Article

End-tidal carbon dioxide as a goal of early sepsis therapy

a b s t r a c t

Objective: To determine the use of end-tidal carbon dioxide as an end point of sepsis resuscitation. Methods: This was a prospective, observational, single-center cohort study of emergency department patients receiving treatment for severe sepsis with a quantitative Resuscitation protocol./a>. Three ETCO2 readings were taken during a 1-minute time frame at 0, 3, and 6 hours of treatment. Linear regression was used to characterize the association between ETCO2 and central venous oxygen saturation (SCVO2) and lactate and also to determine the relationship between their change. Analysis of variance was used to determine the relationship between ETCO2 and disposition. Results: Sixty-nine patients were included in our final analysis. For baseline values, linear regression failed to show a relationship between ETCO2 and SCVO2 (? = -0.04, t(70) = -0.53, P = .60) but showed a nearly significant relationship (? = -0.51, t(70) = -1.90, P = .06) with lactate. There was no significant relationship between ETCO2 and SCVO2 at 3 hours (? = 0.12, t(70) = 1.43, P = .16) or 6 hours (? = 0.05, t(64) = 0.82, P = .67). There was also no significant relationship between 6-hour change in ETCO2 and change in SCVO2 (? = 0.04, t

(64) = 0.43, P = .67) or lactate (? = 0.04, t(59) = 0.52, P = .60) or disposition (F(4) = 0.78, P = .54).

Conclusion: End-tidal carbon dioxide is unlikely to be a useful clinical end point for sepsis resuscitation, although it may be useful as a triage tool in suspected sepsis because baseline values may reflect initial lactate.

(C) 2014

Introduction

Sepsis accounts for approximately 282 000 emergency department (ED) visits annually, 2% of all hospital admissions, and up to 11% of intensive care unit admissions [1-3]. The incidence of severe sepsis and septic shock in the United States is rising [4]. Mortality from severe sepsis is high at approximately 30%, and costs are estimated at

16.7 billion dollars annually in the United States alone [2].

One of the most significant efforts to improve sepsis care is the international guidelines set forth by the Surviving Sepsis Campaign

? Meetings: Preliminary data were presented at the American College of Emergency Physicians Scientific Assembly on October 15th, 2013.

?? Grant support: University of Florida Faculty Dean’s Grant.

? Conflicts of interest: None.

?? Author contributions: F.W.G., D.J.W., and R.L.W. conceived the study. F.W.G., D.J.W.,

M.E.H., C.J.K., A.E.J., and R.L.W. supervised the data collection and medical record reviews. R.L.W., S.D., C.J.K., and A.E.J. provided methodological and statistical advice on study design and data analysis. A.E.J. and S.D. provided expertise on clinical trial design. S.D. provided additional help with manuscript revision for publication. F.W.G., C.J.K., M.E.H., and D.J.W. drafted the manuscript, and all authors contributed substantially to its revision.

* Corresponding author. Faheem Guirgis MD, Department of Emergency Medicine, Division of Research, 655 West 8th St, Jacksonville, FL 32209.

E-mail address: [email protected] (F.W. Guirgis).

[5]. At the center of these guidelines is early quantitative resuscitation (also known as protocolized resuscitation or early goal-directed therapy), which aims to achieve certain predefined hemodynamic and physiologic goals to significantly reduce mortality [6-11]. Included in these goals is the achievement of central venous oxygen saturation (SCVO2) of at least 70% for certain patients [6]. Measurement of SCVO2 has proved difficult in the ED setting, given the time, specialized monitoring, and expertise needed to perform accurate measurements [12,13]. A noninvasive correlate to SCVO2 would be clinically useful.

end-tidal carbon dioxide , or the maximal fraction of carbon

dioxide present at the end of exhalation, can be measured noninva- sively via capnography. Several studies have shown a correlation between arterial carbon dioxide (PaCO2) and ETCO2[14,15]. Previous studies have demonstrated that abnormal EtCO2 values may reflect respiratory failure during moderate sedation [16,17], metabolic disturbances [18], severity of illness [19,20], and lactic acidosis and mortality in sepsis [19,21]. Capnography has also been used to rapidly detect return of spontaneous circulation after cardiac arrest [22-26] and fluid responsiveness in critically ill patients [27].

Capnography provides easily obtained, continuous, reliable read- ings of ETCO2, which makes it ideal for use in the ED. To date, no large studies have prospectively evaluated the relationship between ETCO2 and SCVO2 during early quantitative resuscitation for severe sepsis or

http://dx.doi.org/10.1016/j.ajem.2014.08.036

0735-6757/(C) 2014

septic shock. We also set out to examine the association of ETCO2 with lactate, shock, patient outcome, and organ dysfunction.

Materials and methods

Study design and setting

This was a prospective, observational, single-center Cohort study designed to characterize the relationship between ETCO2 and SCVO2 in patients receiving early quantitative resuscitation for sepsis. The trial took place from June 1, 2012, to January 30, 2014, in the adult ED and intensive care unit at University of Florida (UF) Health Jacksonville. The UF Health Jacksonville ED is a high-acuity, academic, urban ED that treats approximately 90 000 patients per year. The research protocol was approved by the University of Florida College of Medicine, Jacksonville, Institutional Review Board.

Selection of participants

Patients with suspected severe sepsis or septic shock presenting to the ED between the hours of 7 AM and 7 PM or when the principle investigator, sub-I, or research assistant was present were assessed for inclusion. Criteria required that the patient be 18 years or older, have documented severe sepsis (as defined by 2 of 4 systemic inflammatory response syndrome criteria plus a suspected or confirmed source of infection with a lactate N 4 mg/dL or end-organ dysfunction) or septic shock (hypotension not responsive to 30 mL/kg intravenous fluids), and were being treated with early quantitative resuscitation with a central venous catheter in the neck or chest. Patients were excluded if they were incarcerated, were pregnant, required emergency surgery prohibiting end-tidal measure- ments, were receiving treatment with noninvasive ventilation, or had another severe metabolic acidosis of nonsepsis etiology. Patients were enrolled within 3 hours of severe sepsis recognition after informed consent was obtained from patients or their legal representatives.

Methods and measurements

Early quantitative resuscitation for patients with severe sepsis or septic shock

At UF Health Jacksonville, early quantitative resuscitation involves 2 potential Treatment protocols: invasive or noninvasive. Patients who maintain a mean arterial pressure (MAP) greater than 65 mm Hg and are without other signs of hemodynamic instability are treated with the noninvasive protocol. This includes the placement of 2 large bore intravenous catheters to achieve goals for fluid resuscitation (as indicated by inferior vena cava sonographic measurement), urine output, and Lactate clearance of 10% or greater over a 2-hour period. Patients with signs of hemodynamic instability as indicated by a MAP greater than 65 mm Hg or who are showing a lack of improvement or clinical deterioration after initiation of the noninvasive protocol receive an Edwards PreSep Central Venous Oximetry Catheter (Edwards Lifesciences, Irvine, CA) placed in either the internal jugular or subclavian vein for continuous SCVO2 and central venous pressure monitoring. For patients in need of SCVO2 monitoring but without a PreSep catheter, SCVO2 is measured via venous blood gas from the distal port of the central venous catheter drawn every 2 hours. In addition, as part of early quantitative resuscitation, patients treated with both protocols receive bolus antibiotics within 1 hour, MAP monitoring, Foley catheters to measure urine output and temperature, and serial lactate levels. Study patients were recruited from the invasive arm of early quantitative resuscitation.

Main measurements

End-tidal carbon dioxide measurements were taken using the Nihon Kohden TG-920P capnography cable (Nihon Kohden Corp, Tokyo, Japan). For spontaneously breathing patients, ETCO2 values

Table 1

Characteristics of study subjects: demographics, comorbidities, suspected source of infection, features of sepsis, and organ dysfunction, baseline ETCO2, vital signs, SCVO2, and lactate level

Variable

Age (y), mean (SD) 63 (15.8)

Race, white 38 (54)

Race, black 31 (44)

Race, other 2 (3)

Sex, male 37 (52)

Comorbidities

Diabetes mellitus 28 (39)

Chronic obstructive pulmonary disease 14 (20)

End-stage renal disease 5 (7)

Active malignancy 5 (7)

Organ transplant 1 (1)

Indwelling vascular line 1 (1)

Nursing home resident 24 (34)

Human immunodeficiency virus 5 (7)

Suspected source of infection

Pulmonary 34 (48)

Urinary tract 26 (37)

Intra-abdominal 5 (7)

Skin/soft tissue 1 (1)

Blood 1 (1)

Unknown 4 (6)

Features of sepsis

Shock 43 (61)

Culture positive 49 (69)

Blood culture positive 32 (45)

Gram positive 34 (48)

Gram negative 24 (34)

Organ dysfunction

Pulmonary dysfunction 33 (46)

Renal dysfunction 30 (42)

Coagulopathy 21 (30)

Cardiovascular dysfunction 43 (61)

Hepatic dysfunction 4 (6)

Neurologic dysfunction 37 (52)

Baseline values, mean (SD)

ETCO2 28 (7.7)

SBP 103 (29)

HR 99 (21)

MAP 71 (17)

SCVO2 72 (11)

Lactate (mg/dL) 4.7 (3.3)

Values are presented as no. (%) of patients, unless otherwise indicated. SBP, systolic blood pressure; HR, heart rate.

were obtained using a nasal cannula and sidestream capnography. For intubated patients, ETCO2 was obtained via an endotracheal tube adapter and mainstream capnography. Three ETCO2 readings were

Fig. 1. Scatter plot matrix of the relationship between baseline ETCO2 and baseline SCVO2.

taken during a 1-minute time frame on 3 separate occasions during early quantitative resuscitation. Scheduled ETCO2 measurements were taken at 0, 3, and 6 hours of the protocol. At the time of each scheduled ETCO2 measurement, SCVO2, blood pressure, heart rate, respiratory rate, oxygen saturation were recorded as well as Ventilator settings, fraction of inspired oxygen, MAP, CVP, and hourly urine output.

Medical record review

The principle investigator and a trained research assistant performed a medical record review of enrolled patients [28,29]. Duplicate reviews were performed on a 10% subsample of patients to assess reliability. The reviewers were blinded to ETCO2 data. Medical record review included ED and inpatient medical records to confirm sepsis diagnosis and determine age, sex, ethnicity, patient disposition (discharged to home, nursing home, rehabilitation facility, hospice, or death), hospital length of stay , comorbidities (diabetes mellitus, chronic obstructive pulmonary disease [COPD], end-stage renal disease, active malignancy, organ transplant, and human immunodeficiency virus status), source of infection, culture results, organ dysfunction, and the presence of shock. Organ dysfunction was defined according to the Surviving Sepsis Guideline criteria, the modified Sequential Organ Failure Assessment score, and the Mortality in ED Sepsis score [5,30,31].

Analysis

The primary end point was the relationship between ETCO2 and SCVO2 at 0, 3, and 6 hours of early quantitative resuscitation. Secondary end points were the relationship between ETCO2 and lactate, shock, positive culture, disposition (discharged to home, rehabilitation facility, nursing home, hospice, or death), hospital LOS, and organ dysfunction (pulmonary, renal, hepatic, neurologic, coagulopathy, cardio- vascular). We also compared the change in ETCO2 and its relationship to the change in SCVO2 and the change in lactate over the 6-hour resuscitation period. The change in ETCO2 was calculated after the model of lactate clearance as follows: [(ETCO2initial – ETCO2delayed)/ETCO2initial] x 100%, for which ETCO2initial was baseline ETCO2 at 0 hours and ETCO2delayed was ETCO2 at 6 hours [7]. The same was done for change in SCVO2 and change in lactate. A scatterplot matrix was created to determine the nature of the relationship between ETCO2 and SCVO2 and lactate. Preliminary data suggested a linear relationship; therefore, based on the linear regression of our primary end points, a sample size of 70 patients was calculated to achieve 80% power to detect a regression coefficient of greater than or equal to 0.36 based on estimates of SD from our pilot cases (ETCO2: SD ~ 4.00, SCVO2: SD ~ 4.50) and a 2-sided significance

level of .05.

Linear regression was then used to determine the relationship between ETCO2 and SCVO2. This was also done to determine the relationship between ETCO2 and lactate, shock, positive culture, LOS, and individual organ dysfunctions, and modified SOFA score as well as the changes in ETCO2, SCVO2, and lactate. Analysis of variance was used to determine the relationship between baseline ETCO2 or change in ETCO2 and disposition. We also used Student t test to determine the associations between baseline ETCO2, change in ETCO2, initial lactate, second lactate, SCVO2 at 6 hours, and SCVO2 greater than 70% with mortality.

Study data were collected and managed using Research Electronic Data Capture electronic data capture tools hosted at the University of Florida [32]. Research Electronic Data Capture is a secure, Web-based application designed to support data capture for research studies, providing (1) an intuitive interface for validated data entry, (2) audit trails for tracking data manipulation and export procedures, (3) automated export procedures for seamless data downloads to common statistical packages, and (4) procedures for importing data from external sources. Graphical and statistical analyses were performed using Stata Version 12 (StataCorp LP, College Station, TX).

Fig. 2. Scatter plot matrix of the relationship between baseline ETCO2 and baseline lactate.

Results

Eighty-one patients were enrolled in the study, with 12 patients excluded (4 patients had diabetic ketoacidosis, 2 patients were not septic, 5 patients did not have SCVO2 monitoring in place, and we were unable to obtain written consent for 1 patient); therefore, 69 patients were included in our final analysis. Patients were mostly white (54%) and mostly male (52%). The most common source of infection was lung (48%), followed by urinary tract (37%) and intra-abdominal (7%). For organ dysfunction, cardiovascular (61%) and neurologic (52%) were most prevalent, followed by pulmonary (46%), renal (42%), coagulopathy (30%), and hepatic (6%). Overall mortality was 17%.

Sixty-one percent of patients were in shock, and 69% were culture positive with 45% blood culture positive. Gram-positive infections (48%) were more common than gram-negative infections (34%). Patient characteristics and baseline ETCO2, vital signs, SCVO2, and lactate levels can be found in Table 1. Mean ETCO2 upon enrollment was 28 mm Hg, with mean MAP of 71 mm Hg, SCVO2 of 72, and lactate level of 4.7 mg/dL.

For baseline values, linear regression failed to show a relationship between ETCO2 and SCVO2 but showed a nearly significant relationship (? = -0.51, t(69) = -1.90, P = .06) with lactate. See Figs. 1 and 2 for scatter plot matrices of these relationships. There was also a weak relationship between ETCO2 and SCVO2 at 3 hours (? = 0.12, t(69) =

Fig. 3. Scatter plot matrix of the relationship between hour 6 ETCO2 and hour 6 SCVO2.

Table 2

Results of linear regression displaying slope (?), t, R2, F, and P values for baseline ETCO2 and change in ETCO2 vs various end points over the 6-hour resuscitative period

Variable

Slope (?) for baseline ETCO2

t(69) R2 F(1,69) P

Baseline SCVO2

-0.04

-0.53

0.00

0.28

.60

Baseline lactate

-0.51

-1.90

0.05

3.60

.06

Shock

-0.64

-0.34

0.00

0.12

.73

LOS

0.10

1.16

0.02

1.34

.25

Positive culture

-0.14

-0.07

0.00

0.00

.94

Pulmonary dysfunction

2.63

1.45

0.03

2.11

.15

Renal dysfunction

0.29

0.16

0.00

0.02

.15

Coagulopathy

-3.34

-1.70

0.04

2.90

.09

Cardiovascular dysfunction

-0.64

-0.34

0.00

0.12

.73

Hepatic dysfunction

-1.6

-0.41

0.00

0.17

.69

Neurologic dysfunction

-2.01

-1.11

0.02

1.23

.27

Slope (?) for change in ETCO2 T(N) R2 F(1,N) P

Changes in SCVO2

0.04

(63) = 0.43

0.00

(1,63) = 0.19

.67

Change in lactate

0.04

(58) = 0.52

0.00

(1,58) = 0.27

.60

Shock

-0.01

(65) = -0.02

0.00

(1,65) = 0.00

.99

LOS

-0.01

(63) = -0.86

0.01

(1,63) = 0.74

.39

Positive culture

0.02

(65) = 0.42

0.00

(1,65) = 0.18

.67

Pulmonary dysfunction

-0.02

(65) = -0.33

0.00

(1,65) = 0.11

.74

Renal dysfunction

-0.01

(65) = -0.11

0.00

(1,65) = 0.01

.91

Coagulopathy

0.01

(65) = 0.22

0.00

(1,65) = 0.05

.82

Cardiovascular dysfunction

-0.01

(65) = -0.02

0.00

(1,65) = 0.00

.99

Hepatic dysfunction

-0.03

(65) = -0.24

0.00

(1,65) = 0.06

.81

Neurologic dysfunction

-0.02

(65) = -0.38

0.00

(1,65) = 0.14

.70

1.43, P = .16) and at 6 hours (? = 0.05, t(63) = 0.82, P = .67). The

relationship at 6 hours is represented in Fig. 3. For the different relationships examined, there was no significant relationship be- tween baseline ETCO2 and the presence of shock, LOS, positive culture, or any type of organ dysfunction. There was also no significant relationship between change in ETCO2 over the 6-hour period when compared with change in SCVO2, change in lactate, the presence of shock, LOS, positive culture, or any type organ dysfunction (Table 2). To account for pulmonary factors which could have an effect on ETCO2, we performed a t test of the means in patients with vs without COPD, sepsis-induced pulmonary dysfunction, and respiratory failure requiring mechanical ventilation (Table 3) and found no statistically significant difference in ETCO2.

When the association between baseline ETCO2 and disposition was

examined, there was no significant relationship for the 5 potential outcomes of discharged to home, rehabilitation facility, nursing home, hospice, or death (F(4) = 0.63, P = .64). This was also the case when comparing change in ETCO2 to disposition (F(4) = 0.78, P = .54). A box plot representations of the relationship of change in ETCO2 against disposition can be found in Fig. 4.

The strongest predictors of mortality were elevated initial lactate (difference, -4.5; 95% confidence interval [CI], -7.7 to -1.3;

P = .01) and elevated repeat lactate (difference, -4.3; 95% CI, -7.2 to -1.4; P = .001). Central venous oxygen saturation at 6 hours was also significantly associated with mortality (difference, -13.4; 95% CI,

-0.32 to 27.1; P = .05), although SCVO2 greater than 70 was not

(difference, 0.09; 95% CI, -0.25 to 0.44; P = .57). There was no association between baseline ETCO2 (difference, -0.37; 95% CI, -7 to 6; P = .90) or the proportion of change in ETCO2 for 6 hours with mortality (difference, -0.01; 95% CI, -0.16 to 0.14; P = .89).

Discussion

Central venous oxygen saturation and lactate are benchmark resuscitative end points for sepsis therapy. This study attempted to characterize the relationship between these markers and ETCO2 in ED patients undergoing early quantitative resuscitation for sepsis. It also attempted to characterize the change in ETCO2 and its relationship with change in SCVO2 and lactate and other Clinical end points. This prospective study, however, did not demonstrate a clear relationship

between ETCO2 and SCVO2, but did demonstrate a trend toward a significant relationship between ETCO2 and lactate.

Most patients with severe sepsis present to the ED, which is where early quantitative resuscitation must be provided to achieve benefit [6,12,10,33,34,13,35]. Emergency department-based sepsis resusci- tation, however, is complex and difficult for many reasons, and studies have demonstrated a lack of protocol adherence [36-38]. Much of this is due to issues related to nurse staffing and physician skills regarding SCVO2 and CVP monitoring [39-42].

In 2010, the demonstrated noninferiority of lactate clearance to

SCVO2 as a goal for early sepsis therapy changed practice patterns and influenced international guidelines [5]. Normalization of serum lactate was added as a grade 2C recommendation to the Surviving sepsis campaign guidelines based on 2 multicenter, randomized, controlled trials [7,43]. This allowed practitioners (particularly in the ED) to substitute lactate clearance for SCVO2 when SCVO2 monitoring was unavailable. In addition, serum lactate is more easily obtained and is frequently available as a Point-of-care test. Ultimately, the strength of using lactate as an additional goal of sepsis therapy lies in its simplicity and availability. The only inconvenience to following lactate, however, is that levels cannot be provided in real time and require serial Blood draws.

Our study comparing ETCO2 to these 2 criterion standard measures was an attempt at providing a real-time, dependable, and easily obtained measure of resuscitation progress that would be effective in any ED. In order for evidence-based therapies to be effective in an ED, they must contain the aforementioned attributes of ease-of-use and reliability. Although a clear relationship with SCVO2 was not established, we did find some potential use in the comparison of ETCO2 with lactate. However, when the 6-hour change in ETCO2 was compared with the change in lactate, we did not find a significant relationship. This brings to question the clinical use of ETCO2 as an end point of resuscitation.

Hunter et al [21] recently performed a study comparing ETCO2 to lactate and mortality in 201 ED patients with sepsis, of whom 67 patients (40 severe sepsis, 27 septic shock) had either severe sepsis or septic shock. Their study found a similar inverse relationship between ETCO2 and lactate and found that as ETCO2 decreased, lactate increased. They also found that abnormally high and abnormally low ETCO2 levels were associated with mortality. McGillicuddy et al [19] also

Table 3

Comparison of mean ETCO2 and change in ETCO2 between patients with vs without COPD, sepsis-induced pulmonary dysfunction, and mechanical ventilation

Variable

No COPD (mean)

COPD (mean)

95% CI difference

P

Baseline ETCO2

28.1

28.5

5.9 to 5.2

.90

Hour 3 ETCO2

27.1

27.0

7.2 to 7.3

.98

Hour 6 ETCO2

26.5

26.0

5.8 to 6.6

.88

Change in ETCO2

2.3

1.7

5.2 to 3.9

.76

No Pulmonary dysfunction (mean)

Pulmonary dysfunction (mean)

95% CI difference

P

Baseline ETCO2

27.3

29.4

5.6 to 1.4

.24

Hour 3 ETCO2

26.8

28.3

5.7 to 2.7

.47

Hour 6 ETCO2

25.5

27.4

6.6 to 2.7

.40

Change in ETCO2

1.45

1.48

3.0 to 3.1

.98

Spontaneously breathing (mean)

Mechanical ventilation (mean)

95% CI difference

P

Baseline ETCO2

26.3

29.5

7.4 to 1.0

.13

Hour 3 ETCO2

27.3

27.4

3.9 to 3.8

.99

Hour 6 ETCO2

25.1

27.1

6.0 to 2.0

.33

Change in ETCO2

1.25

0.83

3.5 to 2.6

.78

performed a study evaluating the association between ETCO2 and SOFA scores and lactate in 97 febrile ED patients. Their study had only 34 patients with a SOFA score higher than 2, and only 5 patients with a lactate greater than 4 mg/dL. They did, however, find a significant correlation between ETCO2 and SOFA score.

Our study differs from previous studies of ETCO2 in sepsis in that we

measured ETCO2 on 3 separate occasions over the 6-hour resuscitation period, allowing us to compare the change in ETCO2 with the change in SCVO2 and lactate. This was done so that the value of ETCO2 as a resuscitative end point could be determined, rather than as a single measurement obtained while the patient was in the ED. Our data were similar to that of Hunter et al in showing a nearly significant inverse relationship between baseline ETCO2 and lactate, but this relationship was not sustained throughout the resuscitation period. This may indicate that ETCO2 is useful as a triage screening tool in suspected sepsis, but it is not a useful goal for sepsis therapy because the change in ETCO2 does not reflect the change in lactate or SCVO2. End-tidal carbon dioxide was also not related to any of the predefined clinical end points. Our study also differed from that of Hunter and colleagues because our patients had a higher incidence of shock at 61% (42/69) in comparison with only 13% (27/201) in their study.

There were several limitations to this study. First, because only patients receiving the invasive sepsis protocol could be recruited for the study and because we actively use a noninvasive protocol in more stable patients, this study was biased toward patients with higher disease severity because 61% of our patients were in septic shock.

Fig. 4. Box plot representation of change in ETCO2 and disposition.

Therefore, the population of septic patients in our study was different from that of other studies of ETCO2 in sepsis. Second, although this was a prospective study, enrollment was not 24 hours, and therefore, there may have been some bias toward patients in the daytime hours. Third, the predefined N of 70 patients was sufficient for us to detect what we thought would be a clinically significant relationship. Unfortunately, because of the last minute exclusion of 1 patient and several other patients excluded for various reasons, we only achieved 69 patients. Finally, although we had a large number of patients with pulmonary issues (COPD, sepsis-induced lung injury, and/or on mechanical ventilation) and the potential for inaccurate ETCO2 values due to poor alveolar Gas exchange, we were unable to directly answer the question of whether ETCO2 values accurately reflected PaCO2 values because we did not have arterial blood gases on all patients during the 6-hour resuscitative period. We do feel, however, that we addressed this concern by performing a direct comparison of ETCO2 values in patients with or without these pulmonary conditions.

Conclusion

In conclusion, our data demonstrate that ETCO2 is unlikely to be a useful clinical end point for resuscitation in patients with severe sepsis or septic shock, although it may be useful as a triage tool in suspected sepsis. We were unable to demonstrate a relationship between ETCO2 or its change over time and any of the resuscitative benchmarks or useful clinical end points. We do believe, however, that further work to establish reliable and easily obtained measures of resuscitation progress would be beneficial to ED patients with severe sepsis.

Acknowledgments

The authors would like to thank Steven Chadwick, Rita Duke, and Nisha Patel for their tireless efforts enrolling patients and entering data. They would also like to thank Dr Phyllis Hendry, MD, and Dr Steven A. Godwin, MD, for their administrative support and belief in our work.

References

  1. Angus DC, Wax RS. Epidemiology of sepsis: an update. Crit Care Med 2001;29: S109-16.
  2. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and Associated costs of care. Crit Care Med 2001;29:1303-10.
  3. Strehlow MC, Emond SD, Shapiro NI, Pelletier AJ, Camargo Jr CA. National study of emergency department visits for sepsis, 1992 to 2001. Ann Emerg Med 2006;48: 326-31.
  4. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003;348:1546-54.
  5. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock, 2012. Intensive Care Med 2013;41(2):580-637.
  6. Puskarich MA, Trzeciak S, Shapiro NI, Arnold RC, Horton JM, Studnek JR, et al. Emergency Medicine Shock Research Network (EMSHOCKNET). Association between timing of antibiotic administration and mortality from septic shock in patients treated with a quantitative resuscitation protocol. Crit Care Med 2011;39: 2066-71.
  7. Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA, et al. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA 2010;303:739-46.
  8. Jones AE, Brown MD, Trzeciak S, Shapiro NI, Garrett JS, Heffner AC, et al. The effect of a quantitative resuscitation strategy on mortality in patients with sepsis: a meta-analysis. Crit Care Med 2008;36:2734-9.
  9. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, et al. Early goal- directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368-77.
  10. Rivers EP, Katranji M, Jaehne KA, Brown S, Abou Dagher G, Cannon C, et al. Early interventions in severe sepsis and septic shock: a review of the evidence one decade later. Minerva Anestesiol 2012;78:712-24.
  11. Rivers E, McIntyre L, Morro D, Rivers K. Early and innovative interventions for severe sepsis and septic shock: taking advantage of a window of opportunity. Can Med Assoc J 2005;173:1054-65.
  12. Jones AE, Kline JA. Use of goal-directed therapy for severe sepsis and septic shock in academic emergency departments. Crit Care Med 2005;33:1889-90 [1888,9; author reply].
  13. Nguyen HB, Oh J, Otero RM, Burroughs K, Wittlake WA, Corbett SW. Standardization of severe sepsis management: a survey of methodologies in academic and Community settings. J Emerg Med 2010;38:122-30 [quiz 130-2].
  14. Barton CW, Wang ES. Correlation of end-tidal CO2 measurements to arterial PaCO2 in Nonintubated patients. Ann Emerg Med 1994;23:560-3.
  15. Yosefy C, Hay E, Nasri Y, Magen E, Reisin L. End tidal carbon dioxide as a predictor of the arterial PCO2 in the emergency department setting. Emerg Med J 2004;21: 557-9.
  16. Burton JH, Harrah JD, Germann CA, Dillon DC. Does end-tidal carbon dioxide monitoring detect respiratory events prior to current sedation monitoring practices? Acad Emerg Med 2006;13:500-4.
  17. Deitch K, Miner J, Chudnofsky CR, Dominici P, Latta D. Does end tidal CO2 monitoring during emergency department procedural sedation and analgesia with propofol decrease the incidence of hypoxic events? A randomized, controlled trial. Ann Emerg Med 2010;55:258-64.
  18. Kartal M, Eray O, Rinnert S, Goksu E, Bektas F, Eken C. ETCO(2): a predictive tool for excluding metabolic disturbances in nonintubated patients. Am J Emerg Med 2011;29:65-9.
  19. 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. Intern Emerg Med 2009;4:41-4.
  20. Wahlen BM, Bey T, Wolke BB. Measurement of end-tidal carbon dioxide in spontaneously breathing patients in the pre-hospital setting. A prospective evaluation of 350 patients. Resuscitation 2003;56:35-40.
  21. 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. Am J Emerg Med 2013;31:64-71.
  22. Gudipati CV, Weil MH, Bisera J, Deshmukh HG, Rackow EC. Expired carbon dioxide: a noninvasive monitor of cardiopulmonary resuscitation. Circulation 1988;77:234-9.
  23. Weil MH, Bisera J, Trevino RP, Rackow EC. Cardiac output and end-tidal carbon dioxide. Crit Care Med 1985;13:907-9.
  24. Cha KC, Kim HJ, Shin HJ, Kim H, Lee KH, Hwang SO. Hemodynamic effect of external chest compressions at the lower end of the sternum in cardiac arrest patients. J Emerg Med 2013;44:691-7.
  25. Kammeyer RM, Pargett MS, Rundell AE. Comparison of CPR outcome predictors between Rhythmic abdominal compression and continuous chest compression CPR techniques. Emerg Med J 2014;31(5):394-400.
  26. Einav S, Bromiker R, Weiniger CF, Matot I. Mathematical modeling for prediction of survival from resuscitation based on computerized continuous capnography: proof of concept. Acad Emerg Med 2011;18:468-75.
  27. Young A, Marik PE, Sibole S, Grooms D, Levitov A. Changes in end-tidal carbon dioxide and volumetric carbon dioxide as predictors of volume responsiveness in hemodynamically unstable patients. J Cardiothorac Vasc Anesth 2013;27:681-4.
  28. Gilbert EH, Lowenstein SR, Koziol-McLain J, Barta DC, Steiner J. Chart reviews in emergency medicine research: where are the methods? Ann Emerg Med 1996; 27:305-8.
  29. Lowenstein SR. Medical record reviews in emergency medicine: the blessing and the curse. Ann Emerg Med 2005;45:452-5.
  30. Arnold RC, Sherwin R, Shapiro NI, O’Connor JL, Glaspey L, Singh S, et al. Multicenter observational study of the development of progressive organ dysfunction and therapeutic interventions in normotensive sepsis patients in the emergency department. Acad Emerg Med 2013;20:433-40.
  31. Shapiro NI, Wolfe RE, Moore RB, Smith E, Burdick E, Bates DW. Mortality in Emergency Department Sepsis (MEDS) score: a prospectively derived and validated clinical prediction rule. Crit Care Med 2003;31:670-5.
  32. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)–a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009; 42:377-81.
  33. Rivers EP, Kruse JA, Jacobsen G, Shah K, Loomba M, Otero R, et al. The influence of early hemodynamic optimization on biomarker patterns of severe sepsis and septic shock. Crit Care Med 2007;35:2016-24.
  34. Nguyen HB, Rivers EP, Havstad S, Knoblich B, Ressler JA, Muzzin AM, et al. Critical care in the emergency department: a physiologic assessment and outcome evaluation. Acad Emerg Med 2000;7:1354-61.
  35. Nguyen HB, Lynch EL, Mou JA, Lyon K, Wittlake WA, Corbett SW. The utility of a quality improvement bundle in bridging the gap between research and standard care in the management of severe sepsis and septic shock in the emergency department. Acad Emerg Med 2007;14:1079-86.
  36. Varpula M, Karlsson S, Parviainen I, Ruokonen E, Pettila V, Finnsepsis Study Group. Community-acquired septic shock: early management and outcome in a nationwide study in Finland. Acta Anaesthesiol Scand 2007;51:1320-6.
  37. Huh JW, Oh BJ, Lim CM, Hong SB, Koh Y. Comparison of clinical outcomes between intermittent and continuous monitoring of central venous oxygen saturation (SCVO2) in patients with severe sepsis and septic shock: a pilot study. Emerg Med J 2013;30:906-9.
  38. O’Neill R, Morales J, Jule M. early goal-directed therapy for severe sepsis/ septic shock: which components of treatment are more difficult to implement in a community-based emergency department? J Emerg Med 2012;42:503-10.
  39. Lyon RM, McNally SJ, Hawkins M, MacKinnon M. Early goal-directed therapy: can the emergency department deliver? Emerg Med J 2010;27:355-8.
  40. McNally SJ, MacKinnon M, Hawkins M. Practical barriers to the implementation of early goal directed therapy in the UK: trainee skills and awareness. Scott Med J 2009;54:22-4.
  41. Burney M, Underwood J, McEvoy S, Nelson G, Dzierba A, Kauari V, et al. Early detection and treatment of severe sepsis in the emergency department: identifying barriers to implementation of a protocol-based approach. J Emerg Nurs 2012;38:512-7.
  42. Jones AE, Shapiro NI, Roshon M. Implementing early goal-directed therapy in the emergency setting: the challenges and experiences of translating research innovations into clinical reality in academic and community settings. Acad Emerg Med 2007;14:1072-8.
  43. Jansen TC, van Bommel J, Schoonderbeek FJ, Sleeswijk Visser SJ, van der Klooster JM, Lima AP, et al. Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial. Am J Respir Crit Care Med 2010;182:752-61.

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