Prothrombin Time Ratio Research Articles

Oral Absorbable Fat‐soluble Vitamin Formulation in Pediatric Patients With Cholestasis

Fat-soluble vitamin (FSV) deficiencies are common complications in pediatric patients with chronic cholestasis. The aim of the present study was to evaluate the status of FSV deficiencies in patients under present practice and to test the effect of an oral, absorbable, fat-soluble vitamin formulation (OAFSV) in these patients. We recruited a total of 23 pediatric patients receiving conventional FSV supplementation in a single medical center, with diagnosis of biliary atresia (10), progressive familial intrahepatic cholestasis (9), Alagille syndrome (2), and other conditions (2). Ten patients switched to OAFSV and continued for 3 months. Plasma levels of vitamins A, D, and E and an international normalized ratio (INR) for prothrombin time (PT), a surrogate marker for vitamin K deficiency, were measured. The proportion of patients with FSV A, D, E, and K deficiencies under conventional supplementation was 73.9%, 81.8%, 91.3%, and 20.0%, respectively. In patients with total bilirubin levels ≥3.0 mg/dL, the proportion of at least 1 FSV deficiency was 100%; and the deficiency rates of vitamin A, D, E, and K were 78.6%, 100.0%, 100.0% and 21.4%, respectively. Of the 10 patients receiving standard daily dose of OAFSV for 3 months, no adverse events or overdose effects were found. The rates of vitamin A, D, and E deficiency in the patients receiving OAFSV decreased from 80.0%, 100%, and 100%, respectively, to 70.0%, 60.0%, and 60.0% after 3 months of oral supplementation. High rates of FSV deficiency were found in pediatric patients with chronic cholestasis under present follow-up. OAFSV supplementation is safe and potentially effective in pediatric patients with cholestasis.

Clinical phenotype, laboratory features and genotype of 35 patients with heritable dysfibrinogenaemia.

Heritable dysfibrinogenaemia (HD) is a rare qualitative disorder of fibrinogen (FGN). To better describe the clinical, laboratory and genotypic spectrum of HD, we evaluated 35 subjects identified at two UK centres using laboratory criteria. 12/35(34%) subjects with HD experienced bleeding (bleeding score >1 at any site), 3/35(9%) thrombosis and 20/35(57%) were asymptomatic. Amongst subjects with bleeding, symptoms were typically mild, at one anatomical site and seldom occurred after invasive procedures. All subject showed dry clot weight within or above laboratory reference interval (median 3·2 g/l; range 1·9-5·1), reduced Clauss fibrinogen (median 0·52 g/l; range 0·21-1·3), and prolonged thrombin (median 30·7 s; range 21·3-45·7) and reptilase (median 42·0 s; range 20·0-68·0) times. In all subjects, the prothrombin time ratio (PTR), determined by Sysmex CA-1500 coagulometer and Innovin activator, was abnormal (median 1·42; range 1·22-1·61). The activated partial thromboplastin time ratio and PTR with other coagulometers and activators were comparatively insensitive to HD. All subjects with HD harboured heterozygous candidate nucleotide variations within known hotspots in the FGN genes. The HD variants identified in this cross-sectional study seldom have significant clinical manifestations and show similar laboratory features irrespective of genotype. Selection of coagulometer and PT activator may markedly affect the detection of new HD cases using coagulation screening tests.

Prothrombin complex concentrates reduce blood loss in murine coagulopathy induced by warfarin, but not in that induced by dabigatran etexilate

Both established oral anticoagulants such as warfarin and newer agents such as dabigatran etexilate (DE) effectively prevent thromboembolic disease, but may provoke bleeding. Limited clinical data exist linking oral anticoagulant reversal and bleeding tendency, as opposed to surrogate laboratory markers. To quantify bleeding in warfarin-anticoagulated and DE-anticoagulated mice by tail transection with or without pretreatment with potential reversal agents: prothrombin complex concentrate (PCC); activated PCC (APCC); recombinant factor VIIa (rFVIIa); or murine fresh-frozen plasma (FFP). CD1 mice were given warfarin or DE by gavage, and the effects on in vitro coagulation assays, volume of blood loss and the bleeding time following tail transection injury were evaluated with different reversal agents. PCC (14.3 IU kg(-1) ), but not rFVIIa (3 mg kg(-1) ) or FFP (12 mL kg(-1) ), normalized blood loss and bleeding time in mice with warfarin-induced elevations of mean prothrombin time at two intensities (prothrombin time ratios of either 4.3 or 24). Neither separate nor combined PCC and/or rFVIIa treatment nor APCC (100 U kg(-1) ) treatment significantly reduced blood loss in mice anticoagulated with 60 mg kg(-1) DE 75 min prior to tail transection. Both combined PCC plus rFVIIa treatment and APCC treatment significantly reduced bleeding time in the DE-treated mice. Our data suggest that PCC treatment prevents excess bleeding much more effectively in warfarin-induced coagulopathy than in DE-induced coagulopathy.

Evaluation of coagulation abnormalities in acute liver failure

In acute liver failure (ALF), prothrombin time (PT) and its derivative prothrombin time ratio (PTR) are elevated, and are considered predictors of increased bleeding risk. We aimed at determining whether increased PT/PTR reflects the haemostatic potential and bleeding risk in ALF patients. Twenty consecutive ALF patients were recruited. Samples were analysed on admission for standard laboratory clotting tests (e.g. PT), thromboelastography (TEG), individual pro and anticoagulant factors and thrombin generation (TG) kinetics with and without Protac, a snake venom protein C activator, and microparticle assay. TG was also measured in 20 age and sex matched healthy volunteers. PT was significantly raised (50.7s ± 7.2, p=0.0001) but did not correlate with TEG parameters. TEG tracings were consistent with a hypocoagulable state in 20%, normal in 45%, and hypercoagulable in 35% of the patients. There was a concomitant and proportional reduction in plasma levels of both procoagulants and natural anticoagulant proteins, in conjunction with a significant elevation in plasma levels of factors-VIII (FVIII) and Von Willebrand factor, and microparticles, culminating in an overall efficient, albeit reduced, thrombin generation capacity in comparison with healthy individuals. A heparin-like effect (HLE) was also noted in most patients. No significant clinical bleeding complications occurred and no blood transfusions were required. In ALF, despite grossly deranged PT in all patients, estimation of bleeding risk suggests that the coagulation disturbance in ALF patients is complex and heterogeneous for which an individualised approach is required.

Effect of influenza vaccination on international normalized ratio during chronic warfarin therapy

Warfarin is a widely used anticoagulant, well-known for its interactions with medications and foods. Vaccinations, particularly the influenza vaccine, have been thought to potentially interfere with anticoagulation response in those on chronic warfarin. Our objective was to systematically review the literature to assess the validity and clinical significance of this association. A primary literature search was performed using MEDLINE (1966 - June 2011) and EMBASE (1980 - June 2011). Additional studies were obtained by performing a manual bibliographical review of literature from the initial results and by searching The Cochrane Database of Systematic Reviews. All English-language, peer-reviewed publications identified were evaluated. Reviews, case studies and trials reporting anticoagulation response using an unconverted prothrombin time ratio were excluded. Thirty-one abstracts were initially reviewed, and seven studies were identified for inclusion in this review. Significant changes in mean INR post-vaccination between the study and comparator groups were documented in one trial. Through subgroup analysis, another study noted that elderly patients spent more time in the subtherapeutic range post-vaccination when compared with baseline INR levels. No other significant changes in mean INR levels were documented following influenza vaccination. Adverse bleeding events reported after immunization were limited and minor in nature. Overall, our review does not indicate a consistent, clinically relevant effect of influenza vaccines on INR of patients on chronic warfarin therapy. Isolated reports of variations in INR following influenza vaccination are likely due to other factors.

Differential diagnosis of localized and systemic amyloidosis based on coagulation and fibrinolysis parameters

Background: A simple assay that can discriminate between localized and systemic amyloidosis is needed. Methods: Coagulation and fibrinolysis parameters were measured in subjects with active or progressive systemic amyloidosis (Group A; 9 patients), systemic amyloidosis in complete remission (Group B; 6 patients), localized AL amyloidosis (Group C; 6 patients), monoclonal gammopathy of undetermined significance (Group D; 5 patients), chronic glomerulonephritis with proteinuria (Group E; 22 patients), or glomerulonephritis in complete remission (Group F; 11 patients). Results: No significant differences were noted between Group A and the other groups in the international normalized ratio of prothrombin time, activated partial thromboplastin time, and levels of antithrombin and plasminogen. Levels of thrombin–antithrombin (TAT) complexes, fibrinogen, fibrinogen degradation product d-dimers, and plasmin-α2–plasmin inhibitor complexes (PIC) were significantly elevated in Group A. All patients that showed TAT complexes, fibrinogen, and PIC levels greater than 4.2 ng/mL, 399 mg/dL, and 1.4 μg/mL, respectively, had active or progressive systemic amyloidosis. All patients with TAT complex levels less than 3.6 ng/mL, fibrinogen levels less than 355 mg/dL, and PIC levels less than 0.9 μg/mL had localized AL amyloidosis. Conclusion:Analyses of TAT complexes, fibrinogen, and PIC can be used to differentiate localized AL amyloidosis from systemic amyloidosis.

Noninvasive assessment of liver fibrosis via spleen stiffness measurement using acoustic radiation force impulse sonoelastography in patients with chronic hepatitis B or C

Portal hypertension and splenomegaly are common in patients with cirrhosis. However, there is limited previous in vivo research on the correlation between spleen stiffness and stages of liver fibrosis. This study aimed to evaluate the diagnostic value of spleen stiffness measurement (SSM), using acoustic radiation force impulse (ARFI) technology, for liver fibrosis assessment. Eligible patients with chronic hepatitis B or C (n = 163) underwent concurrent liver stiffness measurement (LSM), SSM and percutaneous liver biopsy. Receiver operating characteristic curves estimated the diagnostic performance of SSM, with multiple linear regression models for LSM and SSM determining the significance of explanatory factors. Results indicated significant correlation between LSM and SSM (R(2) = 0.574, P < 0.0001). Using SSM to classify METAVIR fibrosis (METAVIR F) scores, the areas under curves were 0.839 (95% CI: 0.780-0.898) for METAVIR F1 vs F2-4, 0.936 (95% CI: 0.898-0.975) for F1-2 vs F3-4 and 0.932 (95% CI: 0.893-0.971) for F1-3 vs F4, all P < 0.001. Multiple linear regression models identified BMI, spleen stiffness, METAVIR F3 and F4, serum alanine aminotransferase, international normalized ratio of prothrombin time, sodium and platelet count as significant independent explanatory factors for liver stiffness (adjusted R(2) = 0.724, P < 0.001). Male gender, liver stiffness, METAVIR F2, F3 and F4 also significantly and independently explained spleen stiffness (adjusted R(2) = 0.647, P < 0.001). ARFI SSM is potentially useful as a single or adjunct predictor of stages of liver fibrosis.

Mortality risk after liver transplantation in hepatocellular carcinoma recipients: A nonlinear predictive model

The balanced application of a model for the estimate of outcomes of liver transplantation, in concert with assessment of disease severity, would not only improve transplant outcomes and maximize patient benefit from transplantation, but also facilitate informed decision making by patients and their relatives when considering transplantation. So far, however, linear discriminating methods have failed to attain sufficient power to predict post-transplant prognosis. Therefore, our aim was to develop a cancer-specific prognostic model by a nonlinear methodology based on pretransplant characteristics. With data collected retrospectively from 290 liver transplant recipients with HCC from February 1999 to August 2009, a multilayer perceptron (MLP) neural network was constructed to predict mortality risk after transplantation. Its predictive performances at posttransplant 1-, 2-, and 5-year intervals were evaluated using a receiver operating characteristic curve. By the forward stepwise selection in MLP network, donor age, donor body mass index, recipient hemoglobin, serum concentrations of total bilirubin, alkaline phosphatase, creatinine, aspartate aminotransferase, international normalized ratio of prothrombin time, and Na(+); alpha fetoprotein categorization, total diameter, number of tumor lesions, presence of imaging macrovascular invasion, and lobe distribution of the tumor were identified to be the optimal input features. The MLP, employing 24 inputs and 7 hidden neurons, yielded c-statistics of 0.909 (P < .001) in the 1-year, 0.888 (P < .001), in the 2-year, and 0.845 (P < .001) in the 5-year prediction. Post-transplant prognosis is a multidimensional, nonlinear problem, and the specific MLP can achieve high accuracy in the prediction of posttransplant mortality risk for HCC recipients. The pattern recognition methodologies like MLP hold promise for solving outcome prediction after liver transplantation.

Exogenous Normal Lymph Alleviating Kidney Injury by Improving Coagulation Function in Disseminated Intravascular Coagulation Rats

Aim: To investigate the effect of exogenous normal lymph on kidney injury in disseminated intravascular coagulation (DIC) rats and to probe its mechanism. Methods: The DIC model was established by intravenous injection of Dextran 500. After 6 min, normal lymph without cell components was infused in the lymph group. After 40 min, the renal and coagulation function indices and renal histomorphology were observed. Results: Serum urea and creatinine in the model group were significantly higher than in the control and lymph groups. Renal morphological study showed red blood cell silting and casts forming in the model group. The prothrombin time (PT), prothrombin time ratio (PTR), activated partial thromboplastin time (APTT), and thrombin time of lymph and model groups were higher than those in the control group, whereas fibrinogen was lower. The PT, PTR, and APTT were prolonged in the lymph group than in the model group. The platelet functions of the lymph and model groups were higher than in the control group, but platelet aggregation rate and thrombosis-forming indices were lower than in the control group; the platelet adhesive and aggregation rates and thrombosis dry weight of the lymph group were lower than those of the model group. Conclusion: Exogenous normal lymph could alleviate kidney injury in DIC rats, which may be related to the improving coagulation function.

Influence of prehospital volume replacement on outcome in polytraumatized children

IntroductionSevere bleeding after trauma frequently results in poor outcomes in children. Prehospital fluid replacement therapy is regarded as an important primary treatment option. Our study aimed, through a retrospective analysis of matched pairs, to assess the influence of prehospital fluid replacement therapy on the post-traumatic course of severely injured children.MethodsThe data for 67,782 patients from the TraumaRegister DGU® of the German Trauma Society were analyzed. The following inclusion criteria were applied: injury severity score ≥16 points, primary admission, age 1 to 15 years old, systolic blood pressure ≥20 mmHg at the accident site and transfusion of at least one unit of packed red blood cells (pRBC) in the emergency trauma room prior to intensive care admission. As volume replacement therapy depends on age and body weight, especially in children, three subgroups were formed according to the mean value of the administered prehospital volume. The children were matched and enrolled into two groups according to the following criteria: intubation at the accident site (yes/no), Abbreviated Injury Scale (four body regions), accident year, systolic blood pressure and age group.ResultsA total of 31 patients in each group met the inclusion criteria. An increase in volume replacement was associated with an elevated need for a transfusion (≥10 pRBC: low volume, 9.7%; high volume, 25.8%; P = 0.18) and a reduction in the ability to coagulate (prothrombin time ratio: low volume, 58.7%; high volume, 55.6%; P = 0.23; prothrombin time: low volume, 42.2 seconds; high volume, 50.1 seconds; P = 0.38). With increasing volume, the mortality (low volume, 19.4%; high volume, 25.8%; P = 0.75) and multiple organ failure rates (group 1, 36.7%; group 2, 41.4%; P = 0.79) increased. With increased volume, the rescue time also increased (low volume, 62 minutes; high volume, 71.5 minutes; P = 0.21).ConclusionFor the first time, a tendency was shown that excessive prehospital fluid replacement in children leads to a worse clinical course with higher mortality and that excessive fluid replacement has a negative influence on the ability to coagulate.

Haemostatic effects of levothyroxine and selenomethionine in euthyroid patients with Hashimoto’s thyroiditis

The aim of this prospective study was to investigate for the first time whether levothyroxine and selenomethionine, administered alone or in combination, affect coagulation and fibrinolysis in Hashimoto's thyroiditis patients with normal thyroid function tests. A group of 155 ambulatory women with recently diagnosed and previously untreated Hashimoto's thyroiditis, of whom 149 completed the study, were randomly assigned in a double-blind fashion to six months of treatment with levothyroxine, selenomethionine, levothyroxine plus selenomethionine, or placebo. The control group included 39 matched healthy women. The prothrombin time ratio, the activated partial thromboplastin time, and plasma levels/activities of fibrinogen, factor VII, von Willebrand factor, factor X and plasminogen activator inhibitor-1 (PAI-1) were assessed at baseline and after three and six months of treatment. Compared with the healthy subjects, Hashimoto's thyroiditis patients exhibited higher plasma levels/activities of all of the parameters studied, as well as were characterised by the abnormal prothrombin time ratio and activated partial thromboplastin time. All these haemostatic disturbances were reduced or normalised by levothyroxine + selenomethionine treatment, while the effect of levothyroxine or selenomethionine was limited to fibrinogen and PAI-1, respectively. Our results demonstrate that euthyroid women with Hashimoto's thyroiditis are characterised by abnormal coagulation and fibrinolysis. Levothyroxine and selenomethionine, especially if administered together, produce a beneficial effect on haemostasis in euthyroid patients with this disorder.

Live donor hepatectomy for liver transplantation in Egypt: Lessons learned

Purpose:To retrospectively review anesthesia and intensive care management of 145 consented volunteers subjected to right lobe or left hepatectomy between 2003 and 2011.Methods:After local ethics committee approval, anesthetic and intensive care charts, blood transfusion requirements, laboratory data, complications and outcome of donors were analyzed.Results:One hundred and forty-three volunteers successfully tolerated the surgery with no blood transfusion requirements, but with a morbidity rate of (50.1%). The most frequent complication was infection (21.1%) (intraabdominal collections), followed by biliary leak (18.2%). Two donors had major complications: one had portal vein thrombosis (PVT) treated with vascular stent. This patient recovered fully. The other donor had serious intraoperative bleeding and developed postoperative PVT and liver and renal failure. He died after 12 days despite intensive treatment. He was later reported among a series of fatalities from other centers worldwide. Epidural analgesia was delivered safely (n=90) with no epidural hematoma despite significantly elevated prothrombin time (PT) and international normalization ratio (INR) postoperatively, reaching the maximum on Day 1 (16.9±2.5 s and 1.4±0.2, P<0.05 when compared with baseline). Hypophosphatemia and hypomagnesemia were frequently encountered. Total Mg and phosphorus blood levels declined significantly to 1.05±0.18 mg/dL on Day 1 and 2.3±0.83 mg/dL on Day 3 postoperatively.Conclusions:Coagulation and electrolytes need to be monitored perioperatively and replaced adequately. PT and INR monitoring postoperatively is still necessary for best timing of epidural catheter removal. Live donor hepatectomy could be performed without blood transfusion. Bile leak and associated infection of abdominal collections requires further effort to better identify biliary leaks and modify the surgical closure of the bile ducts. Donor hepatectomy is definitely not a complication-free procedure; reported complication risks should be available to the volunteers during consenting.

Anticoagulation Control Quality Affects the D-Dimer Levels of Atrial Fibrillation Patients

Anticoagulation control quality affects the incidence of thromboembolic events in atrial fibrillation (AF) patients. However, the effects of anticoagulation control quality on the prothrombotic state of AF patients are unclear. Ninety-five AF patients who had been treated with warfarin were prospectively followed-up for 449 ± 92 days. We analyzed whether time in the therapeutic range (TTR) of the international normalized ratio (INR) of prothrombin time, percentage of INR values in the range (%INR), and coefficient of variation of INR values (CV-INR) were related to D-dimer levels. The mean values of TTR, %INR, and CV-INR were 62%, 59%, and 0.19, respectively, and their median values were 67%, 63%, and 0.19, respectively. TTR was significantly correlated with %INR (R(2) = 0.917, P<0.01), but not with CV-INR (R(2) = 0.050, P = 0.26). The mean and median D-dimer levels were 0.79 and 0.60 µg/ml, respectively. Low TTR, low %INR, and high CV-INR were found to contribute to high D-dimer levels (P = 0.02, 0.03, and 0.02, respectively). In AF patients treated with warfarin, not only the duration outside the target INR range, but also the fluctuation in INR level may influence the prothrombotic state.

Functional definition and characterization of acute traumatic coagulopathy

To identify an appropriate diagnostic tool for the early diagnosis of acute traumatic coagulopathy and validate this modality through prediction of transfusion requirements in trauma hemorrhage. Prospective observational cohort study. Level 1 trauma center. Adult trauma patients who met the local criteria for full trauma team activation. Exclusion criteria included emergency department arrival >2 hrs after injury, >2000 mL of intravenous fluid before emergency department arrival, or transfer from another hospital. None. Blood was collected on arrival in the emergency department and analyzed with laboratory prothrombin time, point-of-care prothrombin time, and rotational thromboelastometry. Prothrombin time ratio was calculated and acute traumatic coagulopathy defined as laboratory prothrombin time ratio >1.2. Transfusion requirements were recorded for the first 12 hrs following admission. Three hundred patients were included in the study. Laboratory prothrombin time results were available at a median of 78 (62-103) mins. Point-of-care prothrombin time ratio had reduced agreement with laboratory prothrombin time ratio in patients with acute traumatic coagulopathy, with 29% false-negative results. In acute traumatic coagulopathy, the rotational thromboelastometry clot amplitude at 5 mins was diminished by 42%, and this persisted throughout clot maturation. Rotational thromboelastometry clotting time was not significantly prolonged. Clot amplitude at a 5-min threshold of ≤35 mm had a detection rate of 77% for acute traumatic coagulopathy with a false-positive rate of 13%. Patients with clot amplitude at 5 mins ≤35 mm were more likely to receive red cell (46% vs. 17%, p < .001) and plasma (37% vs. 11%, p < .001) transfusions. The clot amplitude at 5 mins could identify patients who would require massive transfusion (detection rate of 71%, vs. 43% for prothrombin time ratio >1.2, p < .001). In trauma hemorrhage, prothrombin time ratio is not rapidly available from the laboratory and point-of-care devices can be inaccurate. Acute traumatic coagulopathy is functionally characterized by a reduction in clot strength. With a threshold of clot amplitude at 5 mins of ≤35 mm, rotational thromboelastometry can identify acute traumatic coagulopathy at 5 mins and predict the need for massive transfusion.

Der leberkranke Patient - wann und bei wem eine Lebertransplantation?

During the past two decades, orthotopic liver transplantation (OLT) emerged to the treatment of choice for patients with end-stage liver disease. In Switzerland, about 100 liver transplantations are performed every year, while the shortage of cadaveric organs considerably outmatches the demand. Common indications for OLT include cirrhosis due to alcoholic liver disease or chronic viral hepatitis related to hepatitis B or C, and hepatocellular carcinoma. With the advent of the new allocation policy in Switzerland in 2007, patients listed for OLT are mainly stratified based on the Model of End-stage Liver Disease (MELD) score. Using a patient's laboratory values for serum bilirubin, serum creatinin, and the international normalized ratio for prothrombin time (INR), the MELD score accurately predicts three-month mortality among patients on the waiting list. Compared to the pre-MELD era, patients with significantly higher MELD scores undergo transplantation which leads in turn to more complications and higher costs yet with a comparable outcome. Timely referral of potential candidates to a transplant center is crucial since thorough evaluation to rule out contraindications such as uncontrolled infection, extrahepatic malignancy or advanced cardiopulmonary disease is essential. Taken together, every patient presenting with acute liver failure, decompensated cirrhosis or suspected hepatocellular carcinoma should be evaluated in a center with liver transplantation capability.

Abnormal Liver Function Tests as Predictors of Adverse Maternal Outcomes in Women With Preeclampsia

ObjectivesTo evaluate whether (1) the absolute magnitude of liver function test values, (2) the percentage change in liver function test values over time, or (3) the rate of change in liver function test values over time predicts adverse maternal outcomes in women with preeclampsia. MethodsWe used data from the PIERS (Pre-eclampsia Integrated Estimate of RiSk) study, a prospective multicentre cohort study assessing predictors of adverse maternal outcomes in women with preeclampsia. Women with at least one liver function test performed at the time of hospital admission were included. Liver functions were tested by serum concentrations of aspartate amino transferase (AST), alanine amino transferase (ALT), lactate dehydrogenase (LDH), albumin, total bilirubin, and the international normalized prothrombin time ratio. Parameters investigated were absolute levels, change within 48 hours of hospital admission, change from admission to delivery or outcome, and rate of change from admission to delivery or outcome of each liver function test. The ability of these parameters to predict adverse outcomes was assessed using logistic regression analyses and by calculating the receiver operating characteristic (ROC) area under the curve (AUC). ResultsOf the 2008 women, 1056 (53%) had at least one abnormal liver function test result. The odds of having an adverse maternal outcome were higher in women with any abnormal liver function test than in women with normal results. When test results were stratified into quartiles, women with results in the highest quartile (lowest quartile for albumin) were at higher risk of adverse outcomes than women in the lowest quartile for all parameters (highest for albumin). The absolute magnitude of AST, ALT, and LDH predicted adverse maternal outcomes (AST: ROC AUC 0.73 [95% CI 0.67 to 0.97]; ALT: ROC AUC 0.73 [95% CI 0.67 to 0.79]; LDH: ROC AUC 0.74 [95% CI 0.68 to 0.81]). Neither change of liver function test results, within 48 hours of admission or from admission to delivery or outcome, nor rate of change were predictive. ConclusionWe found abnormal liver function test results to be associated with an increased risk for adverse maternal outcomes. Levels of AST, ALT, and LDH were found to be modestly predictive of these outcomes.

Analysis of risk factors of prolonged intensive care unit stay of critically ill obstetric patients: a 5-year retrospective review in 3 hospitals in Beijing

To identify the risk factors of prolonged intensive care unit (ICU) stay of critically ill obstetric patients. A retrospective analysis of cases of critically ill obstetric patients admitted to the ICUs of Peking University Third Hospital, Capital Medical University Affiliated Beijing Chaoyang Hospital, and PLA 306 Hospital from January 1st 2006 to December 31st 2010 was made. Data included demographics, causes of critical illness or complications that prompted ICU admission, the acute physiology and chronic health evaluation II (APACHEII) scores, the time intervals between onset of acute symptoms and ICU admission, laboratory test results, treatment measures, length of ICU stay and the final maternal mortality. Data were used to identify univariate and multivariate predictors for prolonged ICU stay. During the 5-year period there were 207 obstetric patients [mean age (31.74±2.32) years old, mean gestational age (34.86±4.72) weeks] were transferred to the ICU for critical care (42 ICU admissions per 10 000 deliveries), and among them 4 women died (mortality rate 1.93%). The pathogenesis of the cases could be divided into direct obstetric pathologies (n=138) and indirect or coincidental pathologies (n=69). The most common obstetric causes of admission were massive postpartum haemorrhage (n=42, 20.29%) and pregnancy associated hypertension (n=36, 17.39%), followed by acute fatty liver of pregnancy (AFLP, n=27, 13.04%), obstetric disseminated intravascular coagulation (DIC, n=23, 11.11%). The most common non obstetric causes of admission were acute heart failure (n=26, 12.56%) and acute respiratory failure (n=22, 10.63%), followed by severe acute pancreatitis (SAP, n=11, 5.31%). The incidence of prolonged ICU stay (ICU stay >3 days) was 52.66% (n=109). Univariate predictors of prolonged ICU stay included inadvertent antenatal care, high serum creatinine, abnormal international normalized ratio of prothrombin time (INR), abnormal oxygenation index (PaO(2)/FiO(2)), AFLP, obstetric DIC, SAP, use of mechanical ventilation, indications for inotropic support, and blood purification, and >24 hour interval between onset of acute symptoms and ICU admission. Multivariate modeling identified that inadvertent and irregular antenatal care [odds ratio (OR) 1.68, 95% confidence interval (95%CI) 1.14-2.69, P=0.011], PaO(2)/FiO(2) (OR 4.73, 95%CI 1.46-11.37, P=0.013), AFLP (OR3.21, 95%CI 1.13-4.76, P=0.026), DIC (OR 2.73, 95%CI 1.28-4.02, P=0.018), SAP (OR 4.78, 95%CI 1.83-7.42, P=0.021 ), indications for inotropic support (OR 1.96, 95%CI 1.24-3.15, P=0.001), blood purification (OR 11.02, 95%CI 3.04-58.02, P=0.015) and >24 hour interval between onset of acute symptoms and ICU admission (OR 2.04, 95%CI 1.21-4.25, P<0.001) were the independent predictors for prolonged ICU stay. The incidence of prolonged ICU stay is high for critically ill obstetric patients. Patients with identified multivariate predictors carry a high risk of prolonged ICU stay, they may benefit from enhanced regular antenatal care, prevention of critical obstetric and medical complications, shortening the interval between onset of acute symptoms and ICU admission and strengthening the support of organ function.

Entecavir versus Lamivudine in the Treatment of Chronic Hepatitis B Patients with Hepatic Decompensation

Lamivudine has been widely used in chronic hepatitis B patients with hepatic decompensation, but its use is limited by drug resistance. This outcome research aimed to investigate the comparative efficacy and safety of entecavir versus lamivudine in decompensated patients. Between November 2004 and February 2010, 126 consecutive treatment-naive patients received either entecavir (n=53) or lamivudine (n=73) for decompensated chronic hepatitis B. All patients presented with both hyperbilirubinaemia and coagulopathy. Primary outcome was mortality within 1 year; secondary outcomes included liver-related mortality, biochemical and virological response, and improvement of hepatic dysfunction. Both treatment groups were comparable in baseline characteristics. A total of 19 (35.8%) entecavir and 33 (45.2%) lamivudine receivers expired within 1 year, respectively (P=0.29, log rank test). Age (hazard ratio [HR] 1.04 per year, 95% CI 1.01, 1.06), cirrhosis (HR 2.07, 95% CI 1.02, 4.23), and international normalized ratio for prothrombin time (HR 1.44, 95% CI 1.20, 1.74) were independent baseline predictors for all-cause mortality. Antiviral therapy was also unrelated to liver-specific death. However, more patients taking entecavir tended to attain aminotransferase normalization (76.5% versus 52.5%; P=0.05) and viral DNA undetectability (100% versus 58.3%; P=0.06). Moreover, entecavir was associated with significantly greater reduction of the model for end-stage liver disease scores (median 10.0 versus 4.3; P=0.02). Overall, 3 (7.5%) lamivudine but no entecavir users acquired drug resistance in 1 year (P=0.25). Entecavir as compared with lamivudine is similar in the effect on short-term mortality but is associated with greater clinical improvement among chronic hepatitis survivors who recovered from hepatic decompensation.

Acute Liver Failure and Aplastic Anemia in an 11-Year-Old Girl

An 11-year-old previously healthy female presented with a 1-week history of jaundice and fatigue. Her aspartate aminotransferase (AST) level was 1,420 U/L, alanine aminotransferase (ALT) 1,044 U/L, total bilirubin 16.5 mg/dL and international normalized ratio (INR) for prothrombin time 1.2. Complete blood count showed a white blood count of 7,700/mm, hematocrit 40.6 g/dL, and platelet count 509,000/mm. Ultrasound demonstrated mild hepatomegaly but was otherwise normal. Serology was negative for hepatitis A, B, and C and Epstein-Barr virus (EBV) and cytomegalovirus (CMV). After discharge, she was followed by her outpatient pediatric gastroenterologist, who noted that she continued to have jaundice and elevated aminotransferase levels. A liver biopsy was recommended, but her parents refused, and the patient was lost to followup for several months. Four months after her initial presentation, the patient represented with a 2-week history of sleepiness, headaches, increased jaundice, and anorexia. During the time she was lost to follow-up, her parents noted an initial improvement of her jaundice and energy. However, 2 weeks prior to her readmission, she had increasing fatigue, jaundice, and epistaxis. Complete blood count revealed a WBC of 2.3 g/mm, hematocrit 33.2 g/dL, and platelet count 13,000/mm. Total bilirubin was 21.8 mg/dL, direct bilirubin 14.6 mg/dL, AST 3,158 U/L, ALT 3,239 U/L, INR 2.0, erythrocyte sedimentation rate 16, C-reactive protein 23 mg/dL, and ammonia 38 lm/L. She was admitted for lethargy in the setting of liver failure and pancytopenia. On admission to the hospital, her vital signs were normal and physical examination revealed an alert, interactive female with marked jaundice. Lungs were clear to auscultation, and heart tones were regular with no murmurs. Her abdomen was soft, nontender and not distended; her liver was palpated 2 cm below the right costal margin, and the spleen tip was palpated 3 cm below the left costal margin. Ultrasound of the abdomen showed mild hepatomegaly and thickened gallbladder wall with no sludge or stones. She was listed for liver transplantation, and began transfusion therapy with fresh frozen plasma and platelets as needed for procedures. Further blood tests showed negative human immunodeficiency virus (HIV) antibody, CMV polymerase chain reaction (PCR), and EBV PCR. Her alpha-1-antitrypsin level was normal, anti liver-kidney microsome antibody negative, antismooth muscle antibody negative, antinuclear antibody negative, drug screen for urine and serum negative, varicella immunoglobulin (Ig)G negative with an equivocal IgM. Ophthalmology consultation was negative for ocular abnormalities and Kayser-Fleischer rings, and her serum ceruloplasmin was 29 mg/dL. A 24-h urine collection for copper was 260 mcg/specimen (normal, less than 60), but the reliability of this test was questioned given that the patient had 4 L of urine collected while receiving furosemide. A magnetic resonance cholangiopancreatography (MRCP) showed no biliary stones or biliary dilatation, a mildly enlarged liver and spleen, thickened gallbladder wall, pericholecystic fluid, trace bilateral pleural effusions, and A. M. Yeh D. Bass (&) Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Stanford University Medical Center, Lucile Packard Children’s Hospital at Stanford, 750 Welch Road, Suite 116, Palo Alto, CA 94304-0126, USA e-mail: dmbass@stanford.edu

Testing Beneficial Therapy in Human Cirrhosis Using Animal Models of Cirrhosis

The study by Minuk and colleagues entitled “Daily Ciprofloxacin Treatment for Patients with Advanced Liver Disease Awaiting Liver Transplantation Reduces Hospitalizations” [1] tested the hypothesis that patients on the liver transplant list may benefit from antibiotics as a method of enhancing hepatic regeneration and improving liver function. The authors had previously shown in a rat model of acute and subacute liver failure that antibiotics improved survival [2, 3] and that antibiotics appeared to also improve survival in a model of chronic liver injury [4]. This benefit correlated in these animal models with improvement in markers of hepatic regeneration. In the current study, the authors asked whether the same benefit might be found in cirrhotic patients on the liver transplant waiting list. This single-site, prospective, randomized, double-blind study measured routine markers of hepatic function (albumin, bilirubin, and international normalized ratio for prothrombin time [INR]), markers of hepatic inflammation (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), and clinical outcomes (hospitalizations, hepatic encephalopathy, etc.) after 1 or 3 months of treatment with placebo or ciprofloxacin 250–500 mg twice daily. Results showed no systematic benefit at 1 or 3 months in markers of hepatic function or inflammation, and a significant improvement in albumin at 1 month was not confirmed at 3 months. However, it should be noted that more precise measurements of hepatic function [5, 6] or markers of regeneration might have shown subclinical benefits that would have been encouraging for further studies. Potential benefits in hospitalizations and clinical outcomes were also assessed. There were fewer hospitalizations for hepatic encephalopathy among subjects receiving ciprofloxacin, but little benefit for other clinical outcomes. As the authors note, antibiotics are helpful in treating encephalopathy and in prophylaxis against spontaneous bacterial peritonitis [7–10]. The effect of antibiotics on improvement in survival among variceal bleeders has been profound [11]. Thus, the reduction in hospitalizations among patients receiving antibiotics in this study is not surprising, and hepatic regeneration is not required to explain this improvement. Thus, the benefits of antibiotics in animal models of acute and chronic liver injury were not confirmed in this clinical trial among patients with advanced cirrhosis on the liver transplant waiting list. Animal models have been very useful in the evaluation of the pathophysiology of portal hypertension, ascites and hepatic fibrosis [12–17]. Why was so little benefit observed when antibiotics were used in humans with cirrhosis as compared with animal models? The answer partially lies in the difference between changes in pathophysiology in animal models of acute liver injury and humans with cirrhosis, who have dense hepatic fibrosis that develops over long periods of time and resolves slowly when the insult is stopped [18, 19]. By contrast, animal models of cirrhosis generally require continued liver injury to produce cirrhosis, and fibrosis resolves rapidly if the insult is stopped [12–17]. Furthermore, there is often a complex interaction of factors contributing to hepatic injury that includes bacterial products such as endotoxin from the gut that may be less important in man [12–14]. Antibiotics markedly decrease injury in most animal models [12–14]. Therefore, study of the pathophysiology of liver injury and complications of liver disease in animal models has been very valuable, but the regression of liver fibrosis differs between humans and animals. Thus, findings in animal models must be confirmed in clinical settings, and we applaud the authors for testing their hypothesis in humans [1]. Unfortunately, this study shows that antibiotics do not enhance hepatic regeneration or improve clinical outcomes by means of regeneration in patients on the liver transplant list. According to several recent studies, there is no experimental model that completely reproduces human liver fibrosis [12–14]. Since there are contraindications to serial liver biopsies in humans with liver disease, studies of genetic and molecular aspects of liver injury and fibrosis should continue. An initial approach should involve exploration of the molecular mechanisms of liver fibrosis in different diseases [20]. This might elucidate areas of potential efficacy of ciprofloxacin and other fluoroquinolones. Ultimately, all benefits in animals must be confirmed by clinical trials in man.