Hypercapnia outcome in COVID-19 acute respiratory distress syndrome patients on mechanical ventilator: A retrospective observational cohort

We include 288 patients by random sampling from the medical records of patients admitted to the ICU of SIDH & RC from August 2020 to August 2022 to assess at least a 3% effect of hypercapnia on mortality in COVID-19 ARDS patients on mechanical ventilator. From 288 patients 137 (47.56%) of the patient developed severe hypercapnia. We had 219 (23%) missing data for predicted body weight which was adjusted statistically by multiple imputations. We used the flow chart Figure 1 to demonstrate number of patients excluded.

Fig. 1.

Study Profile

Fig. 2.

ROC curve for weighted regression

Compared to no severe hypercapnia, severe hypercapnia patients have lower PaO2/FiO2 and higher dead space. Both groups of patients ventilated with similar tidal volume/kg. However, severe hypercapnia patients have higher driving pressure and respiratory rate as shown in Table 1. We also noticed an increased risk of hospital-acquired infection in the severe hypercapnia group. Severe hypercapnia also had prolonged hospital stays but the length of mechanical ventilation was the same in both groups. No difference in other secondary outcomes between the two groups was noticed, as shown in Table 2.

In our study severe hypercapnia when analyzed in univariate analysis show increased mortality with an odds ratio of 3.50 with a 95% confidence interval of 1.46–8.43 and a p-value of 0.005 as shown in Table 3.

To assess the effect of hypercapnia independent of other causes of mortality and confounders that might affect exposure and outcome, a multivariable logistic regression model for adjusted mortality was used. This includes baseline characteristics of patients including age, gender, predicted body weight, disease severity at baseline (SAPS score, PaO2/FiO2 before intubation), comorbid (Charlson comorbidity index), ventilator parameter, and lung mechanics. When adjusting for confounders, as shown in Table 4, severe hypercapnia did not show a significant effect on mortality with an odds ratio of 1.08 with a 95% confidence level of 0.32 – 3.64 with a p-value of 0.89.

This retrospective study explored the effects of severe hypercapnia on mortality in COVID-19 ARDS during mechanical ventilation. We compared patients with severe hypercapnia with PaCO2 more than or equal to 50 mmHg and no severe hypercapnia. Our study results revealed that hypercapnia by itself does not affect mortality when adjusted for disease severity using logistic regression and IPTW. Kergenow et al also showed in their secondary analysis of the ARDS network study that hypercapnia has no effect on mortality after adjustment for disease severity when ventilated with a tidal volume of 6 ml/kg, hypercapnia exerts no effect on mortality [14].

We found that patients with severe hypercapnia had severe lung disease, manifesting as a low PaO2/FiO2 ratio, high dead space, and high driving pressure, as also demonstrated by other researchers in their studies [15,12]. Our study showed that patients in severe hypercapnia group despite receiving ventilation with similar tidal volume in comparison to no severe hypercapnia group demonstrate higher driving pressure. In the severe hypercapnia group due to severe lung disease despite having tidal volume similar to no severe hypercapnia group there is an increase in driving pressure which increases the stress and strain on lungs thus limiting protective lung ventilation. Furthermore, to achieve protective lung ventilation in the severe hypercapnia group increase the respiratory rate to avoid hypercapnia this can further intensify the stress and strain on the lung. Therefore, to ensure protective lung ventilation extracorporeal life support organization (ESLO) guidelines recommend using extracorporeal membrane oxygenation (ECMO) in hypercapnia with acidosis which does not respond to protective mechanical ventilation [16]. Therefore, we need to consider hypercapnia as a marker of disease severity and view it in the context of underlying cause and disease severity. Anissa et al in their post hoc analysis of the PROvent-COVID-19 ARDS also demonstrated that hypercapnia does not affect mortality [11]. Another, randomized trial on carbon dioxide (CO2) removal in ARDS with Extracorporeal CO2 removal (ECCO2R) showed no effect on mortality despite achieving a 20% reduction in carbon dioxide level from baseline [17].

Moreover, another single-center case series in COVID-19 patients used directed hypercapnia to wean from venovenous extracorporeal membrane oxygenation (VV ECMO) revealed that inducing compensatory respiratory acidosis by decreasing sweep gas flow can create metabolic support for early decannulation of ECMO and that compensated hypercapnia is well tolerated [18]. Recently, another single-center study [19] in cardiac arrest patients showed that patients with hypercapnia have improved cardiac performance, and mixed venous oxygen saturation with no effect on right ventricular function and pulmonary vasculature However, another study conducted by Nin N et.al in non-COVID ARDS demonstrated higher mortality in hypercapnia after adjusting for disease severity [10]. This contraindication in grey literature can be because certain phenotypes of ARDS may respond differently resulting in different outcomes as Liu X, argued in their retrospective analysis of data to identify phenotype clusters in ARDS associated with clinical outcome and treatment response [20]. Further, studies can be done to unveil the impact of different phenotypes of ARDS in which hypercapnia may cause adverse outcomes.

Furthermore, there was no difference in the length of mechanical ventilation between the two groups in our study, the severe hypercapnia group patient’s hospital stay was prolonged as compared to the no severe hypercapnia group patients. The potential reason may be due to the effect of hypercapnia on muscle weakness leading to the prolonged need for rehabilitation. Studies on animal models [21,22] demonstrated that hypercapnia can depress anabolism of skeleton muscle via several mechanisms leading to skeleton muscle weakness. Prolonged hospital stay in patients with severe hypercapnia in our study can be explained by available literature. Herridge et al demonstrated that patients surviving ARDS show a reduction in exercise capacity years after discharge [23]. However, we need further studies to evaluate the direct effect of hypercapnia in ARDS patients on muscle strength.

This study showed an increased incidence of hospital-acquired infection in severe hypercapnia group patients as compared to no severe hypercapnia group patients which can be due to the underlying severe lung disease in this group however, we cannot delineate this from the direct impact of hypercapnia on immune response as Gate et.al showed in their study that hypercapnia impairs lung neutrophil function which can increase mortality in murine pseudomonas pneumonia [24].

Moreover, the present study showed high mortality, 88%, in COVID-19 ARDS patients who received mechanical ventilation which is much higher in comparison to studies conducted in other countries [25,11]. This may be due to delays in hospitalization in our country because of a lack of awareness, scarcity of resources, insufficient number of mechanical ventilators, and shortage of trained ICU physicians [26]. Moreover, the baseline median PaO2/FiO2 of both study groups in our study was less than 80 upon initial presentation while it was above 100 in studies conducted in other countries [11], which can also be due to the lack of awareness to seek early medical attention in our general population [27]. Therefore, this study reports the effect of CO2 on ARDS patients with severe disease.

Our study showed that hypercapnia by itself is not associated with mortality when adjusted for disease severity. We used the marginal structural model to adjust for time-varying confounders that affect outcome and exposure including mechanical ventilation parameters, lung mechanics, and disease severity at the onset of hypercapnia and baseline disease severity. This study does not explore the effects of hypercapnia on pulmonary vasculature, right ventricle, and hemodynamic instability. Since it is an observation study, we also did not evaluate the direct causal effect of hypercapnia on mortality. Although this study gives clinical ground for future Randomized clinical trials on interventions to remove CO2 in patients with severe disease. Despite using the structural model for casual interference in longitudinal data unmeasured confounders cannot be adjusted. Furthermore, the dead space in the lungs was calculated from corrected minute ventilation instead of calculated from capnography due to a lack of resources. Similarly, the static lung compliance was calculated from the formula which is less reliable than using esophagus pressure monitoring and pressure/volume curve. This study was conducted in a single center but to decrease type II error we calculated sample size alpha significance, power, and effect size. However, results may not reflect the outcomes of hypercapnia in COVID-19 ARDS patients on mechanical ventilators in other contexts.

Since it was an observational study, it cannot assess the direct causal interference of CO2 on mortality. Studies on the impact of CO2 along with other severity indexes including PaO2/FiO2 ratio, poor compliance, and high dead space in ARDS mechanically ventilated patients and the use of cell-directed therapy like mesenchymal stem cell to dampen the inflammatory response, can play a vital role to improve the outcome in these patients [28]. Furthermore, randomized trials on ECCO2R for CO2 removal including patients with poor compliance and high dead space can also further assess the overall benefit of ECCO2R in ARDS.

The hypercapnia is not found to be associated directly with patient mortality. However, hypercapnia reflects disease severity and therefore, can be used as a marker for disease severity along with the other signs of disease severity and underlying cause of disease.