American Journal of Emergency Medicine xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Original Contribution
Hypoxic hepatitis in survivors of out-of-hospital cardiac arrest☆ Sang Hoon Oh, MD, Han Joon Kim, MD, PhD ⁎, Kyu Nam Park, MD, PhD, Soo Hyun Kim, MD, PhD, Young Min Kim, MD, PhD, Chun Song Youn, MD, Jee Yong Lim, MD Department of Emergency Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea
a r t i c l e
i n f o
Article history: Received 4 April 2015 Accepted 13 May 2015 Available online xxxx
a b s t r a c t Introduction: Hypoxic hepatitis (HH) is commonly observed in out-of-hospital cardiac arrest (OHCA) survivors. The objective of this study was to investigate the incidence, clinical courses, and outcomes of as well as predisposing factors for HH in OHCA survivors. Methods: The study was based on a registry of cardiac arrest cases from 2009 to 2012 at a tertiary university hospital. We assessed patients' serum aminotransferase levels on return of spontaneous circulation (ROSC) and at 6, 12, 24, 48, and 72 hours postarrest. Hypoxic hepatitis was defined as a rapid increase in serum aminotransferase that reached at least 20 times the upper limit of normal. The patients were classified into 2 groups: the HH group and the non-HH group; we then analyzed the outcomes of the HH group. Independent predisposing factors to HH in this cohort were identified. Results: Of a total of 535 OHCA cases, 148 patients were enrolled in this study. Hypoxic hepatitis was identified in 13.5% (n = 20) of them. Serum aminotransferase rapidly increased in the first day after return of spontaneous circulation. Of the patients who developed HH, 5 (25%) survived to hospital discharge, and none of these individuals had good neurologic outcomes (Glasgow-Pittsburgh cerebral performance categories 1 and 2). Using multivariate logistic regression, we found that the no flow time was independent predictors of HH (odds ratio, 1.085 [95% confidence interval, 1.027-1.146]; P = .003). Conclusions: Hypoxic hepatitis occurred frequently in survivors of OHCA. The no flow time was an independent risk factor for HH, which was significantly related to death and poor neurologic outcomes. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Hypoxic hepatitis (HH) is frequently observed in critically ill patients and is associated with poor outcomes [1]. In HH, hypoperfusion with subsequent ischemia and passive congestion of the liver, severe systemic arterial hypoxemia, and/or impaired hepatic oxygen extraction induces centrilobular liver cell necrosis [2-5]. According to Henrion et al [2,6], a diagnosis of HH could be clinically assumed if the following 3 conditions are met: (1) an appropriate clinical setting of cardiac, respiratory or circulatory failure; (2) a sharp increase in serum aminotransferase levels that reach at least 20 times the upper limit of normal; (3) the exclusion of other causes of acute liver cell necrosis, particularly viral or drug-induced hepatitis. Hypoxic hepatitis is commonly observed in out-of-hospital cardiac arrest (OHCA) survivors. During cardiac arrest, ischemic tissue damage occurs because of a loss of blood supply. In addition, reperfusion injuries often develop in the first several hours after the return of spontaneous circulation (ROSC). Ischemia and reperfusion injuries may affect not ☆ Conflicts of interest: The authors do not have any financial or other relationships that might pose any conflicts of interest. ⁎ Corresponding author at: Department of Emergency Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 137-701, Republic of Korea. Tel.: +82 2 2258 1987; fax: +82 2 2258 1997. E-mail address: [email protected] (H.J. Kim).
only the brain but also all of the organs. Finally, cardiac arrest is an important cause of HH. The 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation (CPR) and Emergency Cardiovascular Care recommend the following for patients resuscitated from cardiac arrest: “optimize cardiopulmonary function and vital organ perfusion” and “reduce the risk of multiple organ injury and support organ function” [7]. However, there are little clinical data on extracerebral organ injuries in patients who achieved ROSC. In particular, there is little information on the postresuscitation states associated with HH. We examined patients’ serial aminotransferase levels during the 72 hours after arrest and evaluated the clinical courses of these patients. The aim of this study was to identify the incidence, clinical courses, and outcomes of as well as predisposing factors for HH in OHCA patients who achieved ROSC. 2. Methods This was a single-center retrospective, observational, registry-based study that took place from January 1, 2009, to December 31, 2012. Cardiopulmonary resuscitation and post–cardiac arrest care were performed in accordance with the American Heart Association’s guidelines [7], and the treatment team provided sufficiently prolonged life support to patients who did not regain consciousness. Out-ofhospital cardiac arrest registry data were collected prospectively
http://dx.doi.org/10.1016/j.ajem.2015.05.008 0735-6757/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Oh SH, et al, Hypoxic hepatitis in survivors of out-of-hospital cardiac arrest, Am J Emerg Med (2015), http://dx.doi.org/ 10.1016/j.ajem.2015.05.008
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S.H. Oh et al. / American Journal of Emergency Medicine xxx (2015) xxx–xxx
according to the Utstein Style guidelines at a teaching hospital in South Korea. The institutional review board of the Catholic University of Korea, Seoul Saint Mary’s Hospital, approved the study protocol before data analysis. All adult (age N19 years) patients who achieved ROSC after resuscitation from OHCA and survived for at least 24 hours after ROSC were considered eligible for this study. To eliminate nonhypoxic causes of acute liver injury, exclusion criteria included traumatic cardiac arrest patients, diagnoses of other known causes of acute hepatitis or hepatocellular injury (viral hepatitis infection, ingestion of hepatotoxic toxins or drugs, and other causes), and malignant infiltration. Out-of-hospital records included demographic information, such as sex, age, and underlying diseases. Resuscitation variables included first monitored heart rhythms, the presence of witnesses, bystander CPR performance, total number of defibrillations, cumulative amount of epinephrine given, no flow time (time from collapse to chest compression), and low flow time (time from chest compression to ROSC). The use of therapeutic hypothermia, hospital mortality, and neurologic outcomes at discharge were evaluated. Neurologic outcomes were assessed using the Glasgow-Pittsburgh cerebral performance categories (CPC) assessment and were dichotomized as either good neurologic outcomes (CPC 1 and 2) or poor neurologic outcomes (CPC 3-5) [8]. Serum levels of aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), total bilirubin, lactate dehydrogenase (LDH), creatine phosphokinase (CPK), and lactate and renal function tests were investigated. Serum samples from patients were collected serially immediately after ROSC and 6, 12, 24, 48, and 72 hours after ROSC. In patients with HH, we investigated the time required to return to normal levels of serum aminotransferase. Hypoxic hepatitis was defined as a rapid increase in serum aminotransferase as levels reaching at least 20 times the upper limit of normal with no other obvious explanation for the increase other than HH [2,8-12]. Based on the definition of HH, the patients were classified into 2 groups: the HH group and the non-HH group. The categorical variables were expressed as the numbers and the percentages, and the continuous data were expressed as the means ± SD or the medians and interquartile range (IQR) according to a normal distribution. Comparisons of categorical variables between groups were made using either the χ2 test or Fisher exact test as appropriate. In addition, continuous variables were compared between groups using t tests or Mann-Whitney U test. Predictive factors were evaluated using multivariate logistic regression analyses and odds ratios; 95%
Table 2 Multivariate logistic regression analysis of independent risk factors for hypoxic hepatitis Variables
Odds ratio for hypoxic hepatitis
95% CI
P
Nonshockable rhythm No flow time
3.969 1.085⁎
0.856-18.405 1.027-1.146
.078 .003
⁎ Per minute.
confidence intervals (CIs) were estimated in the logistic regression models. Bivariate associations between aminotransferase and other laboratory values were evaluated using Pearson correlation coefficient. The above statistical analyses were performed using SPSS 16 (SPSS Chicago, IL). A P b .05 was considered statistically significant.
3. Results During the enrollment period, a total of 535 OHCA cases were identified, 259 (35.1%) of which were achieved ROSC. Of these patients, 92 who died within 24 hours after ROSC, 9 who experienced traumatic cardiac arrest, 4 who ingested toxins or drugs, and 6 who had malignant infiltration were excluded. In total, 148 patients were enrolled in the present study. The baseline characteristics, resuscitation variables, survival discharges, and neurologic outcomes of the patients are summarized in Table 1. The mean patient age was 54.8 ± 16.4 years; 107 patients (72.3%) were male, and 41 patients (27.7%) were female. A total of 108 patients (73.0%) had a witness present during cardiac arrest, and 70 patients (47.3%) received basic life support from bystanders. In the first monitored rhythm, shockable rhythm was identified in 45 patients (30.4%). Patients had a median interval from collapse to chest compression of 3.5 minutes (IQR, 0.0-9.0 minutes), and the median low flow time was 23.0 minutes (IQR, 14.0-31.0 minutes). Therapeutic hypothermia was performed in 118 patients (79.7%). Fifty-six patients (37.8%) died before discharge, and 95 patients (64.2%) had a CPC of 3 to 5. Hypoxic hepatitis was identified in approximately 13.5% (n = 20) of the patients. To evaluate the risk factors for HH, we categorized patients into an HH group and a non-HH group (n = 128) and examined the characteristics of each group (Table 1). The percentage of patients with a shockable rhythm was significantly lower in the HH group than in the non-HH group (10.0% and 33.6%, respectively, P = .037). The no flow time was significantly longer in the HH group compared with the
Table 1 Baseline demographic and clinical characteristics of the overall cohort and comparison between the HH and non-HH groups
Male, n (%) Age, mean ± SD, y Underlying disease AMI, n (%) Angina pectoris, n (%) CHF, n (%) Arrhythmia, n (%) Hypertension, n (%) DM, n (%) Lung disease, n (%) Renal disease, n (%) Shockable rhythm, n (%) Witnessed, n (%) Bystander CPR, n (%) Defibrillation, median (IQR) Epinephrine, median (IQR), mg No flow time, median (IQR), min Low flow time, median (IQR), min Therapeutic hypothermia, n (%) Hospital mortality, n (%) Poor neurological outcome, n (%)
Total cohort (n = 148)
HH group (n = 20)
Non-HH group (n = 128)
107 (72.03) 54.8 ± 16.4
11 (55.0) 51.3 ± 19.0
96 (75.0) 55.3 ± 16.0
13 (8.8) 8 (5.4) 10 (6.8) 7 (4.7) 44 (29.7) 28 (18.9) 14 (9.5) 12 (8.1) 45 (30.4) 108 (73.0) 70 (47.3) 1.0 (0.0-2.0) 2.0 (1.0-4.0) 3.5 (0.0-9.0) 23.0 (14.0-31.0) 118 (79.7) 56 (37.8) 95 (64.2)
3 (15.0) 0 (0.0) 3 (15.0) 0 (0.0) 3 (15.0) 2 (10.0) 2 (10.0) 1 (5.0) 2 (10.0) 12 (60.0) 6 (30.0) 0.0 (0.0-1.0) 3.0 (1.0-6.5) 9.0 (0.3-20.8) 25.0 (18.3-36.0) 13 (65.0) 15 (75.0) 20 (100.0)
10 (7.8) 8 (6.2) 7 (5.5) 7 (5.5) 42 (32.8) 26 (20.3) 12 (9.4) 11 (8.6) 43 (33.6) 96 (75.0) 64 (50.0) 1.0 (0.0-2.0) 2.0 (1.0-4.0) 3.0 (0.0-7.0) 22.0 (12.3-30.8) 105 (82.0) 41 (32.0) 75 (58.6)
P .104 .311 .386 .599 .136 .594 .124 .368 1.000 1.000 .037 .180 .147 .085 .123 .023 .137 .130 b.001 b.001
Abbreviations: AMI, acute myocardial infarction; CHF, congestive heart failure; DM, diabetes mellitus.
Please cite this article as: Oh SH, et al, Hypoxic hepatitis in survivors of out-of-hospital cardiac arrest, Am J Emerg Med (2015), http://dx.doi.org/ 10.1016/j.ajem.2015.05.008
S.H. Oh et al. / American Journal of Emergency Medicine xxx (2015) xxx–xxx
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Fig. 1. Serum levels of AST and ALT in the HH and non-HH groups.
non-HH group (9.0 minutes [IQR, 0.3-20.8 minutes] and 3.0 minutes [IQR, 0.0-7.0 minutes], respectively, P = .023), but the low flow time was not significantly different between 2 groups (25.0 minutes [IQR, 18.3-36.0 minutes) and 22.0 minutes [IQR, 12.3-30.8 minutes], respectively, P = .137). There were no significant differences between the 2 groups with respect to the presence of an underlying disease, sex, age, and other resuscitation variables. At discharge, hospital mortality and poor neurologic outcomes were significantly different between the 2 groups (P b .001). In the HH group, only 5 patients (5%) were discharged as survivors, and all of them had CPC scores of 3 or 4. Using multivariate logistic regression, we found that the no flow time was independent predictors of HH (odds ratio, 1.085 [95% CI, 1.027-1.146]; P = .003) (Table 2). Serial serum levels of aminotransferases in both groups are displayed in Fig. 1. Levels of serum aminotransferase were significantly different between the 2 groups immediately after ROSC and at all sampling times (supplementary materials, Table A). In the HH group, 17 people (85%) had a peak in serum aminotransferase within the first 24 hours after ROSC, and 7 patients lived until the aminotransferase level returned to normal, and the median times for AST and ALT levels
to return to normal were 6 days (4-8 days) and 9 days (4-11 days), respectively. The time courses of the changes in serum levels of aminotransferases among patients in the HH group are displayed in Fig. 2. Fig. A in the supplementary materials section displays scatter plots illustrating the associations between peak levels of ALT/AST and other laboratory tests in all of the included patients. We evaluated bivariate associations between aminotransferase and other laboratory values using Pearson correlation coefficients (Table 3). Aminotransferase levels were positively correlated with other laboratory test results. Of these, both AST and ALT were most closely correlated with the serum level of LDH (r = 0.872, P b .001, and r = 0.891, P b .001, respectively). Lactate was moderately correlated with aminotransferases (r = 0.492, P b .001, for AST and r = 0.401, P b .001 for ALT). However, the correlations between aminotransferases and CPK were weak (r = 0.346 for AST, r = 0.212 for ALT). 4. Discussion In this study, we revealed that HH in OHCA survivors was common (13.5%) and that nonshockable rhythm and longer periods of total anoxic time were predisposing factors for HH. In addition, HH was
Fig. 2. Time course of changes in serum levels of AST and ALT among patients in the HH group.
Please cite this article as: Oh SH, et al, Hypoxic hepatitis in survivors of out-of-hospital cardiac arrest, Am J Emerg Med (2015), http://dx.doi.org/ 10.1016/j.ajem.2015.05.008
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S.H. Oh et al. / American Journal of Emergency Medicine xxx (2015) xxx–xxx
Table 3 Bivariate comparison analysis between the peak level of aminotransferase and other laboratory tests in all cardiac arrest patients AST Correlation coefficient⁎ AST ALT BUN Cr Bilirubin, total LDH CPK Lactate
0.853 0.217 0.272 0.333 0.872 0.346 0.492
ALT P b.001 .008 .001 b.001 b.001 b.001 b.001
Correlation coefficient⁎
P
0.853
b.001
0.176 0.179 0.193 0.891 0.212 0.401
.032 .030 .019 b.001 .010 b.001
Abbreviations: BUN, blood urea nitrogen; Cr, creatinine. ⁎ Pearson ρ test.
significantly associated with death and poor neurologic outcomes in these patients. Hypoxic hepatitis, also known as ischemic hepatitis or shock liver, is believed to be the result of a reduction in systemic blood flow and is reported in critically ill patients in the intensive care unit (ICU). Hypoxic hepatitis is caused by underlying conditions such as low cardiac output associated with congestive heart failure, chronic respiratory failure, sepsis, profound anemia, excessive bleeding, carbon monoxide poisoning, heat stroke, cocaine use, ergotamine poisoning, bacterial endocarditis, anaphylactic reactions, extensive burns, hypotensive states, obstructive sleep apnea, CPR, and ketoacidosis [3,4,13-15]. Henrion et al [2] observed an HH incidence of 0.9% in the ICU over a 10-year observation period. In contrast, one study reported that the prevalence of HH in the ICU reached 11.9% [3]. However, the prevalence of HH is unknown in other critical settings, such as in OHCA. The liver is the largest visceral organ in the human body and receives up to 25% of the entire cardiac output. Although the dual blood supply via the hepatic artery and portal system protect against ischemia [16,17], this unique dual blood supply does not play a role during cardiac arrest. Therefore, among the many critical illnesses, cardiac arrest is probably the largest risk factor for HH, and HH is observed more frequently in these patients than in other patients. In the present study, 20 patients were classified as having HH, which accounted for 13.5% of the patients who survived at least 24 hours after OHCA. This prevalence was higher than that found in previous studies that investigated critically ill patients in the ICU. However, in the previous literature related to OHCA, Nam et al [18] documented that HH occurred in 35 of 94 OHCA patients (37.2%) from 2006 to 2008 in Korea. We believe that this discrepancy may be caused by the different diagnostic criteria for HH. Several authors have proposed that an increase in serum aminotransferase levels to at least 20 times the upper limit of normal should be the minimal requirement for a diagnosis of HH [2,8-12], but Nam et al [18] defined HH as an increase in serum aminotransferase levels reaching at least 8 times the upper limit of normal. In the HH group, the first monitored arrest rhythm was identified as nonshockable in most cases (90.0%), and the median time from collapse to chest compression was 9.0 minutes (IQR, 0.3-20.8 minutes). Compared with the non-HH group, fewer patients in the HH group had shockable rhythms, and the median no flow time was significantly longer. In multivariate logistic regression, the no flow time was only independent predictors of HH. A short period of ischemia produces apoptosis only of the sinusoidal endothelial cells, but a longer period of ischemia followed by reperfusion causes apoptosis of both hepatocytes and sinusoidal endothelial cells [19]. In addition, extended periods of hypoxia produce intracellular reactive oxygen, xanthine oxidase, and mitochondria, which contribute to the intracellular oxidative stress [20]. Therefore, the time from collapse to ROSC appears to play an important role in the development of HH. However, in present study regarding cardiac arrest, the low flow time was not associated with the HH. In the present study, the mortality rate in patients with HH was 75.0%. This rate was only slightly higher than those in the 5 largest
studies of HH, which reported mortality rates ranging from 45% to 72% [21]. However, in our study, the lack of withdrawal of life support may have resulted in a mortality rate similar to those of other ICU-based studies, and none of these patients had good neurologic function [22]. In addition to injured hepatocytes leaking these enzymes into the blood stream, another possible cause of aminotransferase elevation after cardiac arrest is the release of serum aminotransferase from other tissues after mechanical chest compression. In our study, there were no statistically significant differences between the HH and nonHH groups with respect to the low flow time representing chest compression. In a regression analysis of the peak laboratory values, aminotransferase was most closely correlated with lactic acid, which represented increased anaerobic metabolism, than CPK, which is created in the skeleton, muscles, and heart. Given these results, the rise in serum aminotransferase may be caused by HH. In the present study, most patients displayed a peak in both transaminases, with the AST levels greater than the ALT levels, within the first 24 hours after ROSC. This finding is consistent with previous literature. According to Ebert [5], the typical pattern of transaminase levels during the course of HH is an initial dramatic rise in both transaminases, with peak AST and LDH levels occurring within 12 to 24 hours after the initiating event. Aminotransferase levels typically fall more than 50% within 3 days of stabilization and elimination of the underlying HH-causing condition, and AST levels decline back to a normal level earlier than ALT levels during this recovery period because of the shorter half-life of AST [23]. In our patients, the median times for AST and ALT levels to return to normal were 6 days and 9 days, respectively. The present study has several limitations. First, this study was a single-center, retrospective, registry-based study; the number of enrolled patients may be too small to draw a significant conclusion, and wide CIs reflect the small sample size. It is possible that a study with a larger scope could have yielded different results. Second, although cardiac arrest was the primary hypoxic insult in these patients, our analysis did not include potential additional variables, such as the hemodynamic status and respiratory function after ROSC. Because of these limitations, our results must be interpreted with caution. 5. Conclusions Hypoxic hepatitis developed in 13.5% of survivors of OHCA. Longer periods of no flow times were independent risk factors for the occurrence of HH. In these patients, HH was significantly related to death and poor neurologic outcomes. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ajem.2015.05.008. References [1] Kramer L, Jordan B, Druml W, Bauer P, Metnitz PG. Austrian Epidemiologic Study on Intensive Care, ASDI Study Group. Incidence and prognosis of early hepatic dysfunction in critically ill patients–a prospective multicenter study. Crit Care Med 2007;35: 1099–104. [2] Henrion J, Schapira M, Luwaert R, Colin L, Delannoy A, Heller FR. Hypoxic hepatitis: clinical and hemodynamic study in 142 consecutive cases. Medicine (Baltimore) 2003;82:392–406. [3] Fuhrmann V, Kneidinger N, Herkner H, Heinz G, Nikfardjam M, Bojic A, et al. Hypoxic hepatitis: underlying conditions and risk factors for mortality in critically ill patients. Intensive Care Med 2009;35:1397–405. [4] Henrion J, Descamps O, Luwaert R, Schapira M, Parfonry A, Heller F. Hypoxic hepatitis in patients with cardiac failure: incidence in a coronary care unit and measurement of hepatic blood flow. J Hepatol 1994;21:696–703. [5] Ebert EC. Hypoxic liver injury. Mayo Clin Proc 2006;81:1232–6. [6] Henrion J, Luwaert R, Colin L, Schmitz A, Schapira M, Heller FR. Hypoxic hepatitis. Prospective, clinical and hemodynamic study of 45 cases. Gastroenterol Clin Biol 1990;14:836–41. [7] Peberdy MA, Callaway CW, Neumar RW, Geocadin RG, Zimmerman JL, Donnino M, et al. American Heart Association. Part 9: post-cardiac arrest care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010;122:S768–86.
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S.H. Oh et al. / American Journal of Emergency Medicine xxx (2015) xxx–xxx [8] Gitlin N, Serio KM. Ischemic hepatitis: widening horizons. Am J Gastroenterol 1992; 87:831–6. [9] Fuhrmann V, Madl C, Mueller C, Holzinger U, Kitzberger R, Funk GC, et al. Hepatopulmonary syndrome in patients with hypoxic hepatitis. Gastroenterology 2006;131:69–75. [10] Gibson PR, Dudley FJ. Ischemic hepatitis: clinical features, diagnosis and prognosis. Aust N Z J Med 1984;14:822–5. [11] Hickman PE, Potter JM. Mortality associated with ischaemic hepatitis. Aust N Z J Med 1990;20:32–4. [12] Rawson JS, Achord JL. Shock liver. South Med J 1985;78:1421–5. [13] Ucgun I, Ozakyol A, Metintas M, Moral H, Orman A, Bal C, et al. Relationship between hypoxic hepatitis and cor pulmonale in patients treated in the respiratory ICU. Int J Clin Pract 2005;59:1295–300. [14] Blich M, Edelstein S, Mansano R, Edoute Y. Ischemic hepatitis induced by severe anemia. Isr Med Assoc J 2003;5:208–9. [15] Szypowska A, Skórka A, Pańkowska E. Acute hypoxic hepatopathy: diabetic ketoacidosis complication in an infant newly diagnosed with type 1 diabetes mellitus. Pediatr Endocrinol Diabetes Metab 2008;14:249–51.
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[16] Vollmar B, Menger MD. The hepatic microcirculation: mechanistic contributions and therapeutic targets in liver injury and repair. Physiol Rev 2009;89:1269–339. [17] Naschitz JE, Slobodin G, Lewis RJ, Zuckerman E, Yeshurun D. Heart diseases affecting the liver and liver diseases affecting the heart. Am Heart J 2000;140:111–20. [18] Nam SH, Choi SP, Youn CS, So BH, Oh YM, Park KN. Hypoxic hepatitis in a postresuscitation state. J Korean Soc Emerg Med 2009;20:65–71. [19] Jaeschke H. Reactive oxygen and ischemia/reperfusion injury of the liver. Chem Biol Interact 1991;79:115–36. [20] Cursio R, Gugenheim J, Ricci JE, Crenesse D, Rostagno P, Maulon L, et al. A caspase inhibitor fully protects rats against lethal normothermic liver ischemia by inhibition of liver apoptosis. FASEB J 1999;13:253–61. [21] Henrion J. Hypoxic hepatitis. Liver Int 2012;32:1039–52. [22] Fuhrmann V, Kneidinger N, Herkner H, Heinz G, Nikfardjam M, Bojic A, et al. Impact of hypoxic hepatitis on mortality in the intensive care unit. Intensive Care Med 2011;37(8):1302–10. [23] Dufour DR, Lott JA, Nolte FS, Gretch DR, Koff RS, Seeff LB. Diagnosis and monitoring of hepatic injury. I. Performance characteristics of laboratory tests. Clin Chem 2000; 46:2027–49.
Please cite this article as: Oh SH, et al, Hypoxic hepatitis in survivors of out-of-hospital cardiac arrest, Am J Emerg Med (2015), http://dx.doi.org/ 10.1016/j.ajem.2015.05.008
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Original Contribution
Hypoxic hepatitis in survivors of out-of-hospital cardiac arrest☆ Sang Hoon Oh, MD, Han Joon Kim, MD, PhD ⁎, Kyu Nam Park, MD, PhD, Soo Hyun Kim, MD, PhD, Young Min Kim, MD, PhD, Chun Song Youn, MD, Jee Yong Lim, MD Department of Emergency Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea
a r t i c l e
i n f o
Article history: Received 4 April 2015 Accepted 13 May 2015 Available online xxxx
a b s t r a c t Introduction: Hypoxic hepatitis (HH) is commonly observed in out-of-hospital cardiac arrest (OHCA) survivors. The objective of this study was to investigate the incidence, clinical courses, and outcomes of as well as predisposing factors for HH in OHCA survivors. Methods: The study was based on a registry of cardiac arrest cases from 2009 to 2012 at a tertiary university hospital. We assessed patients' serum aminotransferase levels on return of spontaneous circulation (ROSC) and at 6, 12, 24, 48, and 72 hours postarrest. Hypoxic hepatitis was defined as a rapid increase in serum aminotransferase that reached at least 20 times the upper limit of normal. The patients were classified into 2 groups: the HH group and the non-HH group; we then analyzed the outcomes of the HH group. Independent predisposing factors to HH in this cohort were identified. Results: Of a total of 535 OHCA cases, 148 patients were enrolled in this study. Hypoxic hepatitis was identified in 13.5% (n = 20) of them. Serum aminotransferase rapidly increased in the first day after return of spontaneous circulation. Of the patients who developed HH, 5 (25%) survived to hospital discharge, and none of these individuals had good neurologic outcomes (Glasgow-Pittsburgh cerebral performance categories 1 and 2). Using multivariate logistic regression, we found that the no flow time was independent predictors of HH (odds ratio, 1.085 [95% confidence interval, 1.027-1.146]; P = .003). Conclusions: Hypoxic hepatitis occurred frequently in survivors of OHCA. The no flow time was an independent risk factor for HH, which was significantly related to death and poor neurologic outcomes. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Hypoxic hepatitis (HH) is frequently observed in critically ill patients and is associated with poor outcomes [1]. In HH, hypoperfusion with subsequent ischemia and passive congestion of the liver, severe systemic arterial hypoxemia, and/or impaired hepatic oxygen extraction induces centrilobular liver cell necrosis [2-5]. According to Henrion et al [2,6], a diagnosis of HH could be clinically assumed if the following 3 conditions are met: (1) an appropriate clinical setting of cardiac, respiratory or circulatory failure; (2) a sharp increase in serum aminotransferase levels that reach at least 20 times the upper limit of normal; (3) the exclusion of other causes of acute liver cell necrosis, particularly viral or drug-induced hepatitis. Hypoxic hepatitis is commonly observed in out-of-hospital cardiac arrest (OHCA) survivors. During cardiac arrest, ischemic tissue damage occurs because of a loss of blood supply. In addition, reperfusion injuries often develop in the first several hours after the return of spontaneous circulation (ROSC). Ischemia and reperfusion injuries may affect not ☆ Conflicts of interest: The authors do not have any financial or other relationships that might pose any conflicts of interest. ⁎ Corresponding author at: Department of Emergency Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 137-701, Republic of Korea. Tel.: +82 2 2258 1987; fax: +82 2 2258 1997. E-mail address: [email protected] (H.J. Kim).
only the brain but also all of the organs. Finally, cardiac arrest is an important cause of HH. The 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation (CPR) and Emergency Cardiovascular Care recommend the following for patients resuscitated from cardiac arrest: “optimize cardiopulmonary function and vital organ perfusion” and “reduce the risk of multiple organ injury and support organ function” [7]. However, there are little clinical data on extracerebral organ injuries in patients who achieved ROSC. In particular, there is little information on the postresuscitation states associated with HH. We examined patients’ serial aminotransferase levels during the 72 hours after arrest and evaluated the clinical courses of these patients. The aim of this study was to identify the incidence, clinical courses, and outcomes of as well as predisposing factors for HH in OHCA patients who achieved ROSC. 2. Methods This was a single-center retrospective, observational, registry-based study that took place from January 1, 2009, to December 31, 2012. Cardiopulmonary resuscitation and post–cardiac arrest care were performed in accordance with the American Heart Association’s guidelines [7], and the treatment team provided sufficiently prolonged life support to patients who did not regain consciousness. Out-ofhospital cardiac arrest registry data were collected prospectively
http://dx.doi.org/10.1016/j.ajem.2015.05.008 0735-6757/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Oh SH, et al, Hypoxic hepatitis in survivors of out-of-hospital cardiac arrest, Am J Emerg Med (2015), http://dx.doi.org/ 10.1016/j.ajem.2015.05.008
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S.H. Oh et al. / American Journal of Emergency Medicine xxx (2015) xxx–xxx
according to the Utstein Style guidelines at a teaching hospital in South Korea. The institutional review board of the Catholic University of Korea, Seoul Saint Mary’s Hospital, approved the study protocol before data analysis. All adult (age N19 years) patients who achieved ROSC after resuscitation from OHCA and survived for at least 24 hours after ROSC were considered eligible for this study. To eliminate nonhypoxic causes of acute liver injury, exclusion criteria included traumatic cardiac arrest patients, diagnoses of other known causes of acute hepatitis or hepatocellular injury (viral hepatitis infection, ingestion of hepatotoxic toxins or drugs, and other causes), and malignant infiltration. Out-of-hospital records included demographic information, such as sex, age, and underlying diseases. Resuscitation variables included first monitored heart rhythms, the presence of witnesses, bystander CPR performance, total number of defibrillations, cumulative amount of epinephrine given, no flow time (time from collapse to chest compression), and low flow time (time from chest compression to ROSC). The use of therapeutic hypothermia, hospital mortality, and neurologic outcomes at discharge were evaluated. Neurologic outcomes were assessed using the Glasgow-Pittsburgh cerebral performance categories (CPC) assessment and were dichotomized as either good neurologic outcomes (CPC 1 and 2) or poor neurologic outcomes (CPC 3-5) [8]. Serum levels of aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), total bilirubin, lactate dehydrogenase (LDH), creatine phosphokinase (CPK), and lactate and renal function tests were investigated. Serum samples from patients were collected serially immediately after ROSC and 6, 12, 24, 48, and 72 hours after ROSC. In patients with HH, we investigated the time required to return to normal levels of serum aminotransferase. Hypoxic hepatitis was defined as a rapid increase in serum aminotransferase as levels reaching at least 20 times the upper limit of normal with no other obvious explanation for the increase other than HH [2,8-12]. Based on the definition of HH, the patients were classified into 2 groups: the HH group and the non-HH group. The categorical variables were expressed as the numbers and the percentages, and the continuous data were expressed as the means ± SD or the medians and interquartile range (IQR) according to a normal distribution. Comparisons of categorical variables between groups were made using either the χ2 test or Fisher exact test as appropriate. In addition, continuous variables were compared between groups using t tests or Mann-Whitney U test. Predictive factors were evaluated using multivariate logistic regression analyses and odds ratios; 95%
Table 2 Multivariate logistic regression analysis of independent risk factors for hypoxic hepatitis Variables
Odds ratio for hypoxic hepatitis
95% CI
P
Nonshockable rhythm No flow time
3.969 1.085⁎
0.856-18.405 1.027-1.146
.078 .003
⁎ Per minute.
confidence intervals (CIs) were estimated in the logistic regression models. Bivariate associations between aminotransferase and other laboratory values were evaluated using Pearson correlation coefficient. The above statistical analyses were performed using SPSS 16 (SPSS Chicago, IL). A P b .05 was considered statistically significant.
3. Results During the enrollment period, a total of 535 OHCA cases were identified, 259 (35.1%) of which were achieved ROSC. Of these patients, 92 who died within 24 hours after ROSC, 9 who experienced traumatic cardiac arrest, 4 who ingested toxins or drugs, and 6 who had malignant infiltration were excluded. In total, 148 patients were enrolled in the present study. The baseline characteristics, resuscitation variables, survival discharges, and neurologic outcomes of the patients are summarized in Table 1. The mean patient age was 54.8 ± 16.4 years; 107 patients (72.3%) were male, and 41 patients (27.7%) were female. A total of 108 patients (73.0%) had a witness present during cardiac arrest, and 70 patients (47.3%) received basic life support from bystanders. In the first monitored rhythm, shockable rhythm was identified in 45 patients (30.4%). Patients had a median interval from collapse to chest compression of 3.5 minutes (IQR, 0.0-9.0 minutes), and the median low flow time was 23.0 minutes (IQR, 14.0-31.0 minutes). Therapeutic hypothermia was performed in 118 patients (79.7%). Fifty-six patients (37.8%) died before discharge, and 95 patients (64.2%) had a CPC of 3 to 5. Hypoxic hepatitis was identified in approximately 13.5% (n = 20) of the patients. To evaluate the risk factors for HH, we categorized patients into an HH group and a non-HH group (n = 128) and examined the characteristics of each group (Table 1). The percentage of patients with a shockable rhythm was significantly lower in the HH group than in the non-HH group (10.0% and 33.6%, respectively, P = .037). The no flow time was significantly longer in the HH group compared with the
Table 1 Baseline demographic and clinical characteristics of the overall cohort and comparison between the HH and non-HH groups
Male, n (%) Age, mean ± SD, y Underlying disease AMI, n (%) Angina pectoris, n (%) CHF, n (%) Arrhythmia, n (%) Hypertension, n (%) DM, n (%) Lung disease, n (%) Renal disease, n (%) Shockable rhythm, n (%) Witnessed, n (%) Bystander CPR, n (%) Defibrillation, median (IQR) Epinephrine, median (IQR), mg No flow time, median (IQR), min Low flow time, median (IQR), min Therapeutic hypothermia, n (%) Hospital mortality, n (%) Poor neurological outcome, n (%)
Total cohort (n = 148)
HH group (n = 20)
Non-HH group (n = 128)
107 (72.03) 54.8 ± 16.4
11 (55.0) 51.3 ± 19.0
96 (75.0) 55.3 ± 16.0
13 (8.8) 8 (5.4) 10 (6.8) 7 (4.7) 44 (29.7) 28 (18.9) 14 (9.5) 12 (8.1) 45 (30.4) 108 (73.0) 70 (47.3) 1.0 (0.0-2.0) 2.0 (1.0-4.0) 3.5 (0.0-9.0) 23.0 (14.0-31.0) 118 (79.7) 56 (37.8) 95 (64.2)
3 (15.0) 0 (0.0) 3 (15.0) 0 (0.0) 3 (15.0) 2 (10.0) 2 (10.0) 1 (5.0) 2 (10.0) 12 (60.0) 6 (30.0) 0.0 (0.0-1.0) 3.0 (1.0-6.5) 9.0 (0.3-20.8) 25.0 (18.3-36.0) 13 (65.0) 15 (75.0) 20 (100.0)
10 (7.8) 8 (6.2) 7 (5.5) 7 (5.5) 42 (32.8) 26 (20.3) 12 (9.4) 11 (8.6) 43 (33.6) 96 (75.0) 64 (50.0) 1.0 (0.0-2.0) 2.0 (1.0-4.0) 3.0 (0.0-7.0) 22.0 (12.3-30.8) 105 (82.0) 41 (32.0) 75 (58.6)
P .104 .311 .386 .599 .136 .594 .124 .368 1.000 1.000 .037 .180 .147 .085 .123 .023 .137 .130 b.001 b.001
Abbreviations: AMI, acute myocardial infarction; CHF, congestive heart failure; DM, diabetes mellitus.
Please cite this article as: Oh SH, et al, Hypoxic hepatitis in survivors of out-of-hospital cardiac arrest, Am J Emerg Med (2015), http://dx.doi.org/ 10.1016/j.ajem.2015.05.008
S.H. Oh et al. / American Journal of Emergency Medicine xxx (2015) xxx–xxx
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Fig. 1. Serum levels of AST and ALT in the HH and non-HH groups.
non-HH group (9.0 minutes [IQR, 0.3-20.8 minutes] and 3.0 minutes [IQR, 0.0-7.0 minutes], respectively, P = .023), but the low flow time was not significantly different between 2 groups (25.0 minutes [IQR, 18.3-36.0 minutes) and 22.0 minutes [IQR, 12.3-30.8 minutes], respectively, P = .137). There were no significant differences between the 2 groups with respect to the presence of an underlying disease, sex, age, and other resuscitation variables. At discharge, hospital mortality and poor neurologic outcomes were significantly different between the 2 groups (P b .001). In the HH group, only 5 patients (5%) were discharged as survivors, and all of them had CPC scores of 3 or 4. Using multivariate logistic regression, we found that the no flow time was independent predictors of HH (odds ratio, 1.085 [95% CI, 1.027-1.146]; P = .003) (Table 2). Serial serum levels of aminotransferases in both groups are displayed in Fig. 1. Levels of serum aminotransferase were significantly different between the 2 groups immediately after ROSC and at all sampling times (supplementary materials, Table A). In the HH group, 17 people (85%) had a peak in serum aminotransferase within the first 24 hours after ROSC, and 7 patients lived until the aminotransferase level returned to normal, and the median times for AST and ALT levels
to return to normal were 6 days (4-8 days) and 9 days (4-11 days), respectively. The time courses of the changes in serum levels of aminotransferases among patients in the HH group are displayed in Fig. 2. Fig. A in the supplementary materials section displays scatter plots illustrating the associations between peak levels of ALT/AST and other laboratory tests in all of the included patients. We evaluated bivariate associations between aminotransferase and other laboratory values using Pearson correlation coefficients (Table 3). Aminotransferase levels were positively correlated with other laboratory test results. Of these, both AST and ALT were most closely correlated with the serum level of LDH (r = 0.872, P b .001, and r = 0.891, P b .001, respectively). Lactate was moderately correlated with aminotransferases (r = 0.492, P b .001, for AST and r = 0.401, P b .001 for ALT). However, the correlations between aminotransferases and CPK were weak (r = 0.346 for AST, r = 0.212 for ALT). 4. Discussion In this study, we revealed that HH in OHCA survivors was common (13.5%) and that nonshockable rhythm and longer periods of total anoxic time were predisposing factors for HH. In addition, HH was
Fig. 2. Time course of changes in serum levels of AST and ALT among patients in the HH group.
Please cite this article as: Oh SH, et al, Hypoxic hepatitis in survivors of out-of-hospital cardiac arrest, Am J Emerg Med (2015), http://dx.doi.org/ 10.1016/j.ajem.2015.05.008
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S.H. Oh et al. / American Journal of Emergency Medicine xxx (2015) xxx–xxx
Table 3 Bivariate comparison analysis between the peak level of aminotransferase and other laboratory tests in all cardiac arrest patients AST Correlation coefficient⁎ AST ALT BUN Cr Bilirubin, total LDH CPK Lactate
0.853 0.217 0.272 0.333 0.872 0.346 0.492
ALT P b.001 .008 .001 b.001 b.001 b.001 b.001
Correlation coefficient⁎
P
0.853
b.001
0.176 0.179 0.193 0.891 0.212 0.401
.032 .030 .019 b.001 .010 b.001
Abbreviations: BUN, blood urea nitrogen; Cr, creatinine. ⁎ Pearson ρ test.
significantly associated with death and poor neurologic outcomes in these patients. Hypoxic hepatitis, also known as ischemic hepatitis or shock liver, is believed to be the result of a reduction in systemic blood flow and is reported in critically ill patients in the intensive care unit (ICU). Hypoxic hepatitis is caused by underlying conditions such as low cardiac output associated with congestive heart failure, chronic respiratory failure, sepsis, profound anemia, excessive bleeding, carbon monoxide poisoning, heat stroke, cocaine use, ergotamine poisoning, bacterial endocarditis, anaphylactic reactions, extensive burns, hypotensive states, obstructive sleep apnea, CPR, and ketoacidosis [3,4,13-15]. Henrion et al [2] observed an HH incidence of 0.9% in the ICU over a 10-year observation period. In contrast, one study reported that the prevalence of HH in the ICU reached 11.9% [3]. However, the prevalence of HH is unknown in other critical settings, such as in OHCA. The liver is the largest visceral organ in the human body and receives up to 25% of the entire cardiac output. Although the dual blood supply via the hepatic artery and portal system protect against ischemia [16,17], this unique dual blood supply does not play a role during cardiac arrest. Therefore, among the many critical illnesses, cardiac arrest is probably the largest risk factor for HH, and HH is observed more frequently in these patients than in other patients. In the present study, 20 patients were classified as having HH, which accounted for 13.5% of the patients who survived at least 24 hours after OHCA. This prevalence was higher than that found in previous studies that investigated critically ill patients in the ICU. However, in the previous literature related to OHCA, Nam et al [18] documented that HH occurred in 35 of 94 OHCA patients (37.2%) from 2006 to 2008 in Korea. We believe that this discrepancy may be caused by the different diagnostic criteria for HH. Several authors have proposed that an increase in serum aminotransferase levels to at least 20 times the upper limit of normal should be the minimal requirement for a diagnosis of HH [2,8-12], but Nam et al [18] defined HH as an increase in serum aminotransferase levels reaching at least 8 times the upper limit of normal. In the HH group, the first monitored arrest rhythm was identified as nonshockable in most cases (90.0%), and the median time from collapse to chest compression was 9.0 minutes (IQR, 0.3-20.8 minutes). Compared with the non-HH group, fewer patients in the HH group had shockable rhythms, and the median no flow time was significantly longer. In multivariate logistic regression, the no flow time was only independent predictors of HH. A short period of ischemia produces apoptosis only of the sinusoidal endothelial cells, but a longer period of ischemia followed by reperfusion causes apoptosis of both hepatocytes and sinusoidal endothelial cells [19]. In addition, extended periods of hypoxia produce intracellular reactive oxygen, xanthine oxidase, and mitochondria, which contribute to the intracellular oxidative stress [20]. Therefore, the time from collapse to ROSC appears to play an important role in the development of HH. However, in present study regarding cardiac arrest, the low flow time was not associated with the HH. In the present study, the mortality rate in patients with HH was 75.0%. This rate was only slightly higher than those in the 5 largest
studies of HH, which reported mortality rates ranging from 45% to 72% [21]. However, in our study, the lack of withdrawal of life support may have resulted in a mortality rate similar to those of other ICU-based studies, and none of these patients had good neurologic function [22]. In addition to injured hepatocytes leaking these enzymes into the blood stream, another possible cause of aminotransferase elevation after cardiac arrest is the release of serum aminotransferase from other tissues after mechanical chest compression. In our study, there were no statistically significant differences between the HH and nonHH groups with respect to the low flow time representing chest compression. In a regression analysis of the peak laboratory values, aminotransferase was most closely correlated with lactic acid, which represented increased anaerobic metabolism, than CPK, which is created in the skeleton, muscles, and heart. Given these results, the rise in serum aminotransferase may be caused by HH. In the present study, most patients displayed a peak in both transaminases, with the AST levels greater than the ALT levels, within the first 24 hours after ROSC. This finding is consistent with previous literature. According to Ebert [5], the typical pattern of transaminase levels during the course of HH is an initial dramatic rise in both transaminases, with peak AST and LDH levels occurring within 12 to 24 hours after the initiating event. Aminotransferase levels typically fall more than 50% within 3 days of stabilization and elimination of the underlying HH-causing condition, and AST levels decline back to a normal level earlier than ALT levels during this recovery period because of the shorter half-life of AST [23]. In our patients, the median times for AST and ALT levels to return to normal were 6 days and 9 days, respectively. The present study has several limitations. First, this study was a single-center, retrospective, registry-based study; the number of enrolled patients may be too small to draw a significant conclusion, and wide CIs reflect the small sample size. It is possible that a study with a larger scope could have yielded different results. Second, although cardiac arrest was the primary hypoxic insult in these patients, our analysis did not include potential additional variables, such as the hemodynamic status and respiratory function after ROSC. Because of these limitations, our results must be interpreted with caution. 5. Conclusions Hypoxic hepatitis developed in 13.5% of survivors of OHCA. Longer periods of no flow times were independent risk factors for the occurrence of HH. In these patients, HH was significantly related to death and poor neurologic outcomes. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ajem.2015.05.008. References [1] Kramer L, Jordan B, Druml W, Bauer P, Metnitz PG. Austrian Epidemiologic Study on Intensive Care, ASDI Study Group. Incidence and prognosis of early hepatic dysfunction in critically ill patients–a prospective multicenter study. Crit Care Med 2007;35: 1099–104. [2] Henrion J, Schapira M, Luwaert R, Colin L, Delannoy A, Heller FR. Hypoxic hepatitis: clinical and hemodynamic study in 142 consecutive cases. Medicine (Baltimore) 2003;82:392–406. [3] Fuhrmann V, Kneidinger N, Herkner H, Heinz G, Nikfardjam M, Bojic A, et al. Hypoxic hepatitis: underlying conditions and risk factors for mortality in critically ill patients. Intensive Care Med 2009;35:1397–405. [4] Henrion J, Descamps O, Luwaert R, Schapira M, Parfonry A, Heller F. Hypoxic hepatitis in patients with cardiac failure: incidence in a coronary care unit and measurement of hepatic blood flow. J Hepatol 1994;21:696–703. [5] Ebert EC. Hypoxic liver injury. Mayo Clin Proc 2006;81:1232–6. [6] Henrion J, Luwaert R, Colin L, Schmitz A, Schapira M, Heller FR. Hypoxic hepatitis. Prospective, clinical and hemodynamic study of 45 cases. Gastroenterol Clin Biol 1990;14:836–41. [7] Peberdy MA, Callaway CW, Neumar RW, Geocadin RG, Zimmerman JL, Donnino M, et al. American Heart Association. Part 9: post-cardiac arrest care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010;122:S768–86.
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