Causes and characteristics of death in patients with acute hypoxemic respiratory failure and acute respiratory distress syndrome: a retrospective cohort study

Acute hypoxemic respiratory failure (AHRF) is among the most common causes of critical illness, with a hospital mortality of approximately 30% [1]. In patients meeting the definition of acute respiratory distress syndrome (ARDS), mortality is approximately 40% [2]. However, while AHRF and ARDS are each defined by severe hypoxemia and associated with high mortality, death due to refractory hypoxemia is reportedly rare. In cohorts of ARDS patients treated in the 1990s, only 13–19% of deaths were due to refractory hypoxemia, while deaths due to multi-organ failure from sepsis were the cause of up to 50% of deaths [3]. These findings suggested that therapies focused on reducing the complications of sepsis would have a greater impact at improving ARDS survival than therapies for severe hypoxia.

Since the 1990s, however, cause of death specifically related to organ system dysfunction has not been described despite substantial evolution in critical care practices. Ventilator management now focuses on minimizing ventilator-induced lung injury, as opposed to normalizing oxygenation and ventilation [4], which may have led to further reduction in death due to refractory hypoxemia. In addition, there has been growing attention to minimization of sedation, early mobilization, and sepsis recognition and treatment, the latter of which may mitigate mortality due to sepsis [5‐8]. Finally, there has been an increased focus on palliative care in the intensive care unit (ICU), which may lead to earlier treatment limitations [9‐11]. Because of these changes in practice and how they may affect causes of death in the ICU, we hypothesized that causes of death among AHRF and ARDS patients may be different from historical cohorts. An updated understanding of the causes of death in these populations would help identify the most important targets for new therapies and help direct future investigation to improve survival. We sought to determine the causes and circumstances of death in a contemporary cohort of AHRF patients, and assess whether causes of death differed among patients with and without ARDS.

We identified 385 adult patients with AHRF who died during a hospitalization in 2016–2017, of whom 127 (33%) had ARDS. The cohort was a median age of 63 years (55–73), 43% female, 82% white, and had a median SOFA score of 12 (10-14) at AHRF onset. Most patients were admitted to a medical ICU (59%). Patients had a median of 2 (1-3) risk factors for AHRF, most commonly non-cardiogenic shock (59% of patients), transfusion (41%), sepsis (39%), and pneumonia (37%, Table 2).

Patients with ARDS had a higher median SOFA score within the first 24 h of AHRF onset (14 vs 12; p = 0.002) and had higher prevalence of pneumonia (52% vs 30%; p <  0.001), aspiration (22% vs 12%; p = 0.01), and non-cardiogenic shock (78% vs 50%; p <  0.001) compared to patients who did not meet the Berlin definition of ARDS (Table 2).

In this contemporary cohort of 385 adult patients with AHRF, the most common primary causes of death were sepsis, pulmonary dysfunction, and neurologic dysfunction. The majority of patients had multi-organ failure prior to death, most commonly due to sepsis. More than half of patients were receiving substantial respiratory support at the time of death and the vast majority of patients died after withdrawal of life support. Sepsis and pulmonary dysfunction were the top two primary causes of death among both patients with and without ARDS.

Our study is consistent with prior reports indicating that sepsis is the leading cause of death among patients with respiratory failure. Stapleton et al. found that sepsis was the most common cause of death in ARDS patients treated in the 1990s [3]. Despite increased attention to earlier identification and treatment of sepsis in the intervening decades [17, 18], our study found that sepsis remained the most common cause of death in AHRF patients. This is consistent with recent studies showing that sepsis is the leading contributor to death among patients hospitalized for any cause [19]. Sepsis was slightly more common in patients with ARDS than those without ARDS, which may reflect the higher rates of pneumonia and sepsis as risk factors for ARDS. However, it may also suggest that ARDS patients are at a heightened risk for secondary infections compared to patients without ARDS. These findings suggest that therapies targeting sepsis-induced multi-organ dysfunction may have the greatest impact on survival among AHRF patients.

We found only small differences in the causes and circumstances of death among AHRF patients with and without ARDS. Patients with ARDS were more likely to have a pulmonary dysfunction as the primary cause of death and more likely to die while receiving substantial pulmonary support than patients without ARDS. This indicates that the Berlin ARDS definition identifies a subset of patients with AHRF who are more likely to die directly from respiratory failure and would benefit from therapies to enhance resolution of respiratory failure. However, the difference in rates of pulmonary dysfunction as the primary cause of death was relatively small among patients with and without ARDS.

Our study confirms the findings in prior studies indicating that insupportable oxygenation and/or ventilation is rare among patients with respiratory failure. One of the major findings of Stapleton et al.’s study was the relatively low proportion of deaths due to insupportable oxygenation or ventilation, occurring in only 13–19% [3]. Given the increased awareness and effort to treat sepsis in the period after this original study, we hypothesized that pulmonary dysfunction may be a more common primary cause of death in a contemporary AHRF cohort. However, we found that only 22% of patients had pulmonary dysfunction as the primary cause of death, and only a handful of patients (2%) had insupportable oxygenation and/or ventilation. There are several potential explanations for these findings. First, with more consistent use of lung protective ventilation, contemporary AHRF patients may be less likely to develop ventilator induced lung injury and progressive respiratory failure [20]. Second, patients with severe ARDS may be more likely to be initiated on extra-corporeal membrane oxygen therapy prior to developing refractory pulmonary dysfunction [21]. Finally, other strategies such as prone positioning may prevent refractory hypoxemia [22]. However, these hypotheses do not explain why a similar proportion of patients still ultimately die from respiratory failure despite not developing insupportable oxygenation and/or ventilation. While some patients may be supported through the initial phase of their respiratory failure, eventually life support is withdrawn when providers are unable to completely reverse their need for significant respiratory support.

Our study also highlights the increasing proportion of deaths that occur after a decision to withdraw or not escalate life support. Stapleton et al. showed that from 1981 to 1998, the proportion of ARDS deaths that occurred after withdrawal of life support rose from 40 to 67% [3]. Similar trends have been reported for all-cause critically ill patients during this time period [9]. Our study suggests that this trend has continued, as we report that 85% of all deaths among AHRF are now occurring after a decision to withdraw or not escalate life support. Our finding is also consistent with a recent study showing that 90% of deaths among critically ill patients treated in Europe from 2015 to 2016 occurred in the setting of treatment limitations [23].

There are likely several explanations for why a growing proportion of deaths occur after withdraw of life support. Stapleton et al. hypothesized that ICU clinicians have earlier and more frequent goals-of-care discussions [3], as is recommended in various clinical practice guidelines [17]. Indeed, early multidisciplinary meetings with patients and families may lead to an earlier transition to palliative care among patients likely to die [24, 25]. More recently, there has been increased emphasis on family involvement in ICU decision-making and treatment planning, for example, as recommended in the ABCDEF treatment bundle [26]. Overall, the greater emphasis on family involvement in early shared decision making may contribute to earlier transitions to palliation among patients who ultimately die in the ICU [27].

Our study has several limitations. First, as a single-center study, it is possible that it may be lacking generalizability. However, we examined all deaths among patients with AHRF over a 2-year period who were treated in 5 distinct ICUs with different practice patterns. As such, we believe these findings are more broadly applicable. Second, while we tried to harmonize our study definitions to those of Stapleton et al. to facilitate cross-study comparisons, some changes had to be made to account for interval changes in definitions (e.g., sepsis) and treatments (e.g., high-flow oxygen). We limited deviations in study definitions to those deemed absolutely necessary to reflect the current state of ICU practice. Third, patients were classified as having undergone withdrawal of life support regardless of the time lag between withdrawal and death. For patients in whom only minutes elapsed between withdrawal of support and death, death may be more accurately representative of the cessation of medical interventions due to futility. However, our approach for determining rates of withdrawal and the rates of withdrawal we observed are consistent with prior reports [9]. Fourth, given a high rate of withdrawal of life support, the most proximate cause of death is cessation of support. However, our methodology identifies which organ dysfunction or syndrome most directly led to that decision, thereby reflecting the primary pathophysiologic cause of death. Fifth, there may be some subjectivity to assigning cause of death. However, we developed a standardized approach to assess causes of death based on the presence of irreversible and severe organ dysfunctions and confirmed excellent inter-rater reliability in identifying the primary cause of death among reviewers, which serves to strengthen the validity of our methodology. Furthermore, chart review was performed by physicians only, as medical training may limit the subjectivity in identifying cause of death.

In this contemporary cohort study of 385 patients who died after AHRF, the most common primary causes of death were sepsis and pulmonary dysfunction. Few patients had insupportable oxygenation or ventilation, but most received substantial respiratory support in the 72 h prior to death. The vast majority of deaths occurred after a decision to withdraw or not escalate life support. Patients with ARDS were more likely to have a primary cause of death of pulmonary dysfunction and to receive substantial respiratory support during the 72 h prior to death.