Effect of hyperbilirubinemia and phototherapy on apoptotic microparticle levels in neonates.

OBJECTIVE: We aimed to evaluate the effect of hyperbilirubinemia and phototherapy on total apoptotic, platelet-derived, endothelial-derived, and tissue factor (TF)-positive apoptotic microparticle (MP) levels in neonates with nonhemolytic pathologic hyperbilirubinemia. METHODS: Thirty-three term neonates with nonhemolytic pathologic hyperbilirubinemia and 25 healthy term neonates were included. MP levels were analyzed by flow cytometry using peripheral blood samples only once for the neonates in the control group and twice for the neonates in the study group (before and after phototherapy). Annexin V-positive MPs were defined as apoptotic MPs. Platelet-derived MPs were defined as those containing CD31. MPs containing CD144 were defined as endothelial-derived MPs, and MPs expressing TF were identified as those containing CD142. RESULTS: The rates of total apoptotic and endothelial-derived apoptotic MPs were significantly higher in the study group than the control group before phototherapy (P = 0.012 and P = 0.003, respectively) and after phototherapy (P = 0.046 and P = 0.001, respectively). Total apoptotic, platelet-derived, endothelial-derived, and TF-positive apoptotic MPs did not show any significant differences before and after phototherapy in the study group (P = 0.908, P = 0.823, P = 0.748, and P = 0.437, respectively). CONCLUSIONS: Our study demonstrated that total apoptotic and endothelial-derived apoptotic MPs are increased in cases of nonhemolytic pathologic hyperbilirubinemia. We showed that phototherapy does not have a significant effect on apoptotic MP levels. Further studies are needed to evaluate the risk of elevated apoptotic MPs on the development of thromboembolism in neonates with nonhemolytic pathologic hyperbilirubinemia.

[Apheresis Techniques for the Treatment of Hyperbilirubinemia in the Nephrology Unit].

Therapeutic apheresis is an important hematological and nephrological method for conditions with altered plasma composition. It is also indicated for the removal of protein-bound molecules, such as bilirubin. Several techniques can remove these compounds, such as the extracorporeal circulation molecular adsorption system (MARS), plasma exchange (PEX), and plasma adsorption and perfusion (PAP). Here we report our experience in the comparison between MARS, PEX and PAP, since current guidelines do not specify which method is the most appropriate and under which circumstances it should be used. The choice of technique cannot be based on the desired plasma bilirubin concentration, since these three techniques show similar results with a similar final outcome (exitus). In fact, PAP, PEX and MARS significantly reduce bilirubin levels, but the degree of reduction is not different among the three. Furthermore, the three techniques do not differ in the rate of cholinesterase change, while less reduction of liver transaminases was found by using PAP. MARS should be preferred in the case of renal involvement (hepatorenal syndrome with hyperbilirubinemia). PAP has the advantage of being simple and inexpensive. PEX remains an option when emergency PAP is not available, but the risk of using blood products (plasma and albumin) must be considered.

Updated Clinical Practice Guidelines for Management of Hyperbilirubinemia in Infants Born at 35 Weeks or More Gestation.

Given the prevalence of jaundice in newborns, and the consequences of untreated hyperbilirubinemia, the long-awaited revised clinical practice guidelines for hyperbilirubinemia were finally released in August 2022 by the American Academy of Pediatrics as an update to the 2004 guidelines on the same topic. As new evidence and data become available, it is important for pediatricians and neonatologists to re-assess their clinical decision-making over time to ensure that patients are receiving the best care possible. With improvements in medical equipment and medical technology, and growing concerns about the overtreatment of hyperbilirubinemia, the newest clinical practice guidelines attempt to tackle the prevention, risk assessment, monitoring, and treatment of hyperbilirubinemia with these things in mind. [Pediatr Ann. 2023;52(12):e436-e439.].

Correlation between Bilirubin Elimination with the Cytokine Adsorber CytoSorb® and Mortality in Critically Ill Patients with Hyperbilirubinemia.

INTRODUCTION: Hyperbilirubinemia is often the first evidence for any kind of liver disorder and over one-third of all patients in intensive care units (ICU) show elevated bilirubin concentrations. In critically ill patients, high concentrations of serum bilirubin are correlated with a poor outcome. Therapies to lower bilirubin concentrations are often just symptomatically and their effect on the patients' outcome is hardly evaluated. Therefore, this study investigates whether the extracorporeal elimination of bilirubin with the cytokine adsorber CytoSorb® (CS) reduces mortality in patients with hyperbilirubinemia. METHODS: Patients with bilirubin concentrations >10 mg/dL at the ICU were screened for evaluation from 2018 to 2020. Patients with kidney replacement therapy and older than 18 years were included. Patients with continuously decreasing bilirubin concentrations after liver transplantation or other liver support systems (i.e., Molecular Adsorbents Recirculating System [MARS®], Advanced Organ Support [ADVOS]) were excluded. CS therapy was used in clinical routine and was indicated by the treating physicians. Statistical analysis was performed with IBM SPSS statistics utilizing a multivariate model. Primary outcome measure was the effect of CS on the 30-day mortality. RESULTS: Data from 82 patients (mean Simplified Acute Physiology Score [SAPS] II: 74 points, mean bilirubin: 18 mg/dL, mean lactate: 3.7 mmol/L) were analyzed. There were no significant differences in patients with and without CS treatment. The multivariate model showed no significant effect of CS therapy (p = 0.402) on the 30-day mortality. In addition, a significant effect of bilirubin concentration (p = 0.274) or Model for End-Stage Liver Disease score (p = 0.928) on the 30-day mortality could not be shown. In contrast, lactate concentration (p = 0.001, b = 0.044) and SAPS II (p = 0.025, b = 0.008) had significant impact on 30-day mortality. CONCLUSION: The use of CS in patients with hyperbilirubinemia did not result in a significant reduction in 30-day mortality. Randomized and controlled studies with mortality as primary outcome measure are needed in the future to justify their use.

Novel hemoperfusion adsorbents based on collagen for efficient bilirubin removal - A thought from yellow skin of patients with hyperbilirubinemia.

Hemoperfusion is a well-developed method for removing bilirubin from patients with hyperbilirubinemia. The performance of adsorbents is crucial during the process. However, most adsorbents used for bilirubin removal are not suitable for clinical applications, because they either have poor adsorption performance or limited biocompatibility. Patients with hyperbilirubinemia usually have distinctive yellow skin, indicating that collagen, a primary component of the skin, may be an effective material for absorbing bilirubin from the blood. Based on this idea, we designed and synthesized collagen (Col) and collagen-polyethyleneimine (Col-PEI) microspheres and employed them as hemoperfusion adsorbents for bilirubin removal. The microspheres have an efficient adsorption rate, higher bilirubin adsorption capacity, and competitive adsorption of bilirubin in the bilirubin/bovine serum albumin (BSA) solution. The maximum adsorption capacities of Col and Col-PEI microspheres for bilirubin are 150.2 mg/g and 258.4 mg/g, respectively, which are higher than those of most traditional polymer microspheres. Additionally, the microspheres exhibit excellent blood compatibility originating from collagen. Our study provides a new collagen-based strategy for the hemoperfusion treatment of hyperbilirubinemia.

Synthetic augmentation of bilirubin metabolism in human pluripotent stem cell-derived liver organoids.

UGT1A1 (UDP glucuronosyltransferase family 1 member A1) is the primary enzyme required for bilirubin conjugation, which is essential for preventing hyperbilirubinemia. Animal models lack key human organic anion transporting polypeptides with distinct epigenetic control over bilirubin metabolism, necessitating a human model to interrogate the regulatory mechanism behind UGT1A1 function. Here, we use induced pluripotent stem cells to develop human liver organoids that can emulate conjugation failure phenotype. Bilirubin conjugation assays, chromatin immunoprecipitation, and transcriptome analysis elucidated the role of glucocorticoid antagonism in UGT1A1 activation. This antagonism prevents the binding of transcriptional repressor MECP2 at the expense of NRF2 with associated off-target effects. Therefore, we introduced functional GULO (L-gulonolactone oxidase) in human organoids to augment intracellular ascorbate for NRF2 reactivation. This engineered organoid conjugated more bilirubin and protected against hyperbilirubinemia when transplanted in immunosuppressed Crigler-Najjar syndrome rat model. Collectively, we demonstrate that our organoid system serves as a manipulatable model for interrogating hyperbilirubinemia and potential therapeutic development.

Gene Therapy in Patients with the Crigler-Najjar Syndrome.

BACKGROUND: Patients with the Crigler-Najjar syndrome lack the enzyme uridine diphosphoglucuronate glucuronosyltransferase 1A1 (UGT1A1), the absence of which leads to severe unconjugated hyperbilirubinemia that can cause irreversible neurologic injury and death. Prolonged, daily phototherapy partially controls the jaundice, but the only definitive cure is liver transplantation. METHODS: We report the results of the dose-escalation portion of a phase 1-2 study evaluating the safety and efficacy of a single intravenous infusion of an adeno-associated virus serotype 8 vector encoding UGT1A1 in patients with the Crigler-Najjar syndrome that was being treated with phototherapy. Five patients received a single infusion of the gene construct (GNT0003): two received 2×1012 vector genomes (vg) per kilogram of body weight, and three received 5×1012 vg per kilogram. The primary end points were measures of safety and efficacy; efficacy was defined as a serum bilirubin level of 300 µmol per liter or lower measured at 17 weeks, 1 week after discontinuation of phototherapy. RESULTS: No serious adverse events were reported. The most common adverse events were headache and alterations in liver-enzyme levels. Alanine aminotransferase increased to levels above the upper limit of the normal range in four patients, a finding potentially related to an immune response against the infused vector; these patients were treated with a course of glucocorticoids. By week 16, serum bilirubin levels in patients who received the lower dose of GNT0003 exceeded 300 µmol per liter. The patients who received the higher dose had bilirubin levels below 300 µmol per liter in the absence of phototherapy at the end of follow-up (mean [±SD] baseline bilirubin level, 351±56 µmol per liter; mean level at the final follow-up visit [week 78 in two patients and week 80 in the other], 149±33 µmol per liter). CONCLUSIONS: No serious adverse events were reported in patients treated with the gene-therapy vector GNT0003 in this small study. Patients who received the higher dose had a decrease in bilirubin levels and were not receiving phototherapy at least 78 weeks after vector administration. (Funded by Genethon and others; ClinicalTrials.gov number, NCT03466463.).

Risk factors for readmission for hyperbilirubinemia in neonates with ABO hemolytic disease: a single-center retrospective cohort study.

OBJECTIVE: ABO hemolytic disease of the newborn (ABO-HDN) is a major risk factor for severe hyperbilirubinemia, a common readmission reason for newborns. In this study, we aimed to assess the risk factors for readmission associated with hyperbilirubinemia in neonates with ABO-HDN. METHODS: A retrospective cohort study was conducted including newborns with gestational age ≥35 weeks and ABO-HDN in 2018. Among 291 newborns, 36 were readmitted for hyperbilirubinemia and defined as the readmission group. The remaining 255 cases were used as a control group. We then performed between-group comparisons of clinical conditions associated with hyperbilirubinemia. Logistic regression was used to select risk predictors of readmission associated with hyperbilirubinemia due to ABO-HDN. RESULTS: Baseline characteristics were similar between both groups (p > .05, respectively). However, total serum bilirubin (TSB) before initiating phototherapy was significantly higher in the readmission group when compared with that in the control group at 0-24 h, 24-48 h, and 48-72 h (183.70 µmol/L [interquartile range (IQR) 161.18-196.48] vs. 150.35 µmol/L [IQR 131.73-175.38], p = .005; 229.90 µmol/L [IQR 212.45-284.30] vs. 212.50 µmol/L [IQR 197.85-230.28], p = .026; 268.10 µmol/L [IQR 257.70-279.05] vs. 249.50 µmol/L [IQR 236.80-268.70], p = .045, respectively). The age of initiation of phototherapy in the readmission group was significantly lower than that in control group (30.0 h [IQR 18.0-49.00] vs. 42.0 h [IQR 23.0-61.0], p = .012). The rate of rebound hyperbilirubinemia after the first phototherapy treatment was significantly higher in the readmission group compared to that in the control group (9 [25%] vs. 13 [5.1%], p = .000), and the rate of positive direct antiglobulin testing was significantly higher than that in control group (17 [47.2%] vs. 74 [29.0%], p = .027). Logistic regression analysis showed that the age of initiation of photography, TSB level before the first phototherapy, and rebound hyperbilirubinemia after first phototherapy were independent risk factors for readmission in newborns with hyperbilirubinemia associated with ABO-HDN. CONCLUSIONS: Earlier age of phototherapy initiation, higher TSB levels at the time of initiating phototherapy and rebound hyperbilirubinemia after the first phototherapy treatment may increase the risk of readmission for hyperbilirubinemia in neonates with ABO-HDN. These factors should be considered in discharge planning and follow-up for newborns with ABO-HDN associated hyperbilirubinemia.

Preparation of chitin/MXene/poly(L-arginine) composite aerogel spheres for specific adsorption of bilirubin.

Currently, hemoperfusion is clinically the most rapid and effective treatment for removing toxins from the blood. The core of hemoperfusion is the sorbent inside the hemoperfusion device. Due to the complex composition of the blood, adsorbents tend to adsorb substances such as proteins in the blood (non-specific adsorption) while adsorbing toxins. Hyperbilirubinemia is caused by excessive levels of bilirubin in the human blood, causing irreversible damage to the patient's brain and nervous system, and even leading to death. High adsorption and high biocompatibility adsorbents with specific bilirubin adsorption are urgently needed to treat hyperbilirubinemia. Herein, poly(L-arginine) (PLA) which can specifically adsorb bilirubin, was introduced into chitin/MXene (Ch/MX) composite aerogel spheres. Ch/MX/PLA prepared by supercritical CO2 technology had higher mechanical properties than Ch/MX and can withstand 50,000 times its own weight. The in vitro simulated hemoperfusion test showed that the adsorption capacity of Ch/MX/PLA was as high as 596.31 mg/g, which was 15.38 % higher than that of Ch/MX. Binary and ternary competitive adsorption tests showed that Ch/MX/PLA also had good adsorption capacity in the presence of a variety of interfering molecules. In addition, hemolysis rate testing and CCK-8 testing confirmed that Ch/MX/PLA had better biocompatibility and hemocompatibility. Ch/MX/PLA can meet the required properties of clinical hemoperfusion sorbents and has the ability to produce mass production. It has good application potential in the clinical treatment of hyperbilirubinemia.

Bilirubin Adsorption with DPMAS: Mechanism of Action and Efficacy of Anion Exchange Resin.

Acute liver failure and acute-on-chronic liver failure are conditions in which the loss of metabolic function of the liver leads to the accumulation of several toxins such as bilirubin. Patients with sepsis or multiple organ dysfunction syndrome have a greater risk of developing liver failure, and hyperbilirubinemia is associated with poor prognosis. Bilirubin removal may not only alleviate signs and symptoms of liver dysfunction but also act as an index of removal of albumin-bound toxins. Conjugated and unconjugated bilirubin, due to their molecular weight and albumin-binding capacity, respectively, cannot be removed by classic dialysis; therefore, different extracorporeal techniques have been developed to remove bilirubin from the blood. Plasma adsorption perfusion is an extracorporeal liver support technique in which bilirubin is removed from the plasma through a specific adsorbing cartridge. Double plasma molecular adsorption system adds a broad-spectrum adsorption column for the removal of inflammatory mediators and antibodies and other medium toxins. Their use in the treatment of hyperbilirubinemia has been established with several emerging data indicating their efficacy when compared to other extracorporeal techniques. However, bilirubin adsorption kinetics has not been sufficiently elucidated, and more studies are needed to improve the quality of treatment in terms of timing and prescriptions.

An Exploratory Analysis of Gastrointestinal Morbidities and Feeding Outcomes Associated with Neonatal Hypoxic-Ischemic Encephalopathy With or Without Hypothermia Therapy.

This study investigates the clinical profile and predictors of gastrointestinal/hepatic morbidities and feeding outcomes among neonates with hypoxic-ischemic encephalopathy (HIE). A single-center retrospective chart review of consecutive neonates >35 weeks of gestation admitted with a diagnosis of HIE between January 1, 2015, and December 31, 2020, and treated with therapeutic hypothermia, if met the institutional eligibility criteria. Outcomes assessed included necrotizing enterocolitis (NEC), conjugated hyperbilirubinemia, hepatic dysfunction, assisted feeding at discharge, and time to reach full enteral and oral feeds. Among 240 eligible neonates (gestational age 38.7 [1.7] weeks, birth weight 3279 [551] g), 148 (62%) received hypothermia therapy, and 7 (3%) and 5 (2%) were diagnosed with stage 1 NEC and stage 2-3 NEC, respectively. Twenty-nine (12%) were discharged home with a gastrostomy/gavage tube, conjugated hyperbilirubinemia (first week 22 [9%], at discharge 19 [8%]), and hepatic dysfunction (74 [31%]). Time to reach full oral feeds was significantly longer in hypothermic neonates compared with neonates who did not receive hypothermia (9 [7-12] days vs. 4.5 [3-9] days, p < 0.0001). Factors significantly associated with NEC were renal failure (odds ratio [OR] 9.24, 95% confidence interval [CI] 2.7-33), hepatic dysfunction (OR 5.69, 95% CI 1.6-26), and thrombocytopenia (OR 3.6, 95% CI 1.1-12), but no significant association with hypothermia, severity of brain injury, or stage of encephalopathy. Transient conjugated hyperbilirubinemia, hepatic dysfunction within first week of life, and need for assistive feeding are more common than NEC in HIE. Risk of NEC was associated with the severity of end-organ dysfunction in the first week of life, rather than severity of brain injury and hypothermia therapy per se.

Decreasing Bilirubin Serum Tests in Healthy Newborns During Birth Hospitalization.

OBJECTIVES: Substantial variability exists in hyperbilirubinemia screening and monitoring leading to unnecessary total serum bilirubin (TSB) testing in healthy newborns. We aimed to assess the impact of value-care interventions to decrease the monthly TSB testing rate per 100 patient-days among healthy newborns in our Mother-Baby Unit by 30% by June 2022. METHODS: We formed a multidisciplinary team to review the current practice for ordering TSB among housestaff in our Mother-Baby Unit. We identified several themes: variation in clinical practice, fear of hyperbilirubinemia, and desire to act for high-intermediate risk bilirubin levels. The interventions consisted of obtaining faculty buy-in, redesigning the hyperbilirubinemia pathway, educating staff on high value-care, producing an instructional video, and prompting staff to incorporate a bilirubin risk assessment via smart phrases in our electronic health record. The primary outcome was the monthly TSB testing rate per 100 patient-days. Universal predischarge bilirubin screening, length of stay, phototherapy rates, and readmission rates were chosen as balancing measures. RESULTS: The monthly rate of TSB testing was reduced from 51 to 26.3 TSB per 100 patient-days, representing a 48% reduction. This improvement was sustained for 12 months. The percentage of infants with at least 1 TSB measurement during birth hospitalization decreased from 48% to 30%. Predischarge bilirubin screening, length of stay, and readmission rates were unchanged. CONCLUSIONS: Our quality improvement initiative led to a significant reduction in the monthly TSB testing per 100 patient-days in healthy newborns without evidence of harm.

Rates of phototherapy among ABO-incompatible newborns with a negative direct antiglobulin test.

OBJECTIVE: We analyze phototherapy rates after implementation of a Hyperbilirubinemia Clinical Pathway (HCP), which placed full-term ABOi DAT negative newborns on the low risk phototherapy nomogram, rather than medium risk, as previously done. STUDY DESIGN: A chart review was performed for ABOi newborns born ≥36 weeks gestation between January 2020 and October 2021. Primary outcome measures were rates of phototherapy across pre- and post-intervention groups and among DAT negative newborns. RESULTS: There was an increased proportion of newborns assigned to the low risk curve after the intervention. There were no significant differences in phototherapy rates among the intervention groups, although there was a non-significant decrease in phototherapy rates among DAT negative newborns after the intervention. There were no increases in adverse outcomes. CONCLUSIONS: Providers adhered to the guidelines after implementation of the HCP. ABOi DAT negative newborns can be viewed as low risk for hyperbilirubinemia requiring phototherapy.

The application of hemoadsorption for hyperbilirubinemia and its impact on bilirubin removal kinetics in critically ill children.

Extracorporeal blood purification (EBP) is increasingly applied for bilirubin removal in critical care setting. We retrospectively reviewed the clinical features of children aged 1 month to 18 years old who received EBP for hyperbilirubinemia and explored the bilirubin removal kinetics by hemoadsorption (HA) in the pediatric intensive care unit of Hong Kong Children's Hospital from 3/2019 to 7/2022. Among the 14 episodes of EBP from six patients with a median age (interquartile range [IQR]) of 9.3(5.5) years old, 57.1% of them received HA, 33.3% received single-pass albumin dialysis (SPAD), and 7.1% received combined SPAD and HA. All HA episodes employed the Cytosorb® column. The median (IQR) pre-HA peak total bilirubin level was 406 (254) µmol/L. The saturation duration per HA episode was significantly shorter than the corresponding total treatment duration (8 vs 24 h, p = 0.012), and the median total and effective HA doses were 9.8(6.8) L/kg and 300.0 (163.4) mL/kg/h respectively. The overall bilirubin removal ratio by HA was 44.6 (14.5)%. A higher HA effective dose and a higher pre-HA bilirubin level were both associated with better bilirubin removal. No major EBP-specific complication was encountered. The liver enzymes showed improvement in all children. No patients required liver transplantation. There was no EBP-related mortality, but the overall PICU mortality of the cohort was 50%. HA was a safe and effective modality for bilirubin removal among children. Future studies should investigate the impact of bilirubin removal on clinical outcomes and explore the factors responsible for better removal efficacy.

Evaluation of thiol-disulfide homeostasis and oxidative stress parameters in newborns receiving phototherapy.

The aim of our study was to evaluate oxidative stress and thiol-disulfide homeostasis in term newborns receiving phototherapy. The study was planned as a single-blind, intervention study in a single center with level 3 neonatal intensive care unit to investigate the effect of phototherapy on the oxidative system in term newborns with hyperbilirubinemia. Neonates with hyperbilirubinemia were treated with total body exposure phototherapy technique for 18 h using a Novos® device. Blood samples of 28 term newborns were taken before and after phototherapy. Total and native thiol, total antioxidant status (TAS) and total oxidant status (TOS), and oxidative stress index (OSI) levels were measured. The 28 newborn patients included 15 (54%) males and 13 (46%) females with a mean birthweight of 3080.1 ± 366.5 g. Native and total thiol levels were found to be decreased in patients receiving phototherapy (p = 0.021, p = 0.010). Besides, significantly lower TAS and TOS levels were found after phototherapy (p < 0.001, p < 0.001). We found that decreased thiol levels were related to increased oxidative stress. We also determined significantly the lower bilirubin levels after phototherapy (p < 0.001). In conclusion, we found that phototherapy treatment induced decreased oxidative stress associated with hyperbilirubinemia in neonates. Thiol-disulfide homeostasis can be used as a marker of oxidative stress due to hyperbilirubinemia in the early period.