The mortality rate in patients with cirrhosis remains high in the intensive care unit (ICU), ranging from 46% to 90% (1–5). Recent studies, however, reported that the outcome of cirrhotic patients with septic shock (1,3) or requiring mechanical ventilation (2) has improved over time. Consequently, ICU admission for many patients with cirrhosis is not necessarily futile. Prognosis of patients with cirrhosis is determined by the number of organ failures, the number of organ support during the ICU stay, and the degree of liver dysfunction (4,6,7). This led us to recognize the acute-on-chronic liver failure syndrome, which refers to an acute deterioration of liver function and subsequently the development of extrahepatic organ dysfunction over a period of weeks following a precipitating event (8). This condition requires one or more organs supported and is associated with high short-term mortality. The concept of acute-on-chronic liver failure highlights the weight of development of each additional organ failure in the prognostic of patients with cirrhosis admitted to the ICU. The acute respiratory distress syndrome (ARDS) is the most severe form of pulmonary dysfunction and is defined as: the acute onset of respiratory failure with bilateral infiltrates on chest radiograph, hypoxemia as defined by a PaO2/FiO2 ratio ≤300 mmHg, and no evidence of cardiogenic edema (9). Over the past 15 years, there have been significant advances in the management and outcome of ARDS patients such as lung protective ventilation, using tidal volumes (Vt) of 6 mL/kg predicted body weight (PBW), plateau pressure below 28 to 30 cmH2O and high positive end-expiratory pressures (PEEPs), which forms the cornerstone of care for patients with diagnosed ARDS (10,11). Other therapeutic measures such as conservative fluid management (12) or early prone positioning (13) improve lung function and may result in better outcome of ARDS patients. Cirrhosis was identified as a prognostic factor of acute lung injury (ALI) and ARDS in very few studies that have been conducted mostly before 2000 (14–17) and cirrhotic patients have been excluded from recent clinical trials assessing therapeutics for ARDS (13,18). Thus, the question is raised as to whether cirrhosis remains a prognostic factor for poor outcome in ARDS patients.
For this purpose, we performed a retrospective study to determine whether cirrhosis was independently associated with 90-day mortality from the diagnosis of ARDS in non-trauma patients and admitted in our ICU from 2006 and over a 7-year and 2-month period.
MATERIALS AND METHODS
Patients and setting
This retrospective study was performed in a mixed 21-bed ICU admitting mostly medical patients and all liver transplant recipients of one of the largest liver transplant centers in France. Patients were identified through our computerized database. The study was approved by the hospital's ethics committee (N°12–22). We included all patients aged over 18 years admitted between October 1, 2006 and December 31, 2013, for ARDS (according to American-European Consensus Conference criteria (19)) with a PaO2/FiO2 ratio <200 mmHg after at least 12 h of lung protective MV with FiO2 ≥50% and a PEEP level ≥5 cmH2O (9,13,18). Patients who received noninvasive ventilation only were excluded from the study. Similarly to that performed in many previous studies (2,4,6,20), the diagnosis of cirrhosis was based on previous histology findings when available or on various associations of clinical, biological, endoscopic, and/or ultrasonographic or imaging findings, including cutaneous manifestations such as jaundice or skin telengiectasias, evidence of portal hypertension such as variceal bleeding, ascites, hepatic encephalopathy, and biological results of liver failure. Child–Pugh score was assessed on the day of ICU admission and calculated as previously described (21) whereas MELD scores (22) were calculated based on the laboratory results obtained on the day the diagnosis of ARDS was made.
All patients were ventilated as follows: assist-control mode, initial tidal volume was targeted at 6 mL per kilogramme of PBW, PEEP level was selected from the PEEP-FiO2 table proposed by the ARDS Network (10), and end-inspiratory plateau pressure was measured hourly to be kept below 30 cm of water until the PaO2/FiO2 ratio was higher than 150 mmHg with a level of PEEP ≤10 and FiO2 ≤60%. Ventilatory modalities for patients with ARDS in our ICU had been protocolized over the study period as our ICU was recruiting patients for two consecutive multicenter trials (13,18). Consequently, the protective ventilatory strategy used in these two clinical trials was applied to every patient with ARDS.
Variables were collected prospectively during the periods of clinical trials (i.e., from March 2006 through March 2008 (18) and from January 2008 through July 2011 (13)) and retrospectively for the remaining period of the study.
ARDS diagnosis and severity
Cirrhotic and non-cirrhotic patients were compared for etiological causes, objective evaluation of cardiac function, ARDS severity, and associated septic shock to determine whether they differed significantly for these major characteristics before analyses. Etiological causes of ARDS were listed as pneumonia, non-pulmonary sepsis, aspiration, and others (9). Evaluation of cardiac function was considered objective when assessed by echocardiography and/or pulmonary artery catheter with wedge pressure measurement. Based on Berlin criteria (9), patients were distinguished whether they had severe ARDS (PaO2/FiO2 ≤100 mmHg) or non-severe ARDS (PaO2/FiO2>100 mmHg). Septic shock was defined according to the previously described criteria (23).
Baseline characteristics of patients
In addition to the diagnosis of liver cirrhosis, the following variables recorded upon ICU admission and during the ICU stay were included as control variables because they were potentially associated with ARDS prognosis (9,24). The data collected for all patients were: age, sex, the Simplified Acute Physiology Score (SAPS) II calculated within 24 h after admission and the Sequential Organ Failure Assessment (SOFA) score (25) calculated on the first 3 days following ARDS diagnosis. The comorbid conditions included in the analysis were diabetes mellitus and previous coronary artery and/or valvular disease with treatment. Diabetes mellitus was defined by a history of diabetes requiring chronic therapy with insulin or an oral hypoglycaemic agent. In addition, aplasia and/or chemotherapy for solid tumor or hematologic disease within 1 month before intubation were also considered.
The respiratory parameters recorded and included in the analysis were the lowest values of PaO2/FiO2, the highest values of expiratory Vt, PEEP applied and ventilator-measured end-inspiratory plateau pressure. The driving pressure calculated as ventilator-measured plateau pressure minus applied PEEP was also considered for analysis (26). Organ supports assessed for prognostic analysis were prone positioning, vasopressor therapy, and renal replacement therapy including hemodialysis and continuous renal replacement therapy.
Respiratory support other than MV
Treatments with inhaled nitric oxide (iNO), prone positioning, and extracorporeal membrane oxygenation (ECMO) were also noted. Treatments with iNO and ECMO were not included in the prognostic analysis because they were used in our ICU as a rescue therapy. Likewise, we used prone positioning as a rescue therapy before our participation in the clinical trial conducted by Guerin et al. (13).
Outcome measure and causes of death
The outcome was 90-day survival from the diagnosis of ARDS (13,18). Additionally, cause-specific death was assessed retrospectively, based on chart abstraction. The proximate cause of death was defined as the pathology leading to the death of the patients or the decision to withhold or withdraw intensive care. Causes of death were distinguished based on the previous study performed by Levesque et al. (2).
Data are expressed as percentages and as medians and interquartile ranges (IQR). The chi-square test was used to compare categorical variables and the Man–Whitney U test to compare continuous variables. Survival curves were constructed until day-90 by using the Kaplan–Meier method and compared by the log rank test. We used a Cox-proportional hazard model to determine whether cirrhosis was independently associated with prognosis at Day 90 in an unadjusted and adjusted analysis. Variables with P value less than 0.10 in the unadjusted analysis were entered in the final model. Tests were two-sided and we considered P < 0.05. Statistical analyses were performed using Statview 5.0 (SAS Institute Inc, Cary, NC).
During the study period, 332 ARDS patients met inclusion criteria among whom 42 patients (13%) had cirrhosis. These patients represented 7% of all patients ventilated in our ICU within this period. Cause of cirrhosis was alcohol in 30 patients (71%), viral hepatitis in two patients (5%), alcohol plus viral hepatitis in five patients (12%), other in five patients (12%). Eight patients (19%) were classified Child–Pugh A, 16 patients (38%) Child–Pugh B, and 18 patients (43%) Child–Pugh C. The median value for MELD score calculated on the day of ARDS diagnosis was of 39 (26–46). Cirrhosis was histologically proven in six patients (14%). Among the 36 without biopsy, cirrhosis was diagnosed in 32 patients before ICU admission when hospitalized in our Digestive and Liver Diseases Division. Among them, seven patients were hospitalized regularly for ascites, three patients presented at least one episode of hepatic encephalopathy, and 13 patients presented signs of portal hypertension diagnosed during a prior upper gastrointestinal endoscopy including five patients who received treatment for bleeding. The 13 other patients, including those with cirrhosis diagnosed in the ICU, all had ultrasonography and/or computed-tomography features suggestive of cirrhosis, three had positive results for elasticity measure (Fibroscan) in addition to abnormalities in clinical examination and/or laboratory tests. Three patients were on a waiting list for liver transplantation. Over the same period, 178 cirrhotic patients without ARDS were admitted to the ICU and received MV. After analysis, cirrhotic and non-cirrhotic ARDS patients did not differ significantly for etiological causes for ARDS, objective evaluation of cardiac function, ARDS severity, and associated septic shock (Table 1). During the first 3 days following the diagnosis of ARDS ventilatory settings did not differ between patients with and without cirrhosis (Table 2). In addition, rescue respiratory supports did not differ significantly between the two groups of patients: 10 patients with cirrhosis (24%) and 80 patients without cirrhosis (28%) received prone positioning (P = 0.60), 9 cirrhotic patients (21%) and 98 non-cirrhotic patients received iNO (P = 0.10), 2 cirrhotic patients (5%) and 26 non cirrhotic patients (9%) received ECMO (P = 0.55).
Prognostic analysis and causes of death
The overall mortality rate at day-90 for the study population was 46%. Patients with cirrhosis had significantly higher mortality (62%) than patients without cirrhosis (43%) (P = 0.02). The mortality rate at day-90 was 59% for the 178 cirrhotic patients without ARDS (P = 0.07 after comparison with cirrhotic patients with ARDS). Kaplan–Meier survival curves were calculated for the 90-day period from the day of ARDS diagnosis to the end of the follow-up. As shown in Figure 1 survival was significantly lower in patients with cirrhosis than in patients without cirrhosis (P = 0.03, as determined by the log-rank test). Results of unadjusted and adjusted analysis are shown in Table 3. Cirrhosis was independently associated with a poorer prognosis at day-90 (adjusted HR = 2.09, 95% CI, 1.27–3.45, P = 0.004). Among the three patients with cirrhosis who were on a waiting list for liver transplantation, two died in the ICU and one received liver transplant 2 months after ICU discharge. There were six liver transplant recipients who were classified among the non-cirrhotic group with ARDS; two died at day-90. Proximate causes of death are listed in Table 4 and differed significantly when compared between cirrhotic and non-cirrhotic patients. Cirrhotic patients died frequently from bleeding complications whereas in non-cirrhotic patients uncontrolled hypoxemia was a frequent cause of death. When compared on the first 3 days of MV, nonpulmonary sequential organ failure assessment (SOFA) scores were significantly higher in cirrhotic patients than in non-cirrhotic patients whereas SOFA scores for pulmonary dysfunctions did not differ significantly (Fig. 2).
In this retrospective study performed on a large population of non-trauma ARDS patients who received protective lung ventilation, cirrhosis remained independently associated with 90-day mortality even after adjustment for important predictors for mortality in ARDS previously described. Furthermore, excess mortality does not appear to be related to lung failure but rather to other organs failures. Of note, as previous authors, we found that increased age, severity of illness score, decreased PaO2/FiO2, and increased driving pressure were associated with ARDS mortality (24,26,27).
There are very few studies assessing the impact of cirrhosis on the prognosis of ARDS patients. Most of these studies combined patients with ALI and ARDS and were performed before that lung-protective mechanical ventilation was recommended. For instance, in 1987, Matuschak et al. (15) in a retrospective study performed on 29 ARDS patients waiting for liver transplantation reported a mortality rate of 93%. In 1995, Doyle et al. (14) stressed the poor outcome of patients with liver cirrhosis developing ALI and found that chronic liver disease, in addition to sepsis and non-pulmonary organ system dysfunction before ICU admission, was associated with poor prognosis in a cohort of patients assessed prospectively. In the study performed on 259 ARDS patients and published in 1998, Monchi et al. (16) found that liver cirrhosis, after adjustment for the McCabe Score, oxygenation index, and the severity of the acute disease, remained predictive of hospital mortality. Cirrhosis was retained in the severity model developed by Monchi et al. (16), although Zilberberg (17) found that cirrhosis was an independent predictor of hospital death for patients with ALI but not for the subgroup of patients with ARDS. Last, cirrhosis was recently included in the final severe hypoxemia associated risk prediction model described by Pannu et al. (28).
There are several potential explanations for increased mortality among cirrhotic patients with ARDS. Overall, patients with cirrhosis requiring mechanical ventilation in ICU have a poor prognosis, as reported by Levesque et al. (2). In our study, we found that SOFA scores without the respiratory component calculated during the first 3 days of ARDS were significantly higher in cirrhotic patients compared with the non-cirrhotic patients whereas PaO2/FiO2 ratios were similar. This suggests that the poorer prognosis noted in cirrhotic patients was not directly related to the severity of hypoxemia, but rather in the development of extrapulmonary organ failures (4,6,8). Numerous factors need to be taken into account to explain this finding. First, it is possible that in cirrhotic patients, applying high levels of PEEP may compromise or worsen hepatic and/or renal perfusion which is already decreased (4,6,8). Second, the alcohol abuse associated effect, done in combination with immune and biological consequences of cirrhosis, could have contributed to the poorer outcome of cirrhotic patients. In the present study, excessive alcohol consumption was implicated in the development of cirrhosis in 83% of the patients. Clark et al. (29) reported recently that severe alcohol misuse was associated with an increased risk of death or persistent hospitalization at 90 days in patients with ALI. Third, we noted that cirrhotic patients were more susceptible than non-cirrhotic patients to bleeding complications leading to death.
Last, in patients with cirrhosis, multiple pathways can promote alveolar epithelial injury and increase vascular permeability in ARDS, including local and systemic inflammation (24,30,31). Cirrhosis is associated with complex dysfunctions of innate and adaptive immunity inducing an enhanced susceptibility to acute inflammatory processes (32). In addition, the liver plays a central role in regulating cytokine kinetics associated with ARDS (8). Consequently, patients with cirrhosis are at high risk to develop prolonged ARDS in association with other organ dysfunctions. Furthermore, several studies have found a decreased concentration of the antioxidant glutathione in the alveolus of alcohol abusers (33) affecting the alveolar–capillary barrier function, leading to an increased alveolar capillary permeability that could be worsened during mechanical ventilation. Indeed, patients with cirrhosis often have ascites and pleural effusion inducing pulmonary atelectasis responsible for the nonuniformity distribution of volume delivered in the whole lung during mechanical ventilation resulting in atelectrauma and ventilator-induced lung injury (24,30).
In addition to the retrospective nature of the study, some limitation should be addressed. This is a single center study, thereby limiting its external validity. The prevalence of ARDS in the present study, 7% of the ventilated patients, is, however, in the range of those reported in most studies varying from 3% to 9% (24,34). The proportion of cirrhotic patients among ARDS patients is higher than in most published studies because our center is a referral for liver transplantation and located in an area in which excessive alcohol consumption is a major health problem. Second, it can be argued that the diagnosis of cirrhosis was not confirmed by biopsy in all the patients although this is a usual situation in clinical practice as reported in recent studies (2,6). Last, we cannot exclude that cirrhotic patients received less aggressive organ support than non-cirrhotic patients even if the proportions of patients who received rescue therapy (prone positioning, iNO, and ECMO) did not differ significantly between the two groups.
In conclusion, our data show that cirrhosis remains a factor of poor prognosis for ARDS patients with lung protective ventilation strategy and was independently associated with 90-day mortality. This increased mortality did not appear to be related to lung failure but rather to other organs failures. Therefore, improving the prognosis of cirrhotic patients with ARDS requires us to prevent extrapulmonary dysfunction or to propose prompt organ support in addition to the early initiation of protective ventilation (35).
The authors thank Eric Barr for his careful review of the manuscript.
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