The influence of hyperbilirubinemia on indexes of kidney function in neonates.

BACKGROUND: To study the influence of hyperbilirubinemia on indexes of neonatal kidney function. METHODS: A prospective cohort study was conducted September 2019 to March 2020 in Neonatology Department of Xuzhou Central Hospital. Neonates with gestational age ≥ 35 weeks and aged ≤ 7 days were included and divided into mild, moderate, and severe groups according to total serum bilirubin level. Epidemiologic and demographic data and daily urine output were recorded. Total serum bilirubin, serum creatinine, serum cystatin C, serum neutrophil gelatinase-associated lipocalin (NGAL), urine NGAL, and kidney injury molecule-1 were tested before and 12~18 h after phototherapy. Parameters of kidney function were compared between groups. RESULTS: Fifty-three, 52, and 49 neonates were included in the mild, moderate, and severe groups, respectively. Urine NGAL was higher in severe (1.36 ± 0.24 µg/L) compared to moderate (1.22 ± 0.19 µg/L) and mild groups (1.16 ± 0.19 µg/L), and differences were statistically significant (P = 0.004 and < 0.001, respectively). Urine NGAL was not significantly different between moderate and mild groups (P > 0.05). No significant differences in other kidney function indexes were observed between the three groups (all P > 0.05). Significant reduction in urine NGAL levels 12~18 h after stopping phototherapy was found in severe group ((1.17 ± 0.28) µg/L vs. (1.35 ± 0.23) µg/L, P < 0.001). Urine NGAL positively correlated with total serum bilirubin (r = 0.575, P < 0.001). Among all cases, neither serum creatinine nor daily urine output met neonatal acute kidney injury diagnostic criteria. CONCLUSION: Severe hyperbilirubinemia may temporarily impair renal tubular reabsorption functions in full-term and near-term neonates, which is likely reversible. However, it has little effect on glomerular filtration function. A higher resolution version of the Graphical abstract is available as Supplementary information.

Curcumin Prevents Cerebellar Hypoplasia and Restores the Behavior in Hyperbilirubinemic Gunn Rat by a Pleiotropic Effect on the Molecular Effectors of Brain Damage.

Bilirubin toxicity to the central nervous system (CNS) is responsible for severe and permanent neurologic damage, resulting in hearing loss, cognitive, and movement impairment. Timely and effective management of severe neonatal hyperbilirubinemia by phototherapy or exchange transfusion is crucial for avoiding permanent neurological consequences, but these therapies are not always possible, particularly in low-income countries. To explore alternative options, we investigated a pharmaceutical approach focused on protecting the CNS from pigment toxicity, independently from serum bilirubin level. To this goal, we tested the ability of curcumin, a nutraceutical already used with relevant results in animal models as well as in clinics in other diseases, in the Gunn rat, the spontaneous model of neonatal hyperbilirubinemia. Curcumin treatment fully abolished the landmark cerebellar hypoplasia of Gunn rat, restoring the histological features, and reverting the behavioral abnormalities present in the hyperbilirubinemic rat. The protection was mediated by a multi-target action on the main bilirubin-induced pathological mechanism ongoing CNS damage (inflammation, redox imbalance, and glutamate neurotoxicity). If confirmed by independent studies, the result suggests the potential of curcumin as an alternative/complementary approach to bilirubin-induced brain damage in the clinical scenario.

Cholestasis affects enteral tolerance and prospective weight gain in the NICU.

BACKGROUND: Intestinal Failure-Associated Liver Disease is characterized by cholestasis and hepatic dysfunction due to parenteral nutrition (PN) therapy. We described key features of cholestatic infants receiving PN to assess overall outcomes in this population at our institution. METHODS: This is a retrospective single center study of 163 neonates grouped into cholestatic (n = 63) and non-cholestatic (n = 100) as defined by peak conjugated bilirubin of ≥2.0 mg/dL or < 0.8 mg/dL, respectively. Univariate and multiple regression models were used to study associations between variables and outcomes of interest. RESULTS: Lower Apgar scores (4 ± 3 vs. 6 ± 3, p-value = <0.005 at 1 min; 6 ± 2 vs. 7 ± 2, p < 0.005 at 5 min) and lower birth weight (adj ß [SE] = 0.62 [0.27], p-value = 0.024) were risk factors for developing cholestasis. Cholestatic infants were more likely to have had gastrointestinal surgery (31 [49%] vs. 15 [15%], p-value <0.005), received PN for a longer duration (40 ± 39 days vs. 11 ± 7 days, p-value <0.005), and started enteral feeds later in life (86 ± 23 days vs. 79 ± 20 days, p-value <0.005) when compared to non-cholestatic infants. Weight percentiles in cholestatic infants were lower both at hospital discharge (14 ± 19 vs. 24 ± 22, p-value <0.005) and at 6 months of age (24 ± 28 vs. 36 ± 31, p-value = 0.05). CONCLUSIONS: Cholestasis in the NICU is a multifactorial process, but it has a long lasting effect on prospective weight gain in infants who receive PN in the NICU. This finding highlights the importance of follow-up for adequate growth and the potential benefit from aggressive nutritional support.

Association of a Delayed Cord-Clamping Protocol With Hyperbilirubinemia in Term Neonates.

OBJECTIVE: To evaluate the implementation of a delayed cord-clamping protocol at an academic medical center, and its short-term associations on term neonates. METHODS: This was a retrospective cohort study of women aged 18 years or older delivering a term neonate at an academic medical center before and 5-7 months after implementation of a universal delayed cord-clamping protocol (October-December 2015 and October-December 2016, respectively). The primary outcome measure was the mean peak neonatal transcutaneous bilirubin level, with secondary outcome measures including mean initial transcutaneous bilirubin levels, mean serum bilirubin levels, number of serum bilirubin levels drawn, incidence of clinical jaundice, and phototherapy. RESULTS: Protocol adherence was 87.8%. Data are presented on 424 neonates. The mean peak neonatal transcutaneous bilirubin levels were significantly higher among neonates in the postprotocol group (10.0±3.4 mg/dL vs 8.4±2.7 mg/dL, P<.01). More neonates in the postprotocol group were diagnosed with jaundice (27.2% vs 16.6%; odds ratio [OR] 1.88; 95% CI 1.17-3.01) and required serum blood draws (43.7% vs 29.4%; OR 1.86; 95% CI 1.25-2.78). However, there were no differences in mean peak serum bilirubin levels between groups (9.7±3.0 mg/dL vs 9.1±3.1 mg/dL, P=.17) or need for phototherapy (5.2% vs 6.6%, OR 1.28; 95% CI 0.57-2.89). CONCLUSION: Implementation of a delayed cord-clamping protocol for term neonates was associated with significantly higher mean transcutaneous bilirubin levels, an increased number of serum blood draws, and more clinical diagnoses of jaundice, although there was no increase in the incidence of phototherapy.

Effect of unconjugated hyperbilirubinemia on neonatal autonomic functions: evaluation by heart rate variability.

BACKGROUND: Serum bilirubin levels beyond the physiological limits, may lead to alterations in autonomic regulation in a newborn infant. Heart rate variability (HRV), is a noninvasive and quantitative marker of the activity of the autonomic nervous system (ANS). To date, few studies have demonstrated the undesirable effects of severe unconjugated hyperbilirubinemia (UHB) on autonomic functions, and only one study has used HRV as a marker of the autonomic activity. However, the relationship between altered cardiac autonomic functions and UHB by using the HRV derived from 24-hour Holter electrocardiography (ECG) recording has not been investigated previously. OBJECTIVE: We aimed to assess whether a relationship exists between severe UHB and cardiac autonomic dysfunction by evaluating HRV via 24-hour Holter ECG recording. METHODS: This single-center, prospective, case-control study was conducted on 50 full-term newborn infants with severe UHB requiring phototherapy and 50 healthy infants as controls. HRV assessment was performed by using 24-hour Holter ECG recording. RESULTS: There was no significant difference in terms of mean average heart rate, mean maximum heart rate and mean RR duration between the groups. However, mean minimum heart rate was significantly lower in the study group. When 24-hour time and frequency domain parameters were compared, time and frequency domain parameters rMSDD as well as high frequency (HF), which represent parasymphathetic activity, were significantly higher in the study group. Furthermore, low frequency to high frequency (LF/HF) ratio, that serves as an indicator of sympathovagal balance, was significantly lower in the study group. CONCLUSION: Severe UHB may cause cardiac autonomic dysfunction in favor of parasympathetic predominance in jaundiced neonates.

Hyperbilirubinemia and phototherapy in newborns: Effects on cardiac autonomic control.

BACKGROUND: Neonatal jaundice and its phototherapeutic treatment can lead to several side effects involving activation of autonomic control mechanisms. AIM: The aims of this study are to investigate the autonomic nervous system changes in icteric neonates using heart rate variability (HRV) and to assess the effect of phototherapy on short-term heart rate dynamics as an indicator of autonomic nervous control of cardiovascular system. METHODS: HRV recordings from 20 icteric full-term neonates before, during and after phototherapy and from 20 healthy controls were analyzed. In addition to traditional time and frequency domain measures, heart rate complexity parameters including normalized complexity index (NCI), normalized unpredictability index (NUPI), pattern classification indices (0V%, 1V%, 2LV%, 2UV%) and irreversibility index (P%) on four time scales were evaluated. All measures were derived from data segments of 1000 RR intervals. RESULTS: The analysis revealed higher values of 1V%, 2LV%, and lower P% in neonates with hyperbilirubinemia compared to controls. While HRV magnitude did not change, mean heart rate increased during and after the phototherapy. Nonlinear analysis showed a decrease of complexity, unpredictability and pattern classification measures 2LV% and 2UV%. In contrast, 0V% and irreversibility index P% were increased during and at least 30min after phototherapy. CONCLUSION: The results suggest a shifted autonomic balance in icteric neonates compared to the controls and its further alterations during phototherapy. As the nonlinear HRV parameters are independent of the linear methods, they can provide new information about the cardiac regulatory mechanisms and their changes in neonates.

Difference in cerebral blood flow velocity in neonates with and without hyperbilirubinemia.

PURPOSE: To evaluate the difference in cerebral blood flow velocity (CBFV) in neonates with and without hyperbilirubinemia. METHODS: CBFV of 70 healthy late-preterm and term newborns with unconjugated hyperbilirubinemia (UCH) reaching the threshold of phototherapy requirement was compared with 70 gestational- and postnatal age-matched controls without hyperbilirubinemia. Resistance index (RI), pulsatility index (PI), peak systolic velocity (PSV) and vascular diameter were measured in internal carotid, vertebral and middle cerebral arteries by transcranial color Doppler ultrasound at the beginning of phototherapy, after 48-72h of starting phototherapy and at 5-7days after its stoppage. In controls CBFV was assessed once at inclusion. RESULTS: Both the groups were comparable. An increase in CBFV (decreased RI and PI, increased PSV and vasodilation) was observed in the UCH group. A further increase in CBFV was noticed after 48h of phototherapy. After 5-7days of stoppage of phototherapy, though there was a significant reduction in CBFV in mild-to-moderate UCH (serum bilirubin ⩽25mg/dL), in severe UCH (serum bilirubin >25mg/dL), CBFV remained increased. Four neonates developed features of acute bilirubin encephalopathy and had significantly higher CBFV compared to those with normal outcome. CONCLUSIONS: An increase in CBFV was observed in neonates with UCH compared to those without hyperbilirubinemia.

Acceleration of the gastrointestinal transit by polyethylene glycol effectively treats unconjugated hyperbilirubinaemia in Gunn rats.

BACKGROUND AND AIMS: Several conditions that delay gastrointestinal transit are associated with unconjugated hyperbilirubinaemia. We hypothesised that the gastrointestinal transit time is directly related to plasma unconjugated bilirubin (UCB) concentrations, and that this relationship can be used to develop a new therapeutic strategy for severe unconjugated hyperbilirubinaemia in the Gunn rat model. METHODS: Gunn rats received, for various time periods, oral polyethylene glycol (PEG) with or without conventional phototherapy treatment to accelerate, or oral loperamide to delay gastrointestinal transit. Gastrointestinal transit time and UCB concentrations in plasma, faeces, intestinal content and bile were determined. Results Within 36 h, PEG administration accelerated gastrointestinal transit by 45% and simultaneously decreased plasma UCB concentrations by 23% (each p<0.001). The decrease in plasma UCB coincided with an increased small intestinal UCB content (+340%, p<0.05) and an increased faecal UCB excretion (+153%, p<0.05). After 2 weeks, PEG decreased plasma UCB by 41% as single treatment, and by 62% if combined with phototherapy (each p<0.001). Loperamide delayed gastrointestinal transit by 57% and increased plasma UCB by 30% (each p<0.001). Dose-response experiments showed a strong, linear relation between the gastrointestinal transit time and plasma UCB concentrations (r=0.87, p<0.001). CONCLUSION: Gastrointestinal transit time and plasma UCB concentrations are linearly related in Gunn rats. This relationship can be exploited by pharmacologically accelerating the gastrointestinal transit, which increases transmucosal UCB diffusion and thereby effectively treats unconjugated hyperbilirubinaemia. Present results support the feasibility of PEG treatment, either solitary or combined with phototherapy, in patients with severe unconjugated hyperbilirubinaemia.

[Effects of hyperbilirubinemia on distortion product otoacoustic emission, auditory brainstem response and mismatch negativity in guinea pigs].

OBJECTIVE: To explore the characteristics of distortion product otoacoustic emission (DPOAE), auditory brainstem response (ABR) and mismatch negativity (MMN) in guinea pigs with hyperbilirubinemia and assess the impact of hyperbilirubinemia on their hearing functions. METHOD: Normal neonatal guinea pigs were randomly divided into normal control, low- and high-dose bilirubin groups. DPOAE, ABR and MMN were tested and compared between the 3 groups of guinea pigs. RESULTS: The DPOAE was comparable between the 3 groups (P>0.05). The guinea pigs with peritoneal injection of low-dose bilirubin exhibited significantly prolonged wave III and V latencies and I-III interwave intervals during the ABR test in comparison with the control group (P<0.05). All the ABR parameters were significantly different between the high-dose bilirubin group and the control group (P<0.05). The detection rates of MMN were significantly different between the 3 groups (Chi(2)=7.438, P=0.024), and the average MMN latency was significantly shorter in the control group than in the high-dose group (P<0.05), but the amplitudes of MMN remained similar between the 3 groups (P>0.05). CONCLUSIONS: Hyperbilirubinemia results impairment primarily of retrocochlear auditory pathway with relative mild damage of the cochlear. Apart from sensorineural auditory impairment, hyperbilirubinemia may also cause central auditory processing abnormalities.

Clinical and cranial magnetic resonance imaging (MRI) findings of 21 patients with serious hyperbilirubinemia.

This study aims to compare neurological examination and cranial magnetic resonance imaging (MRI) findings in patients with serious hyperbilirubinemia. Twenty-one serious hyperbiluribinemic term neonates (6 girls, 15 boys) who underwent exchange transfusions were included in the study. Neurological examination findings, body weight, age at admission, blood culture, urine culture, urine analysis, C-reactive protein, thyroxine, thyroid-stimulating hormone, total and indirect bilirubin levels, causes of hyperbilirubinemia (blood group typing, glucose-6-phosphate dehydrogenase, blood smear, tandem mass), treatment and duration of follow-up, auditory test results, and cranial MRI findings were evaluated. All patients were term neonates with an average body weight of 2943 +/- 533 g. The mean age at admission was 4.47 +/- 2.22 days, and the mean bilirubin level was 35.0 +/- 10.8 mg/dL. Exchange transfusion was performed once in all, except 4 patients who needed 2 transfusions. Kernicterus findings were found in 76% of patients on neurological examination, and cranial MRI detected a pathological finding in 71% of patients. In 2 patients, cranial MRI showed kernicterus findings, despite normal neurological examination. In contrast, in 3 patients, despite kernicterus findings in neurological examination, cranial MRI was normal. Although cranial MRI has an important place in the diagnosis of kernicterus, it does not always correlate with clinical findings. We believe that studies with larger series are warranted.