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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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