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

doi:10.21203/rs.3.rs-157789/v1

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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

https://doi.org/10.21203/rs.3.rs-157789/v1

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Background 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.

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 CO₂ gap—defined as the difference between end tidal CO₂ and PaCO₂—and in-hospital mortality using multivariate logistic regression models.

Results 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 hours 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).

Conclusions 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 higher-than-expected CO2 gap will lead to iatrogenic hypoventilation when normocapnic ventilation is aimed at, and might thereby increase in-hospital mortality.

Critical Care & Emergency Medicine

HEMS

prehospital anesthesia

TBI

end-tidal to arterial carbon dioxide gradient

Treatment recommendations in traumatic brain injury (TBI) include early definitive airway protection as well as normoventilation with a target arterial partial pressure of CO₂ (PaCO₂) of 4.6-5.9 kPa (35 to 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 [3–7]. Using PaCO₂ 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 CO₂ (EtCO₂) determined by capnography has been used as a surrogate marker to estimate PaCO₂assuming a reliable correlation between EtCO₂ and PaCO₂[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 EtCO₂ and PaCO₂ has been known to be accompanied by a tension difference of CO₂ ranging anywhere between 0.26 and 0.66kPa (2 and 5 mmHg) in otherwise healthy individuals undergoing anesthesia [11–16]. However, major trauma accompanying TBI can negatively influence ventilation and perfusion, making the interpolation of PaCO₂ from EtCO₂ in trauma patients unreliable [17–19]. As expected, subgroup analyses have shown the best correlation between EtCO₂and PaCO₂ in isolated TBI when compared to other trauma patients [20].

The primary aim of this study is to describe the correlation between EtCO₂ and PaCO₂ at the time of admission in patients hospitalized with TBI. Furthermore, we investigated the predictive value of tension difference of CO₂ between EtCO₂ and PaCO₂(CO₂ 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 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. EtCO₂ 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. EtCO₂, systolic blood pressure, pulse and SpO₂ 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 EtCO₂ and PaCO₂ was assessed using Pearson’s correlation coefficient and visualized using a scatter plot. Disagreement between EtCO₂and PaCO₂ was visualized using a Bland-Altman plot [21]. Differences in the CO₂ gap between survivors and non-survivors were tested using the Mann-Whitney-Wilcoxon Test. The association between the CO₂ 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 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. As a sensitivity analysis, the association of the time difference between the initial arterial blood gas sample and the first recorded EtCO₂ was explored using a univariate linear regression model.

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.

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, EtCO₂ or PaCO₂ 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 PaO₂ in the initial blood gas samples, p<0.001.

The correlation between EtCO₂ and PaCO₂ at admission was low, Pearson's r=.287, Figure 1. There was a significant difference between EtCO₂ and PaCO₂ at admission. The overall mean CO₂ 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<.001, see Table 2 and Figure 2. Of note, the CO₂ gap (visualized as mean bias on the Bland-Altman plots) was more pronounced in patients with lower EtCO₂ values. This demonstrates that patients with EtCO₂ measures within the target range (4.6 to 5.9 kPa) were unwittingly hypercapnic [1,2]. The overall CO₂ gap decreased to 0.64 ±0.82 kPa at 24h after admission and was no longer significantly 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 CO₂ gap was independently associated with increased mortality in intubated and mechanically ventilated patients with TBI. For every increase of the CO₂ 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, SpO₂ and PaO₂ 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 final model.

The majority of EtCO₂ and PaCO₂ 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 EtCO₂ from monitors on the CO₂ gap was assessed in a univariate linear regression model. This association was not significant, p=.165.

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 EtCO₂ 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 CO₂ gap in this patient cohort and it was more pronounced in patients with lower EtCO₂. This underestimation of PaCO₂ when EtCO₂ was used to guide ventilation caused hypoventilation despite normal EtCO₂ values. An increased CO₂ 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 PaCO₂ estimation or early PaCO₂ sampling in the prehospital management of patients with TBI.

The CO₂ gap

Previous studies have observed that the CO₂ 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 influencing the CO₂ gap are not measurable, detectable or predictable in the initial treatment period in the field or ER. The ability to predict or gauge the CO₂ gap based on the patient’s condition is consequently limited. In this context the CO₂ 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 CO₂ 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 EtCO₂ and PaCO₂, confirming that EtCO₂ 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 CO₂ gap and in-hospital mortality 24 hours 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.

EtCO₂ as a surrogate marker

PaCO₂ 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 CO₂ using EtCO₂ as a surrogate marker leads to impaired CBF and thereby increases mortality.

Recent TBI guidelines rely on the assumption that the CO₂ 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 EtCO₂ was 4.6 ±0.78 kPa, whereas the mean PaCO₂ was 6.26 ±1.03 kPa and far in excess of the target of 4.5 to 5.0 kPa. Therefore, relying on EtCO₂ as a surrogate for PaCO₂ provides a false sense of security, and providers may not achieve optimal prehospital PaCO₂. At present, no reliable alternative to direct ABG sampling seems to exist in order to approximate PaCO₂reliably.

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 EtCO₂. 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 CO₂ gap and ensure more reliable EtCO₂-guided ventilation.

Factors influencing mortality

Our data showed a significant age difference between survivors and non-survivors. 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 EtCO₂ and PaCO₂ was not significantly associated with the time between arterial blood gas sampling and the documented EtCO₂. Still, it is possible that a proportion of the gradient between EtCO₂ and PaCO₂ was due to changes in ventilation settings during this period.

The CO₂ gap is an inconsistent phenomenon in pre-hospital anesthetized TBI patients, making EtCO₂ an unreliable proxy for PaCO₂ when aiming for normocapnic ventilation. The higher-than-expected CO₂ gap can lead to unaware iatrogenic hypoventilation and consequently hypercapnia, which is associated with increased in-hospital mortality.

Ethics approval and consent to participate

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 financial 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 finalized the manuscript. SJS, MF, JK, AE and RA reviewed the manuscript. All authors read and approved the final version of the manuscript.

Acknowledgements

The authors would like to thank Patrick Münger for assistance in acquiring data from the electronic hospital records, Qendi Marku for assistance in acquiring outcome data from electronic hospital records, Mario Tissi and Marlis Planzer for assistance in acquiring data from the HEMS Database and Jeannie Wurz for careful editing of the manuscript.

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Table 1: Baseline characteristics of patients

Variable	Overall n=105	Survivors n=77	Non-survivors n=28
Age, years	49.5 ± 22.6	43.4 ± 21.0	66.3 ± 18.1
Age <18 years, n (%)	9 (9)	8 (10)	1 (4)
Male gender, n (%)	71 (68)	51 (66)	20 (71)
ISS Total, median (IQR)	25 (17 to 34)	25 (14 to 34)	31 (25 to 38)
ISS = 75, n (%)	1 (1)	0	1 (4)
ISS Thorax, median (IQR)	0 (0 to 2)	0 (0 to 2)	0 (0 to 2)
Missing (ISS Thorax), n (%)	12 (11)	9 (12)	3 (11)
Cardiopulmonary parameters
Systolic BP, mmHg	127 ± 33	127 ± 29	125 ± 43
Diastolic BP, mmHg	78 ± 28	80 ± 30	72 ± 21
Pulse, bpm	93 ± 26	92 ± 24	93 ± 32
SpO₂, median (IQR)	100 (98 to 100)	100 (98 to 100)	99.5 (94.8 to 100)
Temperature, °C	35.9 ± 0.93	35.9 ± 0.93	35.9 ± 0.98
Missing, n (%)	16	11	5
Arterial blood gas
pH, median (IQR)	7.31 (7.26 to 7.35)	7.31 (7.28 to 7.36)	7.31 (7.19 to 7.33)
BE, mmol/l median (IQR)	-3.6 (-6.4 to -1.9)	-3.6 (-5.8 to -1.7)	-4.9 (-8.4 to -2.3)
HCO₃^-, mmol/l median (IQR)	21.9 (19.9 to 23.6)	21.5 (20.5 to 23.6)	21.1 (19.6 to 23.4)
Lactate, mmol/l median (IQR)	2.0 (1.2 to 3.4)	1.9 (1.2 to 2.7)	2.8 (1.4 to 4.5)
PaCO₂, kPa median (IQR)^*	6.0 (5.5 to 6.8)	5.9 (5.5 to 6.6)	6.4 (5.7 to 6.8)
PaO₂, kPa median (IQR)	28.2 (17.6 to 48.9)	34.3 (19.6 to 51.5)	23.1 (14.9 to 29.8)
Hemoglobin, g/l	122 ± 21	122 ± 20	119 ±24
Glucose, mmol/l median (IQR)	8.0 (6.3 to 10.1)	7.5 (6.0 to 8.9)	10.2 (8.1 to 13.2)

Footnote:

Data was complete if not otherwise specified. 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; SpO₂ = peripheral capillary oxygen saturation.

* PaCO₂ = Same parameter as shown in detail on Table 2 (initial measure).

Table 2: PaCO₂ and EtCO₂pairs at admission and after 24 hours

Variable	Overall n=105	Survivors n=77	Non-survivors n=28	p value
Initial measures	105 (100)	76 (100)	28 (100)
CO₂gap, kPa	1.64 ± 1.09	1.42 ± 0.92	2.26 ± 1.30	<0.001
PaCO₂, kPa	6.26 ± 1.03	6.17 ± 0.96	6.48 ± 1.18
EtCO₂, kPa	4.61 ± 0.78	4.76 ± 0.74	4.23 ± 0.76
PaCO₂ within 15 min of EtCO₂	42 (40)	30 (39)	13 (46)
PaCO₂ within 30 min of EtCO₂	60 (57)	39 (51)	21 (75)
Measures within 24h	75 (71)	53 (70)	22 (79)
CO₂gap, kPa	0.64 ± 0.82	0.58 ± 0.86	0.78 ± 0.70	0.108
PaCO₂, kPa	5.12 ± 0.60	5.19 ± 0.59	4.91 ± 0.58
EtCO₂, kPa	4.46 ± 0.79	4.59 ± 0.82	4.15 ± 0.63
Hours since admission	18.6 ± 7.8	19 ± 8.0	17.7 ± 7.5

Footnote:

Data was complete. Numbers are presented with percentages of total in parentheses. Continuous variables are reported as mean ± SD (standard deviation). The CO₂ gap and the PaCO₂ variables were skewed; however, the mean ± SD was presented due to the use of these parameters in the Bland-Altman plots. CO₂gap = PaO₂ - EtCO₂

Table 3: Multivariate logistic regression model of survival

Variable	Odds Ratio	95% CI of OR	Standard error	p value
CO₂gap, kPa	2.692	1.283 to 5.646	0.385	0.009
Age, 10 years	1.063	1.026 to 1.102	0.018	0.001
Systolic BP, mmHg	1.002	0.986 to 1.018	0.008	0.822
Pulse, bpm	0.984	0.960 to 1.009	0.013	0.199
SpO₂, %	0.960	0.810 to 1.137	0.106	0.635
PaO₂, kPa	0.966	0.926 to 1.007	0.022	0.101
ISS Thorax	1.030	0.683 to 1.554	0.214	0.887

Footnote:

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.

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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

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