
Riou B N Engl J Med 1988
Macrocirculation level
- Measurement of blood pressure and cardiac index Microcirculation level
- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain
- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)
Hemodynamic monitoring of cardiotoxicant poisonings
Poisonings with tricyclic antidepressants Value of serum concentrations
Boehnert MT N Engl J Med 1985
Prognostic value of serum theophylline concentration
Sessler CN Am J Med 1990
Why does the clinician need toxicological analysis to manage his
patient with cardiotoxicant poisoning
ProCon debate
- Positive diagnosis assessment to confirm a toxic hypothesis
- Differential diagnosis to exclude a toxic hypothesis
- Prognosis evaluation
- Help for treatment indications monitoring and re-evaluation
- Retrospective evaluation medico-legal issue or scientific studies
What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings
t
Severity C blood
t
Severity C blood
Confirm severity Supportive treatments
Prognostic factors Antidotes
Interest of analysis according to drug effects
Injury-inducing drugs
Functional drugs
Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues
Prerequisite availability of toxicological analysis
- Complexity and requirements of the assays
- Dialogue between biologists and clinicians
Importance of conservative plasma and urine sampling (initial and repetitive)
Expert opinion on appropriateness of disposal according to availability of drug screening
Fabbri A Emerg Med J 2003
Does a comprehensive drug screening add to decision making for poisonings in the ED
improve agreement on patient disposal Save potentially hospital resources
Meprobamate poisonings Is serum concentration useful to indicate the
mechanism of shock
Charron C Intensive Care Med 2005
Dose-dependent hypotension with narrowed QRS
- hypovolemia
- vasoplegia if concentrations le 150 mgl
- cardiogenic if concentrations gt 150 mgl
Plasma chloroquine concentration le 12 M No death
12-25 microM death rate 2
gt 25 microM death rate 22
gt 50 microM death rate 60
Chloroquine poisoning In-hospital prognosis assessment using
blood concentrations
Clemessy JL Crit Care Med 1996
TKTD using blood concentrations TKTD using plasma concentrations
Chloroquine poisoning blood vs plasma concentrations
0 25 50 75 100 125 15000
05
10
15
20
25
30
35
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 096
0 10 20 30 40 5000
05
10
15
20
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 091
0 1 2 3 4 5 6 7 8 900
05
10
15
20
Plasma chloroquine concentration (micromolL)
Ep
inep
hri
ne
infu
sio
n r
ate
(mg
h)
0 5 10 15 20 250
1
2
3
4
Plasma chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh)
R2 = 005
R2 = 017
Patient 1
Patient 2
PKPD population modeling in chloroquine poisonings
Meacutegarbane B Clin Tox2010
Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings
Relationship Between PlasmaFlecainide Concentration and
Outcome
Survivors Fatalities
0
1
2
3
4
5
6
7
8
9
10
Outcome of Acute Poisonings
Pla
sm
a F
lecain
ide
Co
ncen
trati
on
s (
mg
L)
Meacutegarbane B Clin Tox 2007
Meacutegarbane B BCPT 2010
Verapamil poisonings
Flecainide poisonings
Meacutegarbane B Clin Tox 2002 (abstract)
0
5
10
15
20
25P
red
icte
d c
on
cen
trati
on
s (n
gm
l)
0
10
0
20
0
30
0
40
0
Time since ingestion (hours)
Predicted concentration profiles
Non suvivors C(t) = 242 exp (-0003t)
Survivors C(t) = 177 exp (-0019t)
Cut-off C(t) = 207 exp (-0011t)
0
20
40
60
80
Co
lch
icin
e p
lasm
a c
on
cen
tra
tion
on
ad
mis
sio
n(n
gm
l)
Alive patients (N = 18)
Dead patients(N = 5)
Colchicine poisonings prognostic value of the time-course of serum concentrations
Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments
Q = body load of glycoside to neutralize
Estimation using ingested amount of digitalis
Estimation using serum glycoside concentration
Q = Weight
(kg)
volume of distribution
digoxin 56 lkg
digitoxin 056 lkg
Serum glycoside concentration
(ngml) x x
Q = x Ingested amount (mg) digoxin bioavailability (60 )
digitoxin bioavailability (100 ) or
One vial of digibind (40 mg) neutralizes 06 mg of digoxin
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
Macrocirculation level
- Measurement of blood pressure and cardiac index Microcirculation level
- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain
- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)
Hemodynamic monitoring of cardiotoxicant poisonings
Poisonings with tricyclic antidepressants Value of serum concentrations
Boehnert MT N Engl J Med 1985
Prognostic value of serum theophylline concentration
Sessler CN Am J Med 1990
Why does the clinician need toxicological analysis to manage his
patient with cardiotoxicant poisoning
ProCon debate
- Positive diagnosis assessment to confirm a toxic hypothesis
- Differential diagnosis to exclude a toxic hypothesis
- Prognosis evaluation
- Help for treatment indications monitoring and re-evaluation
- Retrospective evaluation medico-legal issue or scientific studies
What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings
t
Severity C blood
t
Severity C blood
Confirm severity Supportive treatments
Prognostic factors Antidotes
Interest of analysis according to drug effects
Injury-inducing drugs
Functional drugs
Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues
Prerequisite availability of toxicological analysis
- Complexity and requirements of the assays
- Dialogue between biologists and clinicians
Importance of conservative plasma and urine sampling (initial and repetitive)
Expert opinion on appropriateness of disposal according to availability of drug screening
Fabbri A Emerg Med J 2003
Does a comprehensive drug screening add to decision making for poisonings in the ED
improve agreement on patient disposal Save potentially hospital resources
Meprobamate poisonings Is serum concentration useful to indicate the
mechanism of shock
Charron C Intensive Care Med 2005
Dose-dependent hypotension with narrowed QRS
- hypovolemia
- vasoplegia if concentrations le 150 mgl
- cardiogenic if concentrations gt 150 mgl
Plasma chloroquine concentration le 12 M No death
12-25 microM death rate 2
gt 25 microM death rate 22
gt 50 microM death rate 60
Chloroquine poisoning In-hospital prognosis assessment using
blood concentrations
Clemessy JL Crit Care Med 1996
TKTD using blood concentrations TKTD using plasma concentrations
Chloroquine poisoning blood vs plasma concentrations
0 25 50 75 100 125 15000
05
10
15
20
25
30
35
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 096
0 10 20 30 40 5000
05
10
15
20
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 091
0 1 2 3 4 5 6 7 8 900
05
10
15
20
Plasma chloroquine concentration (micromolL)
Ep
inep
hri
ne
infu
sio
n r
ate
(mg
h)
0 5 10 15 20 250
1
2
3
4
Plasma chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh)
R2 = 005
R2 = 017
Patient 1
Patient 2
PKPD population modeling in chloroquine poisonings
Meacutegarbane B Clin Tox2010
Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings
Relationship Between PlasmaFlecainide Concentration and
Outcome
Survivors Fatalities
0
1
2
3
4
5
6
7
8
9
10
Outcome of Acute Poisonings
Pla
sm
a F
lecain
ide
Co
ncen
trati
on
s (
mg
L)
Meacutegarbane B Clin Tox 2007
Meacutegarbane B BCPT 2010
Verapamil poisonings
Flecainide poisonings
Meacutegarbane B Clin Tox 2002 (abstract)
0
5
10
15
20
25P
red
icte
d c
on
cen
trati
on
s (n
gm
l)
0
10
0
20
0
30
0
40
0
Time since ingestion (hours)
Predicted concentration profiles
Non suvivors C(t) = 242 exp (-0003t)
Survivors C(t) = 177 exp (-0019t)
Cut-off C(t) = 207 exp (-0011t)
0
20
40
60
80
Co
lch
icin
e p
lasm
a c
on
cen
tra
tion
on
ad
mis
sio
n(n
gm
l)
Alive patients (N = 18)
Dead patients(N = 5)
Colchicine poisonings prognostic value of the time-course of serum concentrations
Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments
Q = body load of glycoside to neutralize
Estimation using ingested amount of digitalis
Estimation using serum glycoside concentration
Q = Weight
(kg)
volume of distribution
digoxin 56 lkg
digitoxin 056 lkg
Serum glycoside concentration
(ngml) x x
Q = x Ingested amount (mg) digoxin bioavailability (60 )
digitoxin bioavailability (100 ) or
One vial of digibind (40 mg) neutralizes 06 mg of digoxin
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
Poisonings with tricyclic antidepressants Value of serum concentrations
Boehnert MT N Engl J Med 1985
Prognostic value of serum theophylline concentration
Sessler CN Am J Med 1990
Why does the clinician need toxicological analysis to manage his
patient with cardiotoxicant poisoning
ProCon debate
- Positive diagnosis assessment to confirm a toxic hypothesis
- Differential diagnosis to exclude a toxic hypothesis
- Prognosis evaluation
- Help for treatment indications monitoring and re-evaluation
- Retrospective evaluation medico-legal issue or scientific studies
What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings
t
Severity C blood
t
Severity C blood
Confirm severity Supportive treatments
Prognostic factors Antidotes
Interest of analysis according to drug effects
Injury-inducing drugs
Functional drugs
Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues
Prerequisite availability of toxicological analysis
- Complexity and requirements of the assays
- Dialogue between biologists and clinicians
Importance of conservative plasma and urine sampling (initial and repetitive)
Expert opinion on appropriateness of disposal according to availability of drug screening
Fabbri A Emerg Med J 2003
Does a comprehensive drug screening add to decision making for poisonings in the ED
improve agreement on patient disposal Save potentially hospital resources
Meprobamate poisonings Is serum concentration useful to indicate the
mechanism of shock
Charron C Intensive Care Med 2005
Dose-dependent hypotension with narrowed QRS
- hypovolemia
- vasoplegia if concentrations le 150 mgl
- cardiogenic if concentrations gt 150 mgl
Plasma chloroquine concentration le 12 M No death
12-25 microM death rate 2
gt 25 microM death rate 22
gt 50 microM death rate 60
Chloroquine poisoning In-hospital prognosis assessment using
blood concentrations
Clemessy JL Crit Care Med 1996
TKTD using blood concentrations TKTD using plasma concentrations
Chloroquine poisoning blood vs plasma concentrations
0 25 50 75 100 125 15000
05
10
15
20
25
30
35
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 096
0 10 20 30 40 5000
05
10
15
20
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 091
0 1 2 3 4 5 6 7 8 900
05
10
15
20
Plasma chloroquine concentration (micromolL)
Ep
inep
hri
ne
infu
sio
n r
ate
(mg
h)
0 5 10 15 20 250
1
2
3
4
Plasma chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh)
R2 = 005
R2 = 017
Patient 1
Patient 2
PKPD population modeling in chloroquine poisonings
Meacutegarbane B Clin Tox2010
Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings
Relationship Between PlasmaFlecainide Concentration and
Outcome
Survivors Fatalities
0
1
2
3
4
5
6
7
8
9
10
Outcome of Acute Poisonings
Pla
sm
a F
lecain
ide
Co
ncen
trati
on
s (
mg
L)
Meacutegarbane B Clin Tox 2007
Meacutegarbane B BCPT 2010
Verapamil poisonings
Flecainide poisonings
Meacutegarbane B Clin Tox 2002 (abstract)
0
5
10
15
20
25P
red
icte
d c
on
cen
trati
on
s (n
gm
l)
0
10
0
20
0
30
0
40
0
Time since ingestion (hours)
Predicted concentration profiles
Non suvivors C(t) = 242 exp (-0003t)
Survivors C(t) = 177 exp (-0019t)
Cut-off C(t) = 207 exp (-0011t)
0
20
40
60
80
Co
lch
icin
e p
lasm
a c
on
cen
tra
tion
on
ad
mis
sio
n(n
gm
l)
Alive patients (N = 18)
Dead patients(N = 5)
Colchicine poisonings prognostic value of the time-course of serum concentrations
Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments
Q = body load of glycoside to neutralize
Estimation using ingested amount of digitalis
Estimation using serum glycoside concentration
Q = Weight
(kg)
volume of distribution
digoxin 56 lkg
digitoxin 056 lkg
Serum glycoside concentration
(ngml) x x
Q = x Ingested amount (mg) digoxin bioavailability (60 )
digitoxin bioavailability (100 ) or
One vial of digibind (40 mg) neutralizes 06 mg of digoxin
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
Prognostic value of serum theophylline concentration
Sessler CN Am J Med 1990
Why does the clinician need toxicological analysis to manage his
patient with cardiotoxicant poisoning
ProCon debate
- Positive diagnosis assessment to confirm a toxic hypothesis
- Differential diagnosis to exclude a toxic hypothesis
- Prognosis evaluation
- Help for treatment indications monitoring and re-evaluation
- Retrospective evaluation medico-legal issue or scientific studies
What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings
t
Severity C blood
t
Severity C blood
Confirm severity Supportive treatments
Prognostic factors Antidotes
Interest of analysis according to drug effects
Injury-inducing drugs
Functional drugs
Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues
Prerequisite availability of toxicological analysis
- Complexity and requirements of the assays
- Dialogue between biologists and clinicians
Importance of conservative plasma and urine sampling (initial and repetitive)
Expert opinion on appropriateness of disposal according to availability of drug screening
Fabbri A Emerg Med J 2003
Does a comprehensive drug screening add to decision making for poisonings in the ED
improve agreement on patient disposal Save potentially hospital resources
Meprobamate poisonings Is serum concentration useful to indicate the
mechanism of shock
Charron C Intensive Care Med 2005
Dose-dependent hypotension with narrowed QRS
- hypovolemia
- vasoplegia if concentrations le 150 mgl
- cardiogenic if concentrations gt 150 mgl
Plasma chloroquine concentration le 12 M No death
12-25 microM death rate 2
gt 25 microM death rate 22
gt 50 microM death rate 60
Chloroquine poisoning In-hospital prognosis assessment using
blood concentrations
Clemessy JL Crit Care Med 1996
TKTD using blood concentrations TKTD using plasma concentrations
Chloroquine poisoning blood vs plasma concentrations
0 25 50 75 100 125 15000
05
10
15
20
25
30
35
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 096
0 10 20 30 40 5000
05
10
15
20
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 091
0 1 2 3 4 5 6 7 8 900
05
10
15
20
Plasma chloroquine concentration (micromolL)
Ep
inep
hri
ne
infu
sio
n r
ate
(mg
h)
0 5 10 15 20 250
1
2
3
4
Plasma chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh)
R2 = 005
R2 = 017
Patient 1
Patient 2
PKPD population modeling in chloroquine poisonings
Meacutegarbane B Clin Tox2010
Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings
Relationship Between PlasmaFlecainide Concentration and
Outcome
Survivors Fatalities
0
1
2
3
4
5
6
7
8
9
10
Outcome of Acute Poisonings
Pla
sm
a F
lecain
ide
Co
ncen
trati
on
s (
mg
L)
Meacutegarbane B Clin Tox 2007
Meacutegarbane B BCPT 2010
Verapamil poisonings
Flecainide poisonings
Meacutegarbane B Clin Tox 2002 (abstract)
0
5
10
15
20
25P
red
icte
d c
on
cen
trati
on
s (n
gm
l)
0
10
0
20
0
30
0
40
0
Time since ingestion (hours)
Predicted concentration profiles
Non suvivors C(t) = 242 exp (-0003t)
Survivors C(t) = 177 exp (-0019t)
Cut-off C(t) = 207 exp (-0011t)
0
20
40
60
80
Co
lch
icin
e p
lasm
a c
on
cen
tra
tion
on
ad
mis
sio
n(n
gm
l)
Alive patients (N = 18)
Dead patients(N = 5)
Colchicine poisonings prognostic value of the time-course of serum concentrations
Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments
Q = body load of glycoside to neutralize
Estimation using ingested amount of digitalis
Estimation using serum glycoside concentration
Q = Weight
(kg)
volume of distribution
digoxin 56 lkg
digitoxin 056 lkg
Serum glycoside concentration
(ngml) x x
Q = x Ingested amount (mg) digoxin bioavailability (60 )
digitoxin bioavailability (100 ) or
One vial of digibind (40 mg) neutralizes 06 mg of digoxin
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
Why does the clinician need toxicological analysis to manage his
patient with cardiotoxicant poisoning
ProCon debate
- Positive diagnosis assessment to confirm a toxic hypothesis
- Differential diagnosis to exclude a toxic hypothesis
- Prognosis evaluation
- Help for treatment indications monitoring and re-evaluation
- Retrospective evaluation medico-legal issue or scientific studies
What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings
t
Severity C blood
t
Severity C blood
Confirm severity Supportive treatments
Prognostic factors Antidotes
Interest of analysis according to drug effects
Injury-inducing drugs
Functional drugs
Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues
Prerequisite availability of toxicological analysis
- Complexity and requirements of the assays
- Dialogue between biologists and clinicians
Importance of conservative plasma and urine sampling (initial and repetitive)
Expert opinion on appropriateness of disposal according to availability of drug screening
Fabbri A Emerg Med J 2003
Does a comprehensive drug screening add to decision making for poisonings in the ED
improve agreement on patient disposal Save potentially hospital resources
Meprobamate poisonings Is serum concentration useful to indicate the
mechanism of shock
Charron C Intensive Care Med 2005
Dose-dependent hypotension with narrowed QRS
- hypovolemia
- vasoplegia if concentrations le 150 mgl
- cardiogenic if concentrations gt 150 mgl
Plasma chloroquine concentration le 12 M No death
12-25 microM death rate 2
gt 25 microM death rate 22
gt 50 microM death rate 60
Chloroquine poisoning In-hospital prognosis assessment using
blood concentrations
Clemessy JL Crit Care Med 1996
TKTD using blood concentrations TKTD using plasma concentrations
Chloroquine poisoning blood vs plasma concentrations
0 25 50 75 100 125 15000
05
10
15
20
25
30
35
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 096
0 10 20 30 40 5000
05
10
15
20
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 091
0 1 2 3 4 5 6 7 8 900
05
10
15
20
Plasma chloroquine concentration (micromolL)
Ep
inep
hri
ne
infu
sio
n r
ate
(mg
h)
0 5 10 15 20 250
1
2
3
4
Plasma chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh)
R2 = 005
R2 = 017
Patient 1
Patient 2
PKPD population modeling in chloroquine poisonings
Meacutegarbane B Clin Tox2010
Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings
Relationship Between PlasmaFlecainide Concentration and
Outcome
Survivors Fatalities
0
1
2
3
4
5
6
7
8
9
10
Outcome of Acute Poisonings
Pla
sm
a F
lecain
ide
Co
ncen
trati
on
s (
mg
L)
Meacutegarbane B Clin Tox 2007
Meacutegarbane B BCPT 2010
Verapamil poisonings
Flecainide poisonings
Meacutegarbane B Clin Tox 2002 (abstract)
0
5
10
15
20
25P
red
icte
d c
on
cen
trati
on
s (n
gm
l)
0
10
0
20
0
30
0
40
0
Time since ingestion (hours)
Predicted concentration profiles
Non suvivors C(t) = 242 exp (-0003t)
Survivors C(t) = 177 exp (-0019t)
Cut-off C(t) = 207 exp (-0011t)
0
20
40
60
80
Co
lch
icin
e p
lasm
a c
on
cen
tra
tion
on
ad
mis
sio
n(n
gm
l)
Alive patients (N = 18)
Dead patients(N = 5)
Colchicine poisonings prognostic value of the time-course of serum concentrations
Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments
Q = body load of glycoside to neutralize
Estimation using ingested amount of digitalis
Estimation using serum glycoside concentration
Q = Weight
(kg)
volume of distribution
digoxin 56 lkg
digitoxin 056 lkg
Serum glycoside concentration
(ngml) x x
Q = x Ingested amount (mg) digoxin bioavailability (60 )
digitoxin bioavailability (100 ) or
One vial of digibind (40 mg) neutralizes 06 mg of digoxin
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
- Positive diagnosis assessment to confirm a toxic hypothesis
- Differential diagnosis to exclude a toxic hypothesis
- Prognosis evaluation
- Help for treatment indications monitoring and re-evaluation
- Retrospective evaluation medico-legal issue or scientific studies
What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings
t
Severity C blood
t
Severity C blood
Confirm severity Supportive treatments
Prognostic factors Antidotes
Interest of analysis according to drug effects
Injury-inducing drugs
Functional drugs
Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues
Prerequisite availability of toxicological analysis
- Complexity and requirements of the assays
- Dialogue between biologists and clinicians
Importance of conservative plasma and urine sampling (initial and repetitive)
Expert opinion on appropriateness of disposal according to availability of drug screening
Fabbri A Emerg Med J 2003
Does a comprehensive drug screening add to decision making for poisonings in the ED
improve agreement on patient disposal Save potentially hospital resources
Meprobamate poisonings Is serum concentration useful to indicate the
mechanism of shock
Charron C Intensive Care Med 2005
Dose-dependent hypotension with narrowed QRS
- hypovolemia
- vasoplegia if concentrations le 150 mgl
- cardiogenic if concentrations gt 150 mgl
Plasma chloroquine concentration le 12 M No death
12-25 microM death rate 2
gt 25 microM death rate 22
gt 50 microM death rate 60
Chloroquine poisoning In-hospital prognosis assessment using
blood concentrations
Clemessy JL Crit Care Med 1996
TKTD using blood concentrations TKTD using plasma concentrations
Chloroquine poisoning blood vs plasma concentrations
0 25 50 75 100 125 15000
05
10
15
20
25
30
35
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 096
0 10 20 30 40 5000
05
10
15
20
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 091
0 1 2 3 4 5 6 7 8 900
05
10
15
20
Plasma chloroquine concentration (micromolL)
Ep
inep
hri
ne
infu
sio
n r
ate
(mg
h)
0 5 10 15 20 250
1
2
3
4
Plasma chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh)
R2 = 005
R2 = 017
Patient 1
Patient 2
PKPD population modeling in chloroquine poisonings
Meacutegarbane B Clin Tox2010
Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings
Relationship Between PlasmaFlecainide Concentration and
Outcome
Survivors Fatalities
0
1
2
3
4
5
6
7
8
9
10
Outcome of Acute Poisonings
Pla
sm
a F
lecain
ide
Co
ncen
trati
on
s (
mg
L)
Meacutegarbane B Clin Tox 2007
Meacutegarbane B BCPT 2010
Verapamil poisonings
Flecainide poisonings
Meacutegarbane B Clin Tox 2002 (abstract)
0
5
10
15
20
25P
red
icte
d c
on
cen
trati
on
s (n
gm
l)
0
10
0
20
0
30
0
40
0
Time since ingestion (hours)
Predicted concentration profiles
Non suvivors C(t) = 242 exp (-0003t)
Survivors C(t) = 177 exp (-0019t)
Cut-off C(t) = 207 exp (-0011t)
0
20
40
60
80
Co
lch
icin
e p
lasm
a c
on
cen
tra
tion
on
ad
mis
sio
n(n
gm
l)
Alive patients (N = 18)
Dead patients(N = 5)
Colchicine poisonings prognostic value of the time-course of serum concentrations
Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments
Q = body load of glycoside to neutralize
Estimation using ingested amount of digitalis
Estimation using serum glycoside concentration
Q = Weight
(kg)
volume of distribution
digoxin 56 lkg
digitoxin 056 lkg
Serum glycoside concentration
(ngml) x x
Q = x Ingested amount (mg) digoxin bioavailability (60 )
digitoxin bioavailability (100 ) or
One vial of digibind (40 mg) neutralizes 06 mg of digoxin
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
t
Severity C blood
t
Severity C blood
Confirm severity Supportive treatments
Prognostic factors Antidotes
Interest of analysis according to drug effects
Injury-inducing drugs
Functional drugs
Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues
Prerequisite availability of toxicological analysis
- Complexity and requirements of the assays
- Dialogue between biologists and clinicians
Importance of conservative plasma and urine sampling (initial and repetitive)
Expert opinion on appropriateness of disposal according to availability of drug screening
Fabbri A Emerg Med J 2003
Does a comprehensive drug screening add to decision making for poisonings in the ED
improve agreement on patient disposal Save potentially hospital resources
Meprobamate poisonings Is serum concentration useful to indicate the
mechanism of shock
Charron C Intensive Care Med 2005
Dose-dependent hypotension with narrowed QRS
- hypovolemia
- vasoplegia if concentrations le 150 mgl
- cardiogenic if concentrations gt 150 mgl
Plasma chloroquine concentration le 12 M No death
12-25 microM death rate 2
gt 25 microM death rate 22
gt 50 microM death rate 60
Chloroquine poisoning In-hospital prognosis assessment using
blood concentrations
Clemessy JL Crit Care Med 1996
TKTD using blood concentrations TKTD using plasma concentrations
Chloroquine poisoning blood vs plasma concentrations
0 25 50 75 100 125 15000
05
10
15
20
25
30
35
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 096
0 10 20 30 40 5000
05
10
15
20
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 091
0 1 2 3 4 5 6 7 8 900
05
10
15
20
Plasma chloroquine concentration (micromolL)
Ep
inep
hri
ne
infu
sio
n r
ate
(mg
h)
0 5 10 15 20 250
1
2
3
4
Plasma chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh)
R2 = 005
R2 = 017
Patient 1
Patient 2
PKPD population modeling in chloroquine poisonings
Meacutegarbane B Clin Tox2010
Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings
Relationship Between PlasmaFlecainide Concentration and
Outcome
Survivors Fatalities
0
1
2
3
4
5
6
7
8
9
10
Outcome of Acute Poisonings
Pla
sm
a F
lecain
ide
Co
ncen
trati
on
s (
mg
L)
Meacutegarbane B Clin Tox 2007
Meacutegarbane B BCPT 2010
Verapamil poisonings
Flecainide poisonings
Meacutegarbane B Clin Tox 2002 (abstract)
0
5
10
15
20
25P
red
icte
d c
on
cen
trati
on
s (n
gm
l)
0
10
0
20
0
30
0
40
0
Time since ingestion (hours)
Predicted concentration profiles
Non suvivors C(t) = 242 exp (-0003t)
Survivors C(t) = 177 exp (-0019t)
Cut-off C(t) = 207 exp (-0011t)
0
20
40
60
80
Co
lch
icin
e p
lasm
a c
on
cen
tra
tion
on
ad
mis
sio
n(n
gm
l)
Alive patients (N = 18)
Dead patients(N = 5)
Colchicine poisonings prognostic value of the time-course of serum concentrations
Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments
Q = body load of glycoside to neutralize
Estimation using ingested amount of digitalis
Estimation using serum glycoside concentration
Q = Weight
(kg)
volume of distribution
digoxin 56 lkg
digitoxin 056 lkg
Serum glycoside concentration
(ngml) x x
Q = x Ingested amount (mg) digoxin bioavailability (60 )
digitoxin bioavailability (100 ) or
One vial of digibind (40 mg) neutralizes 06 mg of digoxin
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues
Prerequisite availability of toxicological analysis
- Complexity and requirements of the assays
- Dialogue between biologists and clinicians
Importance of conservative plasma and urine sampling (initial and repetitive)
Expert opinion on appropriateness of disposal according to availability of drug screening
Fabbri A Emerg Med J 2003
Does a comprehensive drug screening add to decision making for poisonings in the ED
improve agreement on patient disposal Save potentially hospital resources
Meprobamate poisonings Is serum concentration useful to indicate the
mechanism of shock
Charron C Intensive Care Med 2005
Dose-dependent hypotension with narrowed QRS
- hypovolemia
- vasoplegia if concentrations le 150 mgl
- cardiogenic if concentrations gt 150 mgl
Plasma chloroquine concentration le 12 M No death
12-25 microM death rate 2
gt 25 microM death rate 22
gt 50 microM death rate 60
Chloroquine poisoning In-hospital prognosis assessment using
blood concentrations
Clemessy JL Crit Care Med 1996
TKTD using blood concentrations TKTD using plasma concentrations
Chloroquine poisoning blood vs plasma concentrations
0 25 50 75 100 125 15000
05
10
15
20
25
30
35
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 096
0 10 20 30 40 5000
05
10
15
20
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 091
0 1 2 3 4 5 6 7 8 900
05
10
15
20
Plasma chloroquine concentration (micromolL)
Ep
inep
hri
ne
infu
sio
n r
ate
(mg
h)
0 5 10 15 20 250
1
2
3
4
Plasma chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh)
R2 = 005
R2 = 017
Patient 1
Patient 2
PKPD population modeling in chloroquine poisonings
Meacutegarbane B Clin Tox2010
Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings
Relationship Between PlasmaFlecainide Concentration and
Outcome
Survivors Fatalities
0
1
2
3
4
5
6
7
8
9
10
Outcome of Acute Poisonings
Pla
sm
a F
lecain
ide
Co
ncen
trati
on
s (
mg
L)
Meacutegarbane B Clin Tox 2007
Meacutegarbane B BCPT 2010
Verapamil poisonings
Flecainide poisonings
Meacutegarbane B Clin Tox 2002 (abstract)
0
5
10
15
20
25P
red
icte
d c
on
cen
trati
on
s (n
gm
l)
0
10
0
20
0
30
0
40
0
Time since ingestion (hours)
Predicted concentration profiles
Non suvivors C(t) = 242 exp (-0003t)
Survivors C(t) = 177 exp (-0019t)
Cut-off C(t) = 207 exp (-0011t)
0
20
40
60
80
Co
lch
icin
e p
lasm
a c
on
cen
tra
tion
on
ad
mis
sio
n(n
gm
l)
Alive patients (N = 18)
Dead patients(N = 5)
Colchicine poisonings prognostic value of the time-course of serum concentrations
Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments
Q = body load of glycoside to neutralize
Estimation using ingested amount of digitalis
Estimation using serum glycoside concentration
Q = Weight
(kg)
volume of distribution
digoxin 56 lkg
digitoxin 056 lkg
Serum glycoside concentration
(ngml) x x
Q = x Ingested amount (mg) digoxin bioavailability (60 )
digitoxin bioavailability (100 ) or
One vial of digibind (40 mg) neutralizes 06 mg of digoxin
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
Expert opinion on appropriateness of disposal according to availability of drug screening
Fabbri A Emerg Med J 2003
Does a comprehensive drug screening add to decision making for poisonings in the ED
improve agreement on patient disposal Save potentially hospital resources
Meprobamate poisonings Is serum concentration useful to indicate the
mechanism of shock
Charron C Intensive Care Med 2005
Dose-dependent hypotension with narrowed QRS
- hypovolemia
- vasoplegia if concentrations le 150 mgl
- cardiogenic if concentrations gt 150 mgl
Plasma chloroquine concentration le 12 M No death
12-25 microM death rate 2
gt 25 microM death rate 22
gt 50 microM death rate 60
Chloroquine poisoning In-hospital prognosis assessment using
blood concentrations
Clemessy JL Crit Care Med 1996
TKTD using blood concentrations TKTD using plasma concentrations
Chloroquine poisoning blood vs plasma concentrations
0 25 50 75 100 125 15000
05
10
15
20
25
30
35
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 096
0 10 20 30 40 5000
05
10
15
20
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 091
0 1 2 3 4 5 6 7 8 900
05
10
15
20
Plasma chloroquine concentration (micromolL)
Ep
inep
hri
ne
infu
sio
n r
ate
(mg
h)
0 5 10 15 20 250
1
2
3
4
Plasma chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh)
R2 = 005
R2 = 017
Patient 1
Patient 2
PKPD population modeling in chloroquine poisonings
Meacutegarbane B Clin Tox2010
Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings
Relationship Between PlasmaFlecainide Concentration and
Outcome
Survivors Fatalities
0
1
2
3
4
5
6
7
8
9
10
Outcome of Acute Poisonings
Pla
sm
a F
lecain
ide
Co
ncen
trati
on
s (
mg
L)
Meacutegarbane B Clin Tox 2007
Meacutegarbane B BCPT 2010
Verapamil poisonings
Flecainide poisonings
Meacutegarbane B Clin Tox 2002 (abstract)
0
5
10
15
20
25P
red
icte
d c
on
cen
trati
on
s (n
gm
l)
0
10
0
20
0
30
0
40
0
Time since ingestion (hours)
Predicted concentration profiles
Non suvivors C(t) = 242 exp (-0003t)
Survivors C(t) = 177 exp (-0019t)
Cut-off C(t) = 207 exp (-0011t)
0
20
40
60
80
Co
lch
icin
e p
lasm
a c
on
cen
tra
tion
on
ad
mis
sio
n(n
gm
l)
Alive patients (N = 18)
Dead patients(N = 5)
Colchicine poisonings prognostic value of the time-course of serum concentrations
Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments
Q = body load of glycoside to neutralize
Estimation using ingested amount of digitalis
Estimation using serum glycoside concentration
Q = Weight
(kg)
volume of distribution
digoxin 56 lkg
digitoxin 056 lkg
Serum glycoside concentration
(ngml) x x
Q = x Ingested amount (mg) digoxin bioavailability (60 )
digitoxin bioavailability (100 ) or
One vial of digibind (40 mg) neutralizes 06 mg of digoxin
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
Meprobamate poisonings Is serum concentration useful to indicate the
mechanism of shock
Charron C Intensive Care Med 2005
Dose-dependent hypotension with narrowed QRS
- hypovolemia
- vasoplegia if concentrations le 150 mgl
- cardiogenic if concentrations gt 150 mgl
Plasma chloroquine concentration le 12 M No death
12-25 microM death rate 2
gt 25 microM death rate 22
gt 50 microM death rate 60
Chloroquine poisoning In-hospital prognosis assessment using
blood concentrations
Clemessy JL Crit Care Med 1996
TKTD using blood concentrations TKTD using plasma concentrations
Chloroquine poisoning blood vs plasma concentrations
0 25 50 75 100 125 15000
05
10
15
20
25
30
35
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 096
0 10 20 30 40 5000
05
10
15
20
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 091
0 1 2 3 4 5 6 7 8 900
05
10
15
20
Plasma chloroquine concentration (micromolL)
Ep
inep
hri
ne
infu
sio
n r
ate
(mg
h)
0 5 10 15 20 250
1
2
3
4
Plasma chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh)
R2 = 005
R2 = 017
Patient 1
Patient 2
PKPD population modeling in chloroquine poisonings
Meacutegarbane B Clin Tox2010
Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings
Relationship Between PlasmaFlecainide Concentration and
Outcome
Survivors Fatalities
0
1
2
3
4
5
6
7
8
9
10
Outcome of Acute Poisonings
Pla
sm
a F
lecain
ide
Co
ncen
trati
on
s (
mg
L)
Meacutegarbane B Clin Tox 2007
Meacutegarbane B BCPT 2010
Verapamil poisonings
Flecainide poisonings
Meacutegarbane B Clin Tox 2002 (abstract)
0
5
10
15
20
25P
red
icte
d c
on
cen
trati
on
s (n
gm
l)
0
10
0
20
0
30
0
40
0
Time since ingestion (hours)
Predicted concentration profiles
Non suvivors C(t) = 242 exp (-0003t)
Survivors C(t) = 177 exp (-0019t)
Cut-off C(t) = 207 exp (-0011t)
0
20
40
60
80
Co
lch
icin
e p
lasm
a c
on
cen
tra
tion
on
ad
mis
sio
n(n
gm
l)
Alive patients (N = 18)
Dead patients(N = 5)
Colchicine poisonings prognostic value of the time-course of serum concentrations
Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments
Q = body load of glycoside to neutralize
Estimation using ingested amount of digitalis
Estimation using serum glycoside concentration
Q = Weight
(kg)
volume of distribution
digoxin 56 lkg
digitoxin 056 lkg
Serum glycoside concentration
(ngml) x x
Q = x Ingested amount (mg) digoxin bioavailability (60 )
digitoxin bioavailability (100 ) or
One vial of digibind (40 mg) neutralizes 06 mg of digoxin
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
Plasma chloroquine concentration le 12 M No death
12-25 microM death rate 2
gt 25 microM death rate 22
gt 50 microM death rate 60
Chloroquine poisoning In-hospital prognosis assessment using
blood concentrations
Clemessy JL Crit Care Med 1996
TKTD using blood concentrations TKTD using plasma concentrations
Chloroquine poisoning blood vs plasma concentrations
0 25 50 75 100 125 15000
05
10
15
20
25
30
35
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 096
0 10 20 30 40 5000
05
10
15
20
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 091
0 1 2 3 4 5 6 7 8 900
05
10
15
20
Plasma chloroquine concentration (micromolL)
Ep
inep
hri
ne
infu
sio
n r
ate
(mg
h)
0 5 10 15 20 250
1
2
3
4
Plasma chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh)
R2 = 005
R2 = 017
Patient 1
Patient 2
PKPD population modeling in chloroquine poisonings
Meacutegarbane B Clin Tox2010
Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings
Relationship Between PlasmaFlecainide Concentration and
Outcome
Survivors Fatalities
0
1
2
3
4
5
6
7
8
9
10
Outcome of Acute Poisonings
Pla
sm
a F
lecain
ide
Co
ncen
trati
on
s (
mg
L)
Meacutegarbane B Clin Tox 2007
Meacutegarbane B BCPT 2010
Verapamil poisonings
Flecainide poisonings
Meacutegarbane B Clin Tox 2002 (abstract)
0
5
10
15
20
25P
red
icte
d c
on
cen
trati
on
s (n
gm
l)
0
10
0
20
0
30
0
40
0
Time since ingestion (hours)
Predicted concentration profiles
Non suvivors C(t) = 242 exp (-0003t)
Survivors C(t) = 177 exp (-0019t)
Cut-off C(t) = 207 exp (-0011t)
0
20
40
60
80
Co
lch
icin
e p
lasm
a c
on
cen
tra
tion
on
ad
mis
sio
n(n
gm
l)
Alive patients (N = 18)
Dead patients(N = 5)
Colchicine poisonings prognostic value of the time-course of serum concentrations
Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments
Q = body load of glycoside to neutralize
Estimation using ingested amount of digitalis
Estimation using serum glycoside concentration
Q = Weight
(kg)
volume of distribution
digoxin 56 lkg
digitoxin 056 lkg
Serum glycoside concentration
(ngml) x x
Q = x Ingested amount (mg) digoxin bioavailability (60 )
digitoxin bioavailability (100 ) or
One vial of digibind (40 mg) neutralizes 06 mg of digoxin
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
TKTD using blood concentrations TKTD using plasma concentrations
Chloroquine poisoning blood vs plasma concentrations
0 25 50 75 100 125 15000
05
10
15
20
25
30
35
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 096
0 10 20 30 40 5000
05
10
15
20
Blood chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh) R2 = 091
0 1 2 3 4 5 6 7 8 900
05
10
15
20
Plasma chloroquine concentration (micromolL)
Ep
inep
hri
ne
infu
sio
n r
ate
(mg
h)
0 5 10 15 20 250
1
2
3
4
Plasma chloroquine concentration (micromolL)
Epi
neph
rine
infu
sion
rat
e (m
gh)
R2 = 005
R2 = 017
Patient 1
Patient 2
PKPD population modeling in chloroquine poisonings
Meacutegarbane B Clin Tox2010
Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings
Relationship Between PlasmaFlecainide Concentration and
Outcome
Survivors Fatalities
0
1
2
3
4
5
6
7
8
9
10
Outcome of Acute Poisonings
Pla
sm
a F
lecain
ide
Co
ncen
trati
on
s (
mg
L)
Meacutegarbane B Clin Tox 2007
Meacutegarbane B BCPT 2010
Verapamil poisonings
Flecainide poisonings
Meacutegarbane B Clin Tox 2002 (abstract)
0
5
10
15
20
25P
red
icte
d c
on
cen
trati
on
s (n
gm
l)
0
10
0
20
0
30
0
40
0
Time since ingestion (hours)
Predicted concentration profiles
Non suvivors C(t) = 242 exp (-0003t)
Survivors C(t) = 177 exp (-0019t)
Cut-off C(t) = 207 exp (-0011t)
0
20
40
60
80
Co
lch
icin
e p
lasm
a c
on
cen
tra
tion
on
ad
mis
sio
n(n
gm
l)
Alive patients (N = 18)
Dead patients(N = 5)
Colchicine poisonings prognostic value of the time-course of serum concentrations
Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments
Q = body load of glycoside to neutralize
Estimation using ingested amount of digitalis
Estimation using serum glycoside concentration
Q = Weight
(kg)
volume of distribution
digoxin 56 lkg
digitoxin 056 lkg
Serum glycoside concentration
(ngml) x x
Q = x Ingested amount (mg) digoxin bioavailability (60 )
digitoxin bioavailability (100 ) or
One vial of digibind (40 mg) neutralizes 06 mg of digoxin
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
PKPD population modeling in chloroquine poisonings
Meacutegarbane B Clin Tox2010
Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings
Relationship Between PlasmaFlecainide Concentration and
Outcome
Survivors Fatalities
0
1
2
3
4
5
6
7
8
9
10
Outcome of Acute Poisonings
Pla
sm
a F
lecain
ide
Co
ncen
trati
on
s (
mg
L)
Meacutegarbane B Clin Tox 2007
Meacutegarbane B BCPT 2010
Verapamil poisonings
Flecainide poisonings
Meacutegarbane B Clin Tox 2002 (abstract)
0
5
10
15
20
25P
red
icte
d c
on
cen
trati
on
s (n
gm
l)
0
10
0
20
0
30
0
40
0
Time since ingestion (hours)
Predicted concentration profiles
Non suvivors C(t) = 242 exp (-0003t)
Survivors C(t) = 177 exp (-0019t)
Cut-off C(t) = 207 exp (-0011t)
0
20
40
60
80
Co
lch
icin
e p
lasm
a c
on
cen
tra
tion
on
ad
mis
sio
n(n
gm
l)
Alive patients (N = 18)
Dead patients(N = 5)
Colchicine poisonings prognostic value of the time-course of serum concentrations
Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments
Q = body load of glycoside to neutralize
Estimation using ingested amount of digitalis
Estimation using serum glycoside concentration
Q = Weight
(kg)
volume of distribution
digoxin 56 lkg
digitoxin 056 lkg
Serum glycoside concentration
(ngml) x x
Q = x Ingested amount (mg) digoxin bioavailability (60 )
digitoxin bioavailability (100 ) or
One vial of digibind (40 mg) neutralizes 06 mg of digoxin
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings
Relationship Between PlasmaFlecainide Concentration and
Outcome
Survivors Fatalities
0
1
2
3
4
5
6
7
8
9
10
Outcome of Acute Poisonings
Pla
sm
a F
lecain
ide
Co
ncen
trati
on
s (
mg
L)
Meacutegarbane B Clin Tox 2007
Meacutegarbane B BCPT 2010
Verapamil poisonings
Flecainide poisonings
Meacutegarbane B Clin Tox 2002 (abstract)
0
5
10
15
20
25P
red
icte
d c
on
cen
trati
on
s (n
gm
l)
0
10
0
20
0
30
0
40
0
Time since ingestion (hours)
Predicted concentration profiles
Non suvivors C(t) = 242 exp (-0003t)
Survivors C(t) = 177 exp (-0019t)
Cut-off C(t) = 207 exp (-0011t)
0
20
40
60
80
Co
lch
icin
e p
lasm
a c
on
cen
tra
tion
on
ad
mis
sio
n(n
gm
l)
Alive patients (N = 18)
Dead patients(N = 5)
Colchicine poisonings prognostic value of the time-course of serum concentrations
Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments
Q = body load of glycoside to neutralize
Estimation using ingested amount of digitalis
Estimation using serum glycoside concentration
Q = Weight
(kg)
volume of distribution
digoxin 56 lkg
digitoxin 056 lkg
Serum glycoside concentration
(ngml) x x
Q = x Ingested amount (mg) digoxin bioavailability (60 )
digitoxin bioavailability (100 ) or
One vial of digibind (40 mg) neutralizes 06 mg of digoxin
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
Meacutegarbane B Clin Tox 2002 (abstract)
0
5
10
15
20
25P
red
icte
d c
on
cen
trati
on
s (n
gm
l)
0
10
0
20
0
30
0
40
0
Time since ingestion (hours)
Predicted concentration profiles
Non suvivors C(t) = 242 exp (-0003t)
Survivors C(t) = 177 exp (-0019t)
Cut-off C(t) = 207 exp (-0011t)
0
20
40
60
80
Co
lch
icin
e p
lasm
a c
on
cen
tra
tion
on
ad
mis
sio
n(n
gm
l)
Alive patients (N = 18)
Dead patients(N = 5)
Colchicine poisonings prognostic value of the time-course of serum concentrations
Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments
Q = body load of glycoside to neutralize
Estimation using ingested amount of digitalis
Estimation using serum glycoside concentration
Q = Weight
(kg)
volume of distribution
digoxin 56 lkg
digitoxin 056 lkg
Serum glycoside concentration
(ngml) x x
Q = x Ingested amount (mg) digoxin bioavailability (60 )
digitoxin bioavailability (100 ) or
One vial of digibind (40 mg) neutralizes 06 mg of digoxin
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments
Q = body load of glycoside to neutralize
Estimation using ingested amount of digitalis
Estimation using serum glycoside concentration
Q = Weight
(kg)
volume of distribution
digoxin 56 lkg
digitoxin 056 lkg
Serum glycoside concentration
(ngml) x x
Q = x Ingested amount (mg) digoxin bioavailability (60 )
digitoxin bioavailability (100 ) or
One vial of digibind (40 mg) neutralizes 06 mg of digoxin
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
Poor prognosticators
- Male
- Age over 55 years
- Underlying heart disease
- Atrioventricular block
- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)
- Hyperkalemia gt 45 mmol L
Indication amp dosage regimen of Fab fragments
Half-molar neutralization for prophylactic treatment
bull Ventricular arrhythmia VF or VT
bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)
bull Hyperkalemia gt 5 mmol L
bull Cardiogenic shock
bull Mesenteric infacrtion
Life-threatening conditions
Molar neutralization for curative treatment
Lapostolle F Crit Care Med 2009
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
050075100125150
00
25
50
75
100 Patient 2
Flecainide concentration (mgl)
Do
bu
tam
ine i
nfu
sio
n(micro
gk
gm
in)
Meacutegarbane B Clin Tox 2005 (abstract)
Assessment of catecholamine limitations in cardiotoxicant poisonings
Dobutamine infusion Epinephrine infusion
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
Baud FJ NEJM 1995
Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
French D Clin Tox 2011
French D Clin Tox 2011
Assessment of usefulness of lipid rescue in cardiotoxicant poisonings
Time-course of PD parameters
Time-course of PK
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
Pichon N Ann Emerg Med 2011 Time-course of PK
Time-course of PD parameters
Assessment of MARS usefulness in diltiazem and verapamil poisonings with
refractory vasoplegic shock
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
Toxicokinetics in severe poisonings requiring ECLS
- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh
Meacutegarbane B Intensive Care Med 2006
Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)
Propafenone poisoning Carbamazepine poisoning
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
Level of interindividual variability and potential drug-drug interactions
Drug-drug PK interactions
AbsorptionExcretion (Membrane transporters)
Gene polymorphism
Metabolism (CYP450)
Pharmacodynamic effects (Recepteurs)
Elimination Renal function
Drug-drug PD interaction
Distribution (Plasma transporters)
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
E0 0
Emax 078 microgkgmin
EC50 239 micromoll
Hill coefficient 179
R2 099
Meacutegarbane B Intensive Care Med 2006
Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability
Hypothesis Slow CYP 2D6 metabolizer
Normal range 025-085 micromoll
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
Elkalioubie A Eur J Clin Pharmacol 2011
Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer
- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio
- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid
metabolizer phenotype
+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)
Tramadol
O-desmethyltramadol (M1)
N-desmethyltramadol (M2)
CYP2D6 CYP2B6CYP3A4
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy
Conclusions
bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death
bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management
bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management
bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy