End-tidal to arterial carbon dioxide gradient in traumatic brain injury after prehospital emergency anesthesia is associated with in-hospital mortality: a retrospective observational study

Background Early denitive airway protection and normoventilation are key principles in the treatment of severe traumatic brain injury. These are currently guided by end tidal CO 2 as a proxy for PaCO 2 . We assessed whether the difference between end tidal CO 2 and PaCO 2 at hospital admission is associated with in-hospital mortality. Method 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 CO 2 gap—dened as the difference between end tidal CO 2 and PaCO 2 —and in-hospital mortality using multivariate logistic regression models. Results 105 patients were included in this study. The mean ±SD CO 2 gap at admission was 1.64 (± 1.09) kPa and signicantly greater in non-survivors than survivors (2.26 ±1.30 kPa vs. 1.42 ±0.92 kPa, p<.001). The correlation between EtCO 2 and PaCO 2 at admission was low (Pearson's r=.287). The mean CO 2 gap after 24 hours was only 0.64 ±0.82 kPa, and no longer signicantly different between non-survivors and survivors. The multivariate logistic regression model showed that the CO 2 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 CO 2 gap (OR 2.692, 95% CI 1.293 to 5.646, p=.009). Conclusions This study demonstrates that the difference between EtCO 2 and PaCO 2 is signicantly associated with in-hospital mortality in patients with traumatic brain injury. EtCO 2 was signicantly lower than PaCO 2 , making it an unreliable proxy for PaCO 2 when aiming for normocapnic ventilation. The higher-than-expected CO2 gap will lead to iatrogenic hypoventilation when normocapnic ventilation is aimed at, and might thereby increase in-hospital mortality.


Background
Treatment recommendations in traumatic brain injury (TBI) include early de nitive airway protection as well as normoventilation with a target arterial partial pressure of CO 2 (PaCO 2 ) of 4.6-5.9 kPa (35 to 45 mmHg) [1,2]. The effects of hypo-or hyperventilation on cerebral blood ow (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 de nitive airway and to guide ventilation during emergency care [9,10]. The assumed correlation between EtCO 2 and PaCO 2 has been known to be accompanied by a tension difference of CO 2 ranging anywhere between 0.26 and 0.66kPa (2 and 5 mmHg) in otherwise healthy individuals undergoing anesthesia [11][12][13][14][15][16].
However, major trauma accompanying TBI can negatively in uence 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.

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 de nitions
Baseline characteristics of patients were obtained from electronic hospital records. Laboratory ndings were obtained by automated retrieval using the unique patient identi cation number in the hospital records. EtCO 2 was measured using main-stream capnographs. 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 analyzed on admission to the Emergency Room (ER) as well as 24 hours 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 coe cient and visualized using a scatter plot. Disagreement between EtCO 2 and PaCO 2 was visualized using a Bland-Altman plot [21]. 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 a multivariable logistic regression model. To minimize confounding, variables potentially associated with the respiratory system and in-hospital mortality were de ned 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. As a sensitivity analysis, the association of the time difference between the initial arterial blood gas sample and the rst recorded EtCO 2 was explored using a univariate linear regression model. Two-sided p-values of <0.05 were considered as statistically signi cant. All statistical analyses were performed using R Studio 3.6.0 on macOS 10.15.7.

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.
The patients' baseline characteristics are displayed in 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=.287, Figure 1. There was a signi cant difference between EtCO 2 and PaCO 2 at admission. The overall mean CO 2 gap at admission was 1.64 ±1.09 kPa and signi cantly larger in non-survivors than survivors, 2.26 ±1.30 kPa vs. 1.42 ±0.92 kPa, p<.001, see Table 2 and Figure 2. Of note, the CO 2 gap (visualized as mean bias on the Bland-Altman plots) was more pronounced in patients with lower EtCO 2 values. This demonstrates that patients with EtCO 2 measures within the target range (4.6 to 5.9 kPa) were unwittingly hypercapnic [1,2]. The overall CO 2 gap decreased to 0.64 ±0.82 kPa at 24h after admission and was no longer signi cantly different between non-survivors and survivors, 0.78 ±0.70 kPa vs. 0.58 ±0.86, p=.108, see Table 2 and Figure 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 to 5.646, p=.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 to 2.641, p=.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 Figure 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 nal model.
The majority of EtCO 2 and PaCO 2 pairs were obtained within 30 minutes, n=60, 57%. As a sensitivity analysis the impact of the time interval between arterial blood gas sampling and the documentation of EtCO 2 from monitors on the CO 2 gap was assessed in a univariate linear regression model. This association was not signi cant, p=.165.

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 rst 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 ndings 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.

The CO 2 gap
Previous studies have observed that the CO 2 gap is multifactorial, with possible causes including ventilation-perfusion mismatch, increased dead space, or, shock with impaired perfusion and temperature [11,24]. However, most of these factors in uencing the CO 2 gap are not measurable, detectable or predictable in the initial treatment period in the eld 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 ndings are in line with our results and showed only moderate correlation between EtCO 2 and PaCO 2 , con rming that EtCO 2 alone should be used with caution to guide ventilation in the critically ill.
In a cohort of cardiac arrest patients, Suominen et al. showed an association between an increased CO 2 gap and in-hospital mortality 24 hours after return of spontaneous circulation (ROSC). Our data is in line with these ndings 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 ow (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 rst 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 to 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 eld. 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.

Factors in uencing mortality
Our data showed a signi cant age difference between survivors and non-survivors. Age was independently and signi cantly associated with mortality. Besides the fact that age might be a surrogate for unrecognized confounders due to comorbidities that negatively in uence mortality, clinical decisionmaking 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 signi cantly 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 signi cantly 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.

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 unaware iatrogenic hypoventilation and consequently hypercapnia, which is associated with increased in-hospital mortality.

Declarations
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).

Consent for publication
Consent for publication was waived as per the ethics approval.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests

Funding
The authors received no nancial support for the research, authorship, and/or publication of this article.
Authors' contributions UP, LM and PD designed the study. PD and UP performed Data collection. LM performed statistical analysis. UP, LM and PD drafted and nalized the manuscript. SJS, MF, JK, AE and RA reviewed the manuscript. All authors read and approved the nal version of the manuscript.
Data was complete if not otherwise speci ed. Continuous variables are reported as mean ± SD = (standard deviation) if normally distributed and not stated otherwise. BP = blood pressure; IQR = Interquartile range; ISS = injury severity score; bpm = beats per minute; SpO 2 = peripheral capillary oxygen saturation. * PaCO 2 = Same parameter as shown in detail on Table 2 (initial measure). Data was complete. Numbers are presented with percentages of total in parentheses. Continuous variables are reported as mean ± SD (standard deviation). The CO 2 gap and the PaCO 2 variables were skewed; however, the mean ± SD was presented due to the use of these parameters in the Bland-Altman plots. CO 2 gap = PaO 2 -EtCO 2 Complete case analysis available for 93 patients. Twelve patients were excluded from the analysis due to missing data (see Table 1). Units of measure and abbreviations as described in Tables 1 and 2. for the same data. The red and blue lines illustrate the mean CO2 gap for deceased and surviving patients, respectively. The mean CO2 gap lines are trimmed, illustrating the EtCO2 range for both groups, respectively. Difference between PaCO2 and EtCO2 was highly signi cant for the initial pairs (p<0.001) but not for the pairs after 24 hours (see Table 2).