Epidemiology, causes, evolution and outcome in a single-center cohort of 1116 critically ill patients with hypoxic hepatitis

The screened population consisted of all consecutive adults (≥ 18 years, n = 29,874) who were admitted to the surgical, cardiac or medical ICU at the Ghent University Hospital between January 1, 2007 and September 21, 2015. HH was defined as a significant but transient increase in AST level above 5 times the upper limit of normal (ULN) after exclusion of other potential causes of liver injury. Different AST cutoff values for defining HH are used in the literature [2]. As HH has been histologically proven to occur even in patients with moderately elevated AST levels (at AST levels of 252 and 300 IU/L in the cohort of Cohen et al. [13] and Bynum et al. [14], respectively), a cutoff of at least 5 times the ULN was used in this study, i.e., 155 and 185 U/L for females and males, respectively. The 4012 identified patients whose AST level exceeded our cutoff value were evaluated for the presence of HH by three independent experts based on the pattern of liver enzyme alterations, the daily clinical notes and the discharge summaries. The sine qua non was the exposure to a hemodynamic or respiratory insult preceding the AST increase and the exclusion of other potential causes of liver injury. A flow diagram of the exclusion criteria is shown in Fig. 1. Reasons for exclusion were (1) acute liver failure, (2) chronic liver failure, (3) other conditions associated with abnormal liver tests such as cholangitis and pancreatitis, (4) liver surgery, (5) surgery near the liver, (6) hepatic vessel injury or thrombosis, (7) rhabdomyolysis, (8) an unclear increase of creatine kinase (CK), (9) post-anesthesia without overt evidence of an acute cardiac or respiratory event perioperatively, (10) missing data and (11) duplicate patients. (In patients having developed multiple episodes of HH during the study period, only the first episode is eligible for analysis.) Rhabdomyolysis was defined as serum CK exceeding 5 times the ULN (i.e., 850 and 974 U/L for females and males, respectively) with a CK-MB/CK ratio below 6% [6]. Patients with elevated CK levels but with unknown CK-MB value were excluded due to the uncertain CK increase. This study was approved by the Ethics Committee of the Ghent University Hospital (project numbers 2015/0796-0797). Due to the retrospective nature of this study, the need for informed consent was waived.

Routinely available biochemical parameters were recorded, including AST (U/L), ALT (U/L), LDH (U/L), bilirubin (mg/dL), alkaline phosphatase (AP) (U/L), gamma-glutamyl transpeptidase (U/L), lipase (U/L), international normalized ratio (INR), platelet count (10³/µL), white blood cell count (10³/µL), hemoglobin (g/dL), CK (U/L), creatinine (mg/dL), urea (mg/dL) and lactate (mg/dL). Values at specific time points were estimated using linear interpolation between consecutive recorded values. Parameters related to patient characteristics included sex, age, body mass index (BMI) and comorbidities (diabetes mellitus, cardiac function and chronic respiratory disease). Parameters related to the episode of HH included cause, severity of illness scores [acute physiology II score (APS-II) and the simplified acute physiology II score (SAPS-II)], supportive therapy (inotropic agents, vasopressor agents, mechanical ventilation, intra-aortic balloon pump (IABP) and need for dialysis), ICU and hospital length of stay, duration of the HH episode, and ICU and in-hospital mortality at 28 days. The peak of HH was defined as the point in time (T-ASTmax) when AST reached its peak value (ASTmax). In this study, the time origin was set to T-ASTmax (designated as time 0) and all recorded values are expressed in time relative to T-ASTmax for optimal comparison. Severity of illness scores were recorded over a time span of 24 h around T-ASTmax. Three categories for severity of HH were used: “5–10× ULN”, “10–20× ULN” and “> 20× ULN”. Seven underlying causes of HH were defined: cardiac failure, septic shock, hypovolemic shock, pulmonary embolism, acute respiratory failure, acute on chronic respiratory failure and hyperthermia.

Categorical data are reported as counts and percentages. Continuous data are reported as the median with the first (Q1) and third (Q3) quartiles. For categorical variables, comparisons between groups are performed using the Pearson’s Chi square test for contingency. For continuous variables, a permutation test based on difference in medians between groups is used. A Tukey-like approach with permutation resampling is applied to adjust P values for multiple pairwise comparisons. All statistical tests are performed as two-sided tests at a significance level of 0.05. The time trend of laboratory variables is graphically assessed using time series plots and stacked bar charts. Kaplan–Meier survival curves until 28 days after T-ASTmax and multi-group log-rank tests are used to compare the all-cause mortality between groups. Statistical analysis is performed using R version 3.3.2 [15].

During the study period, 29,874 adult patients with a male-to-female ratio of approximately 3:2 were admitted to the ICU at our center, of whom 4012 patients had peak AST levels exceeding 5 times the ULN. In 30.0% (1202/4012) of the cases, the elevation of AST was caused by HH, resulting in an overall ICU incidence of 4.0% (1202/29,874). As only the first episode was eligible for analysis in patients with multiple episodes of HH during the study period, the final study cohort comprised 1116 patients.

The all-cause mortality of patients admitted to the ICU at our center during the study period was 7.7% (2302/29,874). Among these non-survivors, 19.8% (455/2302) had developed HH during their ICU stay. The all-cause mortality associated with HH was 45.0% (502/1116) at 28 days, of which 90.6% occurred during ICU stay. The survival curves by cause of HH are presented in Fig. 2.

In our study cohort, the median age was 66.0 (Q1–Q3 55.0–74.0) years with a male-to-female ratio of 3:2. The median SAPS-II score at T-ASTmax was 66.0 (Q1–Q3 43.0–81.0). 74.9% of patients required mechanical ventilation. Vasopressor and inotropic agents were used in 60.8 and 43.2%, respectively, and 9.5% were on dialysis at T-ASTmax. The causes of HH, in decreasing order of frequency, were cardiac failure (49.1%), septic shock (29.8%), hypovolemic shock (9.4%), acute respiratory failure (6.4%), acute on chronic respiratory failure (3.3%), pulmonary embolism (1.4%) and hyperthermia (0.5%). An episode of HH (length of time that AST levels are exceeding 5 times the ULN) had a median duration of 54.3 (Q1–Q3 26.4–94.2) h, during which the median recovery time (duration from peak AST to levels below 5 times the ULN) was 34.7 (Q1–Q3 14.6–67.2) h.

Survivors had significantly lower severity of illness scores (median SAPS-II score of 54.0 vs. 76.0, P < 0.001 and median APS-II score 25.0 vs. 30.0, P = 0.005) as compared to non-survivors. They were less likely to have septic shock (25.6 vs. 35.1%, P = 0.003). Peak AST levels above 20 times ULN were less commonly seen in survivors (33.4 vs. 50.8%, P < 0.001). More characteristics, classified according to survival status, are presented in Table 1.

The three ASTmax subgroups (“5–10× ULN” vs. “10–20× ULN” vs. “> 20× ULN”) were also compared with each other. The causes of HH were equally represented within each subgroup. Patients with higher peak AST levels had higher severity of illness scores (median SAPS-II score of 57.0 vs. 60.0 vs. 73.0, P < 0.001; median APS-II score of 24.0 vs. 26.5 vs. 32.0, P < 0.001) and a higher need for supportive therapy, such as inotropic agents (38.5 vs. 37.9 vs. 50.2%, P < 0.001), vasopressor agents (50.9 vs. 59.4 vs. 70.0%, P < 0.001), dialysis (4.8 vs. 8.4 vs. 14.1%, P < 0.001) and IABP (13.7 vs. 20.7% vs. 18.9%, P = 0.041). In addition, higher peak AST levels were associated with higher 28-day mortality rates (33.2 vs. 44.4 vs. 55.4%, P < 0.001). More characteristics, classified according to severity of HH and to cause of HH, are presented in Tables 2 and 3, respectively.

The time trend of the liver tests is illustrated in Fig. 3. Once the AST level exceeded 5 times the ULN (designated as start of HH), it reached a median peak level of 521.2 (Q1–Q3 269.1–1581.6) U/L within a median of 16.3 (Q1–Q3 7.9–26.8) h. Subsequently, AST started to decline, dropping below 5 times the ULN after a median time of 34.7 (Q1–Q3 14.6–67.2) h and normalizing after a median time of 6.4 (Q1–Q3 3.9–10.9) days in survivors.

ALT and LDH peaked at median values of 332.0 (Q1–Q3 149.4–953.6)  U/L and 1180.6 (Q1–Q3 684.1–2770.8) U/L within a median time of 22.0 (Q1–Q3 9.7–43.0) and 21.4 (Q1–Q3 10.0–43.6) h after start of HH, respectively. In survivors, LDH returned to baseline (< 233 U/L) within a median of 5.1 (Q1–Q3 1.3–15.9) days after its peak. ALT declined more slowly, returning to baseline (< 31 and < 40 U/L for females and males, respectively) within 8.6 (Q1–Q3 3.9–16.5) days after its peak. When considering all patients, including those with AST already exceeding 5 times the ULN at ICU admission, ALT and LDH peaked at T-ASTmax in the majority of patients (65.5 and 53.1%, respectively) and to a lesser extent after T-ASTmax (26.2 and 29.8%, respectively).

The median relative increase of AST, ALT and LDH at T-ASTmax was 15.0, 8.7 and 4.7 times their ULN, respectively. LDH exceeded both AST and ALT at all time points in more than 80% of patients. The median AST/ALT ratio was 1.6 at the start of HH, increased to 1.8 at T-ASTmax and subsequently declined, reversing within a median of 32.5 h after T-ASTmax.

In addition, Fig. 3 illustrates that the median INR, creatinine and bilirubin levels also peaked at T-ASTmax, albeit to a much less extent, with median bilirubin level never exceeding the ULN. This is also illustrated in Fig. 4. Both in survivors and non-survivors, the proportion of patients with bilirubin level above the ULN increased mildly at T-ASTmax and then gradually decreased again. The proportion of survivors with bilirubin above 3 times the ULN was limited and increased slightly later during ICU stay. Likewise, AP remained stable during HH, except for a mild increase later during ICU stay, as illustrated in Figs. 3 and 4.

The pattern of liver enzyme alterations described above was found in all ASTmax subgroups (see Appendix Figs. 5, 6, 7). Median values of other laboratory tests at start of HH and at T-ASTmax are presented in Table 4.

HH was associated with high mortality rates, especially early in its course. 18.5% died within 24 h after T-ASTmax. After this first day, the hazard declined dramatically, but remained quite high, resulting in 40.2 and 45.0% all-cause mortality at 14 and 28 days, respectively. 90.6% of deaths occurred during ICU stay.

Twenty-eight-day mortality rates differed significantly among the causes of HH (P = 0.007). The high number of early deaths in the pulmonary embolism, septic shock and hypovolemic shock subgroups mainly accounted for the early mortality associated with HH. 37.5, 24.3, 25.7% of these patients died within 24 h after T-ASTmax. The mortality rate in the pulmonary embolism subgroup exceeded at all times those of other subgroups and ultimately resulted in 56.2% mortality at 28 days. The septic shock and hypovolemic shock subgroups had a 28-day mortality of 52.9 and 43.8%, respectively. While the early mortality in the cardiac failure subgroup was less pronounced, yet still considerable as 14.8% of these patients died within 24 h, its 28-day mortality of 41.4% ranked fourth among all subgroups. The acute respiratory failure and acute on chronic respiratory failure subgroups had similar survival curves and outcome, with 39.4 and 37.8% mortality at 28 days. The lowest mortality rate of 33.3% at 28 days was observed in the hyperthermia subgroup. The survival curves by cause of HH are presented in Fig. 2.

The 28-day mortality also increased significantly (P < 0.001) with severity of HH, ranging from 33.2% in the “5–10× ULN” subgroup to 55.4% in the “> 20× ULN” subgroup. There was no significant difference (P = 0.363) in 28-day mortality between men (39.8%) and women (42.4%).