Sepsis - medicine.uci.edu · host’s systemic inflammatory response syndrome (SIRS) to infection....

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Sepsis Fundamentals of Acute Care Rohit H. Godbole, MD Pulmonary - Critical Care Fellow UC Irvine Ignaz Semmelweis (1818-1865) Sepsis History. http://www.sepsis-gesellschaft.de/DSG/Englisch/Disease+pattern+of+Sepsis/Sepsis+History

Transcript of Sepsis - medicine.uci.edu · host’s systemic inflammatory response syndrome (SIRS) to infection....

Sepsis

Fundamentals of Acute Care

Rohit H. Godbole, MD Pulmonary - Critical Care Fellow UC Irvine

Ignaz Semmelweis (1818-1865)

Sepsis History. http://www.sepsis-gesellschaft.de/DSG/Englisch/Disease+pattern+of+Sepsis/Sepsis+History

Objectives

● Understand the definition of sepsis

● Know the presenting signs and symptoms of a septic patient

● Understand the basics of sepsis management including IV fluid support, ino-

pressors, early antibiotics

Importance of Sepsis

● Sepsis syndrome was first described in Ancient Egypt and defined as sepsis by

the Greeks (from the Greek word sipsi for “make rotten”)

● Each year, 31 million people worldwide are treated for sepsis out of which 5.3

million people end up dying

● In the US, it is the most expensive medical condition currently treated with a

cost estimate of $23.7 billion

● 80% of deaths may be prevented with early detection and treatment of sepsis

Sepsis History. http://www.sepsis-gesellschaft.de/DSG/Englisch/Disease+pattern+of+Sepsis/Sepsis+History Fleischman C, Scherag A, Adhikari NK, Hartog CS, Tsaganos T, et al. (2016) Assessment of Global Incidence and Mortality of Hospital-treated Sepsis. Current Estimates and Limitations. Am J Respir Crit Care Med 193(3): 259-272. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, et al. (2016). The Third International Consensus Definitions for Sepsis and Septic Shock (sepsis-3). JAMA 315(8): 801-810. Torio CM, Andrews RM (2015) National Inpatient Hospital Costs: The Most Expensive Conditions in Payer: HCUP Stateistical Brief#160. Healthcare Cost and Utilization Project (HCUP) Statistical Briefs [Internet]. Rockville (MD): Agency for Healthcare Research and Quality. Sepsis Alliance. (2016) Sepsis 2016 fact sheet. http://www.sepsisalliance.org/downloads/2016_sepsis_facts_media. pdf

Difficulty Understanding Sepsis

● Syndrome is not well understood

● No specific gold standard diagnostic test

● Definitions and diagnostic criteria continue to evolve

● No universally adopted treatment plan

● Problems with reporting requirements (eg. Core Measures)

● Complicated incentives/disincentives to infections in patients

Surviving Sepsis Campaign

● 1992 - ACCP/SCCM conference proposes definitions for sepsis, severe sepsis, SIRS

● 2001 - expansion of diagnostic criteria for previously defined terms; no change to

prior definition

● 2015 - Sepsis definition changed; SOFA, qSOFA definition proposal

● 2015 - Core Measures implemented by CMS

● 2016 - International Guidelines for Management of Sepsis and Septic Shock

● 2017 - IDSA position paper on not endorsing Surviving Sepsis Guidelines

Sepsis Definition Timeline Hippocrates (460 -

370 BC)

Hugo Schottmüller

(1914)

Sepsis 1 (1992) Sepsis 2 (2001) Sepsis 3 (2016)

Internal rotting or decay

(sipsi in Greek)

Sepsis identified in late

stages of sepsis

“Sepsis is present if a

focus has developed

from which pathogenic

bacteria, constantly or

periodically, invade the

blood stream in such a

way that this causes

subjective and objective

symptoms”

Sepsis results from a

host’s systemic

inflammatory response

syndrome (SIRS) to

infection. Severe sepsis

is sepsis associated

with organ dysfunction,

hypoperfusion, or

hypotension. Septic

shock is sepsis-induced

hypotension persisting

despite adequate fluid

resuscitation.

Keeping definition of

Sepsis 1 but knowing

limitations

Creating diagnostic

criteria

Acknowledging different

stages of sepsis

Sepsis is defined as a

life-threatening organ

dysfunction caused by

a dysregulated host

response to infection.

Septic shock is a

subset of sepsis in

which particularly

profound circulatory,

cellular, and metabolic

abnormalities are

associated with a

greater risk of mortality

than with sepsis alone.

Rittirsch D, Flierl MA, Ward PA. (2008) Harmful Molecular Mechanisms in Sepsis. Nat Rev Immunol 8(10): 776-787. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, et al. (1992) Definitions for Sepsis and Organ Failure and Guidelines for the Use of Innovative Therapies in Sepsis. Chest 101(6):1644-1655.

Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, et al. (2016). The Third International Consensus Definitions for Sepsis and Septic Shock (sepsis-3). JAMA 315(8): 801-810.

Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, et al. (2008) Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2008. Intensive Care Med 34(1): 17-60.

By 2009, sepsis awareness

campaigns helped achieve a 25%

reduction in mortality!

Core Measures

On October 1st, 2015 Centers

for Medicare and Medicaid

Services required a minimum

set of actions at specific time

interval.

The CMS definitions, the

mandates, and withholding of

payment to hospitals became

problematic.

Defining Sepsis (Sepsis-3)

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host

response to infection.

Septic shock is a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Issues with the publication:

● Only US and European patient populations, does not take into account poor resource countries

● Did not include opinions of ER physicians

Management: Goals and Objectives

● Early Goal Directed Therapy (EGDT) ○ Does it help?

● IV fluids ○ How much volume to give

○ What type of fluid to give

● Ino-pressors ○ Inotropes vs. Vasopressors

● Antibiotics ○ Broad-spectrum

○ Can use procalcitonin to inform antibiotic de-escalation

● Mechanical Ventilation ○ Consider early initiation

Management: EGDT

● Early goal directed therapy

In 2001, Rivers et al published their findings of using protocol-based

management in the care of patients with severe sepsis and septic shock

Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368-77

Management: EGDT

● Early goal

directed

therapy

Management: EGDT

● Early Goal Directed Therapy

Three large trials (ProCESS, ARISE, and ProMISe) were

conducted and none of them showed a difference in

mortality between the EGDT arm and Standard care arms

of their studies… but this was attributed to improved

overall care of sepsis even in control arm from improved

sepsis education

ProCESS Investigators, Yealy DM, Kellum JA, et al. A randomized trial of protocol-based care for

early septic shock. N Engl J Med 2014; 370:1683.

ARISE Investigators, ANZICS Clinical Trials Group, Peake SL, et al. Goal-directed resuscitation for

patients with early septic shock. N Engl J Med 2014; 371:1496.

Mouncey PR, Osborn TM, Power GS, et al. Trial of early, goal-directed resuscitation for septic

shock. N Engl J Med 2015; 372:1301.

Management: EGDT

● What is early goal directed

therapy? ○ CVP 8 - 12 mmHg

○ MAP ≥ 65 mmg

○ ScVO2 ≥ 70%

○ UOP 0.5 mL/kg/min

Management: EGDT ● 3.4.1 Early Goal Directed Therapy (EGDT) (See also protocol flowchart in Appendix A)

○ Supplemental O2, Mechanical Ventilation, Target SpO2 ≥ 95%

○ Insert CVC for continuous ScvO2 reading (IJ, subclavian okay, NOT femoral)

○ Start IVF boluses in 500 cc increments every 30 minutes until CVP is 8-12 mmHg

○ Insert arterial line

○ If MAP < 65, initiate vasopressors to titrate MAP between 65-90 mmHg

○ If MAP > 90, consider afterload reduction

○ If ScvO2 is < 70% and Hct is < 30%, transfuse PRBCs until Hct is > 30%

○ If ScvO2 < 70%, Hct is > 30%, inotrope such as dobutamine can be started (initial dosing 2.5

ug/kg/min, increasing until ScvO2 > 70%, HR > 120, arrythmias develop or max dose of 20

ug/kg/min is attained)

○ At 6 hours, subject returns to standard care

ProCESS Investigators, Yealy DM, Kellum JA, et al. A

randomized trial of protocol-based care for early septic

shock. N Engl J Med 2014; 370:1683.

Management: Goals and Objectives

● Early Goal Directed Therapy (EGDT) ○ Does it help?

● IV fluids ○ How much volume to give

○ What type of fluid to give

● Ino-pressors ○ Inotropes vs. Vasopressors

● Antibiotics ○ Broad-spectrum

○ Can use procalcitonin to inform antibiotic de-escalation

● Mechanical Ventilation ○ Consider early initiation

Management: IV Fluids

● Where did we get 30 mL/kg? ○ Rivers et al: 4981 +/- 2984 mL

○ ProCESS: 2800 mL

○ ARISE: 2515 +/- 1244 mL (34.9 mL/kg)

○ ProMISe: 2000 mL (median)

Rough math works out to about 30 mL/kg!

* All values are for EGDT group at initial resuscitation 0-6 hours

ProCESS Investigators, Yealy DM, Kellum JA, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med 2014; 370:1683.

ARISE Investigators, ANZICS Clinical Trials Group, Peake SL, et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med 2014; 371:1496.

Mouncey PR, Osborn TM, Power GS, et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med 2015; 372:1301.

Management: IV Fluids

● Which type of fluid to use? ○ Balanced crystalloids

ORIGINAL ARTICLE

Balanced Crystalloids versus Saline in Critically Ill Adults

Matthew W. Semler, M.D., Wesley H. Self, M.D., M.P.H., Jonathan P. Wanderer, M.D., Jesse M. Ehrenfeld,

M.D., M.P.H., Li Wang, M.S., Daniel W. Byrne, M.S., Joanna L Stollings, Pharm.D., Avinash B. Kumar,

M.D., Christopher G. Hughes, M.D., Antonio Hernandez, M.D., Oscar D. Guillamondegui, M.D., M.P.H.,

Addison K. May, M.D.,

Management: IV Fluids

● Which type of fluid to use? ○ Balanced crystalloids

● 7942 patients in the balanced-crystalloids group vs. 7860 patients in saline group:

○ 1139 (14.3%) had a major adverse kidney event vs. 1211 of 7860 patients (15.4%) in the saline group

(marginal odds ratio, 0.91; 95% confidence interval [CI], 0.84 to 0.99; conditional odds ratio, 0.90; 95%

CI, 0.82 to 0.99; P=0.04).

○ Among patients with sepsis, 30-day in-hospital mortality was 25.2% with balanced crystalloids and

29.4% with saline (adjusted odds ratio, 0.80; 95% CI, 0.67 to 0.97; P=0.02)

Semler M et al. Balanced crystalloids versus saline in critically ill adults. N Engl J Med 2018; 378:829-839

Management: Goals and Objectives

● Early Goal Directed Therapy (EGDT) ○ Does it help?

● IV fluids ○ How much volume to give

○ What type of fluid to give

● Ino-pressors ○ Inotropes vs. Vasopressors

● Antibiotics ○ Broad-spectrum

○ Can use procalcitonin to inform antibiotic de-escalation

● Mechanical Ventilation ○ Consider early initiation

Ino-Pressors ● Inotropic action: Beta receptors

● Vasopressor action: Alpha receptors

Drug Alpha-1 Beta-1 Beta-2 Dopaminergic

Predominant Clinical Effects

(Neosynephrine) Phenylephrine *** 0 0 0 SVR ↑ ↑, CO ↔/↑

(Levophed) Norepinephrine *** ** 0 0 SVR ↑ ↑, CO ↔/↑

(Adrenalin) Epinephrine *** *** ** 0

CO ↑ ↑, SVR ↓ (low dose) SVR/↑ (higher dose)

(Intropin) Dopamine

(mcg/kg/min)

0.5 to 2 0 * 0 ** CO 5 to 10 * ** 0 ** CO ↑, SVR ↑

10 to 20 ** ** 0 ** SVR ↑ ↑

Management: Ino-Pressors

● VASST Trial

Russell JA, Walley KR, Singer J, Gordon AC, Hebert PC, Cooper J et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008; 358:877-887.

Management: Ino-Pressors

● VASST Trial

There was no difference in primary end-

points of 28-day and 90-day mortality in the

NE vs. V groups, but there were no more

complications either

Management: Ino-Pressors

● VANISH Trial

Management: Ino-Pressors

● VANISH Trial

There was no

difference in primary

end-point (kidney

failure-free days for

first 28 days), but

there was a reduction

seen in the incidence

of RRT in vasopressin

groups

(i.e. using

vasopressin early

may avoid HD)

Management: Goals and Objectives

● Early Goal Directed Therapy (EGDT) ○ Does it help?

● IV fluids ○ How much volume to give

○ What type of fluid to give

● Ino-pressors ○ Inotropes vs. Vasopressors

● Antibiotics ○ Broad-spectrum

○ Can use procalcitonin to inform antibiotic de-escalation

● Mechanical Ventilation ○ Consider early initiation

Antibiotics ● Broad spectrum antibiotic with coverage for the organism that most likely is causing

the suspected sepsis syndrome

● When choosing, consider the following: ○ Patient’s history

○ Comorbidities

○ Immune status

○ Risk of MDRO (eg. nursing homes)

○ Foreign objects (lines, ports, prosthetic materials)

○ Local hospital antibiogram

● Common organisms: E. coli, S. aureus, Klebsiella, S. pneumoniae

Antibiotics ● Common regimen depends on likely organism:

● MRSA

● Vancomycin

● Daptomycin (non-pulmonary)

● Linezolid

● Pseudomonas

● Cephalosporin: Ceftazidime, Cefepime

● Carbapenem: Imipenem, Meropenem

● Beta-Lactam/Beta-Lactamase Inhibitor: Piperacillin-Tazobactam

● Aminoglycoside: Amikacin, Tobramycin, Gentamicin

● Atypicals: Azithromycin

● Anaerobes: Metronidazole, Carbapenems, Piperacillin-Tazobactam

Management: Goals and Objectives

● Early Goal Directed Therapy (EGDT) ○ Does it help?

● IV fluids ○ How much volume to give

○ What type of fluid to give

● Ino-pressors ○ Inotropes vs. Vasopressors

● Antibiotics ○ Broad-spectrum

○ Can use procalcitonin to inform antibiotic de-escalation

● Mechanical Ventilation ○ Consider early initiation

Mechanical Ventilation

● Consider in patients with increasing pressor requirements, worsening metabolic

acidosis and compensatory tachypnea resulting in increased work of breathing

● Consequences of not intubating early: ○ Aspiration

○ Myocardial infarction

○ Respiratory muscle fatigue

○ Higher risk intubation when patient is much more ill

When on rounds...

Previous SIRS criteria (1992):

● Two or more of: Temperature >38°C or <36°C

● Heart rate >90/min

● Respiratory rate >20/min or PaCO2 <32 mm Hg (4.3 kPa)

● White blood cell count >12 000/mm3 or <4000/mm3 or >10% immature bands

qSOFA

● Respiratory Rate ≥ 22

● Altered mentation

● Systolic blood pressure ≤ 100 mmHg

qSOFA is not meant for diagnosis or as a

definition of sepsis… it is a mortality predictor,

but can also be used as a trigger to initiate

further work-up

What to do?

● ASSESS FIRST ○ See the patient

○ Obtain vital signs

○ Draw labs

■ Blood cultures

■ Lactate

■ Procalcitonin

○ Does the patient need other work-up?

■ Eg. imaging

● DISCUSS ○ Call for help

■ Attending, Pulm-CC fellow, other

consultants

■ Upgrade level of care

Case 4

A 47-year-old woman is evaluated in the emergency department for progressive lethargy and confusion. Her husband reports a 3-day history of subjective fever and chills, and the development of right-sided lower back pain during the last 24 hours.

She collapsed without loss of consciousness 4 hours ago after rising from a chair. She has noted blood in the urine for about 6 days, was recently diagnosed with a urinary tract infection, and began treatment with empiric oral cephalexin.

She has a history of kidney stones but no chronic kidney disease, hypertension, or other chronic medical conditions.

Case 4 Urine leukocyte count 103,000/µL (103 x 109/L)

Urine leukocyte esterase positive

Urine nitrites positive

Multiple bacteria are observed on microscopic examination of the urine.

Leukocyte count 23,100/µL (23.1 x 109/L)

Neutrophil count 74% with 15% bands

Blood hemoglobin 8.1 g/dL (81 g/L)

Platelet count 115,000/µL (115 x 109/L)

Lactate 4.9 mEq/L (4.9 mmol/L)

Troponin negative

Central venous pressure 10 mm Hg

Case 4

Based on the laboratory studies, the patient is started on two empiric antibiotics intravenously.

She is given 2L (approximately 30 ml/kg) normal saline during the first 3 hours. Her blood pressure after initial intravenous fluid bolus is 70/35 mm Hg and repeat plasma lactate is 4.7 mEq/L (4.7 mmol/L).

A CT scan of the abdomen is ordered but will not be performed for 60 minutes.

Case 4

According to the referenced guidelines, which of the following is the most appropriate management?

A. Crystalloid infusion and titration for target central venous pressure of 14 mm Hg

B. Dopamine infusion and titration to mean arterial pressure greater than 65 mm Hg

C. Norepinephrine infusion and titration to mean arterial pressure greater than 65 mmHg

D. Transfusion with 2 units of packed red blood cells

Summary

● Understand the definition of sepsis

● Know the presenting signs and symptoms of a septic patient

● Understand the basics of sepsis management including IV fluids, ino-pressors, early

antibiotics, mechanical ventilation

References ● Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, et al. (2016). The Third International Consensus Definitions for Sepsis and Septic Shock (sepsis-3).

JAMA 315(8): 801-810.

● Gary T, Damien M, Yenamandra A. The evolving definition of sepsis. arXiv:1609.07214.

● Fleischman C, Scherag A, Adhikari NK, Hartog CS, Tsaganos T, et al. (2016) Assessment of Global Incidence and Mortality of Hospital-treated Sepsis. Current Estimates and

Limitations. Am J Respir Crit Care Med 193(3): 259-272

● Torio CM, Andrews RM (2015) National Inpatient Hospital Costs: The Most Expensive Conditions in Payer: HCUP Stateistical Brief#160. Healthcare Cost and Utilization

Project (HCUP) Statistical Briefs [Internet]. Rockville (MD): Agency for Healthcare Research and Quality.

● Sepsis Alliance. (2016) Sepsis 2016 fact sheet. http://www.sepsisalliance.org/downloads/2016_sepsis_facts_media. Pdf.

● Rittirsch D, Flierl MA, Ward PA. (2008) Harmful Molecular Mechanisms in Sepsis. Nat Rev Immunol 8(10): 776-787.

● Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, et al. (1992) Definitions for Sepsis and Organ Failure and Guidelines for the Use of Innovative Therapies in Sepsis. Chest

101(6):1644-1655.

● Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, et al. (2008) Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic

Shock: 2008. Intensive Care Med 34(1): 17-60.

● Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368-77

● ProCESS Investigators, Yealy DM, Kellum JA, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med 2014; 370:1683.

● ARISE Investigators, ANZICS Clinical Trials Group, Peake SL, et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med 2014;

371:1496.

● Semler M et al. Balanced crystalloids versus saline in critically ill adults. N Engl J Med 2018; 378:829-839

● Russell JA et al. Vasopressin versus norepinephrine in patients with septic shock. N Engl J Med 2008; 358:877-887.

● Gordon AC et al. Effect of early vasopressin versus norepinephrine in patients with septic shock. JAMA. 2016;316(5):509-518.