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Sepsis
Sepsis
ผศ.นพ.ประสิทธ์ิ อุพาพรรณสาขาวชิาโรคติดเช้ือ ภาควชิาอายรุศาสตร์
คณะแพทยศาสตร์มหาวทิยาลยัศีรนครินทรวโิรฒ
Disclosure
• I have no actual or potential conflict of interest in relation to this presentation.
qSOFA
Outline
• Prevalence of sepsis
• New definitions of sepsis
• New Surviving Sepsis Campaign highlights
and application
• Enhancing recovery from sepsis
The Intensive Care Over Nations (ICON) study (10,069 ICU pts)
The Extended Prevalence of Infection (EPIC II) study (13,796 pts)
Infection; 30-51%
Respiratory origin 64 %
Gram negative ; 62 %Gram positive ; 47%
Fungi 19 %
Vincent JL, Lancet Respir Med 2014. and vincent JL, Rello J et,al JAMA. 2009 Dec 2;302(21):2323-9. doi: 10.1001/jama.2009.1754.
Longer ICU stays; Higher rate of infection and ICU mortality rate, more than twice
Sepsis 29.5 %
ICU mortality 25.8%Hospital mortality 35.3%
Surviving Sepsis Campaign (SSC)
To reduce mortality
EDGT, 2001
ProCESSARISE
ProMISE
SSC 2012
SSC 2016
Sepsis-1; 1991
Sepsis-2; 2001
Sepsis-3; 2016
SSC 2008
SSC 2004
CVP can not predict fluid responsiveness
early resuscitation associate with improve survival
positive fluid = bad outcome
delay ABTsignificant increase mortality
dynamic parameterfluid responsiveness starch is danger
Liberal transfusion does not improve outcome
To reduce mortality
Sepsis 2018:; Definitions and Guideline Changes, SURGICAL INFECTIONS, 2018.
Rivers et al. N Engl J Med 2001;345:1368-77.
EMANUEL RIVERS
28 day mortality Standard VS. EGDL
49.2% VS 33.3% (P = 0.01)
Early Goal-Directed Therapy
49.2%
33.3%
0
10
20
30
40
50
60
Standard Therapyn=133
EGDTn=130
P = 0.01*
28-day Mortality
Early Goal-Directed Therapy
Rivers, E. et al. N Engl J Med 2001;345:1368-1377
90-day mortality
Favour EGDTFavour
controlFavour EGDT
Favour
control
1o mortality outcome of each
study
Angus et al. Intensive Care Med, 2015.
Although EGDT is out… It means…
1. Keys to success of treating sepsis is “Time”
(early care).
2. EGDT, in fact, has already become standard of care
since 2001.
Anything new after EGDT?
Keys to Save Lives*
Early DxEarly Resuscitation
Early Treatment
Closed Monitoring
*Suviving Sepsis Campaign Guidelines 2016
Sepsis: Previous Definitions (1991, 2001)
SIRS
• 2 of the following; BT ≥ 38°C (100.4°F) or ≤ 36°C (96.8°F), HR ≥ 90 /min, RR ≥ 20 /min, WBC counts ≥ 12,000 /mm3 or ≤ 4,000 mm3
or > 10 % immature neutrophils
Sepsis• SIRS + presumed or confirm infectious process
Severe sepsis
• Sepsis with ≥ 1 sign of organ failure
Septicshock
• Sepsis-induced hypotension despite adequate fluid resuscitation, with perfusion abnormalities
Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992.
International Sepsis Definitions Conference. Crit Care Med 2003.
Sepsis: Previous Definitions (1991, 2001)
SIRS
• 2 of the following; BT ≥ 38°C (100.4°F) or ≤ 36°C (96.8°F), HR ≥ 90 /min, RR ≥ 20 /min, WBC counts ≥ 12,000 /mm3 or ≤ 4,000 mm3
or > 10 % immature neutrophils
Sepsis• SIRS + presumed or confirm infectious process
Severe sepsis
• Sepsis with ≥ 1 sign of organ failure
Septicshock
• Sepsis-induced hypotension despite adequate fluid resuscitation, with perfusion abnormalities
Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992.
International Sepsis Definitions Conference. Crit Care Med 2003.
SIRS, for mortality; - Sensitivity 64%, Specificity 65 % - Missed 1 in 8 pts with severe sepsis
Severe sepsis; unnecessary (Sepsis is already severe)
The Host Response to an Infection
Vincent J-L (2016) The Clinical Challenge of Sepsis Identification and Monitoring. PLoS Med 13(5): e1002022.
Serum lactate and Hospital mortality
JAMA. 2016;315(8):775-787
Serum lactate 2 to 10 mmol/L mortality 1.4 to 3.03
Sepsis-3: New Definitions (2016)
Sepsis
• Life-threatening organ dysfunction caused by a dysregulated host response to infection
• Hospital mortality > 10 %
Septic shock
(subset of Sepsis)
• Sepsis with persistent hypotension:
• Requiring vasopressiors to maintain MAP ≥ 65 mmHg
• And having a serum lactate level > 2 mmol/L (18 mg/dL) despite adequate fluid resuscitation
• Hospital mortality > 40 %
The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016.
# Sequential (Sepsis-Related) Organ Failure Assessment (Sofa) Score
INFECTION + 2 SOFA#
The Mainstay of Sepsis Management
Early identification
of patients with sepsis
Early antibiotic treatment
Surviving Sepsis Campaign 2016
Sequential (Sepsis-Related) Organ Failure Assessment (Sofa) Score
Sepsis 2018:; Definitions and Guideline Changes, SURGICAL INFECTIONS, 2018
ChallengingComplicated score
Not calculated routinely in ICUs at the bedside
The Predictive Validity for in-Hospital Mortality
Test AUROCcurve (ICU)
AUROCcurve
(non-ICU)
Sensitivityfor mortality
(non-ICU)
Specificityfor mortality
(non-ICU)
SIRS ≥ 2 0.64 0.76 64% 65%
SOFA ≥ 2 0.74 0.79 68% 67%
qSOFA ≥ 2 0.66 0.81 55% 84%
AUROC= area under the receiver operating curve; SIRS = systemic inflammatory response syndrome;
SOFA = Sequential Organ Failure Assessment score; qSOFA = quick Sequential Organ Failure Assessment score.
Assessment of clinical criteria for sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis- 3). JAMA 2016.
Predictive validity for mortality ≠ To reduce mortality
Patient with Suspected Infection
qSOFA ≥ 2
Assess for Evidence of Organ Dysfunction
SOFA ≥ 2
Sepsis
Despite Adequate Fluid Resuscitation:
1. Vasopressors Required to Maintain MAP ≥ 65 mmHg
AND
2. Serum Lactate Level > 2 mmol/L ?
Septic shock Singer M, et al. JAMA 2016;315:801-10.
yes
yes
yes
NOSepsis Still Suspected?
NO
yes
NO
NO
Monitor Clinical
Condition; Re-evaluateFor Possible
Sepsis if Clinically Indicated
Singer M, et al. JAMA. 2016;315:801-10.
Surviving Sepsis Campaign BundlesTopic SSC 2012 SSC 2016
To be completed within 3 hours Compliance 19 % -
Measure lactate level yes Yes
Obtain blood cultures prior to start ATB yes yes
Administer broad spectrum antibiotics yes yes
Administer 30 mL/kg crystalloid for hypotension or lactate ≥ 4 mmol/L
yes yes
To be completed within 6 hours Compliance 36 % -
Apply vasopressors (hypotension, not response to initial fluid, to MAP ≥ 65 mmHg.
yes yes
Persistent hypotension -Measure central venous pressure (CVP)*-Measure central venous oxygen saturation (Scvo2)*
Persistent hypotension - Re-assess volume status and tissue perfusion(Repeat focused exam Or two of the following: CVP, ScvO2, bedside cardio U/S, dynamic assessment of fluid; passive leg raise or fluid challenge.)
Re-measure lactate if initial lactate elevate yes yes
↓odds of dying 40%
The IMPreSS study. Intensive Care Med 2015;41:1620–1628.
↓odds of dying 36%
2016 Descriptor
Strength Strong (32 recommendations) Weak (39 recommendations)
“We recommend”
“We suggest”
Quality High, Moderate, Low, Very low
Ungraded strong recommendation
Best practice statement(18 recommendations)
SSC 2016, 93 Recommendations
No recommendation provided for 4 PICO# questions
Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016.
#Population, intervention, comprison, and outcomes
The Society of Critical Care Medicine (SCCM) and The European Society of Intensive Care Medicine
IDSA ????
Rhodes, Andrew MB BS, Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2016.
After initial bolus, ‘repeat focused exam after initial fluid resuscitation including vital signs, cardiopulmonary, capillary refill, pulse, and skin findings’
or 2 of the following :CVP, ScvO2, bedside U/S or dynamic assessment of fluid
responsiveness (straight leg raise, stroke volume variation and pulse pressure variation).
SSC RECOMMENDATION HIGHLIGHTS
Against using
hydroxyethyl
starches(HESs)
Further fluid resuscitation should be discontinued when there is no longer a physiological response.
Balanced Crystalloids versus Saline
Normal blood
plasma
0.9%Saline(NSS)
Balanced salt solutions
Ringer’s lactate Acetar Plasmalyte
Osmolarity# 295(280-310)
308 273 294 294
Sodium* 140 154 130 130 140
Chloride* 100 154 109 108 98
Potassium* 5 - 4 4 5
Calcium* 4.4 - 3 2.7 0
Buffer* Bicarb 24 28 (Lactate) 28 (Acetate) 0
Others* Mg 2 pH 5.5 pH 6.5 Mg 3, Gluconate 23
ราคา/ลติร (บาท) - 37 44 49
* หน่วย mmol/L #mOsmol/kgวนัจกัร พงษสิ์ทธิศกัด์ิ, ชนิดสารน ้าทางหลอดเลือดด าในผูป่้วยวิกฤติเพื่อลดไตวายเฉียบพลนั,Vajira Medical Journal, Vol. 60 No. 4 October - December 2016.
Application of Fluid Resuscitation in Adult Septic Shock
Intensive Care Med (2017) 43:299–303
Initial Resuscitation
SSC RECOMMENDATION HIGHLIGHTS
Rhodes, Andrew MB BS, Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2016.
Bradycardia ,Low risk tachyarrhythymias
- ACTH stimulation and random cortisol tests; not recommended.
- Steroids should be continued until vasopressors are discontinued,… there is still no clear consensus on the optimal initiation timing andtotal duration of steroid treatment.
The first-line agent
Vasopressor Use for Adult Septic Shock(with guidance for steroid administration)
Intensive Care Med (2017) 43:299–303
Steroids
Use dobutamine (2.5-10 mcg/kg/min)- After resuscitation with fluid+/-vasopressor
and pt. achieve MAP > 65 mmHg but still have evidence of tissue hypoperfusion.
(weak recommend.., low quality of evidence)
Marik Protocol ??? ǃǃǃ
• Vitamin C 1.5 g IV q6h
• Thiamine 200 mg IV q12h
• Hydrocortisone 50 mg IV q6h
Paul Marik, MBBChChief of Pulmonary and Critical Care Medicine
For 4 days, or until patient is discharged from the ICU
• Potent antioxidant/free radical scavenger
• Restores other cellular antioxidants
• Increases endothelial and epithelial tight junctions
• Preserves endothelial function and microcirculatory flow
Vitamin C
CHEST 2017; 151(6):1229-1238
Vitamin C
• Levels are very low or undetectable in critical illness
• Intestinal receptor is saturable, so can not restore levels with oral
• Vit C alone: no help
Steroids
• Vitamin C needs help getting into cells
• Steroids alone: no help
Thiamine
• Shunts metabolism of vitamin C away from oxalate (potential for renal crystallization)
Retrospective before-after clinical study
Marik Protocol
Pt,Severe sepsis or septic shock + procalcitonin ≥ 2 ng/ml)7 months, 47 patients in each group
No differences between the two groups
Study group mortality: 8.5%
(no death or developed progressive organ failure)
Control group mortality: 40.4%
Steroids + Vitamin C: Restored function CHEST 2017; 151(6):1229-1238
- Can only be corrected with IV vitamin C at a dose > 3 g/d. Dose 6 g/d (no S/E or complications)- Doses as high as 100 to 150 g (safe in burn and malignant pts.)
SSC RECOMMENDATION HIGHLIGHTS
Rhodes, Andrew MB BS, Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2016.
Aim, the most likely bacterial pathogen(s)
- Recommend de-escalation with discontinuation of combination therapy within the first few days and daily assessment for de-escalation of antimicrobial therapy.
-Suggest, ATB treatment duration of 7 to 10 days is adequate for most serious infections associated with sepsis and septic shock. (Except, slow clinical response, undrainable foci of infection, bacteremia with S. aureus, or neutropenia pts.)
(2 , different classes)
Antimicrobial Therapy
• Administration of IV antimicrobials as soon as possible after recognition and within one hour for both sepsis and septic shock.
• Multiple drug-resistant organisms (MDROs)
Delayed appropriate of antibiotics• Wait for definite diagnosis and serum Cr
Inadequate empirical therapy • No loading dose and inappropriate ATB
Cheston B. Cunha SMO. What strategies can be used to optimize antibiotic use in the critically ill? Evidence-Based Practice of Critical care2016.
surviving sepsis campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Critical Care Medicine 2016.
Antibiotic: Relevant PK Characteristics in the ICU
Roberts JA, Lipman J. Pharmacokinetic issues for antibiotics in the critically ill patient. Critical care medicine 2009;37:840-51; quiz 59.
• Beta-lactams (Carbapenems, Cephalosporins, Penicillins)• Aminoglycosides• Glycopeptides• Polymyxin B• Fosfomycin
Prolonged or continuous infusion
Loading dose
Stability of Antibiotics
Antibiotic(Solvent; in sterile water)
Stability at 25oC (room temperature) (Hours)
Imipenem 3.3
Meropenem 5.15
Piperacillin/tazobactam > 72
Ceftazidime 24
Vancomycin > 696
Common prolonged-infusion dosing strategies in the literature#
Meropenem 1 g q 8 hr (normal) 1 g q 8 hr (3-hr infusion)
Pip/tazo 3.375-4.5 g q 6 hr 3.375 g q 8 hr (4-hr infusion)
Cefepime 2 g q 8 hr 2 g q 8 hr (3-4 hr infusion)
Critical Care 2009, 13:214
Julius Bolus, Prolonged-Infusion Dosing of Beta-Lactam Antibiotics, US Pharm. 2015;40(4):HS19-23.
#All regimen; loading dose in 30 min.
Antibiotic: Relevant PK Characteristics in the ICU
Roberts JA, Lipman J. Pharmacokinetic issues for antibiotics in the critically ill patient. Critical care medicine 2009;37:840-51; quiz 59.
• Metronidazole• Fluoroquinolones• Clindamycin• Macrolides• Tetracyclines
Maximize peak concentration
Maximize drug dosage consistent with avoidance of toxicity
De-escalation
Duration; ATB
Duration; ATB
PCT in different Infections
Philipp Schuetz, BMC Medicine,2011.
++ good evidence; favor of PCT +++ strong evidence; favor of PCT
Type of infection
Study designs
PCT cut-off (ug/L)
Benefit ,PCT?
Main conclusions
Severe sepsis/Shock
RCT 0.25-0.5; 80-90%↓ +++
PCT reduces ATB exposure in the ICU
without adverse outcomes
Urinary tract infections
observational 0.25 + PCT correlates with severity of UTI
VAP RCT 0.1 - 0.25 ++ PCT reduces ATB exposure without adverse outcomes
PCT Algorithm (Critically Ill Patients in the ICU)Stopping ATB
Philipp Schuetz, BMC Medicine 2011.PRORATA trial group: Use of procalcitonin to reduce patients' exposure to antibiotics in intensive
care units (PRORATA trial): a multicentre randomised controlled trial. Lancet. 2010, 375: 463-474.
Strong recommendations
30 cc/kg crystalloid
(fluid of choice)
first 3 hr
Against HES
Target MAP 65 septic shock
requiring vasopressors
NE as 1st-line vasopressor
ATB within 1 hEmpiric broad antimicrobial
(cover likely pathogens)
RBC transfusion, Hb < 7 g/dL
Target bl. glu< 180 mg/dL
Stress ulcer prophylaxis
(only, risk to GI bleeding)
Early enteralnutrition, against parenteral, first 7 d
From the SSC 2016
Sepsis 2018:; Definitions and Guideline Changes, SURGICAL INFECTIONS, 2018
Unless, MI, severe hypoxemia, acute
hemorrhage
Strong recommendations
Palliative care (Incorporate goals of care) Against
pulmonary artery catheter
sepsis-induced ARDS
Against Ɓ-2 agonist
sepsis-induced ARDS without bronchospasm
Against HFOV
sepsis-induced ARDS
Against omega-3 fatty
acids
as an immune supplement
Pharmacologic VTE
prophylaxis
Elevate head of bed 30-45o
in mechanically ventilated pt
Prone position,
sepsis-induced ARDS with
PaO2/FiO2 < 150
Conservative fluid in ARDS,
pt without hypoperfusion
Target TV 6 cc/kg for ARDS,
plateau pressure upper limit 30
From the SSC 2016
Sepsis 2018:; Definitions and Guideline Changes, SURGICAL INFECTIONS, 2018Heparin or LMWH
Treating Sepsis: The Latest Evidence
Sepsis: pathophysiology and clinical management BMJ 2016.
Outline
• Prevalence of sepsis
• New definitions of sepsis
• New Surviving Sepsis Campaign highlights
and application
• Enhancing recovery from sepsis
Recovery of Sepsis or Septic Shock
Hallie C. Prescott, Enhancing Recovery From Sepsis A Review, JAMA. 2018;319(1):62-75.
19 million, develop sepsis
14 million survive to hospital discharge
50 % of recover1/3 die during the following year
1/6 severe persistent impairments
• 3-fold, prevalence of moderate-severe cognitive impairment (from 6.1% before hospitalization to 16.7% after hospitalization)
• High prevalence of mental health problems
40% Re-hospitalized within 90 days of discharge
Often for conditions that are potentially treatable in the outpatient setting
Enhancing Recovery From Sepsis
Management should focus on
(1) identifying new physical, mental, and cognitive problems and referring for appropriate treatment
(2) reviewing and adjusting long-term medications
(3) evaluating for treatable conditions that commonly result in hospitalization, such as infection, heart failure, renal failure, and aspiration.
Hallie C. Prescott, Enhancing Recovery From Sepsis A Review, JAMA. 2018;319(1):62-75.
Reasons for deterioration of health after sepsis, multifactorialprogression of preexisting chronic conditions, residual organ damage, and impaired immune function.
For patients with poor or declining health after sepsis, it may be appropriate to
focus on palliation of symptoms.
Hallie C. Prescott, Enhancing Recovery From Sepsis A Review, JAMA. 2018;319(1):62-75.
SETTING GOALS OF CARE, within 72 h of ICU admission
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