Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study

Severe acetaminophen hepatotoxicity frequently leads to acute liver failure (ALF). We determined the incidence, risk factors, and outcomes of acetaminophen-induced ALF at 22 tertiary care centers in the United States. Detailed prospective data were gathered on 662 consecutive patients over a 6-year period fulfilling standard criteria for ALF (coagulopathy and encephalopathy), from which 275 (42%) were determined to result from acetaminophen liver injury. The annual percentage of acetaminophen-related ALF rose during the study from 28% in 1998 to 51% in 2003. Median dose ingested was 24 g (equivalent to 48 extra-strength tablets). Unintentional overdoses accounted for 131 (48%) cases, intentional (suicide attempts) 122 (44%), and 22 (8%) were of unknown intent. In the unintentional group, 38% took two or more acetaminophen preparations simultaneously, and 63% used narcotic-containing compounds. Eighty-one percent of unintentional patients reported taking acetaminophen and/or other analgesics for acute or chronic pain syndromes. Overall, 178 subjects (65%) survived, 74 (27%) died without transplantation, and 23 subjects (8%) underwent liver transplantation; 71% were alive at 3 weeks. Transplant-free survival rate and rate of liver transplantation were similar between intentional and unintentional groups. In conclusion, acetaminophen hepatotoxicity far exceeds other causes of acute liver failure in the United States. Susceptible patients have concomitant depression, chronic pain, alcohol or narcotic use, and/or take several preparations simultaneously. Education of patients, physicians, and pharmacies to limit high-risk use settings is recommended.     

RIFLE-based data collection/management system applied to a prospective cohort multicenter Italian study on the epidemiology of acute kidney injury in the intensive care unit

The epidemiology of acute kidney injury (AKI) has been difficult to explore in the past, due to different definitions across various studies. Nevertheless, this is a very important topic today in light of the high morbidity and mortality of critically ill patients presenting renal dysfunction during their stay in the intensive care unit (ICU). The case mix has changed over the years, and AKI is a common problem in critically ill patients often requiring renal replacement therapy (RRT). The RIFLE and AKIN initiatives have provided a unifying definition for AKI, making possible large retrospective studies in different countries. The present study aims at validating a unified web-based data collection and data management tool based on the most recent AKI definition/classification system. The interactive database is designed to elucidate the epidemiology of AKI in a critically ill population. As a test, we performed a prospective observational multicenter study designed to prospectively evaluate all incident admissions in ten ICUs in Italy and the relevant epidemiology of AKI. Thus, a simple user-friendly web-based data collection tool was created with the scope to serve for this study and to facilitate future multicenter collaborative efforts. We enrolled 601 consecutive incident patients into the study; 25 patients with end-stage renal disease were excluded, leaving 576 patients for analysis. The median age was 66 (IQR 53-76) years, 59.4% were male, while median Simplified Acute Physiology Score II and Acute Physiology and Chronic Health Evaluation II scores were 43 (IQR 35-54) and 18 (IQR 13-24), respectively. The most common diagnostic categories for ICU admission were: respiratory (27.4%), followed by neurologic (17%), trauma (14.4%), and cardiovascular (12.1%). Crude ICU and hospital mortality were 21.7% and median ICU length of stay was 5 (IQR 3-14) days. Of 576 patients, 246 patients (42.7%) had AKI within 24 h of ICU admission, while 133 developed new AKI later during their ICU stay. RIFLE-initial class was Risk in 205 patients (54.1%), Injury in 99 (26.1%) and Failure in 75 (19.8%). Progression of AKI to a worse RIFLE class was seen in 114 patients (30.8% of AKI patients). AKI patients were older, with higher frequency of common risk factors. 116 AKI patients (30.6%) fulfilled criteria for sepsis during their ICU stay, compared to 33 (16.7%) of non-AKI patients (p < 0.001). 48 patients (8.3%) were treated with RRT in the ICU. Patients were started on RRT a median of 2 (IQR 0-6) days after ICU admission. AKI patients were started on RRT a median of 1 (IQR 0-4) day after fulfilling criteria for AKI. Median duration of RRT was 5 (IQR 2-10) days. AKI patients had a higher crude ICU mortality (28.8 vs. 8.1%, non-AKI; p < 0.001) and longer ICU length of stay (median 7 vs. 3 days, non-AKI; p < 0.001). Crude ICU mortality and ICU length of stay increased with greater severity of AKI. 225 (59.4% of AKI patients) had complete recovery of renal function, with a serum creatinine at time of ICU discharge which was ≤120% of baseline; an additional 51 AKI patients (13.5%) had partial renal recovery, while 103 (27.2%) had not recovered renal function at the time of death or ICU discharge. The study supports the use of RIFLE as an optimal classification system to stage AKI severity. AKI is indeed a deadly complication for ICU patients, where the level of severity is correlated with mortality and length of stay. The tool developed for data collection was user-friendly and easy to implement. Some of its features, including a RIFLE class alert system, may help the treating physician to systematically collect AKI data in the ICU and possibly may guide specific decisions on the institution of RRT.     

肥胖者重症急性胰腺炎发生率的多中心前瞻性对照研究

目的 观察肥胖的急性胰腺炎(AP)患者在基础内科治疗过程中发展为重症急性胰腺炎(SAP)的概率,探讨肥胖对AP病情发展的影响.方法 采用多中心、前瞻性研究,以APACHEⅡ评分评估AP严重程度,共纳入轻症急性胰腺炎(MAP)患者161例,以体重指数25 kg/m2为标准,分为肥胖组(79例)和非肥胖组(82例).在相同的基础内科治疗条件下观察两组患者血C-反应蛋白(CRP)和三酰甘油水平、并发症发生率、SAP的发生率及病死率.结果 肥胖组的CRP水平为(117±109)mg/L,显著高于非肥胖组的(35±36)mg/L(P＜0.01);肥胖组高三酰甘油血症患者的例数是非肥胖组的1倍,但无显著性差异.两组均无局部并发症,但肥胖组各系统并发症发生率(20.3%)显著高于非肥胖组(6.1%,P＜0.01).肥胖组有16例(20.3%)发展为SAP,显著高于非肥胖组(5例,6.1%,P＜0.01).肥胖组有1例(1.3%)病死,非肥胖组无病死.在APACHEⅡ4-7分的MAP患者中,肥胖组的SAP发生率(43.3%)明显高于非肥胖组(18.5%,P＜0.05).结论 肥胖且 APACHEⅡ评分为4-7分的MAP 患者更易进展为SAP,应给予更积极的临床干预措施.     

重症监护室患者并发急性肾功能衰竭的临床特点及预后评估

目的 探讨重症监护室(ICU)患者并发急性肾功能衰竭(ARF)的特点及对其预后的评估.方法 回顾性收集2004年12月至2005年4月广东省人民医院ARF患者的临床资料,并对每例患者入住ICU 24 h内进行APACHEⅡ、SAPSⅡ、SOFA和ATN-ISI评分,分析影响患者预后的危险因素.结果 ICU患者并发ARF 41例,占同期ICU患者的19.1%,其中死亡21例(51.2%),机械通气比例65.9%,血管活性药物使用率46.3%,少尿发生率41.5%,平均器官衰竭数目2.16个.APACHEⅡ积分17.3分、SAPSⅡ积分52.0分、SOFA积分9.26分、ATN-ISI积分0.54分.Cox回归分析显示,器官衰竭数目和机械通气是ARF患者ICU 28 d死亡的危险因素,RR值分别为2.54[95%可信区间1.316～4.913)(P=0.006)]和6.0[95%可信区间1.102～32.600(P=0.038)].ROC曲线分析显示,APACHEⅡ、SAPSⅡ、SOFA和ATN-ISI 4个积分系统在预测ARF患者病死率时均有意义,曲线下的面积分别为0.848[95%可信区间0.722～0.974(P＜0.001)]、0.880[95%可信区间0.767～0.994(P＜0.001)]、0.851[95%可信区间0.726～0.976(P＜0.001)]和0.956[95%可信区间0.896～1.026(P＜0.001)].结论 重症监护室患者并发ARF时预后差;器官衰竭数目和机械通气是ARF患者死亡的独立危险因素;APACHEⅡ、SAPSⅡ、SOFA和ATN-ISI 4种积分模型对ARF患者的病死率均有较好的预示作用,ATN-ISI的预测效果可能最优.     

Drug-induced acute liver failure: results of a U.S. multicenter, prospective study

Acute liver failure (ALF) due to drug-induced liver injury (DILI), though uncommon, is a concern for both clinicians and patients. The Acute Liver Failure Study Group has prospectively collected cases of all forms of acute liver failure since 1998. We describe here cases of idiosyncratic DILI ALF enrolled during a 10.5-year period. Data were collected prospectively, using detailed case report forms, from 1198 subjects enrolled at 23 sites in the United States, all of which had transplant services. A total of 133 (11.1%) ALF subjects were deemed by expert opinion to have DILI; 81.1% were considered highly likely, 15.0% probable, and 3.8% possible. Subjects were mostly women (70.7%) and there was overrepresentation of minorities for unclear reasons. Over 60 individual agents were implicated, the most common were antimicrobials (46%). Transplant-free (3-week) survival was poor (27.1%), but with highly successful transplantation in 42.1%, overall survival was 66.2%. Transplant-free survival in DILI ALF is determined by the degree of liver dysfunction, specifically baseline levels of bilirubin, prothrombin time/international normalized ratio, and Model for End-Stage Liver Disease scores. Conclusion: DILI is an uncommon cause of ALF that evolves slowly, affects a disproportionate number of women and minorities, and shows infrequent spontaneous recovery, but transplantation affords excellent survival.     

Clinical management and patient outcomes of acute lower gastrointestinal bleeding. A multicenter,prospective, cohort study

Background & aimAlthough acute lower GI bleeding (LGIB) represents a significant healthcare burden, prospective real-life data on management and outcomes are scanty. Present multicentre, prospective cohort study was aimed at evaluating mortality and associated risk factors and at describing patient management.MethodsAdult outpatients acutely admitted for or developing LGIB during hospitalization were consecutively enrolled in 15 high-volume referral centers. Demographics, comorbidities, medications, interventions and outcomes were recorded.ResultsOverall 1,198 patients (1060 new admissions;138 inpatients) were included. Most patients were elderly (mean-age 74±15 years), 31% had a Charlson-Comorbidity-Index ≥3, 58% were on antithrombotic therapy. In-hospital mortality (primary outcome) was 3.4% (95%CI 2.5–4.6). At logistic regression analysis, independent predictors of mortality were increasing age, comorbidity, inpatient status, hemodynamic instability at presentation, and ICU-admission. Colonoscopy had a 78.8% diagnostic yield, with significantly higher hemostasis rate when performed within 24-hours than later (21.3% vs.10.8%, p = 0.027). Endoscopic hemostasis was associated with neither in-hospital mortality nor rebleeding. A definite or presumptive source of bleeding was disclosed in 90.4% of investigated patients.ConclusionMortality in LGIB patients is mainly related to age and comorbidities. Although early colonoscopy has a relevant diagnostic yield and is associated with higher therapeutic intervention rate, endoscopic hemostasis is not associated with improved clinical outcomes [ClinicalTrial.gov number: NCT 04364412].     

An assessment of the management of acute bleeding varices: a multicenter prospective member-based study

OBJECTIVE: Bleeding from esophagogastric varices is a major complication of portal hypertension. Despite recent practice guidelines for the management of bleeding esophageal or gastric varices, the widespread application of these measures by gastroenterologists has not been evaluated. The purpose of this study was to continue the concept of membership-based research within diverse practice settings by expanding the American College of Gastroenterology (ACG) GI Bleeding Registry to assess the management and outcome of acute variceal bleeding. METHODS: All ACG members (domestic and foreign) were invited to participate during the 1997 Annual Fall meeting and by mail. Data were collected over 12 months. Information obtained included physician training, practice demographics, patient demographics, disease etiology and severity, clinical presentation, medications, transfusion needs, therapy, complications, and rebleeding within 2 wk. RESULTS: A total of 93 physicians/centers (79.6% domestic, 26.9% university and affiliated, 3.2% Veterans Affairs) participated. Complete demographic data were available for 725 of the 741 patients enrolled with index bleeding. The median age of these 725 patients was 52 yr and 73.3% were male. The most common single etiology for portal hypertension was cirrhosis (94.3%). The most common causes of cirrhosis were alcohol (56.7%), hepatitis C virus (30.3%), and hepatitis B virus (10.0%). Hemodynamic instability was noted in 60.7% of the patients (22.3% tachycardic, 9.7% orthostatic, 28.7% hypotensive). Index interventions included banding (40.8%; median five bands), sclerotherapy (36.3%), combination banding/sclerotherapy (6.2%), octreotide (52.6%; median 3 days), balloon tamponade (5.5%), transjugular intrahepatic portosystemic shunt (TIPS) (6.6%), liver transplantation (1.1%), surgical shunt (0.7%), and embolization (0.1%). Transfusion of packed red blood cells, fresh frozen plasma, and platelets was given in 83.4%, 44.7%, and 24.6% of the patients with index bleeding, respectively. Median transfusion was four units of packed red blood cells, three units of fresh frozen plasma, and 1.5 units of platelets. Rebleeding occurred in 92 of the 741 patients (12.6%) at a median of 7 days (mean 11 days) and was treated by banding (18.5%; median six bands), sclerotherapy (30.4%), octreotide (63%; median 2 days), balloon tamponade (17.4%), TIPS (15.2%), and surgical shunt (3.3%). Complications from the index bleeding and rebleeding within 2 wk included ulceration (2.6%, 2.2%), aspiration (2.4%, 3.3%), medication side effects (0.8%, 0%), dysphagia (2.3%, 0%), odynophagia (2.2%,0%), encephalopathy (13%,17.4%), and hepatorenal syndrome (2.4%, 2.2%), respectively. After the index bleeding, 46.2% of patients were treated with beta-blockers and 8.2% with nitrates. The majority of patients with index bleeding had Child's B cirrhosis (61.5%). Patients presenting with recurrent bleeding had mostly Child's B (46.7%) or Child's C cirrhosis (44.6%). The overall short-term mortality after index bleeding was 12.9%. CONCLUSIONS: Acute variceal hemorrhage occurs more often in patients with Child's B and C cirrhosis. Endoscopic banding is the most common single endoscopic intervention. Adjunctive pharmacotherapy is prevalent acutely and after stabilization. Both morbidity and mortality may be lower than reported in previous studies.     

Cause and prognosis of acute renal failure in Kuwait: a 2-year prospective study

At the Mubarak Al-Kabeer University Hospital of Kuwait (Arabian Gulf), 77 episodes of acute renal failure were collected prospectively over 2 years, yielding a mean annual incidence rate of 9.5/100,000 population. Forty-four episodes occurred in hospital, a rate of 1.3 per 1000 admissions. In this group, acute tubular necrosis was the commonest cause (27 episodes). Thirty-three episodes occurred in the community, acute tubular necrosis accounting for 11 episodes. In contrast to hospital-acquired renal failure there was a tendency for increased incidence of community-acquired renal failure in the summer months. A more striking observation was the lower mortality in the community-acquired form. The mortality was not related to severity of renal failure even within the group with acute tubular necrosis.     

Accurate prediction of fulminant hepatic failure in severe acute viral hepatitis: multicenter study

Background: We have attempted to predict the development of fulminant hepatic failure at the stage of severe acute hepatitis before the onset of coma. This prediction is valuable because it may be used to block the development of fulminant hepatic failure with appropriate medical treatment. Methods: To establish a discrimination formula, we retrospectively compared 13 clinical and laboratory variables in 36 patients with acute viral hepatitis and prothrombin levels of 40% or less of the control value who later developed fulminant hepatic failure with these variables in 12 patients who recovered spontaneously. A prospective study of 58 patients who developed fulminant hepatic failure and 18 who spontaneously recovered confirmed the validity of this formula. Results: In the retrospective study, we established the following discrimination equation: Z = −0.89 + 1.74 × (causal viruses, 1 point for type A or type B in acute hepatitis B virus [HBV] infection, 2 points for others) + 0.056 × (total bilirubin, mg/dl) −0.014 × (cholinesterase, U/ml). A positive Z value indicates that fulminant hepatic failure will develop. In the prospective study, the specificity, sensitivity, predictive accuracy, and positive and negative predictive values were 0.833, 0.983, 0.947, 0.950, and 0.938, respectively. Conclusions: The present study indicated that fulminant hepatic failure can be predicted, by a simple discrimination equation, at the stage of severe acute hepatitis. Received: September 4, 2001 / Accepted: May 31, 2002 Acknowledgments. Supported by a grant from the Ministry of Health and Welfare of Japan. Reprint requests to: M. Yoshiba     

Multiple myeloma and severe renal failure: a clinicopathologic study of outcome and prognosis in 34 patients

Renal failure (RF) occurring in the course of multiple myeloma is often judged irreversible and generally considered an ominous complication. The aim of the present study was to re-evaluate the outcome, triggering conditions and prognostic factors of severe RF in a series of 34 patients, 33 to 90 years old. RF was totally reversible in 7 patients and partially reversible in 9 although 6 of them had to be temporarily dialyzed. However, the improvement in renal function was often very slow as indicated by an average recovery time of 115 days. The high rate of RF reversibility was associated with markedly lengthened survival. Review of triggering events confirmed the leading role of dehydration and hypercalcemia, but further suggested that intake of nonsteroidal anti-inflammatory drugs and renal infection might play a part in the development of RF. Systematic statistical analysis of potential prognostic factors showed that the outcome was significantly more severe in females, but age, myeloma characteristics including tumor mass, calcemia, and triggering events had no predictive value. The most reliable prognostic indicators were provided by analysis of kidney biopsy performed in 30 patients. Complete recovery from RF was observed only in the absence of global tubular atrophy and interstitial damage. In contrast, cast-induced tubular obstruction detected by the presence of Tamm-Horsfall protein in urinary space of glomeruli did not seem to influence the outcome of RF. Finally, we analyzed the prognostic value of immunochemical properties of light chains (LC). Lambda LC were unexpectedly detected in 2 of 3 patients, as compared to a ratio of 1 to 3 in the population of normal and monoclonal Ig, but LC type did not correlate with the course of RF. Isoelectric points of LC measured in 32 patients were dispersed from 5.2 to 8.9 and bore only weak prognostic significance. These results underline the value of kidney biopsy and justify aggressive treatment including dialysis and chemotherapy.     

A prospective study of acute hypoxic respiratory failure

A prospective study of acute hypoxic respiratory failure was carried out by nine centers in a collaborative NIH study from 1 September 1975 to 1 March 1977. Serious hypoxic respiratory failure was defined in 713 patients by the presence of (1) endotracheal intubation and positive airway pressure for at least 24 hours, and (2) the administration of at least 50 percent oxygen. The 490 patients between 12 to 65 years of age had a mortality of 61 percent. Mortality increased with increasing organ failure: one organ system failure (lung only) 40 percent; two, 54 percent; three, 72 percent; four, 84 percent, five, 100 percent. Only 103 patients died with isolated lung failure, whereas 353 died of a combination of lung and other organ failures. Both the overall mortality (66 percent) and the mortality of those with only isolated lung failure (40 percent) were much higher than anticipated for the selection criteria.     

Risk factors and outcome of hospital-acquired acute renal failure. Clinical epidemiologic study

In order to evaluate potential risk factors for the development of hospital-acquired acute renal failure, a case-control study was performed, comparing patients with hospital-acquired acute renal failure with control subjects matched on age, sex, hospital, service of admission, and baseline renal function. The same patients were then reanalyzed utilizing a cohort study design to investigate outcomes from this syndrome. The following elevated odds ratios (95 percent confidence interval) were found while simultaneously adjusting for possible confounding variables using logistic regression: volume depletion, 9.4 (2.1 to 42.8); aminoglycoside use, 5.6 (1.3 to 23.7); congestive heart failure 9.0 (2.1 to 38.9); radiocontrast exposure, 4.9 (1.2 to 19.7); and septic shock, approached infinity, p less than 0.0001. The effect of volume depletion was markedly accentuated in those with diabetes (odds ratio = 1.9) (p less than 0.05). The risk from aminoglycoside use markedly increased with increasing age (p less than 0.002). Finally, the development of hospital-acquired acute renal failure was associated with a marked increase in the risk of dying--the relative risk (95 percent confidence interval) was 6.2 (2.6 to 14.9)--and a marked increase in length of stay, from a median of 13 days in control subjects to a median of 23 days in case subjects (p = 0.005). In conclusion, hospital-acquired acute renal failure is a serious illness. Attempts to prevent it should focus on proved risk factors.     

Drug therapy in the management of acute renal failure

Pharmacologic intervention aimed at altering the natural history of acute renal failure is a routine practice without scientific support of efficacy. Oliguria has become a separate disease entity with an apparent disregard for the underlying condition that caused it. Volume expansion is clearly beneficial in preventing many volume depleted patients from progressing to acute renal failure. While mannitol and furosemide have been used to "convert" oliguric acute renal failure to the more easy to manage non-oliguric acute renal failure, published reports suggest that responders were not as ill as non-responders. The use of dopamine to increase urine flow in patients with established acute renal failure is the current fashion, but there is little evidence that this drug raises the glomerular filtration rate or shortens the course of acute renal failure. These pharmacologic therapies increase the complexity and cost of care with little tangible evidence of benefit to the patient or the physician caring for the patient.     

Etiology and mortality in severe acute pancreatitis: A multicenter study in Japan

Background/ObjectivesSevere acute pancreatitis (SAP) has a high mortality rate despite ongoing attempts to improve prognosis through a various therapeutic modalities. This study aimed to delineate etiology-based routes that may guide clinical decisions for the treatment of SAP.MethodsUsing data from a recent retrospective multicenter study in Japan, we analyzed the association between clinical outcomes, mainly in-hospital mortality and pancreatic infection, and various etiologies while considering confounding factors. We performed additional multivariate analyses and built decision tree models.ResultsThe 1097 participating patients were classified into the following groups by etiology: alcohol (n = 436, 39.7%); cholelithiasis (n = 230, 21.0%); idiopathic (n = 227, 20.7%); and others (n = 204, 18.6%). Mortality at hospital discharge was 8.4%, 12.2%, 16.7%, and 16.2% in the alcohol, cholelithiasis, idiopathic, and others groups, respectively. According to multivariable analysis, early enteral nutrition (EN) was significantly associated with reduced in-hospital mortality only in the cholelithiasis group. However, there was a consistent association between age and the need for mechanical ventilation and increased mortality, regardless of etiology. Our decision tree models presented different contributing factors depending on the etiology and patient background. Interaction analysis showed that EN and the use of prophylactic antibiotics may influence these results differently according to etiology.ConclusionsNo study has yet used comprehensive models to investigate etiology-related prognostic factors for SAP; our results can, therefore, be used as a reference for improving clinical decisions.     

A multicenter, prospective study of posttransfusion hepatitis in Milan

We studied the risk of posttransfusion hepatitis in recipients of blood collected from volunteer donors who tested negative for HBsAg and had serum ALT levels less than 1.5 times the upper limit of the normal range. Between October, 1983 and September, 1984, 676 consecutive patients who needed blood or plasma transfusions during or after elective surgery, who had no history of liver disease and had never received blood previously, were studied. The patients were given a total of 4,813 (mean = 7) units. Ninety-six patients developed posttransfusion hepatitis, which yielded a hepatic incidence of 20 cases per 1,000 units of transfused blood. Ninety-two patients had non-A, non-B hepatitis, 3 had hepatitis B and 1 had cytomegalovirus infection. The incubation periods for non-A, non-B hepatitis ranged from 2 to 26 (mean = 9.5 +/- 4) weeks. In 68 (73%) patients, the hepatitis was completely asymptomatic; only 24 (27%) patients developed symptoms, including jaundice and hepatomegaly. There were no cases of fulminant hepatitis. Sixty per cent of the patients still had elevated serum ALT levels 1 year after the onset of hepatitis. The 96 patients with hepatitis had received a mean of 9.6 blood units, as compared to a mean of 6.7 units for the unaffected patients (p less than 0.001). This study demonstrated that non-A, non-B hepatitis remains a common and important complication of blood transfusion despite screening of blood donors for HBsAg and elevated serum ALT levels.