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. Author manuscript; available in PMC: 2019 Mar 1.
Published in final edited form as: Crit Care Med. 2018 Mar;46(3):e213–e220. doi: 10.1097/CCM.0000000000002918

Association between partial pressure of arterial carbon dioxide and survival to hospital discharge among patients diagnosed with sepsis in the emergency department

Brian W Roberts 1, Nicholas M Mohr 3, Enyo Ablordeppey 4,5, Anne M Drewry 4, Ian T Ferguson 7, Stephen Trzeciak 1,2, Marin H Kollef 6, Brian M Fuller 4,5
PMCID: PMC5825256  NIHMSID: NIHMS925064  PMID: 29261567

Abstract

Objective

The objective of this study was to test the association between the partial pressure of arterial carbon dioxide (PaCO2) and survival to hospital discharge among mechanically ventilated patients diagnosed with sepsis in the emergency department (ED).

Design

Retrospective cohort study of a single center trial registry.

Setting

Academic medical center.

Patients

Mechanically ventilated ED patients. Inclusion criteria: age ≥ 18, diagnosed with sepsis in the ED, and mechanical ventilation initiated in the ED.

Interventions

Arterial blood gases obtained after initiation of mechanical ventilation were analyzed. The primary outcome was survival to hospital discharge. We tested the association between PaCO2 and survival using multivariable logistic regression adjusting for potential confounders. Sensitivity analyses, including propensity score matching were also performed.

Measurements and Main Results

Six hundred subjects were included and 429 (72%) survived to hospital discharge. The median [interquartile (IQR)] PaCO2 was 42 (34-53) mmHg for the entire cohort and 44 (35-57) and 39 (31-45) mmHg among survivors and non-survivors respectively (p < 0.0001 Wilcox rank-sum test). On multivariable analysis, a 1 mmHg rise in PaCO2 was associated with a 3% increase in odds of survival [aOR 1.03, 95% confidence interval (CI) 1.01-1.04] after adjusting for tidal volume and other potential confounders. These results remained significant on all sensitivity analyses.

Conclusion

In this sample of mechanically ventilated sepsis patients we found an association between increasing levels of PaCO2 and survival to hospital discharge. These findings justify future studies to determine the optimal target PaCO2 range for mechanically ventilated sepsis patients.

Keywords: mechanical ventilation, partial pressure of arterial carbon dioxide, PaCO2, sepsis

Introduction

Sepsis incidence is increasing, and it continues to have high mortality and costs of care. Sepsis-associated respiratory failure is common,(1) and often requires mechanical ventilation in the emergency department (ED) and the intensive care unit (ICU). The mortality for mechanically ventilated sepsis patients remains unacceptably high at over 40%.(1) Thus finding new interventions to improve outcomes in this patient population is of the utmost importance.

Prescribing low tidal volume and limiting inspiratory pressures to prevent ventilator-associated lung injury (VALI) is associated with improved outcomes in mechanically ventilated sepsis patients.(2) However, this strategy can result in elevated levels of partial pressure of arterial carbon dioxide (PaCO2).(3, 4) The literature has conflicting assessments of PaCO2 and its effects on clinical outcomes. Elevated PaCO2 (i.e. hypercapnia) has been shown to impair alveolar epithelial and neutrophil function and could in theory suppress immune responses and resistance to bacterial infection.(5-8) In addition, the acidosis induced by hypercapnia can potentially decrease antibiotic efficacy.(9) A recent secondary analysis of three cohort studies found severe hypercapnia (PaCO2 > 50 mmHg) to be associated with increased mortality among patients with acute respiratory distress syndrome (ARDS).(10) Alternatively, hypercapnia can modulate several biologically-important mechanisms, which could be beneficial in the setting of sepsis, including provision of anti-inflammatory modulators, mitigation of VALI, and modulation of gene expression, which could be important in sepsis survival.(11-15) In addition, elevated PaCO2 may inhibit bacterial growth, thus decreasing the overall infectious insult.(16)In an analysis of a heterogeneous group of mechanically ventilated patients without ARDS, our group previously found hypercapnia (PaCO2 > 45 mmHg) was associated with increased survival.(17) Given these conflicting reports, the effects of PaCO2 on clinical outcomes among sepsis patients remains unclear.

The objective of this study was to test the association between PaCO2 early after the initiation of mechanical ventilation and survival to hospital discharge among patients diagnosed with sepsis-associated respiratory failure requiring mechanical ventilation in the ED.

Material and Methods

Setting

We analyzed an ED registry of patients with acute initiation of mechanical ventilation, at a tertiary academic center (September 2009 to March 2016).(18) This registry was compiled as part of the Lung-Protective Ventilation Initiated in the Emergency Department (LOV-ED) trial.(19) That investigation was a before-after study, which evaluated the effectiveness of an ED-based lung-protective mechanical ventilation protocol on reducing the incidence of pulmonary complications [ARDS and ventilator-associated conditions (VACs)]. This registry was previously used in a secondary analysis to evaluate the relationship between PaCO2 and survival among a heterogeneous group of mechanically ventilated patients (i.e. not specifically patients with sepsis).(17)

Participants

We included patients enrolled in the LOV-ED trial with initiation of mechanical ventilation in the ED. Inclusion criteria were: 1) age ≥ 18 years; 2) mechanical ventilation via an endotracheal tube, 3) diagnosis of sepsis [i.e. presumed infection plus two systemic inflammatory response syndrome (SIRS) criteria].(20) Exclusion criteria were: 1) death or discontinuation of mechanical ventilation within 24 hours; 2) chronic mechanical ventilation; 3) presence of a tracheostomy; 4) transfer to another hospital; and 5) presence of acute respiratory distress syndrome (ARDS) during ED presentation.(21) This study was approved by the institutional review board under waiver of informed consent, and is reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: Guidelines for Reporting Observational Studies.(22)

Procedures

Data on baseline demographics, comorbid conditions, illness severity [i.e. Acute Physiology and Chronic Health Evaluation II (APACHE)], and blood pressure were collected in the ED as part of the primary study. Pertinent treatment variables in the ED were also recorded. The results of cultures drawn for suspected sepsis along with the source of positive cultures were recorded. We recorded the initial arterial blood gas (ABG) analyses performed after the initiation of mechanical ventilation, as well as the initial mechanical ventilator variables. We also collected ICU ventilation settings twice daily for up to two weeks.

Static compliance (mL/ cm H2O) of the respiratory system (CRS) was calculated as: tidal volume/[plateau pressure – positive end expiratory pressure (PEEP)]. Driving pressure (cm H2O) was calculated as: plateau pressure - PEEP. For purposes of these analyses the initial measured plateau pressure, CRS, and driving pressure were used. The corrected minute ventilation for a normal PaCO2 (VEcorr) was used as a surrogate for dead space to account for changes in dead space as PaCO2 increases. This correction factor has been similarly reported in previous studies.(10, 23) We calculated VEcorr as: initial minute ventilation × actual PaCO2/40 mmHg.(10, 23) All data was exported into Stata/SE 14.1 for Mac, StataCorp LP (College Station, TX, USA) for analysis.

Statistical analysis

Categorical variables were compared using the chi-square test. Continuous variables were compared using student's t-test or Wilcoxon rank-sum test as appropriate based on the distribution of data. Spearman's correlation coefficient (r) was used to assess the relationship between PaCO2, and VEcorr and pH.

The primary outcome was survival to hospital discharge. To test the relationship between PaCO2 after initiation of mechanical ventilation and survival to hospital discharge, a multivariable logistic regression model was constructed. PaCO2 was entered into the model as a continuous variable. A priori, identification of candidate co-variables for inclusion in the model was performed in two steps. First, we included patient characteristics and illness severity that were statistically significant in univariate analysis at p < 0.10. All variables were entered into a model and backwards elimination with a criterion of p < 0.05 for retention in the model was used. We then added in ventilator variables with clinically relevant differences that were statistically significant in univariate analysis at p < 0.10. Again backwards elimination was used with a criterion of p < 0.05 for retention in the final model. Statistical interactions and collinearity were assessed. Goodness-of-fit of the final model was evaluated with the Hosmer-Lemeshow test. To test if our model was correctly specified we used the linktest command in Stata. We performed several additional subgroup analyses for the primary outcome using multivariable logistic regression modeling (Supplemental material).

To test if a threshold effect between PaCO2 and survival existed, PaCO2 was entered into a logistic regression model as a categorical variable using ascending ranges (i.e. < 35, 35-45, 46-55, 56-65, > 65 mmHg), with 35-45 mmHg as the reference range. The model was adjusted for variables that were retained in the original model. Given PaCO2 is the function of gas exchange and minute ventilation we also forced VEcorr and initial minute ventilation into this model. Odds ratios for ascending PaCO2 ranges were graphed and this graph was visually inspected to assess if there was a threshold signal for survival over the PaCO2 ranges. For all models, robust standard errors to reduce the risk of type I error was used.

Finally, we performed a sensitivity analysis calculating the average treatment effect for hypercapnia (PaCO2 > 45 mmHg) compared to normocapnia (PaCO2 35-45 mmHg) using propensity score matching. The propensity that a patient had hypercapnia (i.e. propensity score) was modeled using logistic regression as a function of the co-variables. We used co-variables, which were included in the original logistic regression model to determine the propensity score. We then performed, nearest neighbor matching [with 0.15 set as the largest absolute difference compatible with a valid match (i.e. caliper width)] on the basis of hypercapnia exposure (yes/no) and the propensity score to calculate the average treatment effect for hypercapnia. We evaluated for covariate imbalance between the hypercapnia and matched normocapnia groups using Rubins' B (the absolute standardized difference of the means of the linear index of the propensity score in the hypercapnia and matched normocapnia groups) and Rubin's R (the ratio of the hypercapnia vs. matched normocapnia variances of the propensity score index). A Rubins' B <0.25 and a R between 0.5-2 is generally considered sufficiently balanced.(24)

Sample Size Calculation

For multivariable logistic modeling, it is common to assume an event per co-variable ratio of 10:1 is necessary to ensure adequate power.(25, 26) Our “event” in this study is non-survival to hospital discharge (i.e. the less frequent outcome). Based on the number of patients who did not survive to hospital discharge we were powered to evaluate 17 co-variables in a model.

Results

Six hundred patients met all inclusion and no exclusion criteria. Baseline characteristics of the entire cohort, as well as for survivors and non-survivors are shown in Table 1. The median (IQR) APACHE II score for the entire cohort was 17 (13-22). Non-survivors were more likely to have a malignancy compared to survivors. Non-survivors were also more likely to receive a vasopressor infusion, central venous catheter, or blood product transfusion.

Table 1.

Subject characteristics in the emergency department.

Variables All Subjects n = 600 Survivors n = 429 Non-survivors n = 171 p - values
Age [mean (SD)] 61 (16) 60 (16) 65 (16) <0.001
Female gender, n (%) 282 (47) 205 (48) 77 (45) 0.541
Race, n (%)
 Black 314 (52) 223 (52) 91 (53)
 White 277 (46) 202 (47) 75 (44) 0.170
 Other 9 (2) 4 (1) 5 (3)
Body mass index 27 (23-23) 27 (23-23) 25 (22-22) 0.020
Predicted body weight (kg) 65 (55-73) 66 (55-73) 64 (55-73) 0.929
Comorbidities, n (%)
 Chronic obstructive pulmonary disease 174 (29) 131 (31) 43(25) 0.189
 Malignancy 131 (22) 76 (18) 55 (32) <0.001
 Congestive heart failure 168 (28) 124 (29) 44 (26) 0.435
 Diabetes mellitus 229 (38) 170 (40) 59 (35) 0.243
 End stage renal disease 53 (9) 33 (8) 20 (12) 0.119
 Cirrhosis 46 (8) 28 (7) 18 (11) 0.096
APACHE II score 17 (13-13) 17 (13-13) 18 (14-14) 0.019
Mean arterial pressure (mmHg) 77 (63-97) 78 (63-97) 76 (63-98) 0.774
Hypotension (MAP < 65 mmHg), n (%) 169 (28) 117 (27) 52 (30) 0.441
ED Interventions
 IVF administration (L) 2 (1-1) 2 (1-1) 2 (1-1) 0.634
 Vasopressor infusion, n (%) 215 (36) 143 (33) 72 (42) 0.043
 Central line insertion, n (%) 267 (45) 178 (41) 89 (52) 0.019
 Blood product administration, n(%) 78 (13) 37 (9) 41 (24) <0.001
InitialLab values
 Creatinine (mg/dL) 1.36 (0.87-2.56) 1.35 (0.86-2.38) 1.45 (0.91-2.74) 0.167
 Total bilirubin (mg/dL) 0.5 (0.3-0.9) 0.5 (0.3-0.9) 0.6 (0.4-1.0) 0.002
 Platelets (× 103 / μL) 207 (146-283) 217 (159-293) 175 (107-252) <0.001
 INR 1.3 (1.1-1.6) 1.2 (1.1-1.5) 1.4 (1.2-1.8) <0.001
 Albumin (g/dL) 3.1 (2.6-3.6) 3.2 (2.7-3.7) 2.8 (2.3-3.5) <0.001
Culture positive, n (%) 470 (78) 328 (77) 142 (83) 0.085
Culture source, n (% of culture positive)
 Tracheal/BAL 268 (57) 198 (60) 70 (49) 0.026
 Urine 104 (22) 79 (24) 25 (18) 0.120
 Blood 142 (30) 84 (26) 58 (41) 0.001
 CSF 8 (2) 6 (2) 2 (1) 0.746
 Other 28 (6) 12 (4) 16 (11) 0.001
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Continuous variables are reported as median (interquartile range) unless otherwise noted.

APACHE, acute physiology and chronic health evaluation; BAL, branchoaveolar lavage; CSF, cerebral spinal fluid; ED, emergency department; INR, international normalized ratio; IVF, intravenous fluid; MAP, mean arterial pressure; SD, standard deviation.

Table 2 displays the post-intubation ventilator variables. The median (IQR) PaCO2 for the entire cohort was 42 (34-53) mmHg. The median (IQR) was significantly higher among survivors compared to non-survivors [44 (35-57) vs. 39 (31-45) mmHg respectively, p < 0.001]. PaCO2 was found to have a strong correlation with VEcorr (r = 0.81, p < 0.001), but only a modest correlation with pH (r = -0.48, p < 0.001). Non-survivors and survivors had similar PaO2 [148 (92-208) vs. 132 (88-204) respectively, p = 0.128].

Table 2. Post-intubation ventilator variables.

Variables All Subjects n = 600 Survivors n = 429 Non-survivors n = 171 p - values
Initial ventilator settings
 Tidal volume (mL/kg PBW) 7.3 (6.4-8.7) 7.3 (6.4-8.5) 7.6 (6.7-9.1) 0.063
 Lung-protective tidal volume,a n (%) 378 (63) 274 (64) 104 (61) 0.485
 Respiratory rate 16 (14-14) 16 (14-14) 15 (14-14) 0.182
 Minute Ventilation (mL/kg PBW*min) 122 (105-141) 122 (104-144) 122 (105-140) 0.777
 FiO2 100 (50-100) 100 (50-100) 100 (60-100) 0.010
 PEEP 5 (5-5) 5 (5-5) 5 (5-5) 0.035
Initial arterial blood gas measurements
 pH 7.31 (7.22-7.40) 7.30 (7.21-7.39) 7.33 (7.24-7.42) 0.239
 PaCO2 (mmHg) 42 (34-53) 44 (35-57) 39 (31-45) <0.001
 PaO2 (mmHg) 137 (89-204) 132 (88-204) 148 (92-208) 0.128
 Hypoxia (PaO2 < 60 mmHg), n (%) 31 (5) 26 (6) 5 (3) 0.117
 PaO2/ FiO2 211 (132-305) 212 (135-312) 206 (125-298) 0.371
 Corrected minute ventilation (L/kg*min) 8.1 (6.2-10.8) 8.5 (6.5-11.3) 7.4 (5.9-9.2) <0.001
Initial pulmonary Mechanics
 Plateau pressure (cm H2O) 20 (17-17) 20 (17-17) 20 (17-17) 0.302
 Plateau pressure >30 cm H2O, n (%) 55 (9) 34 (8) 21 (12) 0.097
 Static compliance (mL/ cm H20) 33 (26-46) 33 (26-46) 33 (25-46) 0.916
 Driving pressure (cm H2O) 15 (11-11) 15 (11-11) 15 (11-11) 0.558
Intensive care unit
 Tidal volume (mL/kg PBW) 8 (7-7) 8 (7-7) 8 (7-7) 0.329
 Lung-protective tidal volume,a n (%) 396 (66) 284 (66) 112 (66) 0.870
 FiO2 44 (40-51) 43 (40-49) 47 (41-59) <0.001
 PEEP 5 (5-5) 5 (5-5) 5 (5-5) 0.143
 pH 7.39 (7.35-7.43) 7.39 (7.36-7.43) 7.37 (7.32-7.42) 0.002
Duration of mechanical ventilation (hours) 103 (52-197) 103 (52-197) 103 (52-194) 0.920
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a

tidal volume of ≤ 8 mL/kg predicted body weight (PBW).

FiO2, fraction of inspired oxygen; PaO2, partial pressure of arterial oxygen; PaCO2; partial pressure of arterial carbon dioxide; PEEP, positive end expiratory pressure;

Seventy-two percent (429/600) of subjects survived to hospital discharge. Table 3 displays the multivariable logistic regression model with PaCO2 treated as a continuous variable and survival to hospital discharge as the dependent variable. After adjusting for all identified significant confounders, elevated PaCO2 was an independent predictor of survival to hospital discharge [aOR 1.03, 95% confidence interval (CI) 1.01-1.04, p = 0.001]. Thus for every 1 mmHg rise in PaCO2 the odds of survival to hospital discharge increased by 3%. Our final model was found to have good fit (Hosmer-Lemeshow test, p = 0.73), and to be correctly specified (ŷ, p < 0.001; ŷ2, p = 0.88). These results remained consistent across multiple subgroup analyses (Supplemental material).

Table 3.

Final multivariable logistic regression model with partial pressure of arterial carbon dioxide (PaCO2) entered as a continuous variable and survival to hospital discharge as the dependent variable.

Variables Odds Ratio 95% CI p-value
PaCO2 1.03 1.01 - 1.04 0.001
Agea 0.77 0.67 - 0.89 <0.001
Malignancy 0.41 0.26 - 0.65 <0.001
Initial total bilirubin 0.68 0.51 - 0.91 0.010
Blood product administered 0.47 0.26 - 0.86 0.013
Positive culture 0.56 0.34 - 0.93 0.025
ICU FiO2 0.96 0.94 - 0.98 <0.001
ICU pH 1.63 1.25 - 2.11 <0.001
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a

Calibrated for a rise of 10 years. CI, confidence interval; ED, emergency department; FiO2, fraction of inspired oxygen; ICU, intensive care unit

Removed for non-significance: ED Acute Physiology and Chronic Health Evaluation (APACHE) II score (p = 0.701); vasopressor infusion (p = 0.648); initial international normalized ratio (INR) (p = 0.566); body mass index (p = 0.528): liver cirrhosis (p = 0.494); central venous catheter insertion (p = 0.328); initial albumin (p = 0.074); corrected minute ventilation for a normal PaCO2 (VEcorr) (p = 0.713); initial tidal volume (p = 0.618); initialpositive end expiratory pressure (p = 0.169); initial FiO2 (p = 0.357); initial platelets (p = 0.077); initial plateau pressure (p = 0.216).

Figure 1 displays odds ratios for survival to hospital discharge across ascending ranges of PaCO2. We found increased odds of survival to hospital discharge among all PaCO2 ranges above 45 mmHg compared to the reference range of 35-45 mmHg, after adjusting for VECorr and initial minute ventilation.

Figure 1.

Figure 1

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Adjusted odds ratios (circles) with 95% confidence intervals (horizontal lines) for survival to hospital discharge across ascending partial pressure of arterial carbon dioxide ranges.

*Odds ratios were calculated using multivariable logistic regression analysis (reference range 35-45 mmHg) adjusting for age, malignancy, initial total bilirubin, ED blood product administration, positive culture, intensive care unit (ICU) faction of inspired oxygen, ICU pH, corrected minute ventilation for a normal PaCO2 (VEcorr), and initial minute ventilation.

Two hundred and thirty patients were found to have hypercapnia and 210 subjects had normocapnia. Survival to hospital discharge occurred in 83% vs. 68% of patients with hypercapnia vs normocapnia respectively (p < 0.001). Using propensity score matching, we were able to include 206 subjects in the normocapnia group and 221 in the hypercapnia group and found the average treatment effect for hypercapnia was 0.17 (95% CI 0.07-0.27, p = 0.001). This suggests that hypercapnia increased the probability of survival to hospital discharge by 17%. The Rubins B was 0.21 and Rubins R was 1.34.

Discussion

In this study we analyzed 600 mechanically ventilated sepsis patients and tested the association between PaCO2 after initiation of mechanical ventilation and survival to hospital discharge. After adjusting for multiple potential confounders and performing propensity score matching we found higher PaCO2 levels to be independently associated with survival to hospital discharge in this patient population. Given that elevated PaCO2 can be a marker of minute ventilation, we adjusted our original model for initial tidal volume, and adjusted our sensitivity model for initial minute ventilation. When entered into the model with PaCO2, tidal volume was removed for non-significance, suggesting that the association between PaCO2 and survival is independent of the tidal volume. Our findings remained consistent across several sensitivity and subgroup analyses, even when adjusted for other ventilator settings, severity of illness, and lactate acid production. These findings suggest hypercapnia during the initial mechanical ventilation period may be beneficial in patients with severe sepsis.

The effects of PaCO2 among critically ill patients have been unclear. Several studies have suggested a beneficial effect of hypercapnia in the setting of sepsis. Hypercapnia has been demonstrated to attenuate key components of the over-amplified inflammatory pathways seen in sepsis, as well as to reduce the severity of lung injury. First, hypercapnia decreases tumor necrosis factor-α and interleukin (IL)-1 production, which contributes to tissue injury in septic patients.(27, 28) Second, hypercapnia attenuates neutrophil activity through lowered intracellular pH.(29, 30) Third, in pulmonary endothelial cells, hypercapnia decreases the DNA-binding activity of nuclear factor (NF)-κB, a regulator of pro-inflammatory pathways. This decreased binding attenuates IL-8 production, with a corresponding decrease in endothelial cell injury.(31) Fourth, hypercapnia has been demonstrated to reduce endogenous nitric oxide (NO).(15, 32, 33) Endogenous NO production resulting from high-pressure mechanical ventilation has been demonstrated to be harmful in models of endotoxemia.(34) In addition, hypercapnia suppression of endogenous NO production has been demonstrated to augment hypoxic pulmonary vasoconstriction, resulting in improved ventilation-perfusion matching.(33) Finally, hypercapnia can inhibit bacterial growth, thus decreasing the overall infectious insult.(16)In summary, our findings are biologically plausible and congruent with the pre-clinical data that demonstrates a potential beneficial role to manipulating PaCO2 to improve outcome in septic patients.

Our results differ from previous observational studies of patients with community-acquired pneumonia, which found an association between hypercapnia and in-hospital mortality.(35, 36) However, it is possible that in these previous studies hypercapnia was a marker of increased dead-space(37) (i.e. worse pneumonia) as opposed to the cause of poor outcomes. The strong correlation between PaCO2 and VEcorr in our study, suggests elevated PaCO2 could be a marker for dead-space. However, we entered VEcorr into our logistic regression model, as previously described,(10) and found when PaCO2 and VEcorr were entered into the model together, VEcorr was not found to be significantly associated with survival (removed from the final model for non-significance). This suggests PaCO2 was associated with survival independent of dead-space. A recent secondary analysis of three cohort studies found an association between severe hypercapnia (PaCO2 ≥ 50 mmHg) and mortality among patients with ARDS after adjusting for VEcorr.(10) Our study excluded patients with ARDS and it is likely that our cohort was less ill compared to those patients with ARDS upon presentation to the ED. The differences in the relationship between PaCO2 and survival between these two studies may suggest PaCO2 is associated with worse outcomes in patients who already have a high degree of lung injury and increased dead-space,(10, 35, 36) while conferring a beneficial effect on subjects at risk for severe lung injury.(14, 15, 38) In addition, patients with ARDS can have a higher degree of dead-space, which may not be completely corrected for by VEcorr.

This study has several limitations. First, this observational cohort study can only describe associations and cannot suggest causal inference. Although we used VEcorr as a marker for dead-space, there still remains the possibility that elevated PaCO2 is a marker for dead-space and not independently associated with survival. However, given increased dead-space has been demonstrated to be associated with mortality in mechanically ventilated patients, the positive association between PaCO2 and dead-space is unlikely to confound the association between PaCO2 and survival in a positive direction. In addition, although we used multivariable logistic regression analyses to adjust for multiple potential confounders, there still exists the possibility that an unmeasured PaCO2-associated confounder drove the observed association between hypercapnia and survival, thus our results must be interpreted with caution. Second, hypercapnia may also reflect a patient population that is less ill and therefore has a higher likelihood to survive. A higher APACHE II score in the hypercapnic group compared to the non-hypercapnic group [median (IQR) 19 (14-24) vs. 16 (12-21) respectively, p < 0.001] suggests that this was not the case. Third, we analyzed the initial PaCO2 after mechanical ventilation as a surrogate for total post-intubation PaCO2 exposure similar to methodologies used in previous studies of other disease processes.(39, 40) However, there was no standardization with respect to the time to analysis. While our study is representative of real-world care, it is possible that it does not accurately represent the true PaCO2 exposure (i.e. measurement bias). Finally, although there was no association between initial pH and survival to hospital discharge, we did find a lower pH during ICU stay to be associated with increased in-hospital mortality. Given the interdependence of PaCO2 and pH, any clinical intervention to intentionally maintain an elevation of PaCO2 will lead to a lower pH, possibly negating some (if not all) of the potential benefit. However, we found only a moderate correlation between initial PaCO2 and initial pH with an r2 = 0.23, suggesting PaCO2 is only responsible for 23% of the variation in pH. As such these findings should be considered hypothesis generating and further research is warranted to determine the clinical implications of targeting hypercapnia in this patient population.

Conclusion

In this cohort study of mechanically ventilated sepsis patients, we found increasing PaCO2 levels are associated with increased survival to hospital discharge. These findings suggest that permissive hypercapnia is safe among patients diagnosed with sepsis in the ED and future clinical investigation into early manipulation of PaCO2in this patient population is warranted.

Supplementary Material

Supplemental Data File _.doc_ .tif_ pdf_ etc._

Acknowledgments

Funding: BMF and AMD were funded by the KL2 Career Development Award, and this research was supported by the Washington University Institute of Clinical and Translational Sciences (Grants UL1 TR000448 and KL2 TR000450) from the National Center for Advancing Translational Sciences (NCATS). BMF was also funded by the Foundation for Barnes-Jewish Hospital Clinical and Translational Sciences Research Program (Grant # 8041-88). AMD was also funded by the Foundation for Anesthesia Education and Research. NMM was supported by grant funds from the Health Resources and Services Administration. EAA was supported by Washington University School of Medicine Faculty grant and the Foundation for Barnes Jewish Hospital grant. MHK was supported by the Barnes-Jewish Hospital Foundation. BWR was supported by a grant from the National Institutes of Health/National Heart, Lung, and Blood Institute (K23HL126979).

Dr. Roberts, Drewry, and Fuller received support for article research from National Institutes of Health (NIH). Dr. Roberts' institution received funding from National Heart, Lung, and Blood Institute. Dr. Ablordeppey's institution received funding from the Washington University School of Medicine and the Barnes Jewish Hospital Foundation. Dr. Drewry's institution received funding from the NIH. Dr. Fuller's institution received funding from the Foundation for Barnes-Jewish Hospital Clinical and Translational Sciences Research Program (Grant # 8041-88) and a KL2 Career Development Award, and this research was supported by the Washington University Institute of Clinical and Translational Sciences (Grants UL1 TR000448 and KL2 TR000450) from the National Center for Advancing Translational Sciences (NCATS).

Footnotes

Clinical Trial Registration: ClinicalTrials.gov Identifier NCT02543554

Declarations of interests: All authors declare no competing interests.

Contributors: BMF and BWR conceived the study. ITF and BMF were responsible for acquisition and quality of the data. BWR did the analysis. All authors were involved in interpretation of the data and participated in writing and revision of the manuscript. BMF and BWR wrote the first and final draft.

Copyright form disclosure: The remaining authors have disclosed that they do not have any potential conflicts of interest.

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