Sedation and Pain Management in ICU

Gagan Kumar MDFellow, Pulmonary & Critical Care

Medical College of Wisconsin

Why do we need sedation & pain control ?

• Patient comfort• Facilitate patient-ventilator synchrony• Optimize oxygenation.• Delirium and delusional memories influence

the likelihood of patients having long term psychological effects

Chest 2008;133;552-565

Predisposing and precipitating factors

• Medical conditions. E.g. chronic pain, arthritis• Postoperative factors• Interventions. E.g. IMV• Withdrawal or rebound of chronic symptoms

occur if home medications are withheld for too long

Analgesia

Amnesia

Anxiolysis

Sedation

Sedatives

HypnoticsAnalgesics

Delirium• 80% of ICU patients have delirium

fluctuating mental status

disorganized thinking

altered level of consciousness*

*may or may not be accompanied by agitation

Hypoactive delirium

Calm appearance

Inattention

Decreased mobility

Psychomotor retardation

Obtundation

Recommendation

• Routine assessment for the presence of delirium is recommended. (The CAM-ICU is a promising tool for the assessment of delirium in ICU patients.) (Grade of recommendation B)

Delirium Evaluation

• Confusion Assessment Method for the ICU• Cognitive Test for Delirium• Delirium Screening Checklist (ICDSC)• Nursing Rating Scale for ICU Delirium

• Unfortunately these are “rarely performed”.

CAM-ICU• Critical care nurses can complete delirium assessments with the

CAM-ICU in an average of 2 minutes with an accuracy of 98%

• Routine assessment for the presence of delirium is recommended. (The CAM-ICU is a promising tool for the assessment of delirium in ICU patients.) (Grade of recommendation B)

Ely EW, Margolin R, Francis J, et al: Evaluation of delirium in critically ill patients: Validation of the confusion assessment method for the intensive care unit (CAMICU). Crit Care Med 2001; 29:1370–1379

Neuroleptic agents

• Chlorpromazine – anticholinergic, sedative, and α-adrenergic antagonist effects

• Haloperidol • Droperidol

– more potent than haloperidol– associated with frightening dreams– higher risk of inducing hypotension because of its direct vasodilating

and antiadrenergic effects

• Exert a stabilizing effect on cerebral function by antagonizing dopamine-mediated neurotransmission at the cerebral synapses and basal ganglia.

Haloperidol

• Long half-life (18–54 hours)

• Loading regimen starting with a 2-mg dose, followed by repeated doses (double the previous dose) every 15–20 minutes while agitation persists

Advantages

• Hallucinations, delusions, and Unstructured thought patterns, is inhibited, but the patient’s interest in the environment is diminished, producing a characteristic flat cerebral affect.

• These agents also exert a sedative effect.

Disadvantages

• Dose dependent QT prolongation– A history of cardiac disease appears to predispose patients– Incidence of torsades de pointes associated with halperidol use is

unknown, although a historical case-controlled study suggests it may be 3.6%

• Slowly eliminated active metabolite of haloperidol appears to cause EPS– discontinuing the neuroleptic agent – diphenhydramine or benztropine mesylate

• May prolong the duration of posttraumatic amnesia

Atypical Neurolepts

• No data regarding the newer atypical agents, such as ‘risperidone’ and ‘quetiapine’ (seroquel) in delirium in ICU.

• Other atypical antipsychotics: – Olanzapine (Zyprexa)– Aripiprazole (Abilify)– Ziprasidone (Geodon)

definition of "atypicality" was based upon the absence of extrapyramidal side effects, but there is now a clear understanding that atypical antipsychotics can still induce these effects ,though to a lesser degree

Quetiapine

• Second generation atypical antipsychotic• Serotonin and Dopamine antagonist• Most sedating of all anti-psychotics

• Disadvantages– Neuroleptic malignant syndrome– Tardive dyskinesia

Sedatives

HypnoticsAnalgesics

PAIN

Unrelieved pain evokes a stress response • Tachycardia• Increased myocardial oxygen consumption• Hypercoagulability• Immunosuppression• Persistent catabolism• Pulmonary dysfunction through localized

guarding of muscles

Pain evaluation• Most reliable and valid indicator of pain is the patient’s self-report

– verbal rating scale (VRS)– visual analogue scale (VAS)– numeric rating scale (NRS)

• “unable to communicate”

• Surrogates /Family members could estimate the presence or absence of pain in 73.5% of patients, they less accurately described the degree of pain (53%)*

• Verbal descriptive scale vs. behavioral pain scale : moderate correlation (r = 0.60)**

*Desbiens NA, Mueller-Rizner N: How well do surrogates assess the pain of seriously ill patients? Crit Care Med 2000; 28: 1347–1352** Mateo OM, Krenzischek DA: A pilot study to assess the relationship between behavioral manifestations of pain and self-report of pain in post anesthesia care unit patients. J Post Anesth Nurs 1992; 7:15–21

Recommendations

• The level of pain reported by the patient must be considered the current standard for assessment of pain and response to analgesia whenever possible. Use of the NRS is recommended to assess pain. (Grade of recommendation B)

• Patients who cannot communicate should be assessed through subjective observation of pain-related behaviors (movement, facial expression, and posturing) and physiological indicators (heart rate, blood pressure, and respiratory rate) and the change in these parameters following analgesic therapy. (Grade of recommendation B)

Analgesics

NSAIDs

Acetaminophen

Critically ill patients are different

• Pharmacokinetics of various drugs are altered including - drug bioavailability, volume of distribution, and clearance.– Hepatic dysfunction– Decreased hepatic blood flow– Renal dysfunction– Alteration in volume status– Plasma protein binding

Opiates

• Comparative trials of opioids have not been performed in critically ill patients.

• The selection of an agent depends on its pharmacology and potential for adverse effects.

• Titrate opioid therapy using a validated pain assessment tool (either verbal or nonverbal) or other physiologic endpoints (eg, heart rate, blood pressure, or respiratory rate)

• The oral, transdermal, and intramuscular routes of administration are generally not recommended in patients who are hemodynamically unstable

Opiates

• μ- and κ-receptors are most important for analgesia.

• Although opioids may produce sedating effects, they do not diminish awareness or provide amnesia for stressful events.

• Tolerance: fentanyl > morphine– Antagonism of central NMDA receptors through the use of

methadone/ketamine is another strategy that may slow the development of tolerance

Metabolism of opiates

Fentanyl Morphine Hydromorphone

InactiveInactive

Oxidation Glucoronization

Active

Fentanyl

• μ-opioid receptors• Highly lipophilic• Rapid onset• T½ : 2-4hr• Repeated dosing may cause accumulation esp.

in renal dysfunction• Less nausea, as well as less histamine-

mediated itching, in relation to morphine

Drug interactions

• Fentanyl is a substrate CYP3A4 and is affected by – Inhibitors

• Fluconazole • Ciprofloxacin• Diltiazem• Haloperidol

– Inducers• Phenytoin• Carbamazepine • Rifampin• Ritonavir

Fentanyl patch

• Patch usually provides consistent drug delivery but the extent of absorption varies depending on – the permeability– temperature– perfusion– thickness of the skin

• There is a large inter-patient variability in peak plasma concentrations.

• Not for acute analgesia : 12-24 hour delay to peak effect and similar lag time to complete offset once the patch is removed.

Morphine

• Predominantly μ-opioid receptor• Metabolized primarily in the liver • Onset: 15-30min• T½ : 1.7-4.5hrs• 60% of morphine is converted to morphine-3-glucuronide

(inactive), and 6–10% is converted to morphine-6-glucuronide (1/2 as active).

• Hypotension may result from vasodilatation• Active metabolite may cause prolonged sedation in

the presence of renal insufficiency.

Hydromorphone

• Hydrogenated ketone of morphine• 6-8 times stronger than morphine• μ-opioid agonist• Lacks a active metabolite (hence drug of

choice in ESRD)• Minimal histamine release.• Glucuronidation in the liver• Strongest of the anti-tussive drugs

Remifentanil

• Specific μ-receptor agonist• Marketed by GlaxoSmithKline and Abbott as Ultiva• Potent (250 times morphine)

• Onset : 1 minute• T½ = 4 minutes after a 4 hour infusion.

• Synergism between remifentanil and hypnotic drugs (such as propofol) the dose of the hypnotic can be substantially reduced Resulting in more hemodynamic stability

Advantages

• Has ester linkage - rapid hydrolysis by non-specific tissue and plasma esterases to metabolized to remifentanil acid which is almost inactive excreted in kidneys

• No dose adjustments in renal or liver disease

Disdvantages

• Reduction in sympathetic nervous system tone • Respiratory depression• Pruritus is due to excessive serum histamine

levels• Bolus injections of remifentanil may cause

‘thoracic muscle rigidity’ with difficult mask or pressure-controlled ventilation

• Acute withdrawal syndrome

Alfentanil

• μ-agonist.• analogue of fentanyl with – around 1/4 the potency– around 1/3 of the duration of action– onset of effects 4x faster than fentanyl

• less cardiovascular complications but stronger respiratory depression

Disadvantages

• Respiratory depression• Hypotension – esp. in hemodynamically unstable– sympatholysis– vagally mediated bradycardia– histamine release

• Depression of the level of consciousness• Hallucinations• Gastric retention and ileus• May increase intracranial pressure with traumatic brain

injury, although the data are inconsistent.

Meperidine (Demerol)

• κ opioid receptor• Also has

– strong anticholinergics effect– local anesthetic activity due to blockage of sodium ion channels.– increases cerebral serotonin concentration

• Has an active metabolite (normeperidine) that causes neuroexcitation (apprehension, tremors, delirium, and seizures) – accumulates in renal insufficiency

• Interact with antidepressants (contraindicated with MAOI and best avoided with SSRI)

PAMORAs

• Peripherally acting mu opioid receptor antagonists– Methylnaltrexone– Alvimopan

• Do not cross the blood-brain barrier• Antagonize the peripheral side effects of opioids—

notably constipation and ileus—while preserving analgesia

• Methylnaltrexone reverses opioid-induced delayed gastric emptying time

? Advantages

• Pseudomonas aeruginosa: has mu opioid receptors, which when activated produce factors that enhance gut wall permeability.

• Methylnaltrexone blocks the production of these factors !!!!

NSAIDs

• Nonselective, competitive inhibition of cyclooxygenase.

• Significant adverse effects– Gastrointestinal bleeding: bleeding secondary to platelet

inhibition,– renal insufficiency. – Increased risk in

• hypovolemia or hypoperfusion• Elderly• CKD

• Asthma & Aspirin sensitivity.

Ketorolac (toradol)

• Parenteral NSAID• Prolonged use (> 5 days) of ketorolac has been

associated with a two-fold increase in the risk of renal failure and an increased risk of gastrointestinal and operative- site bleeding

Acetaminophen

• Mild to moderate pain at best• With an opioid, acetaminophen produces a greater analgesic

effect than higher doses of the opioid alone

• Potentially hepatotoxic especially in patients with depleted glutathione stores resulting from hepatic dysfunction or malnutrition.

• Acetaminophen should be maintained at – less than 2 g per day for patients with a significant history of alcohol

intake or poor nutritional status– less than 4 g per day for others

Sedatives

HypnoticsAnalgesics

Sedation Evaluation

Should be integral component of treatment algorithms• precise dosing• reduced sedative and analgesic drug use • shorter duration of MV• reduced need for vasopressor therapy• reduced incidence of over sedationRecommendation: Sedation of agitated critically ill patients should be started only after

providing adequate analgesia and treating reversible physiological causes. (Grade of recommendation C)

PTSD in ICU survivors• PTSD may be experienced by 4–15% of ICU survivors*• The Impact of Events Scale (IES) : used for measuring post-traumatic stress. It

has two subscales– re-experiencing the trauma (e.g. nightmares) – avoiding situations/thoughts that are associated with the trauma. – Scores on the IES subscales for intrusions and avoidance have been stratified as

follows:• 8 or less: mild or absent symptoms• 9 to 19: medium level of symptoms • 20 or more: high levels of symptoms

*Scragg P, Jones A, Fauvel N: Psychological problems following ICU treatment. Anaesthesia 2001; 56:9–14

Sedation evaluation Scales

• Ramsay Sedation Scale• Sedation Agitation Scale• Motor Activity Assessment Scale• Richmond Agitation-Sedation Scale (RASS)• Adaptation to the Intensive Care Environment

(ATICE) instrument• Minnesota Sedation Assessment Tool (MSAT).

Sessler CN, Gosnell M, Grap MJ, Brophy GT, O'Neal PV, Keane KA et al. The Richmond Agitation- Sedation Scale: validity and reliability in adult intensive care patients. Am J Respir Crit Care Med 2002; 166:1338-1344

Measurement of Brain Activity

• Bispectral index (BIS)• Patient state index• Cerebral state index• Narcotrend index

•Objective physiologic parameters•Numerical display•Near-continuous measurement

BIS

• Weighted sum of EEG parameters – “algorithm is proprietary information”

• Yields a single numerical value from – 0 (complete EEG suppression)– to 100 (awake).

• 40 and 60 indicates an appropriate level for general anesthesia

BIS

• Prone to artifacts• ‘Electromyography‘ activity interferes with BIS measures of

sedation• Confounding factors that may influence BIS scores

– Hypoglycemia– Sleep– temperature– Age– Drugs

• aminophylline, epinephrine, and ketamine.

• Increase variability of BIS in the critically ill patient• Cannot be relied upon in circulatory arrest or hypothermia

Correlation between the Sedation-Agitation Scale and the Bispectral Index in ventilated patients in the intensive care unit. Heart Lung. 2009 Jul-Aug;38(4):336-45.

r = 0.50r2 of .252 implies that the BIS scores explained only 25.2% of the variance in SAS scores.

The majority of studies reported correlations between BIS and subjective sedation scores between r of 0.37 and r of 0.69.

Mixed results• BIS monitoring to be a helpful addition to traditional sedation monitoring

whereas others found that BIS monitoring was not helpful.

• Review of 19 studies with BIS - reported that more data are needed to evaluate the routine use of BIS in the ICU*

• More research is necessary to evaluate the use of BIS monitoring in sedated ICU patients

• BIS is likely to be useful when patients are – “deeply comatose” or – under “neuromuscular blockade”.

*LeBlanc JM, Dasta JF, Kane-Gill SL. Role of the bispectral index in sedation monitoring in the ICU. Ann Pharmacother 2006;40:490-500

Sedative-Hypnotics

• Benzodiazepines• Propofol• Dexmedetomidine• Ketamine• Etomidate• Thiopental

Benzodiazepines

• Increase the frequency of chloride channel opening events which leads to inhibition of the action potential

• Only anterograde amnesia

• Have an opioid-sparing effect by moderating the anticipatory pain response

Pharmacodynamic response

• Patient-related factors can affect the BZD response– age– concurrent pathology– prior alcohol use– concurrent therapy with other sedative drugs

Higher volume of distribution and slower clearance in elderly.

Midazolam (Versed)• High lipid solubility• Onset: 2-3 minutes• Duration: variable (Accumulates in fats)• Avoid if hepatic/renal failure• Inhibition of midazolam metabolism has

been reported with inhibitors of cytochrome P450

– propofol– diltiazem– Erythromycin– Itraconazole

• Obese (high lipid soluble) or patients with reduced serum albumin levels have prolonged sedative effect

α-Hydroxymidazolam(active)

Cyt P450

Lorazepam (Ativan)• Less lipid solubility• Onset: 5-10min• T½ : 12- to 15hrs• Propylene glycol is

diluent used to facilitate drug solubility*

Inactive metabolite

Conjugation

*Crit Care Med 2002 Vol. 30, No. 1

In liver failure, lorazepam accumulates lesser than midazolam.

Lorazepam & Propylene glycol*• Propylene glycol : hyperosmolarity, acute tubular necrosis,

lactic acidosis, metabolic acidosis

• Toxicity is typically observed after* – prolonged ( >7 d) – high-dose (average of >18 mg/h)– continuous lorazepam infusion– renal and hepatic derangement– pregnancy– age less than 4 years– metronidazole

• An infusion of 2 mg/h of lorazepam will lead to 19.9 g of propylene glycol per day (> 11 times the WHO’s recommended daily intake for a 70 kg adult.)

• Monitor a daily serum osmolal gap (if 50 mg or 1 mg/kg )

Lorazepam vs. Midazolam

Swart EL, van Schijndel RJ, van Loenen AC, et al. Continuous infusion of lorazepam versus medazolam in patients in the intensive care unit: sedation with lorazepam is easier to manage and is more cost-effective. Crit Care Med 1999;27:1461–1465

Recommendations

• Midazolam or diazepam should be used for rapid sedation of acutely agitated patients. (Grade of recommendation C)

• Midazolam is recommended for short term use only, as it produces unpredictable awakening and time to extubation when infusions continue longer than 48–72 hours. (Grade of recommendation A)

• Lorazepam is recommended for the sedation of most patients via intermittent i.v. administration or continuous infusion. (Grade of recommendation B)

Advantages & Disadvantages

• Possess anticonvulsant effects• Benzodiazepine antagonist: flumazenil - is not recommended

after prolonged benzodiazepine therapy - risks of inducing withdrawal symptoms and increasing myocardial oxygen consumption. If you have to give, use lower dose of 0.15 mg*.

• Moderate hypotension: MAP ↓ by 10 to 25%• No analgesia• Paradoxical agitation : may be the result of drug-induced

amnesia or disorientation*Breheny FX: Reversal of midazolam sedation with flumazenil. Crit Care Med 1992; 20:736–739

PTSD & BZD• The amount of benzodiazepine administered during the

ICU stay correlates with the severity of PTSD symptoms (n=43)*.

*Girard TD, Shintani AK, Jackson JC, et al. Risk factors for post-traumatic stress disorder symptoms following critical illness requiring mechanical ventilation: a prospective cohort study. Crit Care 2007;11(1):R28.

Propofol

• Potentiation and direct activation of GABAA receptors. • Increase extracellular dopamine and may block

dopamine reuptake• Onset: 1-2min• T ½ : 1-3 hrs• Elimination by hepatic conjugation inactive metabolites• No changes in kinetic parameters have been reported in

patients with renal or hepatic dysfunction• Consensus recommendations that administration of

propofol be limited to 24 to 48 h*.*Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med 2002 Vol. 30, No. 1

Advantages

• Sedation + Amnesia – propofol did not produce amnesia as often as midazolam

in ICU but does in volunteers*• Reduces airway resistance• Neuroinhibitory effects: – decrease cerebral blood flow and metabolism– Reduce elevated intracranial pressure (ICP)

• Does not prolong the QT interval• In postoperative patients with sedation <36 h,

weaning is faster with propofolWeinbroum AA, Halpern P, Rudick V, et al: Midazolam versus propofol for long-term sedation in the ICU: A randomized prospective comparison. Intensive Care Med 1997; 23:1258–1263

Disadvantages• Suppresses sympathetic activity : – myocardial depression– peripheral vasodilation

• Decrease in MAP* (about 10mmHg): – relative risk 2.5 [95% CI, 1.3 to 4.5] 4.5]– number-needed-to treat :12

• Prolonged use (>48 hours) of high doses of propofol (66 μg/kg/min infusion) has been associated with lactic acidosis, bradycardia, and lipidemia in pediatric patients

*Walder B, Elia N, Henzi I, et al. A lack of evidence of superiority of propofol versus midazolam for sedation in mechanically ventilated critically ill patients: a qualitative and quantitative systematic review. Anesth Analg 2001; 92:975–983

Disadvantages

• Does not provide analgesia• Increased ‘serum triglycerides’: – relative risk 12.1 [95%CI, 2.9 to 49.7]; – number-needed-to-treat= 6

• 1.1 kcal/mL from fat• Pain upon peripheral venous injection• Pancreatitis (increased ‘serum lipase’)• Zinc depletion

Disadvantages• Vehicle may cause allergic reaction - Prepared in “egg” &

“soyabean oil”

• Requires a dedicated i.v. catheter when administered as a continuous infusion because of the potential for drug incompatibility and infection. Hence may contain preservatives

• May have “Sodium metabisulfite” (propofol, Gensia Sicor) which may produce allergic reactions in susceptible patients.

• May have “Edetic acid” (Diprivan, AstraZeneca) and the manufacturer recommends a drug holiday after more than seven days of infusion to minimize the risk of trace element abnormalities.

Green urine

• Urine may turn green from excretion of “phenol metabolites”

http://lifeinthefastlane.com/2009/11/unusual-urine-002/

Propofol Infusion Syndrome*

*Vasile B, Rasulo F, Candiani A, et al. The pathophysiology of propofol infusion syndrome: a simple name for a complex syndrome. Intensive Care Med 2003; 29:1417–1425

Propofol increases the activity of malonyl coenzyme A↓

inhibits carnitine palmitoyl transferase I (CPT I)↓

long-chain FFA cannot enter the mitochondrion.

Uncouples β-spiral oxidation & respiratory chain at complex II

↓medium- nor short-chain FFA,

cannot freely cross the mitochondrionmembranes, hence cannot be utilized.

Low energy production↓

lead to cardiac and peripheral muscle necrosis

From Vasile B, Rasulo F, Candiani A, et al. The pathophysiology of propofol infusion syndrome: a simple name for a complex syndrome. Intensive Care Med 2003; 29:1417–1425

PRISClinical features– rhabdomyolysis,

• metabolic acidosis• renal failure

– cardiac failure • Risks– Critical illness, head injury, SAH, Status epilepticus– Catecholamine infusion– Glucocorticoids – High dose propofol (≥5mg/Kg/Hr X >48hrs)

Fong JJ, Sylvia L, Ruthazer R, et al. Predictors of mortality in patients with suspectedpropofol infusion syndrome. Crit Care Med 2008;36:2281–7.

PRIS

Fong JJ, Sylvia L, Ruthazer R, et al. Predictors of mortality in patients with suspectedpropofol infusion syndrome. Crit Care Med 2008;36:2281–7

Midazolam vs. Propofol

Walder et al. A Lack of Evidence of Superiority of Propofol Versus Midazolam for Sedation in Mechanically Ventilated Critically Ill Patients: A Qualitative and Quantitative Systematic Review. Anesth Analg 2001;92:975–83

Recommendations

• Propofol is the preferred sedative when rapid awakening (e.g., for neurologic assessment or extubation) is important. (Grade of recommendation B)

• Triglyceride concentrations should be monitored after two days of propofol infusion, and total caloric intake from lipids should be included in the nutrition support prescription. (Grade of recommendation B)

Crit Care Med 2002 Vol. 30, No. 1

Dexmedetomidine

• Centrally acting α2 agonist– (like clonidine but 7 times

stronger)• first approved in 1999 by the FDA• Hepatic Cytochrome P450 and

glucuronidation (clearance may decrease by 50% in severe liver Dz)

• T½ : 6min then 2hrs• Highly protein bound

Dexmedetomidine

Analgesia

Amnesia

Anxiolysis

Sedation

Sympatholytic

• Arousability is maintained at deep levels of sedation, with good correlation between the level of sedation (Richmond agitation-sedation scale) and the bispectral (BIS) EEG

• Sedation induced by dexmedetomidine has the respiratory pattern and EEG changes commensurate with natural sleep – “activates endogenous non–rapid eye movement sleep–promoting pathways”

Mechanism of action• Reduction of central CNS activity (alpha 2a) – hypotension• Reduction of presynaptic NE release (alpha 2a & 2c) –

hypotension• Stimulation of Vascular Smooth Muscle cells (alpha 2b) – increase

BP • Stimulation of endothelium• Stimulation of central imidazoline receptors• Vagomimetic activity - bradycardia• Suppress shivering (alpha-2B in the hypothalamic

thermoregulatory center)• Attenuation of ischemia-reperfusion injury• Withdrawal of drugs: alcohol

SEDCOM studySafety and Efficacy of Dexmedetomidine Compared With Midazolam

Riker et al. Dexmedetomidine vs Midazolam for Sedation of Critically Ill Patients . JAMA. 2009;301(5):489-499

SEDCOM studySafety and Efficacy of Dexmedetomidine Compared With Midazolam

Riker et al. Dexmedetomidine vs Midazolam for Sedation of Critically Ill Patients JAMA. 2009;301(5):489-499

MENDS study

Pandharipande et al. Effect of dexmedetomidine versus lorazepam on outcome in patients with sepsis: an a priori-designed analysis of the MENDS randomized controlled trial. Critical Care 2010, 14:R38

Dexmedetomidine vs. lorazepam

Riker et al. Altering Intensive Care Sedation Paradigms to Improve Patient Outcomes. Crit Care Clin 25 (2009) 527–538

Advantages

• Reduction in the incidence of delirium• Reduction in time on mechanical ventilation • Reduction in tachycardia and hypertension• Opiate sparing

• Hypotension appears to be similar between benzodiazepines and dexmedetomidine.

• Little effect on respiratory drive/alertness but “may cause upper airway obstruction”

• Unlike clonidine, cessation of administration does not appear to be associated with rebound hypertension or agitation

Bradycardia

• Bradycardia (doses of ≤0.7 μg/kg/h, bradycardia occurred in less than 15% of patients)*

• Average response is 20% reduction in HR• Usually is not clinically significant unless patient has

co-existing cardiac disease• Baroreflexes are reset but intact – hence HTN will

reduce HR further• Observed asystole/sinus pauses are from vagal

stimmulus.• Treatment: atropine

Jones et al. High-dose dexmedetomidine for sedation in the intensive care unit: an evaluation of clinical efficacy and safety Ann Pharmacother. 2011 Jun;45(6):740-7.

Hemodynamic response

Venn RM et al. Br. J Anaeth. 2001;87: 684-690

at high-bolus IV doses (50–75 mg), a transient initial hypertensive response may be seen because of activation of peripheral vascular alpha-2 receptors before the centralsympatholytic effect on the vasomotor center

Respiratory response

Ebert et al. The Effects of Increasing Plasma Concentrations of Dexmedetomidine in Humans. Anesthesiology, V 93, No 2, Aug 2000

Disadvantages

• Hypotension is observed in 20- 30%*• Expensive $$$$• Tolerance to the drug has been seen and there are

concerns for a rebound effect when used beyond 24 to 48 h (in animals)

• Dystonia has been reported and may be due to its effect on acetylcholine release

• Deep sedation levels may be attained less easily• Amnesia < that with BZD

Jones et al. High-dose dexmedetomidine for sedation in the intensive care unit: an evaluation of clinical efficacy and safety Ann Pharmacother. 2011 Jun;45(6):740-7.

Ketamine

• NMDA receptor • Σ opiate receptor• provides analgesia and apparent anesthesia with

relative hemodynamic stability - ‘‘battlefield anesthetic’’• dissociative anesthesia: – unresponsive to nociceptive stimuli, but – keep their eyes open and – Maintain their reflexes : Blood pressure is maintained, and

spontaneous breathing and laryngeal reflexes are preserved.

Pharmacokinetics

• Onset: 1 min• T½ : 10-15min• Actions:– Positive inotropic action– Induces vasoconstriction– Inhibits endothelial nitric oxide production– Bronchodilator activity– Increase oral secretions

increases myocardial oxygen demand

Advantages

• Provides analgesia + amnestic + sedative effects• Preserves respiratory drive - "awake" intubation• Release of catecholamines –

– ↑ heart rate, – ↑contractility, – ↑MAP– ↑ cerebral blood flow – causes bronchodilation

• most hemodynamically stable of all of the available sedative induction agents

• beneficial effects on stunned myocardium• minimize the adverse sympathetic stimulation of laryngoscopy

Advantages

• low-dose (60–120 mg/kg/h) ketamine infusions in combination with opioids may not be associated with untoward effects and may improve outcomes in the critically ill.– morphine consumption decreased– does not inhibit bowel mobility– Ketamine antagonizes the NMDA receptor to block

central sensitization and hyperalgesia– Anti-inflammatory properties

Disadvantages

• Re-emergence phenomenon: experience disturbing dreams

• ↑ intracranial pressure• Increased oral secretions• Potential for exacerbating myocardial ischemia.• ? Risk for elevating ICP – “does not increase

cerebral blood flow or ICP if normal carbon dioxide levels are maintained”

• This slide is intentionally left blank…

Cost

Crit Care Clin 25 (2009) 431–449

How to implement ?

No sedation

• single centre and unblinded• 18% of the inter vention group did not tolerate the no sedation strategy• both groups received some sedation with morphine

Lancet 2010; 375: 475–80

Intermittent vs. Continuous sedation

• Intermittent therapy or provision of schedule daily interruption of sedation (DIS) is often employed to avoid excessive and prolonged effects

• Focusing first on providing analgesia rather than initially on anxiolysis may provide more effective and shorter duration of MV

Intermittent vs. Continuous sedation

Kollef MH, Levy NT, Ahrens TS, et al. The use of continuous i.v. sedation is associated with prolongation of mechanical ventilation. Chest 1998; 114:541–548

Combination of sedatives + analgesics is better

Richman PS, Baram D, Varela M, et al. Sedation during mechanical ventilation: a trial of benzodiazepine and opiate in combination. Crit Care Med 2006; 34:1395–1401

Daily interruption of sedative drug infusions decreases the duration of mechanical ventilation and the length of stay in the ICU

Kress JP, Pohlman AS, O’Connor MF, et al. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 2000; 342(20):1471–7.

Daily interruption of sedation & analgesia

• Allows better assessment of a patient’s sedative needs

• Reduces drug bioaccumulation

• Reduced incidence of posttraumatic stress disorder

• Reduced complications of critical illness

• More ventilator-free days and earlier ICU and hospital discharge, at the expense of a higher incidence of self-extubation

Paralytics

…. that’s for next time

Questions & Comments