CLINICAL EVIDENCE GUIDE

SEPSIS AND END-TIDAL CO2 IN THE EMERGENCY DEPARTMENT

US emergency departments (ED) treat approximately 571,000 patients annually for suspected severe sepsis.1 Early recognition and timely intervention is key to improving outcomes in these patients.2 End-tidal CO2 (etCO2) measurements via Microstream™ capnography provide clinicians with a rapid, non-invasive indicator of sepsis-induced acidosis.3

INTRODUCTION

TABLE OF CONTENTS

HUNTER 2016

HUNTER 2013

McGILLICUDDY 2009

REFERENCES

2

TABLE OF CONTENTS

3 INTRODUCTION Introduction to the relationship between sepsis and etCO2 in the emergency department

5 HUNTER 2016Review of: Hunter CL, Silvestri S, Ralls G, Stone A, Walker A, Papa L. A prehospital screening tool utilizing end-tidal carbon dioxide predicts sepsis and severe sepsis. The American journal of emergency medicine. 2016;34(5):813-819.

7 HUNTER 2013Review of: Hunter CL, Silvestri S, Dean M, Falk JL, Papa L. End-tidal carbon dioxide is associated with mortality and lactate in patients with suspected sepsis. The American journal of emergency medicine. 2013;31(1):64-71.

10 MCGILLICUDDY 2009

Review of: McGillicuddy DC, Tang A, Cataldo L, Gusev J, Shapiro NI. Evaluation of end-tidal carbon dioxide role in predicting elevated SOFA scores and lactic acidosis. Internal and emergency medicine. 2009;4(1):41-44.

12 REFERENCES Works cited.

TABLE OF CONTENTS

INTRODUCTION

TABLE OF CONTENTS

HUNTER 2016

HUNTER 2013

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3

Early recognition of sepsis in the ED is critical to initiate timely interventions that can significantly reduce patient morbidity and mortality.2,4

∙ For each hour that antimicrobial treatment is delayed, mortality increases 7.6 percent.4

∙ Early goal directed therapy for patients presenting with severe sepsis has been repeatedly demonstrated to reduce mortality.2

The Surviving Sepsis Campaign Hour-1 Bundle, developed by Society for Critical Care Medicine and European Society of Intensive Care Medicine, identifies the most critical actions clinicians should implement to assure early recognition and immediate intervention in adult patients presenting with sepsis or septic shock.5

∙ The initial step in the bundle involves measuring serum lactate as a prognostic marker for the early recognition of septic patients who are at-risk for end-organ dysfunction and are therefore eligible for aggressive resuscitation therapy.5

∙ Acting as either a marker of poor perfusion or impaired clearance secondary to organ dysfunction, elevated serum lactate assists in identifying patients with tissue hypoperfusion prior to hypotension who are at risk for organ dysfunction and mortality.6,7

∙ Due to the time sensitive nature of initiating early goal-directed therapy in sepsis patients, “lactate levels must be available with rapid turnaround time.”6

∙ Unfortunately, receiving lactate values may significant delay the initiation of treatment. Goyal et al. determined that median time from ED triage to whole blood lactate results is 172 minutes.8

INTRODUCTION

SURVIVING SEPSIS CAMPAIGN HOUR-1 BUNDLE OF CARE5

1. Measure lactate level. Remeasure if initial lactate level > 2 mmol/L.

2. Obtain blood cultures before administering antibiotics.

3. Administer broad-spectrum antibiotics.

4. Begin rapid administration of 30mL/kg crystalloid for hypotension or lactate level ≥ 4 mmol/L.

5. Apply vasopressors if patient is hypotensive during or after fluid resuscitation to maintain MAP ≥ 65 mm Hg.

INTRODUCTION

INTRODUCTION

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HUNTER 2016

HUNTER 2013

McGILLICUDDY 2009

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4

EtCO2 measurements via Microstream™ capnography may provide clinicians with a rapid, non-invasive surrogate measure of lactate acidosis

∙ EtCO2 has been demonstrated as a reliable method for identifying patients with acidosis in emergency department patients suffering from multiple conditions.3,9-13

∙ Several studies have demonstrated an association between etCO2 and lactate, mortality, SOFA scores, and in patients with suspected sepsis.3,14,15

∙ Institution that integrate etCO2 into sepsis screening protocols have improved success in early recognition of septic patients.16

Model demonstrating the relationship between severity of sepsis-induced acidosis and end-tidal carbon dioxide values.3

Severe-Sepsis Induced Hypoperfusion

Lactic Acidosis Compensatory Respiratory Alkalosis

Reduced EtCO2

INTRODUCTION (cont’d.)

INTRODUCTION

INTRODUCTION

TABLE OF CONTENTS

HUNTER 2016

HUNTER 2013

McGILLICUDDY 2009

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5

Hunter CL, et al.A prehospital screening tool utilizing end-tidal carbon dioxide predicts sepsis and severe sepsis.Am J Emerg Med. 2016 May;34(5):813-9.

HUNTER 2016

STUDY INFORMATION

PURPOSEEvaluate the utility of pre-hospital sepsis screening protocol to recognize patients with hospital diagnosis of sepsis or severe sepsis

STUDY DESIGN Prospective, single cohort study

METHODS

Prospective analysis of sepsis alerts initiated by emergency medical service in 12 months after activation of new sepsis screening protocol. Sepsis alerts were initiated when patients met any of the following criteria:

∙ Suspected infection

∙ Two or more of the following:– Temperature > 38 degrees C or < 36 degrees C

– Respiratory Rate > 20 breaths/min

– Heart Rate > 90 beats/min

∙ EtCO2 ≤ 25 mmHg

Patient outcome was compared among patients where EMS personnel followed all diagnostic criteria of the protocol (e.g. the protocol compliant group) and those where EMS personnel did not (e.g. the protocol non-compliant group).

Primary outcome: Diagnosis of severe sepsis and sepsis

Secondary outcome: Mortality and in-hospital lactate levels

HUNTER 2016

INTRODUCTION

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HUNTER 2016 (cont’d.)

STUDY INFORMATION

RESULTS

330 alerts were activated

183 (55%) were protocol compliant and 147 (45%) were protocol non-compliant

Compliant group Non-compliant group P Value

Diagnosed with sepsis 78% 43% <0.001

Diagnosed with severe sepsis

47% 7% 0.001

Mortality 11% 5% 0.036

Area under receiver operating characteristic curve of low EtCO2 as predictor for outcomes

Area under the curve 95% Confidence Interval

Sepsis 0.99 0.99-1.00

Severe sepsis 0.80 0.73-0.86

Mortality 0.70 0.57-0.83

Predictive value of protocol compliant sepsis alerts for outcomes

Sensitivity Specificity PPV NPV

Sepsis 69% 67% 78% 99%

Severe sepsis 90% 58% 47% 93%

Mortality 76% 46% 11% 95%

ICU admission 67% 50% 41% 75%

CONCLUSIONSPrehospital sepsis screening protocol may assist in identifying at-risk patients and potentially speed intervention. EtCO2 was the strongest predictor of sepsis diagnosis and patient outcome among all the prehospital variables.

Hunter CL, et al.A prehospital screening tool utilizing end-tidal carbon dioxide predicts sepsis and severe sepsis.Am J Emerg Med. 2016 May;34(5):813-9.

HUNTER 2016

INTRODUCTION

TABLE OF CONTENTS

HUNTER 2016

HUNTER 2013

McGILLICUDDY 2009

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7

HUNTER 2013Hunter CL et al. End-tidal carbon dioxide is associated with mortality and lactate in patients with suspected sepsis. Am J Emerg Med. 2013 Jan;31(1):64-71.

STUDY INFORMATION

PURPOSEEvaluate the association of etCO2 with mortality and lactate levels in patients with suspected sepsis admitted to the emergency department

STUDY DESIGN Prospective, single cohort observational trial

METHODS

A convenience sample of 201 patients presenting with suspected sepsis simultaneously received serum lactate blood samples and etCO2 measurements. After disposition, study participants were retrospectively assigned into the following disease severity categories:

∙ Sepsis - 2 or more SIRS criteria with suspected infection

∙ Severe sepsis – sepsis plus organ dysfunction, lactate >4 mM/L, altered mental status, or hypoxemia

∙ Septic shock – Severe sepsis plus hypotension unresponsive to initial fluid resuscitation

Inclusion criteria consisted of the following:

∙ 18 years of age

∙ Suspected infection

∙ ≥ 2 SIRS criteria (temperature >38 or < 36 degrees C, heart rate > 90 beats/min, and respiratory rate > 20 BPM)

The primary outcomes included the association of etCO2 values with the following:

∙ In-hospital mortality

∙ Serum lactate

HUNTER 2013

INTRODUCTION

TABLE OF CONTENTS

HUNTER 2016

HUNTER 2013

McGILLICUDDY 2009

REFERENCES

8

HUNTER 2013 (cont’d.)Hunter CL et al. End-tidal carbon dioxide is associated with mortality and lactate in patients with suspected sepsis. Am J Emerg Med. 2013 Jan;31(1):64-71.

STUDY INFORMATION

RESULTS

Presenting vital signs in three sepsis categories

Sepsis Severe sepsis Septic shock P Value

Lactate (mmol/L) 1.79 6.2 4.9 0.001

EtCO2 (mmHg) 33 28 30 0.013

Correlation coefficient – etCO2 and lactate

Correlation coefficient – etCO2 and lactate

P Value

Sepsis -0.421 <0.001

Severe sepsis -0.597 <0.001

Septic shock -0.482 0.011

Receiver operating characteristic curve performance of etCO2 and lactate in predicting mortality by disease severity

All Patients Sepsis Severe Sepsis Septic Shock

EtCO2 (area under the curve)

0.73 0.6 0.67 0.078

Lactate (area under the curve)

0.75 0.61 0.96 0.74

HUNTER 2013

INTRODUCTION

TABLE OF CONTENTS

HUNTER 2016

HUNTER 2013

McGILLICUDDY 2009

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HUNTER 2013 (cont’d.)Hunter CL et al. End-tidal carbon dioxide is associated with mortality and lactate in patients with suspected sepsis. Am J Emerg Med. 2013 Jan;31(1):64-71.

STUDY INFORMATION

RESULTS

Receiver operating characteristic curve performance of etCO2 and lactate in predicting mortality in intubated versus non-intubated patients.

Intubated Nonintubated

EtCO2 (area under the curve) 0.77 0.72

Lactate (area under the curve) 0.82 0.64

Independent predictors of mortality

Adjusted Odds Ratio 95% Confidence Interval

Abnormal EtCO2 6.48 1.06 -39.54

Lactate (area under the curve) 2 0.64

CONCLUSIONSEtCO2 is associated with mortality in emergency department with suspected sepsis patients regardless of disease severity. Additionally, a significant inverse relationship exists between etCO2 and lactate in all categories of sepsis.

HUNTER 2013

INTRODUCTION

TABLE OF CONTENTS

HUNTER 2016

HUNTER 2013

McGILLICUDDY 2009

REFERENCES

10

McGillicuddy DC, et al. Evaluation of end-tidal carbon dioxide role in predicting elevated SOFA scores and lactic acidosis. Intern Emerg Med. 2009 Feb;4(1):41-4.

McGILLICUDDY 2009

STUDY INFORMATION

PURPOSEInvestigate the relationship between etCO2 and organ dysfunction and acidosis in febrile patients presenting to the ED.

STUDY DESIGN Pilot, prospective, observations

METHODS

In this study, participants consisted of a non-consecutive convenience sample of patients >18 years of age presenting to the ED with a temperature of > 38 degrees C. Upon triage, etCO2 measurements were collected in addition to baseline demographic information, vital signs, sequential organ failure assessment (SOFA) score, and lactic acid levels.

Study outcomes included the following:

∙ Correlation of etCO2 and SOFA scores

∙ Correlation of etCO2 and lactate level

∙ Sensitivity, specificity, negative predictive value, and positive predictive value of etCO2 < 35 for predicting or a SOFA >2 or lactate ≥ 4 mmol/L.

RESULTS

EtCO2 < 35 (Mean (95% CI)) EtCO2 ≥ 35 (Mean (95% CI)) P Value

SOFA Score 2. 0 (1.5-2.6) 1.0 (0.4-1.5) <0.02

Lactate (mmol/L) 2.1 (1.3-2.2) 1.8 (1.3-2.2) 0.36

Correlation between etCO2 and markers of disease severity in sepsis

Correlation between etCO2 and SOFA r=-0.35 P<0.01

Correlation between etCO2 and lactate r=-0.35 P<0.01

McGILLICUDDY 2009

INTRODUCTION

TABLE OF CONTENTS

HUNTER 2016

HUNTER 2013

McGILLICUDDY 2009

REFERENCES

11

McGillicuddy DC, et al. Evaluation of end-tidal carbon dioxide role in predicting elevated SOFA scores and lactic acidosis. Intern Emerg Med. 2009 Feb;4(1):41-4.

McGILLICUDDY 2009 (cont’d.)

STUDY INFORMATION

RESULTS

EtCO2 < 35 predicting Lactate ≥ 4

AUC 0.62

Sensitivity (95% CI) 73% (56-85%)

Specificity (95% CI) 50% (38-62%)

Negative Predictive Value (95% CI) 95% (82-99%)

Positive Predictive Value (95% CI) 5% (1-15%)

EtCO2 < 35 predicting SOFA > 2

AUC 0.69

Sensitivity (95% CI) 73% (56-85%)

Specificity (95% CI) 50% (38-62%)

Negative Predictive Value (95% CI) 78% (62-88%)

Positive Predictive Value (95% CI) 44% (32-57%)

CONCLUSIONSEtCO2 correlates with lactate and Sepsis-related Organ Failure Assessment scores in febrile (Temp ≥ 38C) patients. However, the limited sensitivity and specificity of etCO2 < 35 mmHg for predicting disease severity (SOFA > 2 or lactate > 4) may undermine its clinical decision-making utility.

McGILLICUDDY 2009

INTRODUCTION

TABLE OF CONTENTS

HUNTER 2016

HUNTER 2013

McGILLICUDDY 2009

REFERENCES

1. Wang HE, Shapiro NI, Angus DC, Yealy DM. National estimates of severe sepsis in United States emergency departments. Critical care medicine. 2007;35(8):1928-1936.

2. Xu JY, Chen QH, Liu SQ, et al. The Effect of Early Goal-Directed Therapy on Outcome in Adult Severe Sepsis and Septic Shock Patients: A Meta-Analysis of Randomized Clinical Trials. Anesthesia and analgesia. 2016;123(2):371-381.

3. Hunter CL, Silvestri S, Dean M, Falk JL, Papa L. End-tidal carbon dioxide is associated with mortality and lactate in patients with suspected sepsis. The American journal of emergency medicine. 2013;31(1):64-71.

4. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Critical care medicine. 2006;34(6):1589-1596.

5. Levy MM, Evans LE, Rhodes A. The Surviving Sepsis Campaign Bundle: 2018 Update. Critical care medicine. 2018;46(6):997-1000.

6. Surviving Sepsis Campaign. 3-Hour Bundle. Available at: http://www.survivingsepsis.org/sitecollectiondocuments/bundle-three-hour-ssc.pdf. 2015.

7. Perman SM, Goyal M, Gaieski DF. Initial emergency department diagnosis and management of adult patients with severe sepsis and septic shock. Scandinavian journal of trauma, resuscitation and emergency medicine. 2012;20:41.

8. Goyal M, Pines JM, Drumheller BC, Gaieski DF. Point-of-care testing at triage decreases time to lactate level in septic patients. The Journal of emergency medicine. 2010;38(5):578-581.

9. Caputo ND, Fraser RM, Paliga A, et al. Nasal cannula end-tidal CO2 correlates with serum lactate levels and odds of operative intervention in penetrating trauma patients: a prospective cohort study. The journal of trauma and acute care surgery. 2012;73(5):1202-1207.

10. Fearon DM, Steele DW. End-tidal carbon dioxide predicts the presence and severity of acidosis in children with diabetes. Academic emergency medicine : official journal of the Society for Academic Emergency Medicine. 2002;9(12):1373-1378.

11. Hunter CL, Silvestri S, Ralls G, Bright S, Papa L. The sixth vital sign: prehospital end-tidal carbon dioxide predicts in-hospital mortality and metabolic disturbances. The American journal of emergency medicine. 2014;32(2):160-165.

12. Kartal M, Eray O, Rinnert S, Goksu E, Bektas F, Eken C. EtCO2: a predictive tool for excluding metabolic disturbances in nonintubated patients. The American journal of emergency medicine. 2011;29(1):65-69.

13. Nagler J, Wright RO, Krauss B. End-tidal carbon dioxide as a measure of acidosis among children with gastroenteritis. Pediatrics. 2006;118(1):260-267.

14. Hunter C, Silvestri S, Stone A. The Use Of End-Tidal Carbon Dioxide Levels As Criteria To Activate A Sepsis Alert Protocol In The Emergency Department. Academic Emergency Medicine. 2015;22(5 Suppl 1):S130.

15. McGillicuddy DC, Tang A, Cataldo L, Gusev J, Shapiro NI. Evaluation of end-tidal carbon dioxide role in predicting elevated SOFA scores and lactic acidosis. Internal and emergency medicine. 2009;4(1):41-44.

16. Hunter CL, Silvestri S, Ralls G, Stone A, Walker A, Papa L. A prehospital screening tool utilizing end-tidal carbon dioxide predicts sepsis and severe sepsis. The American journal of emergency medicine. 2016;34(5):813-819.

REFERENCES

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