Elsevier

Journal of Hepatology

Volume 60, Issue 6, June 2014, Pages 1187-1193
Journal of Hepatology

Research Article
Statin therapy is associated with reduced incidence of hypoxic hepatitis in critically ill patients

https://doi.org/10.1016/j.jhep.2014.01.019Get rights and content

Background & Aims

Hypoxic hepatitis (HH) is a frequent and life-threatening complication associated with states of oxygen depletion in critically ill patients. Ischemia and reperfusion contribute to liver injury in HH. Experimental data suggest beneficial effects of statins in hepatic ischemia/reperfusion injury. This study was conducted to investigate whether statin treatment prior to intensive care unit (ICU) admission affects incidence rates and severity of HH.

Methods

Eight hundred fifty-one patients admitted consecutively to three medical ICUs between December 2008 and December 2009 were prospectively screened for new occurrence of HH within 48 h following ICU admission. Statin treatment prior to ICU admission was assessed. 28-day-, 90-day-, and 1-year-survival as well as new-onset of complications in HH patients were prospectively documented.

Results

Eighty-seven patients (10%) developed HH. Statin treatment prior to ICU admission was significantly associated with decreased incidence of HH within 48 h after ICU admission in the multivariate analysis (adjusted OR = 0.42 (95% CI 0.19–0.95); p <0.05). Cardiogenic shock (p <0.001), septic shock (p <0.001) and active alcohol consumption (p <0.01) were identified as independent risk factors for development of HH. 28-day-, 90-day-, and 1-year-mortality rates in HH were 58%, 67%, and 74%, respectively. Statins were associated with improved 28-day-survival in the total study cohort (p <0.05), but did not affect 90-day- and 1-year-mortality, respectively.

Conclusions

Cardiogenic shock, septic shock, and active alcohol consumption were independent factors predisposing patients to new onset of HH. Statin treatment prior to ICU admission was the only protective factor regarding the new occurrence of HH in critically ill patients.

Introduction

Since their introduction in the late 1980’s, 3-hydroxyl-3-methyl-glutaryl coenzyme A reductase inhibitors, commonly referred to as statins, have become one of the most frequently prescribed drugs in developed countries [1], [2]. Statins are among the most potent lipid-lowering agents, and their efficacy in reducing the incidence of coronary events has been repeatedly demonstrated [3], [4], [5]. Statin use is recommended in current guidelines for treatment of hypercholesterolemia [6] and coronary heart disease [7].

Apart from their lipid-lowering capacities, statins exert pleiotropic effects that may contribute to the beneficial features. Experimental models suggest that statins improve hepatic microcirculation and endothelial function [8], [9], reduce platelet recruitment [10], [11], decrease vascular [12] and systemic inflammation [13], and attenuate hepatic ischemia/reperfusion (I/R) injury [14], [15], [16]. Recently, it has been shown that treatment with simvastatin attenuated lipopolysaccharide-induced hepatic sinusoidal dysfunction in rodents [9]. Additionally, simvastatin and atorvastatin attenuated hepatic injury and fibrosis following bile-duct-ligation in rats [17], [18]. These experimental data indicate that statins have beneficial effects on hepatic perfusion and may have potential effects in preventing and treating ischemic liver injury.

Hypoxic hepatitis (HH), also known as shock liver or ischemic hepatitis, is a life-threatening event associated with high morbidity and mortality [19], [20], [21], [22], [23]. HH is characterized by diffuse hepatic injury resulting from cardio-circulatory or respiratory impairment [19], [20], and its presence is suggested by a marked, transient and potentially reversible increase of aminotransferase levels in the appropriate clinical setting [19], [20], [21], [22], [23]. In critically ill patients at the medical intensive care unit (ICU), incidence rates of up to 11% with an ICU-mortality rate of 57% were observed [22]. Treatment of the underlying condition is currently the only therapy. As ischemia/reperfusion injury, inflammation, and endothelial/sinusoidal dysfunction are cardinal factors contributing to development of HH [24], statins may influence incidence and course of HH in critically ill patients.

Therefore, we investigated whether statin treatment prior to ICU admission affects incidence rates, severity and complications of HH in this prospective study in critically ill patients at the medical ICU.

Section snippets

Patients and methods

This prospective study was performed at 3 medical ICUs located at the Medical University Vienna (Vienna, Austria). All patients admitted to the 3 ICUs, between December 2008 and December 2009, were eligible for inclusion in the study. A total of 851 consecutive patients were included and studied prospectively.

All patients were prospectively screened for new onset of HH within 48 h after ICU admission. This observation window was chosen due to the reported time frame of rise of aminotransferase

Patients’ characteristics

Clinical characteristics of the total study cohort stratified to statin use are illustrated in Table 1. 851 patients were included in the study. Primary reasons for ICU admission were cardiogenic events and/or cardiopulmonary resuscitation (n = 274, 32%), infections/sepsis (n = 192, 23%), post-operative care (n = 144, 17%), respiratory insufficiency (n = 98, 11%), neurologic diseases (n = 58, 7%), bleeding (n = 25, 3%), and other (n = 60, 7%). 155 (18%) patients were on statin therapy prior to ICU admission.

Discussion

Liver dysfunction is associated with high morbidity and mortality at the ICU [22], [23], [39]. Hypoxic liver injury is one of the leading types of hepatic impairment in critically ill patients with reported incidence rates exceeding 10 percent [22]. Short-term-mortality in these patients is extremely high exceeding 50% by far. However, apart from treatment of the underlying condition, there are no established therapeutic opportunities or prophylactic measures. We report results of the first

Conflict of interest

The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

References (57)

  • J.G. Abraldes et al.

    Simvastatin lowers portal pressure in patients with cirrhosis and portal hypertension: a randomized controlled trial

    Gastroenterology

    (2009)
  • C. Zafra et al.

    Simvastatin enhances hepatic nitric oxide production and decreases the hepatic vascular tone in patients with cirrhosis

    Gastroenterology

    (2004)
  • I. Kurose et al.

    Oxidative stress-mediated apoptosis of hepatocytes exposed to acute ethanol intoxication

    Hepatology

    (1997)
  • T. Walley et al.

    Trends in prescribing and utilization of statins and other lipid lowering drugs across Europe 1997–2003

    Br J Clin Pharmacol

    (2005)
  • M. Stagnitti

    Trends in statins utilization and expenditures for U.S. civilian noninstitutionalized population, 2000 and 2005

    Med Expenditure Panel Surv

    (2008)
  • R.P. Byington et al.

    Reduction in cardiovascular events during pravastatin therapy. Pooled analysis of clinical events of the pravastatin atherosclerosis intervention program

    Circulation

    (1995)
  • J. Shepherd et al.

    Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland coronary prevention study group

    N Engl J Med

    (1995)
  • F. Taylor et al.

    Statins for the primary prevention of cardiovascular disease

    Cochrane Database Syst Rev

    (2011)
  • A.L. Catapano et al.

    ESC/EAS Guidelines for the management of dyslipidaemias: the task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS)

    Atherosclerosis

    (2011)
  • P.T. O’Gara et al.

    2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: executive summary: a report of the American college of cardiology foundation/American heart association task force on practice guidelines

    Circulation

    (2013)
  • V. La Mura et al.

    Effects of simvastatin administration on rodents with lipopolysaccharide-induced liver microvascular dysfunction

    Hepatology

    (2013)
  • P. Pignatelli et al.

    Immediate antioxidant and antiplatelet effect of atorvastatin via inhibition of Nox2

    Circulation

    (2012)
  • E. van der Meij et al.

    A clinical evaluation of statin pleiotropy: statins selectively and dose-dependently reduce vascular inflammation

    PLoS One

    (2013)
  • H. Harada et al.

    Sexual dimorphism in reduced-size liver ischemia and reperfusion injury in mice: role of endothelial cell nitric oxide synthase

    Proc Natl Acad Sci U S A

    (2003)
  • L. Russo et al.

    Addition of simvastatin to cold storage solution prevents endothelial dysfunction in explanted rat livers

    Hepatology

    (2012)
  • S. Dold et al.

    Simvastatin protects against cholestasis-induced liver injury

    Br J Pharmacol

    (2009)
  • J. Henrion

    Hypoxic hepatitis

    Liver Int

    (2012)
  • J. Henrion et al.

    Hypoxic hepatitis: clinical and hemodynamic study in 142 consecutive cases

    Medicine

    (2003)
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