Unresponsive patients commonly receive endotracheal intubation and mechanical ventilation in the absence of cardiopulmonary failure [1]. This is typically done to prevent the sequelae of aspiration, namely pneumonia, which could occur in those without a sufficient gag reflex. Trauma societies generally support recommendations in favor of endotracheal intubation for patients with severe head trauma defined by a Glasgow Coma Scale score of 8 or less, but providers often also elect to perform this procedure in patients with medical delirium or other non-trauma-related indications [1,2]. However, endotracheal intubation and mechanical ventilation are associated with numerous risks such as aspiration, hypotension, ongoing delirium, and nosocomial pneumonia [3,4]. Patients who are intubated will ultimately remain hospitalized and in the intensive care unit for longer periods of time and may experience increased mortality [5]. Although these outcomes are mostly a consequence of acute illness and underlying comorbidities, endotracheal intubation and mechanical ventilation may independently impact outcomes due to direct or indirect effects on virtually every organ system [6]. Their use for strong indications such as cardiopulmonary failure is often unavoidable, but no randomized controlled trials have demonstrated that elective intubation for the sole purpose of airway protection is beneficial. A number of prospective and retrospective observational studies have attempted to address this issue among patients with trauma, medical delirium, or gastrointestinal bleeding with mixed results [7,8]. Consequently, it remains unclear whether this practice is clinically justified on a routine basis.

Among those with toxic-metabolic encephalopathies, patients with decompensated cirrhosis are especially vulnerable to the risks of mechanical ventilation with in-hospital mortality among this subset of patients exceeding 50% [9,10]. This is a consequence of factors such as impaired immunity, altered drug metabolism, circulatory dysfunction, and sarcopenia [11]. However, patients with grade IV hepatic encephalopathy often undergo this procedure early in their clinical course, prior to the implementation of diagnostic and therapeutic interventions and in the absence of other indications [12]. Previous observational studies have not assessed its relative impact on mortality in patients with cirrhosis, and society guidelines have not specifically addressed the issue [13]. The aim of this exploratory study is to determine whether early endotracheal intubation and mechanical ventilation for airway protection can affect clinical outcomes among patients with cirrhosis and grade IV encephalopathy. Our hypothesis is that this practice may be associated with increased in-hospital mortality.

Our findings suggest that early endotracheal intubation for airway protection among patients with cirrhosis and grade IV hepatic encephalopathy may be associated with increased in-hospital mortality. Our analysis excluded patients who may have had strong indications for mechanical ventilation, namely cardiopulmonary failure, and assessed the impact of other covariates such as demographics, cirrhosis etiology and severity, and relevant acute and chronic comorbidities. The application of mechanical ventilation was the strongest predictor of mortality in all of our regression models. The aOR for mechanical ventilation was approximately 3, an effect size that is clinically meaningful for a study that excluded patients who have the highest risk for in-hospital death (i.e., those with shock and respiratory failure). The mortality rate for ventilated patients with hepatic encephalopathy in our study was comparable with rates cited in other recent studies and additional predictors of mortality in our multivariable models, including ascites and acute kidney injury, are well-established prognostic factors among patients with cirrhosis, suggesting that our cohort is similar to external cohorts [9,20,21]. Although the association between chronic kidney disease and decreased mortality was unexpected, a post-hoc sensitivity analysis suggested that this finding may be partially explained by the fact that a number of these patients received hemodialysis, an intervention that can be used to treat hepatic encephalopathy and may have thus facilitated clinical improvement.

In addition to being consistent with previous reports in the literature, we believe that our findings have a strong physiologic basis. Patients with cirrhosis and hepatic encephalopathy are particularly susceptible to the complications of mechanical ventilation because of possible underlying circulatory, neurologic, and immunologic dysfunction [11]. Because mechanical ventilation itself may be associated with further impairment in cardiovascular and cognitive function and immune defense, patients with cirrhosis may be at a greater risk for developing shock, progressive delirium, and infection, among other complications [22-24].

Although our findings are physiologically plausible and largely representative of the larger body of work involving mechanical ventilation in cirrhosis, our study is impacted by important limitations, largely due to the retrospective observational nature of the design. It may be influenced by multiple types of bias, including the effects of unmeasured confounding variables. Because we utilized a publicly-available deidentified dataset, our analysis was limited to covariates that were already present, and thus other key factors such as vital signs and laboratory parameters could not be included in our analyses. We attempted to exclude all patients with cardiopulmonary failure by using appropriate ICD-10 diagnosis and procedure codes, but we suspect that some individuals who received endotracheal intubation and mechanical ventilation may have been more critically ill than those who did not receive these interventions in ways that we were unable to capture. Additional liver-specific prognostic factors such as model for end-stage liver disease (MELD) scores and Child-Turcotte-Pugh (CTP) classification were also unavailable, but by including only those with grade IV encephalopathy, our study effectively consisted of patients with CTP scores of 7 or higher (i.e., CTP B or C status). Furthermore, studies utilizing administrative datasets are commonly impacted by inaccurate or incomplete coding. Therefore, our study design focused on applying a fairly restrictive coding scheme that required separate diagnostic codes for grade IV hepatic encephalopathy (i.e., hepatic failure with coma) and cirrhosis for screening to increase the specificity of our cohort. However, it is possible that patients in the non-intubated group who were coded as having hepatic failure with coma may have actually had grade II or III hepatic encephalopathy whereas those who were intubated had true grade IV hepatic encephalopathy. Finally, we were unable to assess for differences in the medical management patients received (i.e., use of lactulose and/or rifaximin), which could have impacted outcomes as well.

In conclusion, this study is the first to our knowledge to demonstrate that mechanical ventilation for patients with cirrhosis and grade IV hepatic encephalopathy may be associated with increased in-hospital mortality in a comparative fashion. Our findings suggest that, in the absence of other strong indications for mechanical ventilation, it may be reasonable to consider deferring early endotracheal intubation for airway protection in select patients who are otherwise clinically stable and may respond to prompt medical management for hepatic encephalopathy. However, it is crucial to note that these preliminary findings should be interpreted cautiously in the context of our study limitations. Future retrospective studies that incorporate more granular patient data or prospective trials are necessary before specific clinical recommendations can be provided.