Bilirubin Threshold Research Articles

Clinical findings and prognostic factors for immediate survival in 33 dogs undergoing surgery for biliary peritonitis.

To report demographics, clinical signs, physical examination, diagnostic test results, surgical findings, and prognostic factors for in-hospital postoperative mortality following biliary peritonitis surgery in dogs. Retrospective, multi-institutional cohort study. Thirty-three client-owned dogs. The medical records of dogs that underwent surgery for biliary peritonitis between 2015 and 2021 were reviewed. Dogs were included if they had a definitive diagnosis of biliary peritonitis and a surgery report. Information on demographics, clinical signs and duration, physical examination findings, laboratory and diagnostic imaging results, surgery, perioperative medical treatment, and complications for each patient was obtained. Statistical analyses were performed to identify risk factors that affected survival. Cholecystectomy was the procedure most frequently performed (31/33, 94%). The overall mortality rate was 36% (12/33). Survival was affected negatively by hyperbilirubinemia (p = .049), administration of vasopressors (p = .002), renal dysfunction (p = .008), and number of postoperative complications (p = .005). A mortality rate of 50% was observed in dogs with a total bilirubin level greater than 60.5 μmol/L. There was no difference in mortality rate between septic and nonseptic biliary effusions. New prognostic factors associated with in-hospital postoperative mortality in dogs treated surgically for biliary peritonitis were identified, while others that had been reported previously were confirmed. A preoperative bilirubin threshold value associated with a 50% mortality was identified. Additional information that could help to predict survival in dogs with biliary peritonitis has been provided. However, further research is warranted.

Non-invasive detection of bilirubin concentrations during the first week of life in a low-resource setting along the Thailand–Myanmar border

BackgroundNeonatal hyperbilirubinaemia (NH) is a common problem worldwide and is a cause of morbidity and mortality especially in low-resource settings.MethodsA study was carried out at Shoklo Malaria Research Unit (SMRU)...

Combined Predictors of Long-Term Outcomes of Kasai Surgery in Infants with Biliary Atresia.

Biliary atresia (BA) is the leading cause of neonatal cholestasis (25-45%). The primary treatment is hepatic portoenterostomy (Kasai procedure), but only 20-40% provide long-term benefits. This study aimed to develop a predictive model for surgical efficacy by comparing preoperative and early postoperative indicators in infants with different outcomes. We enrolled 166 infants with BA (93 girls, 73 boys) who underwent the Kasai procedure between September 2002 and December 2021, dividing them into favorable or adverse outcome groups. Over 40 parameters were measured, and the diagnostic significance of the prognostic model was evaluated. Kasai surgery was efficacious in 69 patients (42%) and non-efficacious in 97 (58%). Our model assesses efficacy by day 14 after surgery, improving on the <34 µmol/L direct bilirubin threshold established for 3-6 months after the procedure. Including the Desmet fibrosis score refined the model. Blood cholesterol below 5.41 mmol/L, direct bilirubin below 56.3 µmol/L on postoperative days 14±3, and a low Desmet score indicate a high probability of efficacious Kasai surgery in infants with BA.

Implementing Higher Phototherapy Thresholds for Jaundice in Healthy Infants 35 Plus Weeks.

To determine the impact of higher bilirubin thresholds on testing and treatment of healthy infants during the neonatal period. This quality improvement study included infants born at ≥35 weeks gestation and admitted to the well-baby nursery between July 2018 and December 2020. We assessed the transition from infants treated according to the 2004 AAP guidelines (pregroup) with those following the Northern California Neonatal Consortium guidelines (postgroup). We examined the proportion of infants receiving phototherapy and total serum bilirubin (TSB) assessments as outcome measures. We examined critical hyperbilirubinemia (TSB above 25 mg/dL or TSB within 2 mg/dL of threshold for exchange transfusion), exchange transfusion, and readmission for jaundice as balancing measures. We compared the differences in outcomes over time using Statistical Process Control p charts. Balancing measures between the pre and postgroups were compared using χ square tests and t-tests. In our population of 6173 babies, there was a significant shift in the proportion receiving phototherapy from 6.4% to 4%. There were no significant changes in incidences of bilirubin >25 mg/dL (0 of 1472 vs 7 of 4709, P = .37), bilirubin within 2 mg/dL of exchange transfusion thresholds (4 of 1472 vs 5 of 4709, P = .15), exchange transfusion (0 of 1472 vs 1 of 4709, P = .70) or readmission for phototherapy (2.9% versus 2.4%, P = .30), between the 2 groups. Higher thresholds for phototherapy treatment of neonatal hyperbilirubinemia can decrease the need for phototherapy without increasing critical hyperbilirubinemia or readmission rate.

Association between congenital heart disease and parenteral nutrition-associated liver disease in neonates: A retrospective cohort study.

Infants receiving parenteral nutrition (PN) are at increased risk of PN-associated liver disease (PNALD), which can lead to hepatic fibrosis. Congenital heart disease (CHD) represents a risk factor for hepatic fibrosis, so this study sought to better understand whether infants with CHD were at elevated risk of PNALD when receiving long-term PN. This study includes a retrospective cohort of infants at a level IV neonatal intensive care unit from 2010 to 2020 who received long-term PN during the first 8 weeks of life. A time-varying Cox survival model was used to model risk of PNALD between infants with and without CHD, adjusted for demographics, surgical intervention, and PN exposure, using a 5000-iteration bootstrap estimation. Secondary analyses evaluated risk against discrete CHD diagnoses, and sensitivity analysis was performed on the magnitude and quantity of direct bilirubin laboratory measurements making up the PNALD definition. Neonates with CHD were found to be at higher risk for PNALD during or soon after long-term PN exposure. A pattern of increasing association strength with increasing bilirubin threshold suggests infants with CHD may also experience higher degrees of injury. This work offers a step in understanding how diagnoses can be factored into neonate PN prescription. Future work will explore modifications in lipid profiles and timing to mitigate risk in patients with CHD.

Patterns of lipid-injectable emulsion use in neonatal intensive care units across the United States: A multi-institution survey.

Lipid-injectable emulsions (ILEs) are a necessity for neonates dependent on parenteral nutrition (PN). In this manuscript, we describe the patterns of ILE use in neonatal intensive care units (NICUs) in the United States (US). An electronic survey was sent to 488 NICUs across the US between December 2020 and March 2021. Survey fields included availability and utilization of various ILE in neonates. The response rate was 22% (107 out of 488). Soybean oil ILE (SO-ILE) and soybean oil, medium-chain triglycerides, olive oil, fish oil ILE (SO, MCT, OO, FO-ILE) had similar availability (87% vs 86%, respectively), and SO, MCT, OO, FO-ILE was more commonly used (SO-ILE, 71% vs SO, MCT, OO, FO-ILE, 86%). Fish oil-ILE (FO-ILE) was used by 55% of centers. SO-ILE was most frequently used with PN and needs <4 weeks without cholestasis (79%). The most common reason for SO, MCT, OO, FO-ILE use was cholestasis (71%). ILE minimization was used by 28% of SO-ILE and 22% of SO, MCT, OO, FO-ILE users; 95% of these centers restrict SO, MCT, OO, FO-ILE to doses ≤2 g/kg/day. Twenty-two percent of centers started FO-ILE at direct bilirubin of >5 mg/dl. The results of this survey reveal significant variability in ILE usage across the US. Lipid minimization with SO, MCT, OO, FO-ILE and initiation of FO-ILE for cholestasis at higher bilirubin thresholds are prevalent. Such reports are crucial for a better understanding of ILE use in the NICU and in future ILE development.

Managing argatroban in heparin-induced thrombocytopenia: Aretrospective analysis of 729 treatment days in 32 patients with confirmed heparin-induced thrombocytopenia.

Managing argatroban in heparin-induced thrombocytopenia: Aretrospective analysis of 729 treatment days in 32 patients with confirmed heparin-induced thrombocytopenia.

Validation of visual estimation of neonatal jaundice in low-income and middle-income countries: a multicentre observational cohort study

ObjectiveDetermine the sensitivity and specificity of neonatal jaundice visual estimation by primary healthcare workers (PHWs) and physicians as predictors of hyperbilirubinaemia.DesignMulticentre observational cohort study.SettingHospitals in Chandigarh and Delhi, India; Dhaka,...

Impact of GBT440 on Unconjugated Bilirubin and Jaundice in Sickle Cell Disease: A Patient Case Report

Background: Sickle cell disease (SCD) is an inherited chronic hematological disorder which causes significant morbidity and reduced life expectancy. For many patients with SCD, jaundice can be a significant clinical disease manifestation and may have an underappreciated impact on patient well-being and quality of life. We report a case of a patient with SCD and chronic jaundice treated with GBT440, a novel small molecule hemoglobin modifier and potential disease-modifying therapy for SCD. GBT440 is a potent anti-sickling agent, reduces hemolysis and has demonstrated good safety and tolerability.Case Presentation: A structured interview was conducted to provide the patient's description and experience with jaundice before, during, and after GBT440 treatment. The patient is a 27-year-old Black male diagnosed with SCD at birth who recalls learning about his SCD from the age of 7 years. In this patient, jaundice has manifested as scleral icterus. Relevant medical history in the previous 12 months as of March 2016 included 2 hospitalizations due to painful crises, no blood transfusions, and no treatment with hydroxyurea. SCD symptoms included pain, fatigue, yellow eyes, stress, and a feeling of being overwhelmed. Minor crises occurred 2-3 times per week. Total and unconjugated bilirubin at baseline were 112 and 101 µmol/L (6.5 and 5.9 mg/dL), respectively, and hemoglobin was 9.9 g/dL. The patient participated in two GBT440 trials; GBT440-001 in which he received placebo, and a follow-on extension, in which he received GBT440 900 mg orally once daily for 6 months.Before GBT440 treatment, the patient reported that his eyes had been yellow since he was young. He reported no pain associated with jaundice and in general, the jaundice did not impact his daily life functioning and socializing; he stated he had learned to cope with it. However, he reported that his eyes did “go really, really yellow” when a crisis was coming. The patient wore tinted glasses, suggesting that he was bothered by his appearance and that others noticed it.During GBT440 treatment, the patient's eyes cleared within 1 week of taking the study medication; his eyes were “back to normal with no sign of yellow” and stayed completely white throughout the trial. Friends and family noticed the change in his eyes and the patient stopped wearing tinted glasses. The patient reported that he had more energy and felt stronger, and the minor crises stopped. He also indicated “a sense of delight, much happier, great feeling”. GBT440 treatment reduced bilirubin over time (Figure); unconjugated bilirubin was reduced by up to 76% (Table). The decline in unconjugated bilirubin in this patient is consistent with that previously reported (median decrease of 43% at the 900 mg/d dose; Howard et al. ASH 2016 meeting poster), and was below the bilirubin threshold typically associated with clinical jaundice (3 × upper limit of normal, 51 μmol/L) for most of the treatment period. In GBT440-001, for the patients dosed for ≥90 days, there were two additional patients with bilirubin elevated to the range of jaundice at baseline; they had a similar resolution of hyperbilirubinemia while receiving study drug. In this patient, hemoglobin improved from 9.9 g/dL at baseline to 11.1 g/dL at 90 days.After stopping GBT440, the patient's eyes “returned to how they were before the trial, yellow”, which started “as soon as I stopped the medicine”. While receiving GBT440, the patient “felt so much better; the SCD pain was gone; felt happier, took away the stress and worrying about pain”, and now feels worse while off the study medication. The patient rated the study medication as very beneficial. He indicated that “since birth, nothing has made my eyes go clear; I tried so many different things and they didn't help and within a short time on the medication, my eyes were clear”.Summary: The case patient had a long history of SCD with clinical jaundice and scleral icterus. He learned to cope with his jaundice so it did not significantly impact his activities of daily living. The patient reported that his jaundice cleared within 1 week of starting GBT440, that he felt much better with more energy, and that he was relieved/very happy after his eyes cleared. The jaundice returned after the patient stopped GBT440. Jaundice impacts many adults with SCD, significantly impacting self-image. GBT440 treatment was associated with reduced bilirubin levels and improved jaundice in our case patient. [Display omitted] DisclosuresTelfer:Kyora Kirin: Research Funding; Mundi Pharma: Research Funding; Bluebird Bio: Consultancy; Terumo: Honoraria; ApoPharma: Honoraria; Pfizer: Other: Participation in EDMC; Global Blood Therapeutics, Inc.: Consultancy; Novartis: Consultancy. Lehrer:Global Blood Therapeutics, Inc.: Employment, Equity Ownership. Agodoa:Global Blood Therapeutics, Inc.: Employment, Equity Ownership. Jurek:Global Blood Therapeutics, Inc.: Employment, Equity Ownership. Landsman:Global Blood Therapeutics, Inc.: Employment, Equity Ownership. Mant:Quintiles: Employment, Research Funding.

Simplifying Hyperbilirubinemia Risk Estimation.

Jaundice impacts more than half of term and late preterm newborns in the first week of life. Although in most cases, jaundice is benign, the consequences of severe hyperbilirubinemia are debilitating; thus, identification of newborns likely to exceed bilirubin treatment thresholds is needed. The American Academy of Pediatrics (AAP) recommends stratification of predischarge total serum bilirubin (TSB) levels by using the Bhutani Nomogram to help determine the appropriate timing of newborn follow-up. A separate nomogram is then used to determine if an infant meets criteria for phototherapy.1Kuzniewicz et al2 aim to simplify the process and more precisely determine when a newborn requires outpatient follow-up for jaundice with a simple equation. Starting with a retrospective cohort study of a diverse sample of 148 162 newborns born at ≥35 weeks’ gestation at 11 Kaiser Permanente Northern California facilities from 2012 to 2017, the researchers identified newborns whose TSB measurements did not exceed phototherapy levels and did not receive phototherapy during the birth hospitalization. Using the newborn’s last TSB value before hospital discharge (predischarge TSB), the authors calculated the difference between the predischarge total serum bilirubin and the corresponding American Academy of Pediatrics phototherapy threshold (in milligrams/deciliter) (Δ-TSB). Newborns who required phototherapy after discharge were identified. The authors compared the ability of the Δ-TSB model to predict postdischarge TSB above phototherapy thresholds to the Bhutani Nomogram. Examining additional variables, they also compared a more complicated Δ-TSB-Plus model. Although all 3 models performed well for those at highest and lowest risk of subsequent severe hyperbilirubinemia, both Δ-TSB and Δ-TSB-Plus models differentiated newborns in the intermediate zones better than the Bhutani Nomogram. Forty-four percent of newborns in Bhutani’s high-intermediate risk zone (who would have follow-up recommended within 48 hours) had a Δ-TSB between −4 and −5 mg/dL. In these newborns, the risk of ever having a subsequent TSB measurement greater than the AAP threshold was only 1.6%, suggesting follow-up within 48 hours might not be indicated.The Δ-TSB measurements used in this study relied on clinician discretion in follow-up; therefore, the predictive accuracy of the Δ-TSB models may be inflated because of differential verification bias as the authors mention. Only TSB measurements were included, but many hospitals and clinics use transcutaneous bilirubinometry.3 Although one can extrapolate the Δ-TSB for low bilirubin levels, the additional uncertainty involved when transcutaneous bilirubin measurements are used to approximate TSB levels has the potential to impact effective implementation of the Δ-TSB risk prediction approach.4 The 2004 AAP bilirubin thresholds were used in this study, but some clinicians caring for the patients studied may have followed other recommendations. For example, if the Northern California Neonatal Consortium criteria were used,5 some newborns may not have received a TSB assessment. Because nearly half of treated newborns were provided home phototherapy, we suspect their bilirubin levels were close to AAP thresholds. Clinicians may want to understand which newborns returned with bilirubin levels nearing or exceeding exchange thresholds and if they were predictable6; these data were not provided. Given the wide range of gestational ages in the AAP phototherapy risk strata (35–38 weeks; >38 weeks), a more delineated approach by gestational age and sex would be helpful because we know lower gestational age and male sex contribute to a higher risk of hyperbilirubinemia.7,8 An implementation study across different health systems will improve the generalizability of the Δ-TSB strategy.Despite any limitations, this study could have significant impact on the experience of care for new families and curb health care overuse. Currently, the AAP Bright Futures Guidelines recommend timing the initial newborn posthospitalization continuing care visit within 3 to 5 days after birth and 48 to 72 hours after discharge. This recommendation is based primarily on concern for jaundice and feeding problems leading to excessive weight loss.9 Implementation of a Δ-TSB approach has the potential to simplify postdischarge phototherapy risk estimation and might decrease unnecessary health care visits and extra hospital days for newborns previously stratified to the high-intermediate and low-intermediate risk zones on the Bhutani Nomogram. Select newborns could be discharged at 24 hours rather than 48 hours given this new evidence supporting an enhanced understanding of bilirubin trajectories. Some newborns with intermediate risk could safely defer in-person follow-up through weekends, holidays, and inclement weather days, whereas others may avoid daily outpatient bilirubin sampling with more optimally timed follow-up. This research also highlights, with large numbers, how truly low risk some newborns are for developing significant hyperbilirubinemia. With increasing adoption of telemedicine,10 those newborns who are also at low risk of feeding problems could be safely cared for in their homes.We thank Arthur Jaffe, MD, for reviewing and editing this commentary.

Treatment criteria for infants with hyperbilirubinemia in Japan

With the availability of blue light-emitting diode phototherapy devices capable of delivering high-intensity irradiance, neonatologists in Japan are requesting revisions of the 1992 Kobe University treatment criteria for hyperbilirubinemia using total serum/plasma bilirubin (TB) and serum unbound bilirubin (UB) threshold values, especially for indications for exchange transfusion (ET). Retrospective data analysis of 1,184 infants born between January 2012 and November 2014 when the 1992 criteria were followed, we applied revised criteria proposed in 2017 to these infants to assess consequent changes in treatment recommendations. We found that the estimated number of infants with ET indications decreases from 48 to 20, with intensive phototherapy recommended for the remaining 28. Also, the estimated number of infants with phototherapy indications decreases from 446 to 195. We conclude that use of the revised criteria will lead to judicious use and reduction of phototherapy and ET in infants with hyperbilirubinemia.

Goals of Treatment for Improved Survival in Primary Biliary Cholangitis: Treatment Target Should Be Bilirubin Within the Normal Range and Normalization of Alkaline Phosphatase.

In primary biliary cholangitis (PBC), bilirubin and alkaline phosphatase (ALP) are widely established as independent predictors of prognosis. Current treatment goals do not aim for normalization of surrogate markers because their association with survival has not been defined. The patient cohort from the GLOBAL PBC Study Group was used, comprising of long-term follow-up data from European and North American centers. Ursodeoxycholic acid-treated and untreated patients with bilirubin levels ≤1 × upper limit of normal (ULN) at baseline or 1 year were included. The association of normal ALP with transplant-free survival was assessed in a subgroup with ALP ≤1.67 × ULN at 1 year. Optimal thresholds of bilirubin and ALP to predict liver transplantation (LT) or death were evaluated. There were 2,281 patients included in the time zero cohort and 2,555 patients in the 1-year cohort. The bilirubin threshold with the highest ability to predict LT or death at 1 year was 0.6 × ULN (hazard ratio 2.12, 95% CI 1.69-2.66, P < 0.001). The 10-year survival rates of patients with bilirubin ≤0.6 × ULN and >0.6 × ULN were 91.3% and 79.2%, respectively (P < 0.001). The risk for LT or death was stable below the bilirubin levels of 0.6 × ULN, yet increased beyond this threshold. Ursodeoxycholic acid-induced reduction in bilirubin below this threshold was associated with an 11% improvement in 10-year survival. Furthermore, ALP normalization was optimal, with 10-year survival rates of 93.2% in patients with ALP ≤ 1 × ULN and 86.1% in those with ALP 1.0-1.67 × ULN. Attaining bilirubin levels ≤0.6 × ULN or normal ALP are associated with the lowest risk for LT or death in patients with PBC. This has important implications for treatment targets.

Qualitative and quantitative variations in liver function thresholds among clinical trials in cancer: a need for harmonization.

The liver is critically involved in drug metabolism pathways and the potential for hepatic toxicity is significant with specific cancer therapeutics. Variations in the definition of liver function thresholds that may generate heterogeneity of toxicity and efficacy outcomes across therapeutics trials in cancer require assessment. A random sample of therapeutic trials in cancer (n = 500, general category), trials using hepatotoxic drugs (abiraterone, pazopanib: n = 181), trials using drugs metabolized by the liver (doxorubicin, vincristine: n = 606), and therapeutic trials in hepatic dysfunction (n = 49) were each identified on clinicaltrials.gov. Definitions of liver function thresholds and their distribution were collated and categorized in each group. A third of all trials listed on clinicaltrials.gov across the four categories failed to provide an explicit definition of liver function. Among trials with an explicit definition, a combination of bilirubin and transaminase levels was used in 33-64%, whereas a miscellaneous combination of definitions (in the general category consisting of 11 unique liver function parameters creating 17 unique combinations) was used 29-58% of the time across the four categories of studies. The Child-Pugh or National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria were rarely employed (0-12% studies). Allowance for Gilbert's disease in bilirubin thresholds was identified in only 6-23% studies and for liver metastases in 2-15% of studies. There is a marked heterogeneity in the liver function definitions used across cancer clinical trials even when the potential for drug toxicity and altered drug metabolism is significant. Harmonization of criteria will streamline eligibility and mitigate variations in key outcomes across trials.

Bilirubin Correlation May Preclude MRCP in Acute Cholecystitis Patients With Normal Common Bile Duct Diameter.

OBJECTIVE. In patients with acute cholecystitis (AC), accurate identification of a common bile duct (CBD) stone before cholecystectomy is of concern for surgeons, gastroenterologists, and radiologists. This study evaluates the utility of preoperative MRCP taking into consideration both sonographic findings and biochemical predictors for choledocholithiasis. MATERIALS AND METHODS. Fifty-seven patients (58% women; mean age, 54 years old) with signs of AC on right upper quadrant (RUQ) ultrasound (US) who underwent subsequent MRCP from 2007 to 2017 were identified using a text-based search and retrospectively analyzed, using ERCP as the reference standard. RESULTS. For patients with AC who had a normal CBD diameter on initial RUQ US, we found a significant difference in the total and direct bilirubin levels of patients who had positive (1.94 vs 4.02 mg/dL, respectively; p = 0.013) and negative (0.71 vs 2.13 mg/dL, respectively; p = 0.02) findings for CBD stone on MRCP. ROC curve analysis showed an increased total bilirubin threshold of > 2.3 mg/dL (standard threshold, 1.2 mg/dL), which yielded a negative predictive value (NPV) of 95%. An increased direct bilirubin threshold of > 0.9 mg/dL (standard threshold, 0.2 mg/dL) yielded an NPV of 100%. CONCLUSION. In patients with AC who have a normal CBD diameter on RUQ US, normal or even mildly elevated bilirubin levels below a calculated threshold may obviate preoperative MRCP. Radiologists should be active participants in clinical decision-making; discussion between referring physicians and radiologists regarding biochemical markers and sonographic findings will lead to more appropriate use of preoperative imaging.

Incidence and Predictors of Hepatic Veno-Occlusive Disease after Reduced Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation

Introduction: Hepatic veno-occlusive disease (VOD)/Sinusoidal Obstruction Syndrome (SOS) is a serious complication of hematopoietic stem cell transplantation (HSCT) that is triggered, at least in part, by conditioning regimen-induced sinusoidal endothelial cell injury. VOD is thus commonly, but not exclusively, associated with myeloablative conditioning (MAC). The incidence of VOD in reduced intensity conditioning (RIC) HSCT was ≈2% in a single center series (Carreras et al. BBMT 2011), and risk factors for VOD in RIC HSCT remain poorly defined. Methods: We performed a retrospective review to confirm all cases of VOD among patients undergoing RIC HSCT at the Dana-Farber Cancer Institute/Brigham and Women9s Cancer Center between January 2007 and June 2017. Diagnosis of VOD was based on modified Seattle or Baltimore criteria and/or liver biopsy or RUQ ultrasound in conjunction with fluid retention/ascites and hepatomegaly/RUQ pain. Diagnosis dates for all VOD cases were confirmed and clinico-laboratory values collected in the 10 days preceding the diagnosis. The same data were collected for a randomly selected control non-VOD RIC cohort, calculated from the median day of VOD onset derived from the cases. Acute kidney injury was defined as an absolute increase in creatine by 0.3 mg/dL or a relative increase of > 50% within a 48-hour period. Increased platelet transfusion requirement was defined as requiring a platelet transfusion on 2 consecutive days in the 7 days prior to VOD diagnosis, excluding transfusions for procedures. Incidence of VOD at D50 was calculated using a competing risk framework. Cox regression was used to identify significant features for predicting VOD. Survival was compared to a concurrent cohort of 76 patients with VOD after MAC HSCT recently published from our center (Roeker et al. BBMT 2018). Results: A total of 1492 patients underwent RIC HSCT, of whom 1070 (67.8%) received sirolimus (Sir) with tacrolimus (Tac) as part of the GVHD prophylaxis, and 1217 (82%) received intravenous busulfan(Bu) 3.2 or 6.4mg/kg with fludarabine(Flu) as conditioning. Twenty-six developed VOD (median day of diagnosis = d+26, range 5-48 days), for a cumulative incidence of 1.6% (95%CI 1.1%-2.4%). The median bilirubin at diagnosis was 1.1 mg/dL(range 0.6-5.2). Only 5 (19.2%) patients had a bilirubin of ≥2.0 mg/dL on the date of VOD diagnosis, although total bilirubin peaked at ≥ 2 mg/dL in 17 of 26 (65.4%). VOD was mild/moderate in 16 and severe in 10 patients. Sixteen had received ursodiol as VOD prophylaxis. Defibrotide was used as treatment in 17 cases. The 2-year overall survival (OS) was 54% from VOD onset. VOD was associated with increased risk for NRM (HR 4.02, 95% CI 2.1-7.7, p 1, increasing platelet transfusion requirements, and increasing Tac and Sir trough levels (Table 1, Fig 1). Conclusions: The incidence of VOD in this large modern cohort of 1492 RIC HSCT patients was 1.6%, and was associated with the use of Sir with Tac. Onset of VOD in RIC patients was delayed (median D+26 vs. D+14) and 2 yr-OS is superior compared to MAC patients. Only 19% of the RIC VOD cases met the bilirubin threshold for Baltimore and Seattle criteria at diagnosis, suggesting that the rise in bilirubin is a later event in these RIC VOD cases, whereas increasing platelet transfusion requirements, sudden rise in Tac and Sir levels, elevated serum creatinine and acute renal injury appear to be early clinical predictors. Disclosures Nikiforow:Kite Pharma: Consultancy. Antin:Jazz Pharmaceuticals: Membership on an entity9s Board of Directors or advisory committees. Richardson:Jazz Pharmaceuticals: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity9s Board of Directors or advisory committees; Janssen: Membership on an entity9s Board of Directors or advisory committees; Amgen: Membership on an entity9s Board of Directors or advisory committees; Oncopeptides: Membership on an entity9s Board of Directors or advisory committees; Takeda: Membership on an entity9s Board of Directors or advisory committees, Research Funding; BMS: Research Funding. Soiffer:Jazz Pharmaceuticals: Membership on an entity9s Board of Directors or advisory committees. Ho:Jazz Pharmaceuticals: Consultancy.

Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome: Diagnostic Patterns Among United States and European Union Hematologists and Oncologists Managing Patients Receiving Stem Cell Transplantation

Introduction Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable, potentially fatal complication of hematopoietic stem cell transplantation (HSCT) and high-dose chemotherapy. The VOD/SOS pathologic cascade is initiated by endothelial and hepatocyte damage. VOD/SOS is usually diagnosed using Baltimore criteria (≤21 days post transplant: bilirubin >2 mg/dL, plus 2 or more of hepatomegaly, ascites, and weight gain ≥5%) or modified Seattle criteria (≤20 days post transplant: 2 or more of bilirubin >2 mg/dL, hepatomegaly or right upper quadrant pain, and weight gain >2%). Severe VOD/SOS, usually characterized by multi-organ dysfunction (ie, pulmonary and/or renal dysfunction), may develop in a substantial number of high-risk patients and may be associated with >80% mortality. To understand the diagnostic patterns for VOD/SOS in the United States (US) and European Union (EU), a quantitative online survey was conducted among HSCT specialists. Methods Participating hematology-oncology specialists for pediatric and adult patients had ≥2 years direct involvement in performing HSCT, spent ≥25% of their time in direct patient care, and managed ≥10 HSCT patients (≥10 allogeneic) in the past year. Their facilities were accredited and performed ≥80 adult HSCT procedures in the US (≥50 in the EU) or ≥20 pediatric HSCT procedures (US or EU). In this survey, VOD/SOS severity was rated as early (milder) or severe (with multi-organ dysfunction). On average, the online survey took 30 to 40 minutes to complete. Results Surveys were completed by 100 US physicians (70 adult, 30 pediatric) and 153 EU physicians (122 adult, 31 pediatric; from France, Germany, Italy, Spain, and the United Kingdom). Each physician directly managed an average of 179 (US) or 95 (EU) HSCT patients in the past year. In adult patients, the median percentages of patients treated for severe/early VOD/SOS were 7%/7% in the US and 3%/6% in the EU; in pediatric patients, the median percentages were 9%/12% in the US and 5%/10% in the EU. The most commonly used VOD/SOS diagnostic signs and symptoms (Table) were weight gain and bilirubin level. The median level of weight gain to trigger follow-up action (action not specified but could include further diagnostic testing) was 10% in the US and 5% in the EU, for both adult and pediatric patients; the Baltimore and Seattle criteria specify a weight gain of 5% and 2%, respectively. US physicians were less likely than EU physicians to take action at weight gain of ≤5% (Figure): about half as likely for adults (29% vs 56%) and about a fifth as likely for pediatric patients (14% vs 67%). In addition, at ≤5% weight gain, US physicians of pediatric patients were about twice as likely to take action as US physicians of adult patients. The median bilirubin levels at which US physicians initiated action were 3 mg/dL in adults and 4 mg/dL in pediatric patients, compared with 2 mg/dL for EU physicians in both adult and pediatric patients (Figure); the Baltimore and modified Seattle criteria specify a bilirubin level of 2 mg/dL. Conclusions The survey results show that a substantial proportion of US HSCT physicians take follow-up action at weight gain or bilirubin thresholds higher than those in the Baltimore or modified Seattle criteria. Treatment patterns in the EU, particularly among pediatric physicians, appear to be more closely aligned with the diagnostic criteria. The established criteria have limitations; neither set takes into account late onset of VOD/SOS or presentation of edema and weight gain in the absence of other signs and symptoms. As discussed in a recent publication (Mohty M et al. BMT. 2015;50[6]:781-789), elevated bilirubin may be absent in VOD/SOS developing late after HSCT and in children, which prompted the authors to suggest the need for a criteria update. Support: Jazz Pharmaceuticals. Participants received financial remuneration for their survey participation. Disclosures Corn:Jazz Pharmaceuticals: Employment, Equity Ownership. Ogram:Jazz Pharmaceuticals: Employment, Equity Ownership. Doede:Jazz Pharmaceuticals: Employment, Equity Ownership.

Towards an absolute bilirubin threshold for preoperative biliary decompression in patients undergoing whipple.

381 Background: There is no consensus as to when preoperative biliary decompression is indicated in patients with obstructive jaundice prior to pancreatoduodenectomy. The purpose of this study is to identify a bilirubin level whereby biliary decompression provides clear benefit despite potential drawbacks. Methods: Serial logistic regression analyses were undertaken to identify the bilirubin threshold upon which biliary decompression was associated with significant improvement in overall complications, mayor complications (Clavien-Dindo ≥ 3), length of stay, readmission rates and mortality. Results: Biliary decompression independently predicted a higher incidence of overall complications in patients presenting with bilirubin ≤ 10mg/dl, (p = 0.02). For patients with bilirubin &gt; 10mg/dl - &lt; 15mg/dl, there were no differences in complications, mortality, length of stay or readmissions. Biliary decompression in patients with bilirubin ≥ 15mg/dl independently predicted fewer overall (72% vs 100%), and mayor complications (11 % vs 50%), p &lt; 0.05, and lower readmission rates (27.7% vs 62.5%), p = 0.02. Patients not undergoing biliary decompression underwent resection on average two weeks sooner than those having decompression (4.7 days vs 17.2 days), p = 0.01, with no significant change in bilirubin levels between presentation and surgery. Patients with bilirubin &lt; 15mg/dl at presentation, who underwent biliary decompression, had a bilirubin decrease of more than 50% ( 6.3mg/dl to 2.5mg/dl), and the time to resection increased by more than one week (28 days vs 20.4 days), p &lt; 0.001. Conclusions: All patients presenting with bilirubin ≥ 15mg/dl should undergo preoperative biliary decompression to minimize the risk of complications and readmissions. Patients presenting with bilirubin ≤ 10 mg/dl should forego stent placement to avoid stent related complications without clear benefit. The decision to stent between &gt; 10mg/dl to &lt; 15 mg/dl should be made on a case by case basis, taking into account anticipated bilirubin level at the time of surgery.

Percutaneous biliary drainage effectively lowers serum bilirubin to permit chemotherapy treatment.

For digestive tract cancers, the bilirubin threshold for administration of systemic chemotherapy can be 5 or 2 mg/dL (85.5 or 34.2 μmol/L) depending upon the regimen. We examined the ability of percutaneous biliary drainage (PBD) in patients with malignant biliary obstruction to achieve these clinically relevant endpoints. 106 consecutive patients with malignant biliary obstruction and a baseline serum bilirubin >2 mg/dL underwent PBD. Time to achieve a bilirubin of 5 mg/dL (85.5 μmol/L), 2 mg/dL (34.2 μmol/L), and survival was estimated by Kaplan-Meier analysis. Potential technical and clinical prognostic factors were subjected to univariate and multivariate analysis. Categorical variables were analyzed by the log rank test. Hazard ratios were calculated for continuous variables. Median survival was 100 days (range 1-3771 days). Among 88 patients with a pre-drainage bilirubin >5 mg/dL, 62% achieved a serum bilirubin ≤5 mg/dL within 30 days and 84% within 60 days, median 21 days. Among 106 patients with a pre-drainage bilirubin >2 mg/dL, 37% achieved a serum bilirubin ≤2 mg/dL by 30 days and 70% within 60 days, median 43 days. None of the technical or clinical factors evaluated, including pre-drainage bilirubin, were significant predictors of time to achieve a bilirubin ≤2 mg/dL (p = 0.51). Size and type of biliary device were the only technical variables found to affect time to bilirubin of 5 mg/dL (p = 0.016). PBD of malignant obstruction achieves clinically relevant reduction in serum bilirubin in the majority of patients within 1-2 months, irrespective of the pre-drainage serum bilirubin, sufficient to allow administration of systemic chemotherapy. However, the decision to undergo this procedure for this indication alone must be considered in the context of patients' prognosis and treatment goals.

Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome: Diagnostic Patterns Among United States and European Union Hematologists and Oncologists Managing Patients Receiving Stem Cell Transplantation

IntroductionHepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable, potentially fatal complication of hematopoietic stem cell transplantation (HSCT) and high-dose chemotherapy. The VOD/SOS pathologic cascade is initiated by endothelial and hepatocyte damage. VOD/SOS is usually diagnosed using Baltimore criteria (≤21 days post transplant: bilirubin >2 mg/dL, plus 2 or more of hepatomegaly, ascites, and weight gain ≥5%) or modified Seattle criteria (≤20 days post transplant: 2 or more of bilirubin >2 mg/dL, hepatomegaly or right upper quadrant pain, and weight gain >2%). Severe VOD/SOS, usually characterized by multi-organ dysfunction (ie, pulmonary and/or renal dysfunction), may develop in a substantial number of high-risk patients and may be associated with >80% mortality.To understand the diagnostic patterns for VOD/SOS in the United States (US) and European Union (EU), a quantitative online survey was conducted among HSCT specialists.MethodsParticipating hematology-oncology specialists for pediatric and adult patients had ≥2 years direct involvement in performing HSCT, spent ≥25% of their time in direct patient care, and managed ≥10 HSCT patients (≥10 allogeneic) in the past year. Their facilities were accredited and performed ≥80 adult HSCT procedures in the US (≥50 in the EU) or ≥20 pediatric HSCT procedures (US or EU). In this survey, VOD/SOS severity was rated as early (milder) or severe (with multi-organ dysfunction). On average, the online survey took 30 to 40 minutes to complete.ResultsSurveys were completed by 100 US physicians (70 adult, 30 pediatric) and 153 EU physicians (122 adult, 31 pediatric; from France, Germany, Italy, Spain, and the United Kingdom). Each physician directly managed an average of 179 (US) or 95 (EU) HSCT patients in the past year. In adult patients, the median percentages of patients treated for severe/early VOD/SOS were 7%/7% in the US and 3%/6% in the EU; in pediatric patients, the median percentages were 9%/12% in the US and 5%/10% in the EU.The most commonly used VOD/SOS diagnostic signs and symptoms (Table) were weight gain and bilirubin level. The median level of weight gain to trigger follow-up action (action not specified but could include further diagnostic testing) was 10% in the US and 5% in the EU, for both adult and pediatric patients; the Baltimore and Seattle criteria specify a weight gain of 5% and 2%, respectively. US physicians were less likely than EU physicians to take action at weight gain of ≤5% (Figure): about half as likely for adults (29% vs 56%) and about a fifth as likely for pediatric patients (14% vs 67%). In addition, at ≤5% weight gain, US physicians of pediatric patients were about twice as likely to take action as US physicians of adult patients. The median bilirubin levels at which US physicians initiated action were 3 mg/dL in adults and 4 mg/dL in pediatric patients, compared with 2 mg/dL for EU physicians in both adult and pediatric patients (Figure); the Baltimore and modified Seattle criteria specify a bilirubin level of 2 mg/dL.ConclusionsThe survey results show that a substantial proportion of US HSCT physicians take follow-up action at weight gain or bilirubin thresholds higher than those in the Baltimore or modified Seattle criteria. Treatment patterns in the EU, particularly among pediatric physicians, appear to be more closely aligned with the diagnostic criteria. The established criteria have limitations; neither set takes into account late onset of VOD/SOS or presentation of edema and weight gain in the absence of other signs and symptoms. As discussed in a recent publication (Mohty M et al. BMT. 2015;50[6]:781-789), elevated bilirubin may be absent in VOD/SOS developing late after HSCT and in children, which prompted the authors to suggest the need for a criteria update.Support: Jazz Pharmaceuticals. Participants received financial remuneration for their survey participation.TableVOD/SOS Assessment Measures Used by PhysiciansBaltimore/Seattle ItemUS(n=95), %EU(n=152), %Weight increaseY5078*Bilirubin increaseY4662*HepatomegalyY3657*AscitesY3649*Ultrasound2747*Liver Doppler2329PainY1629*JaundiceY2528Liver functionY2526Distention/SwellingY2218*P <.05 vs US. [Display omitted] DisclosuresCorn:Jazz Pharmaceuticals: Employment, Equity Ownership. Ogram:Jazz Pharmaceuticals: Employment, Equity Ownership. Doede:Jazz Pharmaceuticals: Employment, Equity Ownership.

Increased Clearance of Storage-Damaged Red Blood Cells Induces an Acute Phase Response in Critically-Ill Children

BACKGROUND: Current FDA standards allow refrigerated red blood cell (RBC) units to be stored for up to 42 days before transfusion; these are based on several criteria, including that, on average, <25% of the RBCs transfused into healthy volunteers will be cleared from the circulation in the first 24 hours. However, the 24-hour post-transfusion RBC recovery is less in ill adult patients than in healthy adult volunteers, an issue that has not yet been studied in pediatric patients.AIMS: To compare the effects of transfusion of packed RBCs after various storage durations on iron metabolism, hemolysis, and inflammation.METHODS: In this prospective observational study, we recruited 73 transfused critically-ill children. Blood samples were collected before and 4-hours after a RBC transfusion. Furthermore, as a control, blood samples were similarly collected in 14 critically-ill children infused with saline or albumin for volume replacement. Plasma non-transferrin bound iron (NTBI) was quantified by an ultrafiltration assay, serum hepcidin levels by an immunoassay, free hemoglobin by Drabkin’s assay, and other routine laboratory parameters by standard methods. Correlations and the effect of covariates were determined by linear regression. Difference between means was assessed by one-way ANOVA.RESULTS: The median storage duration of transfused RBCs was 24 days (range: 4-39 days). RBC storage duration was significantly and positively associated with increases in total bilirubin (R2=0.12; P<0.01) and serum iron (R2=0.11; P<0.01), with a positive trend in NTBI (R2=0.04; P=0.07) (see Figure) and a negative trend in haptoglobin levels (R2=0.03; P=0.09; not shown). No association was observed between storage duration and increases in plasma hemoglobin, hepcidin, or C-reactive protein (CRP). These data suggest that, in critically-ill children, RBC storage duration alone relatively poorly predicts the extent of hemolysis observed after transfusion, explaining only ~10% of the variability. Four hours after transfusion, measures of inflammation were not significantly associated with RBC storage duration. Nonetheless, a subset of patients (17 of 73) with a greater extent of hemolysis (defined by an increase in total bilirubin >0.4 mg/dL) developed a significant increase in CRP relative to the saline/albumin infused controls (i.e., a mean increase of 23.5 [3.7-43.4] mg/L; P<0.05; see Figure). A similar result was obtained using an indirect bilirubin threshold of >0.2 mg/dL (i.e., a mean increase in CRP of 22.4 [3.0-41.8] mg/L relative to the saline/albumin infused controls). These results suggest that increases in bilirubin above a certain post-hoc threshold may be predictive of an acute phase response. Finally, transfusion of irradiated RBC units trended towards increased post-transfusion bilirubin levels (P=0.08).CONCLUSIONS: The main conclusion of this study is that increased RBC storage duration results in a variable amount of both intra- and extra-vascular hemolysis. Although circulating haptoglobin levels in transfusion recipients decreased somewhat with increasing storage duration, haptoglobin was not completely consumed and free hemoglobin was absent 4-hours after transfusion. Nonetheless, post-transfusion levels of circulating bilirubin, iron, and NTBI did increase after prolonged RBC storage. In addition, the extent of hemolysis, evidenced by increased serum bilirubin levels above a certain threshold, predicted an acute phase response in critically-ill children. Importantly, storage duration alone poorly predicted post-transfusion consequences resulting from the RBC storage lesion, explaining, for example, only 10% of the variability in the degree of hemolysis in critically-ill pediatric patients. This suggests that other, as yet unknown, donor and recipient factors play a more significant role in this setting. If hemolysis of transfused refrigerator storage-damaged RBCs induces adverse clinical sequelae, this suggests that randomized studies aimed at studying the role of RBC storage duration on patient outcome may be underpowered, if they assume that storage duration alone is the most suitable predictor of outcome. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.