End-tidal to arterial carbon dioxide gradient is associated with increased mortality in patients with traumatic brain injury: a retrospective observational study

Early definitive airway protection and normoventilation are key principles in the treatment of severe traumatic brain injury. These are currently guided by end tidal CO2 as a proxy for PaCO2. We assessed whether the difference between end tidal CO2 and PaCO2 at hospital admission is associated with in-hospital mortality. We conducted a retrospective observational cohort study of consecutive patients with traumatic brain injury who were intubated and transported by Helicopter Emergency Medical Services to a Level 1 trauma center between January 2014 and December 2019. We assessed the association between the CO2 gap—defined as the difference between end tidal CO2 and PaCO2—and in-hospital mortality using multivariate logistic regression models. 105 patients were included in this study. The mean ± SD CO2 gap at admission was 1.64 ± 1.09 kPa and significantly greater in non-survivors than survivors (2.26 ± 1.30 kPa vs. 1.42 ± 0.92 kPa, p < .001). The correlation between EtCO2 and PaCO2 at admission was low (Pearson's r = .287). The mean CO2 gap after 24 h was only 0.64 ± 0.82 kPa, and no longer significantly different between non-survivors and survivors. The multivariate logistic regression model showed that the CO2 gap was independently associated with increased mortality in this cohort and associated with a 2.7-fold increased mortality for every 1 kPa increase in the CO2 gap (OR 2.692, 95% CI 1.293 to 5.646, p = .009). This study demonstrates that the difference between EtCO2 and PaCO2 is significantly associated with in-hospital mortality in patients with traumatic brain injury. EtCO2 was significantly lower than PaCO2, making it an unreliable proxy for PaCO2 when aiming for normocapnic ventilation. The CO2 gap can lead to iatrogenic hypoventilation when normocapnic ventilation is aimed and might thereby increase in-hospital mortality.

Treatment recommendations in traumatic brain injury (TBI) include early definitive airway protection as well as normoventilation with a target arterial partial pressure of CO 2 (PaCO 2 ) of 4.6-5.9 kPa (35-45 mmHg) 1,2 . The effects of hypo-or hyperventilation on cerebral blood flow (CBF), with the potential for hypoxemia or hyperemia of cerebral tissue and their negative impact on outcome, have been widely studied [3][4][5][6][7] . Using PaCO 2 to monitor ventilation requires arterial blood gas (ABG) analyses, but the necessary lab equipment is not yet widely available in the prehospital environment. Therefore end-tidal CO 2 (EtCO 2 ) determined by capnography has been used as a surrogate marker to estimate PaCO 2 assuming a reliable correlation between EtCO 2 and PaCO 2 8 . Capnography is considered the gold standard, both to determine correct placement of a definitive airway and to guide ventilation during emergency care 9,10 . The assumed correlation between EtCO 2 and PaCO 2 has been Scientific Reports | (2021) 11:10391 | https://doi.org/10.1038/s41598-021-89913-x www.nature.com/scientificreports/ known to be accompanied by a tension difference of CO 2 ranging anywhere between 0.26 and 0.66 kPa (2 and 5 mmHg) in otherwise healthy individuals undergoing anesthesia [11][12][13][14][15][16] . However, major trauma accompanying TBI can negatively influence ventilation and perfusion, making the interpolation of PaCO 2 from EtCO 2 in trauma patients unreliable [17][18][19] . As expected, subgroup analyses have shown the best correlation between EtCO 2 and PaCO 2 in isolated TBI when compared to other trauma patients 20 .
The primary aim of this study is to describe the correlation between EtCO 2 and PaCO 2 at the time of admission in patients hospitalized with TBI. Furthermore, we investigated the predictive value of tension difference of CO 2 between EtCO 2 and PaCO 2 (CO 2 gap) for in-hospital mortality.

Methods
Study participants, setting and ethics approval. This retrospective observational single-center cohort study included all consecutive patients with TBI who were intubated on the scene and transported by the helicopter emergency medical service (HEMS) (Swiss Air-Rescue, Rega) to a Level 1 trauma center (Kantonsspital St. Gallen, Switzerland) between January 1st of 2014 and December 31st of 2019. Exclusion criteria were patients who were not intubated before admission, patients with traumatic injuries requiring intubation for other reasons than TBI, and secondary transport missions including patients with traumatic brain injury who were transported from another hospital to this trauma center.
The local ethics committee of St. Gallen (EKOS) granted permission to use patient data without individual consent according to the federal act on research involving human beings and the ordinance on human research with the exception of clinical trials. The permission also covered the use of patient data regarding the HEMS operation (EKOS St. Gallen 7.7.2020, BASEC Nr. 2020-01737 EKOS 20/122).

Data and definitions.
Baseline characteristics of patients were obtained from electronic hospital records.
Laboratory findings were obtained by automated retrieval using the unique patient identification number in the hospital records. EtCO 2 was measured using main-stream capnographs (ZOLL Medical Corporation, Chelmsford, USA). Information on the ventilator settings at admission was prospectively entered into the patients' electronic hospital records.
Outcome information (i.e., survival status) was documented prospectively as part of the routine electronic hospital records and obtained from the corresponding record.
The Injury Severity Score Thorax was determined at admission. EtCO 2 , systolic blood pressure, pulse and SpO 2 were recorded on admission to the Emergency Room (ER) as well as 24 h after admission.

Statistics.
Patients' characteristics were summarized and presented in tables. Continuous variables were summarized by mean ± SD (standard deviation) if normally distributed or by median and IQR (interquartile range) if skewed. Normality was tested using the Shapiro-Wilk test. Categorical variables were summarized with counts and percentages for each level of the variable. Outliers were assessed using the Grubbs test for continuous variables if normally distributed.
Correlation between EtCO 2 and PaCO 2 was assessed using Pearson's correlation coefficient and visualized using a scatter plot. Disagreement between EtCO 2 and PaCO 2 was visualized using a Bland-Altman plot 21 . To assess the impact of the time interval between the initial arterial blood gas sample and the first recorded EtCO 2 at admission, a linear regression was conducted.
Differences in the CO 2 gap between survivors and non-survivors were tested using the Mann-Whitney-Wilcoxon Test. The association between the CO 2 gap and the in-hospital mortality was further assessed using univariate and multivariable logistic regression models. To minimize confounding, variables potentially associated with the respiratory system and in-hospital mortality were defined a priori based on a literature review and clinical experience 22 . The variables included age, heart rate, systolic blood pressure, peripheral capillary oxygen saturation, pressure of oxygen in arterial blood (paO2), and severity of chest injury documented by the ISS (Injury Severity Score) thoracic sub-score. All variables were coded as continuous variables. Complete case analyses were performed due to the low number of missing data and therefore the low risk of bias.
Two-sided p-values of < 0.05 were considered as statistically significant. All statistical analyses were performed using R Studio 3.6.0 on macOS 10.15.7.
Ethics approval and consent to participate. The local ethics committee of St. Gallen (EKOS) granted permission to use patient data without individual consent according to the federal act on research involving human beings and the ordinance on human research with the exception of clinical trials. The permission also covered the use of patient data regarding the HEMS operation (EKOS St. Gallen 7.7.2020, BASEC Nr. 2020-01737 EKOS 20/122).

Results
This study adheres to the STROBE Statement (Strengthening the Reporting of Observational Studies in Epidemiology) 23 . From January 2014 to December 2019 a total of 181 patients were admitted to our trauma center by HEMS after TBI and intubation. Seventy-six patients were excluded. Reasons were mechanisms of injury besides TBI, an alternate reason for unconsciousness, missing ISS, EtCO 2 or PaCO 2 data, or early extubation in the ER.
Of the 105 patients admitted to the ICU, 28 (27%) died and 77 (73%) were discharged alive. Information on neurological function at discharge was not available.  Table 1. Of note, non-survivors were on average more than 20 years older than survivors and had a lower PaO 2 in the initial blood gas samples, p < 0.001.
The correlation between EtCO 2 and PaCO 2 at admission was low, Pearson's r = 0.287, Fig. 1. There was a significant difference between EtCO 2 and PaCO 2 at admission. The overall mean CO 2 gap at admission was 1.64 ± 1.09 kPa and significantly larger in non-survivors than survivors, 2.26 ± 1.30 kPa vs. 1.42 ± 0.92 kPa, p < 0.001, see Table 2 and Figs. 2 and 3. The majority of EtCO 2 and PaCO 2 pairs were obtained within 30 min, n = 60, 57%. However, there was no significant association between the time intervals of the first arterial blood gas sampling and the first documented EtCO 2 on the CO 2 gap in a univariate linear regression, p = 0.165.
The overall CO 2 gap decreased to 0.64 ± 0.82 kPa at 24 h after admission and was no longer significantly different between non-survivors and survivors, 0.78 ± 0.70 kPa vs. 0.58 ± 0.86, p = 0.108, see Table 2 and Fig. 2.
The multivariate logistic regression model showed that the CO 2 gap was independently associated with increased mortality in intubated and mechanically ventilated patients with TBI. For every increase of the CO 2 gap by 1 kPa, mortality was 2.7 times higher, OR 2.692, 95% CI 1.293-5.646, p = 0.009. Higher age was independently associated with an increased mortality rate as well, OR 1.842 for every increase of 10 years, 95% CI 1.106-2.641, p = 0.001. Systolic blood pressure, heart rate, thoracic trauma, SpO 2 and PaO 2 were not associated with survival status in this multivariate model, see Table 3 and Fig. 4. Inclusion of further parameters from the arterial blood gas samples (ABG samples), the total ISS, or other cardiopulmonary parameters in the regression model led to multicollinearity; these parameters were therefore excluded from the final model.

Discussion
Our results show that end-tidal capnography is an unreliable tool for monitoring and targeting invasive ventilation at least in the initial treatment of patients with severe TBI. Although the majority of the patients in this study were ventilated within the target range of EtCO 2 values, many were unwittingly hypercapnic in the first blood gas sample after arriving in the hospital. Our data show a large variability in the calculated CO 2 gap in this patient cohort and it was more pronounced in patients with lower EtCO 2 . This underestimation of PaCO 2 when EtCO 2 was used to guide ventilation caused hypoventilation despite normal EtCO 2 values. An increased CO 2 gap and the resulting hypercapnia were associated with increased in-hospital mortality. This underlines the clinical importance of these findings and the need for either a more reliable surrogate parameter for PaCO 2 estimation or early PaCO 2 sampling in the prehospital management of patients with TBI. including ventilation-perfusion mismatch, increased dead space, or, shock with impaired perfusion and temperature 11,24 . However, most of these factors influencing the CO 2 gap are not measurable, detectable or predictable in the initial treatment period in the field or ER. The ability to predict or gauge the CO 2 gap based on the patient's condition is consequently limited. In this context the CO 2 gap might be both, an indicator of severity of injury, and a predictor of impaired survival in patients with severe traumatic brain injury. Two recent publications investigated the CO 2 gap in critically ill patients after prehospital emergency anesthesia 25,26 . Their findings are in line with our results and showed only moderate correlation between EtCO 2 and PaCO 2 , confirming that EtCO 2 alone should be used with caution to guide ventilation in the critically ill.
This was further strengthened by our data wherein, the CO 2 gap (visualized as mean bias on the Bland-Altman plots) was more pronounced in patients with lower EtCO 2 values demonstrating that patients with EtCO 2 measures within the target range (4.6-5.9 kPa) were unwittingly hypercapnic.  showed an association between an increased CO 2 gap and in-hospital mortality 24 h after return of spontaneous circulation (ROSC). Our data is in line with these findings and reinforces the plausibility of this association by controlling for potential confounding due to shock or hypoperfusion in a multivariate logistic regression model. EtCO 2 as a surrogate marker. PaCO 2 is considered to be the major determinant of cerebral blood flow (CBF) through its effects on cerebral vascular tone 27 . This reinforces the importance of precise ventilatory control in the initial management of TBI. It is known that even modest hypercapnia can result in substantial increases in ICP and can cause dangerous cerebral ischemia when intracranial compliance is poor 28 . Therefore, we hypothesize that the hypoventilation due to underestimation of the arterial CO 2 using EtCO 2 as a surrogate marker leads to impaired CBF and thereby increases mortality.
Recent TBI guidelines rely on the assumption that the CO 2 gap is approximately 0.5 kPa (3.8 mmHg). However, these assumptions are based on data of individuals undergoing general anesthesia without major comorbidities or trauma 11,29 . In this study, the mean first EtCO 2 was 4.6 ± 0.78 kPa, whereas the mean PaCO 2 was 6.26 ± 1.03 kPa and far in excess of the target of 4.5-5.0 kPa. Therefore, relying on EtCO 2 as a surrogate for PaCO 2 provides a false sense of security, and providers may not achieve optimal prehospital PaCO 2 . At present, no reliable alternative to direct ABG sampling seems to exist in order to approximate PaCO 2 reliably.
However, to our best knowledge, there is no data supporting the routine use of point-of-care blood gas analyses in patients mechanically ventilated in the field. This lack of data could be due to the fact that up to now the importance of point-of-care testing in prehospital care has been underestimated, due to the high reliance on proxy markers like EtCO 2 . Further studies on the optimal timing of sampling after intubation and the beginning of mechanical ventilation, as well as the optimal sampling interval, are needed. We postulate that a single ABG sample post-intubation could gauge the individual CO 2 gap and ensure more reliable EtCO 2 -guided ventilation. The mean CO2 gap lines are trimmed, illustrating the EtCO2 range for both groups, respectively. Difference between PaCO2 and EtCO2 was highly significant for the initial pairs (p < 0.001) but not for the pairs after 24 h (see Table 2 www.nature.com/scientificreports/ Factors influencing mortality. Our data showed a significant age difference between survivors and nonsurvivors. Age was independently and significantly associated with mortality. Besides the fact that age might be a surrogate for unrecognized confounders due to comorbidities that negatively influence mortality, clinical decision-making may also play a role. In daily routine, palliation might be considered at an earlier stage in elderly trauma victims with limited rehabilitation potential, whereas younger trauma patients may receive maximum therapeutic interventions 30 . In our cohort, systolic blood pressure and ISS thorax scores were not significantly associated with mortality in the multivariate analysis.
Limitations. This study had several limitations. First, it is a retrospective and single-center cohort study with a limited sample size. However, data was almost complete and multivariate adjustments were performed. Second, in order to increase the number of eligible patients in this study, we included patients who had an ABG sample up to 30 min after hospital arrival. However, a sensitivity analysis showed that the observed gradient between EtCO 2 and PaCO 2 was not significantly associated with the time between arterial blood gas sampling and the documented EtCO 2 . Still, it is possible that a proportion of the gradient between EtCO 2 and PaCO 2 was due to changes in ventilation settings during this period. Furthermore, if this time difference was longer than 15 min apart there was no second set of hemodynamic data to statistically evaluate at these two different timepoints.
Lastly, ventilation mode selected in the preclinical setting was not taken into account in analysis of the data. We cannot exclude bias through varying influence of ventilation mode on dead space.

Conclusions
The CO 2 gap is an inconsistent phenomenon in pre-hospital anesthetized TBI patients, making EtCO 2 an unreliable proxy for PaCO 2 when aiming for normocapnic ventilation. The higher-than-expected CO 2 gap can lead to iatrogenic hypoventilation when normocapnic ventilation is aimed for and might thereby increase in-hospital mortality."

Data availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Twelve patients were excluded from the multivariate analysis due to missing data (see Table 1). Units of measure and abbreviations as described in Tables 1 and 2.