Characteristics of nonoliguric hyperkalemia in preterm infants: A case-control study in a single center.

BACKGROUND: Preterm infants often present with hyperkalemia during the first days after birth without showing oliguria. This is known as nonoliguric hyperkalemia (NOHK). As its clinical features have not been completely understood to date, we aimed to elucidate the characteristics of NOHK, including its risk factors, in preterm infants. METHODS: For this case-control study, we reviewed the files of all infants born before 32 weeks of gestational age in our neonatal intensive care unit between 2011 and 2018. We distinguished the NOHK and non-NOHK groups and compared their characteristics and blood potassium levels. Nonoliguric hyperkalemia was defined as peak blood potassium concentration of ≥6.0 mmol/L during the first 72 h of life with a urine output of ≥1 mL/kg/h. RESULTS: Of the 99 infants enrolled, 21 (21%) demonstrated NOHK. Infants with NOHK were more likely to have been exposed to antenatal magnesium sulfate (MgSO4 ) (P = 0.019) than those in the non-NOHK group. Acute morbidities and mortality were not statistically different. Multivariate analysis indicated that administration of maternal MgSO4 for longer than 24 h at any point before delivery was a risk factor for NOHK. Its adjusted odds ratio and 95% confidence interval were 4.0 and 1.4-12.3, respectively (P = 0.012). CONCLUSIONS: In this study, maternal MgSO4 administration for longer than 24 h proved to be a risk factor for NOHK in infants born before 32 weeks of gestational age. Infants born to mothers who have received MgSO4 should be regularly monitored for their electrolytes.

Increased Incidence of Late-Onset Circulatory Collapse after Changing Clinical Practice: A Retrospective Investigation of Causative Factors.

OBJECTIVE: Acute primary profound circulatory failure responsive to glucocorticoid therapy after the first week of age in preterm infants is termed late-onset circulatory collapse (LCC). This study was performed to identify factors that notably increased the incidence of LCC after various management practices were changed. STUDY DESIGN: We retrospectively studied the clinical characteristics of infants (<29 weeks' gestation) before (n=26) and after (n=35) implementing the following practice changes: stress reduction, conservative replacement of thyroid hormone, positive antenatal glucocorticoid administration, sedation with fentanyl (<7 days after birth), and hydrocortisone therapy for hypotension. RESULTS: After the aforementioned changes, the incidence of LCC increased from 4 to 43%, and that of intraventricular hemorrhage decreased from 42 to 9%. Antenatal glucocorticoids (75 vs. 20%), fentanyl (94 vs. 53%), and hydrocortisone (63 vs. 31%) (<2 weeks of age) were given to infants with LCC and non-LCC. After the practice changes, infants with LCC had lower serum sodium levels than did infants without LCC at 7 to 14 days of age. CONCLUSION: Relative hyponatremia was an early sign of imminent LCC. In addition to adrenal prematurity, the antenatal administration of glucocorticoids and fentanyl, which influence adrenal function, might increase the incidence of LCC.

Premature rupture of membranes and neonatal respiratory morbidity at 32-41 weeks' gestation: a retrospective single-center cohort study.

AIM: To ascertain whether premature rupture of membranes (PROM) independently affects the risk of neonatal respiratory morbidity at 32-41 weeks' gestation because previous reports have given insufficient consideration to the mode of delivery and labor onset. METHODS: Data on 4,629 consecutive singleton infants were retrospectively collected. Respiratory morbidity was limited to respiratory distress syndrome and transient tachypnea of the newborn, both of which are related to prematurity. Delivery modes were divided into four groups based on the existence of PROM and of labor onset, and the respiratory morbidity was examined according to the number of weeks of gestational age. Multivariate analysis including PROM and delivery mode was conducted to examine the association of respiratory morbidity. RESULTS: Respiratory morbidity or a positive pressure requirement delivered after PROM and intact amniochorionic membranes accompanied by labor were similar at all weeks. Around 37 weeks, the absence of labor onset was associated with a risk of respiratory morbidity or positive pressure requirement. Significant respiratory risk was not associated with the incidence of PROM (adjusted odds ratio [aOR], 0.98; 95% confidence interval [CI], 0.52-1.83), interval from rupture to delivery (aOR, 1.00; 95% CI, 0.99-1.01), clinical chorioamnionitis, induction management, pregnancy-related complications, or neonatal sex. Delivery by Cesarean section and early gestational age presented a significant risk for respiratory morbidity. CONCLUSIONS: Neither PROM nor latency after PROM at 32-41 weeks affected neonatal respiratory morbidity. Avoiding Cesarean section instead of simply increasing the time to delivery may help to reduce respiratory morbidity.

Late-onset glucocorticoid-responsive circulatory collapse in preterm infants: clinical characteristics of 14 patients.

Preterm infants may develop acute systemic hypotension that responds to glucocorticoid therapy, but not to volume loading or vasopressors, during the postnatal period. This condition is termed late-onset circulatory collapse (LCC) that develops a few weeks after birth in relatively stable infants. LCC may cause periventricular leukomalacia, periventricular necrosis in the white matter. The aim of this study was to identify the clinical characteristics of LCC. We retrospectively reviewed the clinical data of infants with LCC. Among 41 infants born at < 29 weeks of gestation between 2010 and 2014, we identified 14 infants (median gestational age 25.6 weeks) with LCC. All infants were stable before the acute onset of circulatory collapse at a median age of 21 days, which is characterized by the decreased physical activity, systolic blood pressure (12 mmHg decrease), urine output (76% decrease), and serum sodium level (4 mEq/L decrease), and the increased resistance index in the cerebral and renal arteries on Doppler ultrasonography. Both left ventricular dimension and contraction were well preserved. Three infants developed hyperkalemia. The median time from the initial hydrocortisone dose to improvements was 4 h (interquartile range 3-5 h). Hydrocortisone therapy was effective, but had to be withdrawn slowly to prevent relapse. The median duration of hydrocortisone therapy was 23 days. There was no evidence of periventricular leukomalacia in any of the infants. None of the infants developed adrenal insufficiency during the follow-up period. During the acute stage of LCC, the main priority is the early initiation of glucocorticoid therapy.

Oscillometric and intra-arterial blood pressure in preterm and term infants: extent of discrepancy and factors associated with inaccuracy.

OBJECTIVE: Securing an arterial line to monitor continuous blood pressure (BP) is difficult in infants. We aimed to reveal the extent of discrepancies between oscillometric and direct BP. STUDY DESIGN: Infants who required continuous BP monitoring were prospectively enrolled. Direct and indirect BP were simultaneously recorded. Disposable BP cuffs matching one-half to two-thirds of the upper arm circumference were used. RESULTS: A total of 74 infants were studied (gestational age [GA], 24-42 weeks). The correlation coefficients of systolic, diastolic, and mean arterial BP of indirect and direct measurements were 0.87, 0.82, and 0.84, respectively (p < 0.001). The mean differences in systolic, diastolic, and mean arterial BP (indirect minus direct BP) were 2.2 ± 5.7, - 6.0 ± 5.8, and - 1.3 ± 5.7 mm Hg, respectively. Oscillometric measurements significantly underestimated systolic BP in light-for-gestational-age infants and diastolic BP in infants without fentanyl administration. There were no significant correlations between discrepant BP measurements and edema, vasopressor administration, arterial line location, GA, postnatal age, body weight, pulse rate, or hemoglobin level. In 4.1% of infants, systolic BP increased by 10 to 15 mm Hg at the time of cuff expansion. CONCLUSION: We recommend intra-arterial BP measurement when the BP values seriously influence the therapeutic protocol.

Heparin-induced hyperkalemia in an extremely-low-birth-weight infant: a case report.

Heparin may cause hyperkalemia by blocking aldosterone biosynthesis in the adrenal gland. Dizygotic twin sisters were born by Cesarean section at 25 weeks' gestation. The younger sister developed acute hyperkalemia (7.4 mEq/L) at 10 days of age. At the time of the development of the hyperkalemia, there were no signs of systemic infection, cardiac or renal failure, adrenal insufficiency, or sudden anemia. She was receiving no medication other than heparin to maintain the vascular catheter. Heparin was changed to dalteparin at 12 days of age. The plasma potassium level normalized after 14 days of age. After this change, the urinary potassium concentration and the aldosterone and plasma renin activity increased. The urinary aldosterone levels before and after the changes were 31 and 183 pg/µg creatinine, respectively. When heparin-induced hyperkalemia is suspected, stopping the heparin administration facilitates diagnosis and treatment; if anticoagulant therapy is required; one treatment option is changing from unfractionated heparin to low-molecular-weight heparin.

Neonatal hyperbilirubinemia and the bilirubin uridine diphosphate-glucuronosyltransferase gene: the common -3263T > G mutation of phenobarbital response enhancer module is not associated with the neonatal hyperbilirubinemia in Japanese.

BACKGROUND: Neonatal hyperbilirubinemia is frequent and severe in Japanese newborns. Previously, it has been reported that half of the Japanese neonates with severe hyperbilirubinemia carried the 211G > A (p.G71R) mutation of the bilirubin uridine diphosphate-glucuronosyltransferase (UGT1A1) gene causing Gilbert syndrome. Recently, it was reported that the -3263T > G mutation in the phenobarbital response enhancer module in UGT1A1 was associated with the majority of cases of Gilbert syndrome. The gene frequency of the -3263T > G mutation was determined and the relation with neonatal hyperbilirubinemia in Japanese was studied. METHODS: UGT1A1 in 119 neonates born at Yamagata University Hospital, Yamagata, Japan, and 26 subjects who had undergone phototherapy due to severe hyperbilirubinemia at four other hospitals were studied. The gene frequency of -3263T > G mutation in Japanese, Korean, Chinese and German healthy adult controls was also determined. Hyperbilirubinemia was assessed with a Jaundice Meter and UGT1A1 was analyzed by sequence determination or restriction enzyme method. RESULTS: The gene frequency of the -3263T > G mutation was 0.26 in Japanese subjects and was similar to the prevalence in Korean, Chinese and German populations. However, there was no significant increase in the gene frequency of the mutation in the neonates who required phototherapy for hyperbilirubinemia compared to that in the neonates without severe hyperbilirubinemia. In addition, neonates with or without the mutation did not show a significant change in the level of bilirubin and the mutation also did not show a synergic effect with the 211G > A mutation on the level of bilirubin. CONCLUSION: The -3263T > G mutation is not likely to be associated with the neonatal hyperbilirubinemia in Japanese.

Molecular analysis of congenital central hypoventilation syndrome.

Congenital central hypoventilation syndrome (CCHS or Ondine's curse; OMIM 209880) is a disorder characterized by an idiopathic failure of the automatic control of breathing. CCHS is frequently complicated with neurocristopathies such as Hirschsprung's disease (HSCR). The genes involved in the RET-GDNF signaling and/or EDN3-EDNRB signaling pathways have been analyzed as candidates for CCHS; however, only a few patients have mutations of the RET, EDN3, and GDNF genes. Recently, mutations of the PHOX2B gene, especially polyalanine expansions, have been detected in two thirds of patients. We studied the RET, GDNF, GFRA1, PHOX2A, PHOX2B, HASH-1, EDN1, EDN3, EDNRB, and BDNF genes in seven patients with isolated CCHS and three patients with HSCR. We detected polyalanine expansions and a novel frameshift mutation of the PHOX2B gene in four patients and one patient, respectively. We also found several mutations of the RET, GFRA1, PHOX2A, and HASH-1 genes in patients with or without mutations of the PHOX2B gene. Our study confirmed the prominent role of mutations in the PHOX2B gene in the pathogenesis of CCHS. Mutations of the RET, GFRA1, PHOX2A, and HASH-1 genes may also be involved in the pathogenesis of CCHS. To make clear the pathogenesis of CCHS, the analysis of more cases and further candidates concerned with the development of the autonomic nervous system is required.

Neonatal hyperbilirubinemia in Japanese neonates: analysis of the heme oxygenase-1 gene and fetal hemoglobin composition in cord blood.

Neonatal hyperbilirubinemia is frequent and severe in Japanese infants. Although the G71R mutation of the bilirubin uridine diphosphate-glucuronosyltransferase gene is associated with severe neonatal hyperbilirubinemia in this population, it accounts for only half of the neonates with severe hyperbilirubinemia. It was suggested that increased bilirubin production would also be associated with severe neonatal hyperbilirubinemia in Japanese infants. To elucidate the genetic factors causing severe hyperbilirubinemia in these patients, we studied two notable factors associated with bilirubin production: heme oxygenase-1, a key enzyme of heme metabolism, and fetal Hb composition, a factor possibly associated with heme load in neonates. We first determined the sequences of promoter and all coding regions of the heme oxygenase-1 gene in Japanese neonates who had undergone phototherapy, but found no mutation except for the polymorphic (GT)n repeats in the promoter region. These repeats modulate the transcription of the heme oxygenase-1 gene, and the longer repeat sequences are known to reduce the transcription. We detected a significant difference in the allele frequencies of each number of (GT)n repeats between Japanese and German populations. However, we could not find a relation between those polymorphisms and neonatal hyperbilirubinemia. We next analyzed the state of Hb switching of the gamma- to beta-globin chain and the phenotype of gamma-globin chain isoforms in cord blood. We found no relation between fetal Hb composition and neonatal hyperbilirubinemia. Further studies are required to elucidate genetic or environmental factors in neonatal hyperbilirubinemia in Japanese infants.

Congenital central hypoventilation syndrome: a novel mutation of the RET gene in an isolated case.

Recently, a few genetic abnormalities were identified in congenital central hypoventilation syndrome (CCHS or Ondine's curse). CCHS is often associated with other neurocristopathies, especially with Hirschsprung's disease (HSCR). Mutations of the genes involved in the receptor tyrosine kinase RET (REarranged during Transfection) (RET)-glial cell line-derived neurotrophic factor (GDNF) and/or endothelin 3 (EDN3)-endothelin receptor-B (EDNRB) signaling pathway have been found in some of HSCR patients. In this study, we analyzed candidates for HSCR, namely the RET, GDNF, EDN3 and EDNRB genes in three isolated CCHS patients to confirm the hypothesis that some CCHS patients have a common genetic abnormality with patients having HSCR or other neurocristopathies. We found a novel R114H mutation of the RET gene in one patient. The R114H mutation is unlikely to be a polymorphism and appears to be associated with CCHS. In addition, we also examined the HOX11L2 (RNX) gene, for which knock-out mice showed CCHS-like syndrome in these isolated CCHS patients and did not detected any mutation. Further cases should be analyzed for more candidates to clarify the pathophysiology of CCHS.