Pediatric Advance Care Planning for a Patient with a Severe Motor and Intellectual Disorder through Cooperation between an Acute Care Hospital and a Residential Facility.

Background: With the rapid progress of medical technology, the number of children with medical complexities who require advanced medical care, including mechanical ventilators, has been increasing steadily in Japan. Accordingly, the issue of how to provide holistic care and support for the entire life of the children with severe motor and intellectual disabilities (SMID) who live at home has become a new challenge. Case Presentation: We present the case of a three-year-old boy with SMID due to HHV-6B-induced hemorrhagic shock encephalopathy who was cared for at home by the home visit medical team of Osaka Developmental Rehabilitation Center (ODRC; residential facilities with the department of home medical treatment and care). He developed septic shock triggered by an urinary tract infection and was admitted to Osaka General Medical Center (OGMC; acute care facility not directly affiliated with ODRC), where he deteriorated to a terminal stage. After discussing advance care planning (ACP) with his parents, along with the medical team, an ACP document with parental wishes was created through collaboration between the two facilities. The document was approved by the Ethics Committee at OGMC and the parents signed the document. Special end-of-life care planning was given by nurses at OGMC based on the best interests of the patient and the family. The patient passed away peacefully surrounded by his family in a private room of OGMC according to the ACP, despite special limitations caused by the coronavirus disease 2019 (COVID-19) pandemic. Conclusions: ACP provides a good opportunity to think about the best total care for a child with SMID, for whom it is too difficult to express his or her wishes, together with the parents, who are the legal representatives. The collaboration between two institutions with different roles brought out the best of each, and the resulting ACP was beneficial to the patient and their family.

Factors associated with high care burden of primary caregivers of children with medical complexity after completing a discharge-support program in a recovery center.

INTRODUCTION: Recently, many seriously ill children requiring medical equipment are being recommended to transition from hospital to home care in Japan. Since 2011, our recovery center has provided a support program for the transfer process from hospital to home for ill children and their families. The purpose of this study was to evaluate the factors related to high care burden after completing the discharge-support program. METHODS: A questionnaire-based cross-sectional study was conducted on all primary caregivers whose children received the program in our center and moved from hospital to home (30 children and 29 families) from May 2011 to May 2018. Fifteen children came from the neonatal intensive care unit. The questionnaire consisted of three parts: characteristics of children and families and life after the program; the Zarit Burden Interview (ZBI); and the Positive and Negative Affect Schedule (PANAS). RESULTS: Twenty-three primary caregivers responded (79% response rate). All children received tracheostomy and 71% received home mechanical ventilation. Primary caregivers were all mothers. High ZBI score was not related to the severity and type of medical equipment. There were relationships between high ZBI score and following factors: 'unimproved relationship between patients and family members without primary caregivers' and 'additional medical equipment after discharge'. The result of PANAS showed that positive attitude was not different between those with high and low ZBI scores. CONCLUSION: It is crucial to reach out to family members without a primary caregiver. Additional medical care/equipment after the program is related to the care burden of primary caregivers.

Impact of intra- and extrauterine growth on bone mineral density and content in the neonatal period of very-low-birth-weight infants.

BACKGROUND: Very-low-birthweight infants (VLBWIs) are at high risk for suboptimal bone mineral density (BMD) and bone mineral content (BMC). Small-for-gestational-age (SGA) status also causes reduced bone mineralization in full-term infants. However, the impact of intrauterine and postnatal extrauterine growth on BMD and BMC in VLBWIs is inconclusive. METHODS: We retrospectively investigated n=68 VLBWIs, comprising 45 appropriate-for-gestational-age (AGA) and 23 SGA infants who underwent lumbar spine dual-energy X-ray absorptiometry at term-equivalent age. RESULTS: BMD and BMC did not differ between AGA and SGA VLBWIs. Subgroup analyses of infants with birthweight<1000 g vs 1000-1500 g, and GA<27 weeks vs ≥ 27 weeks also showed no differences in BMD and BMC between AGA and SGA infants. In contrast, infants with extrauterine growth restriction (EUGR) showed significantly lower values than those without (BMD: 0.124 ± 0.023 vs 0.141 ± 0.032 g/cm(2), P=0.02; BMC: 0.80 ± 0.26 vs 0.94 ± 0.23 g, P=0.04). There were no differences between AGA and SGA infants with EUGR. However, in the AGA cohort, infants with EUGR showed significantly lower values than those without (BMD: 0.121 ± 0.022; 0.141 ± 0.03 g/cm(2), P=0.02; BMC: 0.73 ± 0.23 vs 0.94 ± 0.23 g, P=0.005). Multiple regression analyses showed GA, weight and head circumference at birth, and weight percentile at term correlated with term BMD. Conversely, only weight percentile at term significantly correlated with term BMC. CONCLUSION: EUGR, rather than IUGR, is a risk factor for reduced BMD and BMC in the neonatal period in VLBWIs.

Current incidence of clinical kernicterus in preterm infants in Japan.

Clinical kernicterus in preterm infants has recently been reported in Japan, diagnosed on the basis of clinical findings during the neonatal and infancy periods. We investigated the incidence of clinical kernicterus in preterm infants <30 weeks gestational age (GA) based on a nationwide survey conducted in 233 certified educational facilities for neonatologists. The numbers of infants admitted and infants who died within 14 days after birth during 2011, and the number of infants who subsequently developed clinical kernicterus, were recorded. A total of 2720 infants were analyzed, representing 59% (2720/4623) of all preterm live births <30 weeks GA in Japan in 2011. Of these, 159 (5.8%) died within 14 days after birth, similar to the national rate. Five infants developed clinical kernicterus in infancy (5/2720, 0.18%). The current incidence of clinical kernicterus in Japan is therefore estimated at 1.8 per 1000 live births <30 weeks GA.

Serum unbound bilirubin as a predictor for clinical kernicterus in extremely low birth weight infants at a late age in the neonatal intensive care unit.

BACKGROUND: This study aimed to evaluate peak serum total bilirubin (TB) and unbound bilirubin (UB) levels in preterm infants with clinical kernicterus (KI) who were diagnosed by clinical findings during infancy. DESIGN/SUBJECTS: For this multicenter retrospective study, 18 Japanese extremely low birth weight (ELBW) infants with clinical KI were included. Clinical KI was diagnosed based on the presence of motor developmental impairment with/without athetosis, and abnormal magnetic resonance imaging or brainstem auditory evoked potential findings during infancy. High and low TB or UB levels were defined as serum TB levels ⩾ and <15 mg/dL or serum UB levels ⩾ and <0.8 µg/dL, respectively. The clinical characteristics of KI preterm infants were analyzed. The proportion of infants with high or low serum TB levels and with high or low serum UB levels was then investigated. Sensitivity and specificity were calculated. RESULTS: In 18 KI infants, the median age when serum TB levels peaked was 28 days after birth. In eight KI infants with low serum TB levels, 88% of them had high serum UB levels. For comparison of the number of infants who had high or low serum TB and UB levels, the sensitivity was 90% and specificity was 13%. CONCLUSIONS: Serum TB and UB levels peak at a later age than expected. Chronic serum UB monitoring may be helpful for identifying ELBW infants at risk for developing KI, even when they do not have high serum TB levels.

Role of levothyroxine supplementation in extremely low birth weight infants who have transient hypothyroidism without thyroid-stimulating hormone elevation.

BACKGROUND: Preterm infants show transient hypothyroxinemia without thyroid-stimulating hormone (TSH) elevation. In addition, the degree of neurodevelopmental delay in preterm infants become severe according to the decreasing gestational age (GA). Because of the crucial role of thyroid hormones in brain development, hypothyroxinemia has the potential to cause developmental delay; however, the effectiveness of thyroxine (T4) supplementation on developmental outcomes remains controversial. To resolve these issues, we evaluated the clinical course of transient hypothyroxinemia and the effects of levothyroxine (LT4) supplementation in extremely low birth weight (ELBW) infants. METHODS: Serum levels of free T4 (FT4) and TSH were examined in 36 ELBW infants from 7 days after birth. LT4 (5-10 microg/kg/day) was orally administered to 18 of 36 infants with a low serum FT4 level (< 0.4 ng/dL) or normal serum FT4 levels and a clinical manifestation of hypothyroidism, whereas remaining 18 patients without a low serum FT4 level or clinical hypothyroidism were not given LT4 supplementation as control subjects. Infants were followed-up at a corrected age of 12 months, and clinical outcome was compared between infants that received LT4 and those that did not. RESULTS: ELBW infants showed low serum FT4 levels without TSH elevation. During hospitalization and at follow-up, LT4-administered infants with low serum FT4 levels showed a shorter GA compared with the control group. There were no other statistically significant differences in clinical outcomes at 12 months of corrected age between LT4-administered and control groups. CONCLUSIONS: Our results show that shorter GA is associated with lower serum FT4 levels. Shorter GA is known to cause developmental delay, however, LT4 supplementation prevents the developmental delay of ELBW infants with transient hypothyroxinemia.

Nucleated red blood cell counts: an early predictor of brain injury and 2-year outcome in neonates with hypoxic-ischemic encephalopathy in the era of cooling-based treatment.

BACKGROUND: Raised nucleated red blood cell (NRBC) counts in neonates may indicate in utero hypoxia and brain damage. OBJECTIVE: The study aimed to examine the use of NRBC counts as a predictor of brain injury and neurodevelopmental outcomes in neonates with hypoxic-ischemic encephalopathy (HIE) treated under current cooling-based strategy. METHODS: Forty-three neonates with asphyxia between 2004 and 2010 were retrospectively investigated. Twenty neonates with moderate/severe HIE underwent hypothermia (HT), and 23 with mild HIE were treated in normothermia (NT). Neonates were divided into groups according to the presence of cerebral parenchymal lesions on magnetic resonance imaging (MRI) at 2 weeks after birth. All patients were followed-up neurologically for ⩾ 24 months. NRBC counts during the first 3 days were compared between groups. RESULTS: Eleven HT (HT-N) and 21 NT (NT-N) neonates had normal MRI, and 9 HT (HT-L) and 2 NT (NT-L) neonates had parenchymal lesions. NRBC counts, both absolute and /100 white blood cells (WBC) counts, during the first 3 days in HT-L and NT-L were significantly higher than those in HT-N and NT-N, particularly within 6 hours after birth (HT-N: 502 [0-3060]/mm(3) vs HT-L: 2765 [496-6192]; 0 [0-3417] vs NT-L: 4384 [3978-4789], median [range]). Neonates with /100 white blood cells ⩾ 6/mm(3) and absolute NRBC counts ⩾ 1324/mm(3) within 6 hours of birth had high risks of abnormal MRIs and 2-year outcomes. CONCLUSIONS: NRBC counts can predict brain injury and neurological outcomes in cooled and non-cooled asphyxiated neonates.

Predictors of neurological outcome in cooled neonates.

BACKGROUND: We define clinical predictors of neurological outcome in neonates with hypoxic-ischemic encephalopathy undergoing hypothermia therapy. METHODS: Twenty-one neonates who underwent selective head cooling between 2004 and 2010 and were followed neurologically for ≥ 24 months were investigated retrospectively. Patients were divided according to the neurological outcome at 2 years of age into group A (n = 11), patients with normal neurological function, and group B (n = 10), patients with neurological disabilities (n = 9) or those who died (n = 1). Predictors were determined by χ(2) and Mann-Whitney U-tests, anova, Spearman rank correlations and receiver-operator curves. RESULTS: Group B showed higher average blood lactate levels during the first day, particularly at 24 h of life; lower day-3 cerebral blood flow resistance index; higher maximum dobutamine dose used; higher rate of thiamylal sodium used; more severe background electroencephalogram suppression during the first week (group A: 11/11 cases ≤ grade 3; group B: 7/9 cases at grade 4-5) and higher rate of cerebral lesions on magnetic resonance imaging in the second week (group A: 1/11 case; group B: 9/10 cases) than group A. The most useful predictor of poor prognosis was cerebral parenchymal lesions on magnetic resonance imaging with 90%, 90% and 90% of sensitivity, specificity and accuracy, followed by week-1 background electroencephalogram ≥ grade 4 with 70%, 100% and 85% and day-3 cerebral blood flow resistance index < 0.46 with 71%, 88% and 80%, respectively. CONCLUSIONS: Prediction of post-cooling neurological outcome could be improved substantially by evaluating multiple factors.

Low-dose vasopressin infusion therapy for refractory hypotension in ELBW infants.

BACKGROUND: Severe hypotension in infants, especially in preterm infants, is associated with poor neurological outcome and high mortality. In adults, low-dose vasopressin (arginine vasopressin: AVP) infusion therapy has been effective for treating hypotension that is refractory to vasopressors and inotropes. METHODS: The effects of AVP infusion therapy for refractory hypotension were retrospectively evaluated in extremely low-birthweight infants. Between January 2002 and November 2005, 22 infants with refractory hypotension treated with low-dose AVP infusion were reviewed. The average birthweight was 658 g (+/-142 g), and the average gestational age was 24.9 weeks (+/-1.4). The changes in blood pressure, urinary output, and other parameters in response to AVP therapy were analyzed in all the infants. RESULTS: After AVP infusion, systolic blood pressure increased from 30 mmHg to 43 mmHg (P < 0.0001), and the diastolic pressure increased from 15 mmHg to 24 mmHg (P < 0.0001). The urine output dramatically increased from 1.5 mL/kg per h to 4.0 mL/kg per h (P < 0.0001). AVP infusion, however, was not effective in four of the 22 patients (18%). The sodium concentration in the serum decreased mildly after administration. In six patients the serum sodium concentration decreased below 130 mEq/L. Severe mitral regurgitation was observed in two patients. Three infants showed a transient decrease in the platelet count during AVP infusion. CONCLUSIONS: Low-dose AVP therapy should be considered as rescue therapy when high-dose catecholamine therapy and/or steroid administration do not produce sufficient increase in the blood pressure. Further investigations are required to prove the efficacy and safety of AVP infusion therapy in preterm infants.

Iopamidol enema treatment for meconium obstruction of prematurity in extremely low-birth weight infants: a safe and effective method.

BACKGROUND/PURPOSE: Meconium obstruction of prematurity (MO) often occurs in extremely low-birth weight (ELBW) infants, and its treatment is quite a challenge for neonatologists. We attempted to establish a method of primary treatment for MO of prematurity in ELBW infants. METHODS: An iopamidol enema with 50 cm H(2)O static pressure was performed as the primary treatment. This procedure is safe and effective and we recommend this as the first treatment for MO in ELBW infants. RESULTS: The procedure was performed 50 times in 23 infants and no complications occurred. Out of 23 patients, 20 (88%) improved, but the other 3 did not. In the failure group, the procedure was performed on a significantly later date and the mortality rate was higher (12.5 vs. 67%). CONCLUSIONS: This procedure is safe and effective. We recommend this as the first treatment for MO in ELBW infants.

[A questionnaire study on psychological problems in home medical care for children with chronic illness].

We performed a questionnaire study on psychological problems in home medical care, including mechanical ventilation, oxygen therapy, continuous ambulatory peritoneal dialysis and parenteral nutrition, for children with chronic illnesses in Osaka prefecture, Japan. One hundred two pediatricians (46%) answered the questionnaire. The majority of the doctors regarded psychological support for the children and their families as an important issue. In some cases, home medical care was interrupted because of psychological problems such as psychological burden, anxiety and stress of the children and/or their families. And some other cases, home medical care was impossible because of parental refusal to treatment and/or their child. The cases with mechanical ventilation and oxygen therapy mainly accounted for these cases. Since the number of cases undergoing home medical care is estimated to increase in the future, medical staff should be more aware of psychological support for the families as well as their children.

Behavioral outcome including attention deficit hyperactivity disorder/hyperactivity disorder and minor neurological signs in perinatal high-risk newborns at 4-6 years of age with relation to risk factors.

BACKGROUND: Diagnostic problems with the criteria of attention deficit hyperactivity disorder (ADHD) in the Diagnostic Statistical Manual, 4th edn, have been identified. The aim of this study was to clarify whether the minor neurological signs test (MNT) the authors had previously reported was a predictor for the criteria of ADHD or hyperactivity disorder (HD) in perinatal risk children at 4-6 years of age and what kind of risk factors related to MNT. METHODS: A total of 136 children discharged from neonatal intensive care units were examined at the age of 4-6 years by a developmental neuropediatrician using both MNT and diagnostic criteria of DSM-IV ADHD/ICD-10 (International Classification of Diseases, 10th edn) HD. SPSS base and professional were used for statistical analysis. RESULTS: On comparison of diagnostic criteria between ADHD (11.0%) and HD (27.5%), the incidence in the same subjects showed significant difference. MNT scores showed significant correlation with criteria of ADHD (P < 0.01) and HD (P < 0.05). Diagnostic validity of MNT for predicting ADHD was demonstrated with 78% sensitivity and 79% specificity. High positive rates on MNT did not show a significant difference between the very low birthweight (VLBW) and non-low birthweight (NLBW) groups. Behavioral outcome with relation to risk factors were analyzed using multiple regression analysis. Apgar 5 in the NLBW group and toxemia of pregnancy and small for gestational age (SGA) in VLBW group were highly correlated with behavioral outcome. CONCLUSIONS: Minor neurological signs test score was a significant predictor for criteria of ADHD and HD. High incidences of positive MNT were suspected in not only VLBW children but also NLBW children and Apgar 5 in NLBW children and toxemia of pregnancy and SGA in VLBW children influenced behavioral outcome.

Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity.

von Willebrand factor (VWF) is synthesized primarily in vascular endothelial cells and secreted into the plasma as unusually large VWF multimers. Normally, these multimers are quickly degraded into smaller forms by a plasma metalloproteinase, VWF-cleaving protease (VWF-CP). Decreases in the activity of this enzyme result in congenital and acquired thrombotic thrombocytopenic purpura (TTP). The human VWF-CP has recently been purified. Cloning of the corresponding cDNA revealed that the 1,427-aa polypeptide is a member of the ADAMTS gene family, termed ADAMTS13. Twelve rare mutations in this gene have been identified in patients with congenital TTP. Here, we report missense and nonsense mutations in two Japanese families with Upshaw-Schulman syndrome, congenital TTP with neonatal onset and frequent relapses. The comparison of individual ADAMTS13 genotypes and plasma VWF-CP activities indicated that the R268P, Q449stop, and C508Y mutations abrogated activity of the enzyme, whereas the P475S mutant retained low but significant activity. The effects of these mutations were further confirmed by expression analysis in HeLa cells. Recombinant VWF-CP containing either the R268P or C508Y mutations was not secreted from cells. In contrast, Q449stop and P475S mutants were normally secreted but demonstrated minimal activity. Genotype analysis of 364 Japanese subjects revealed that P475S is heterozygous in 9.6% of individuals, suggesting that approximately 10% of the Japanese population possesses reduced VWF-CP activity. We report on a single-nucleotide polymorphism associated with alterations in VWF-CP activity; it will be important to assess this single-nucleotide polymorphism as a risk factor for thrombotic disorders.

A study of bone mineral density and physical growth in very low birth-weight infants after their discharge from hospital.

The lumbar spinal bone mineral density (BMD) of very low birth-weight (VLBW) infants was determined by dual-energy X-ray absorptiometry, and its relationship with physical growth was analyzed. The influence of birth-related factors on changes in BMD after discharge from the hospital were also investigated. The BMD increased rapidly until the age of 2 years, in association with improvements in nutritional status and the increase in physical growth after discharge. The Z score, which indicates the degree of attainment of the age-specific standard BMD, was determined to be almost 90% at the age of around 2 years and older. Significant increases in the BMD continued to be noted after the age of 2 years, along with increases in body weight and body height. At the age-adjusted value at less than 1 year, however, the Z score tended to be low when the birth weight (<1000 g) and birth height (<36 cm) were low (P < 0.02, respectively), suggesting that the birth weight and birth height influence the BMD at this age. These results indicate that the condition at birth and nutritional management during hospitalization affect the BMD soon after discharge, but that the nutritional condition after discharge becomes a more important factor at the age of 2 years and older.