Phthalates cause a low-renin phenotype commonly found in premature infants with idiopathic neonatal hypertension.

Since the 1970s, when the initial reports of neonatal hypertension related to renal artery thromboembolism were published, other secondary causes of neonatal hypertension have been reported. Those infants with no identifiable cause of hypertension were labeled with a variety of terms. Herein, we describe such infants as having idiopathic neonatal hypertension (INH). Most, but not all, of these hypertensive infants were noted to have bronchopulmonary dysplasia (BPD). More recently, reports described common clinical characteristics seen in INH patients, whether or not they had BPD. This phenotype includes low plasma renin activity, presentation near 40 weeks postmenstrual age, and a favorable response to treatment with spironolactone. A small prospective study in INH patents showed evidence of mineralocorticoid receptor activation due to inhibition of 11ß-HSD2, the enzyme that converts cortisol to the less potent mineralocorticoid-cortisone. Meanwhile, phthalate metabolites have been shown to inhibit 11ß-HSD2 in human microsomes. Premature infants can come in contact with exceptionally large phthalate exposures, especially those infants with BPD. This work describes a common low-renin phenotype, commonly seen in patients categorized as having INH. Further, we review the evidence that hypertension in INH patients with the low-renin phenotype may be mediated by phthalate-associated inhibition of 11ß-HSD2. Lastly, we review the implications of these findings regarding identification, treatment, and prevention of the low-renin hypertension phenotype seen in premature infants categorized as having INH.

Pathology findings in pediatric patients with COVID-19 and kidney dysfunction.

BACKGROUND: Acute kidney injury (AKI) is seen in one-fifth of pediatric patients with COVID-19 requiring hospital admission, and is associated with increased morbidity, mortality, and residual kidney impairment. The majority of kidney pathology data in patients with COVID-19 is derived from adult case series and there is an overall lack of histologic data for most pediatric patients with COVID-19. METHODS: We assembled a multi-institutional cohort of five unvaccinated pediatric patients with COVID-19 and associated kidney dysfunction with available histology. RESULTS: Three complex patients with current or prior SARS-CoV-2 infection had multifactorial thrombotic microangiopathy with clinical features of hemolytic uremic syndrome (in two) or disseminated intravascular coagulation (in one); one died and another developed chronic kidney disease stage 5. Two with recently preceding SARS-CoV-2 infection presented with nephrotic syndrome; one had IgA vasculitis and one had minimal change disease. Within a short follow-up time, none has returned to baseline kidney function. CONCLUSION: Although uncommon, COVID-19-associated kidney injury can have significant morbidity in the unvaccinated pediatric and adolescent population. A higher resolution version of the Graphical abstract is available as Supplementary information.

Sutural deformation during bone-anchored maxillary protraction.

INTRODUCTION: Bone-anchored maxillary protraction (BAMP) is an emerging treatment option for orthopedic correction of maxillary deficiency in young patients. Compared to reverse pull headgear (RPHG), it is believed that forces generated during BAMP result in greater circum-maxillary sutural separation, mandibular retrusion, and improved maxillary protraction. Mechanical loading of the circum-maxillary sutures during BAMP is still poorly understood. METHODS: 20 ex-vivo pig heads were used. Miniplates and molar tubes were installed like clinical procedures. A series of five 200 â€‹g-force (gf) elastics were applied on the right and left side until 1000gf were reached. Strain gauges were installed across the zygomatico-maxillary (ZMS), zygomatico-temporal (ZTS), and nasofrontal suture (NFS). Differential variable reluctance transducers (DVRTs) were installed across the ZTS. Deformation of the sutures during BAMP and RPHG was measured and compared. RESULTS: Higher average sutural deformation of the ZTS and ZMS was seen in BAMP than RPHG: 36.6 â€‹± â€‹20.6µÎµ vs 18.0 â€‹± â€‹12.4µÎµ and 54.7 â€‹± â€‹28.5µÎµ vs 12.5 â€‹± â€‹14.8µÎµ, respectively. Similarly, higher NFS deformation was seen in BAMP (18.4 â€‹± â€‹12.9µÎµ vs. -0.8 â€‹± â€‹12.0µÎµ). DVRT data showed higher ZTS separation in BAMP than RPHG (6.3 â€‹± â€‹5.2 â€‹µm vs. 1.7 â€‹± â€‹2.1 â€‹µm). These differences were all statistically significant using the Wilcoxon-signed rank test. CONCLUSION: Both RPHG and BAMP forces separate the ZTS and ZMS. BAMP resulted in higher levels of sutural separation at the ZTS and ZMS by 2- and 5-fold, respectively.

Elimination of Intravenous Di-2-Ethylhexyl Phthalate Exposure Abrogates Most Neonatal Hypertension in Premature Infants with Bronchopulmonary Dysplasia.

(1) Background: The incidence of hypertension in very low birthweight (VLBW) infants in a single neonatal intensive care unit (NICU) dropped markedly during a 2-year period when the IV fluid (IVF) in both the antenatal unit and the NICU temporarily changed to a di-2-ethylhexyl phthalate (DEHP)-free formulation. The objective of the current report is to document this observation and demonstrate the changes in incidence of hypertension were not associated with the variation in risk factors for hypertension; (2) Methods: The charts of all VLBW infants born in a single NICU during a 7-year span were reviewed. This time includes 32 months of baseline, 20 months of DEHP-free IVF, 20 months of IVF DEHP re-exposure, and two 4-month washout intervals. The group of interest was limited to VLBW infants with bronchopulmonary dysplasia (BPD). Chi-square analysis was used to compare incidence of hypertension among periods. Vermont Oxford NICU Registry data were examined for variation in maternal and neonatal risk factors for hypertension; Results: Incidence of hypertension in VLBW infants with BPD decreased from 7.7% (baseline) to 1.4% when IVF was DEHP-free, rising back to 10.1% when DEHP-containing IVF returned to use. Risk factors for neonatal hypertension were stable across the 3 study periods in the NICU's group of VLBW infants; (3) Conclusions: Serendipitous removal of IVF containing DEHP resulted in near elimination of hypertension in one NICU-an effect entirely reversed after the same brand of DEHP-containing IVF returned to clinical use. These results suggest that DEHP exposure from IVF plays a major role in neonatal hypertension.

Phthalate Exposures in the Neonatal Intensive Care Unit.

BACKGROUND: Di-2-ethylhexyl phthalate (DEHP), a phthalate compound found in medical devices, may cause toxic effects in premature infants. In this study, the objective is to quantify DEHP exposures from various intravenous and respiratory therapy devices, and to use these values to predict typical exposure for an infant in a neonatal unit. METHODS: Common IV products used on infants are directed through various types of IV tubing (IVT) and analyzed for DEHP content. DEHP exposure for infants receiving respiratory therapy was determined indirectly through analysis of urine DEHP metabolites. By deriving these values for DEHP we calculated the daily exposure to DEHP from common IV fluids (IVF) and respiratory devices during hospitalization in a neonatal unit. RESULTS: IVF labeled DEHP-positive showed very high concentrations of DEHP, but when passed through IVT, substantial amounts were adsorbed. DEHP was undetectable with all DEHP-negative IVF tests, except when passed through DEHP-positive IVT. The DEHP leached from most respiratory devices was relatively modest, except that detected from bubble CPAP. In 14 very low birthweight infants, the mean DEHP exposure was 182,369 mcg/kg over 81.2 days of the initial hospitalization. Ninety-eight percent of the exposure was from respiratory devices, with bubble CPAP accounting for 95% of the total DEHP exposure in these infants. CONCLUSIONS: The DEHP exposure in our neonatal unit can be reduced markedly by avoiding or modifying bubble CPAP equipment and avoiding IV tubing containing DEHP.

Phthalate-associated hypertension in premature infants: a prospective mechanistic cohort study.

BACKGROUND: Phthalates are associated with increased blood pressure in children. Large exposures to di-(2-ethylhexyl) phthalate (DEHP) among premature infants have been a cause for concern. METHODS: We conducted a prospective observational cohort study to determine if DEHP exposures are related to systolic blood pressure (SBP) in premature infants, and if this exposure is associated with activation of the mineralocorticoid receptor (MR). Infants were monitored longitudinally for 8 months from birth. Those who developed idiopathic hypertension were compared with normotensive infants for DEHP exposures. Appearance of urinary metabolites after exposure was documented. Linear regression evaluated the relationship between DEHP exposures and SBP index and whether urinary cortisol/cortisone ratio (a surrogate marker for 11ß-HSD2 activity) mediated those relationships. Urinary exosomes were quantified for sodium transporter/channel expression and interrogated against SBP index. RESULTS: Eighteen patients met the study criteria, nine developed transient idiopathic hypertension at a postmenstrual age of 40.6 ± 3.4 weeks. The presence of urinary DEHP metabolites was associated with prior IV and respiratory tubing DEHP exposures (p < 0.05). Both IV and respiratory DEHP exposures were greater in hypertensive infants (p < 0.05). SBP index was related to DEHP exposure from IV fluid (p = 0.018), but not respiratory DEHP. Urinary cortisol/cortisone ratio was related to IV DEHP and SBP index (p < 0.05). Sodium transporter/channel expression was also related to SBP index (p < 0.05). CONCLUSIONS: Increased blood pressure and hypertension in premature infants are associated with postnatal DEHP exposure. The mechanism of action appears to be activation of the MR through inhibition of 11ß-HSD2.

Pulmonary Function and Systolic Blood Pressure in Very Low Birth Weight Infants at 34 - 36 Weeks of Corrected Age.

PURPOSE: Preterm infants are at increased risk of systemic hypertension compared to term infants. Bronchopulmonary dysplasia (BPD) has been shown to be associated with hypertension in preterm infants albeit with no causation reported. BPD is characterized by abnormal pulmonary function tests (PFTs), specifically elevated passive respiratory resistance (Rrs), decreased passive respiratory compliance (Crs) and decreased functional residual capacity (FRC). There have been no studies comparing PFTs in very low birth weight (VLBW) infants with and without hypertension. We hypothesized that stable VLBW infants with hypertension will have altered PFTs. PATIENTS AND METHODS: Retrospective cohort study of infants < 1500 grams at birth (VLBW) who had PFTs performed near 34-36 weeks of corrected gestational age (CGA). We excluded infants with congenital anomalies, known hypertensive disorders or those at risk of medication-induced hypertension. Data obtained included PFT parameters (Rrs, Crs, FRC) and mean systolic blood pressure (SBP). RESULTS: 59 VLBW infants were identified for analysis, 14 with and 45 without hypertension. Hypertensive and normotensive patients were similar in terms of mean gestational age (26.6 vs 27.4 weeks), mean CGA at PFTs (36.1 vs 34.6 weeks) and proportion of BPD (36% vs 36%). The Rrs was significantly higher in hypertensive versus normotensive patients [median Rrs of 0.080 (0.069, 0.090) versus 0.066 (0.054, 0.083) cmH2O/mL/sec; p = 0.04]. There was no difference in systolic blood pressure in the infants with and without BPD. CONCLUSION: In this cohort of contemporary VLBW infants, those with hypertension had increased Rrs. This finding warrants a prospective study with a larger sample size and long-term follow-up.

Efficacy and safety of sevelamer carbonate in hyperphosphatemic pediatric patients with chronic kidney disease.

BACKGROUND: Treatment for hyperphosphatemia in chronic kidney disease (CKD) involves dietary control of phosphorus intake, dialysis, and treatment with oral phosphate binders, none of which were approved by the Federal Food and Drug Administration in pediatric patients at the time of this study. METHODS: This was a phase 2, multicenter study (NCT01574326) with a 2-week, randomized, placebo-controlled, fixed-dose period (FDP) followed by a 6-month, single-arm, open-label, dose-titration period (DTP), with the aim to evaluate the safety and efficacy of sevelamer carbonate (SC) in hyperphosphatemic pediatric patients with CKD. Following a 2-4 week screening phase, pediatric patients with a serum phosphorus level higher than age-appropriate levels were randomized to receive either SC or placebo as powder/tablets in 0.4-1.6 g doses, based on body surface area. The primary efficacy outcome was the change in serum phosphorus from baseline to end of the FDP in the SC versus placebo arms (analysis of covariance). The secondary outcome was mean change in serum phosphorus from baseline to end of DTP by treatment group and overall. Treatment-emergent/serious adverse events (AEs) were recorded. RESULTS: Of 101 enrolled patients (29 centers), 66 completed the study. The majority of patients were adolescents (74%; mean age 14.1 years) and on dialysis (77%). Renal transplant was the main reason for discontinuation. SC significantly reduced serum phosphorus from baseline levels (7.16 mg/dL) during the FDP compared to placebo (least square mean difference - 0.90 mg/dL, p = 0.001) and during the DTP (- 1.18 mg/dL, p < 0.0001). The safety and tolerability of SC and placebo were similar during the FDP, with patients in both groups reporting mild/moderate gastrointestinal AEs during the DTP. CONCLUSIONS: Sevelamer carbonate significantly lowered serum phosphorus levels in hyperphosphatemic children with CKD, with no serious safety concerns identified.

Characteristics of hypertension in premature infants with and without chronic lung disease: a long-term multi-center study.

BACKGROUND: Many causes for neonatal hypertension in premature infants have been described; however in some cases no etiology can be attributed. Our objectives are to describe such cases of unexplained hypertension and to compare hypertensive infants with and without chronic lung disease (CLD). METHODS: We reviewed all cases of hypertension in premature infants referred from 18 hospitals over 16 years. Inclusion criteria were hypertension occurring at <6 months of age and birth at <37 weeks gestation; the main exclusion criterion was known secondary hypertension. Continuous variables were compared using analysis of variance. Nominal variables were compared using chi-square tests. RESULTS: A total of 97 infants met the inclusion criteria, of whom 37 had CLD. Among these infants, hypertension presented at a mean of 11.3 ± 3.2 chronological weeks of age and a postmenstrual age of 39.6 ± 3.6 weeks. Diagnostic testing was notable for plasma renin activity (PRA) being <11 ng/mL/h in 98% of hypertensive infants. Spironolactone was effective monotherapy in 51 of 56 cases of hypertension. Hypertension resolved in all infants, with an average treatment duration of 25 weeks. Significant differences between the two groups of infants were a 0.4 kg lower birthweight and a 2.5 weeks younger gestational age at birth in those with CLD (p < 0.01, p < 0.01, respectively). Hypertension presented in those with CLD 1.8 weeks later, but at the same postmenstrual age as those without CLD (p < 0.01, p = 0.45, respectively). CONCLUSION: Premature infants with unexplained hypertension, with and without CLD, presented at a postmenstrual age of 40 weeks with low PRA, transient time course, and a favorable response to spironolactone treatment.

No-fault compensation for ventilator-dependent children: a reasonable settlement value for lifetime attendant care.

Severe neurological outcomes sustained in childhood often result in lifetime health care needs that are beyond the financial means of most families. When severe neurological deficits are alleged to have resulted from professional negligence, relief may be sought through litigation; however, the American tort system often yields inconsistent results or no compensation for patients. We sought to identify a reasonable, objective, and data-based monetary range for a no-fault compensation system with high- and low-financial limits for those with severe neurological deficits. Based on documented life expectancies and attendant care cost studies, the data analysis indicates a no-fault settlement payment ranging from US$479,712.24 to $3,098,504.16, reasonably ensures care and services for life.

Mandatory presuit mediation: 5-year results of a medical malpractice resolution program.

The Florida Patient Safety and Presuit Mediation Program (FLPSMP) is a mandatory mediation program designed to provide deserving patients with fast, fair compensation while limiting the healthcare provider expenses incurred during traditional litigation. Mediation occurs before litigation begins; therefore, patients with meritorious claims receive compensation often years earlier than they would with extended litigation. This early mediation fosters confidential and candid communication between doctors and patients, which promotes early fact-finding and candid discussion. The program went into effect across the University of Florida (UF) Health system on January 1, 2008. In an article previously published in this journal, we discussed the positive trend observed 2 years after the implementation of the FLPSMP. This article incorporates 5 years of data, which includes new benchmarks with state and national data, to demonstrate that the program can be used successfully as a medical malpractice solution.

Grant award program partnerships with your professional liability insurance carrier: an innovative approach to loss prevention and improved patient safety.

The financial success of a malpractice insurance program is directly influenced by how effectively the covered providers respond to risk. This article describes a University Self-Insurance Program partnership to provide small grants to providers who have the expertise and passion for a specific risk reduction activity that is cost effective and measurable and has a high probability of improving patient care and reducing claims or lawsuits. Implementation of this small grant concept can be tailored to become operational in virtually any setting from an independent medical practice to a multistate healthcare system.

The utility of the IGF-I generation test in children with chronic kidney disease.

BACKGROUND: To determine if the insulin-like-growth factor (IGF-I) generation test is a marker for growth hormone (GH) sensitivity in children with chronic kidney disease (CKD). METHODS: This was a randomized cross-over study in which children with CKD received low-dose (0.025 mg/kg/day) and high-dose (0.05 mg/kg/day) GH therapy in the framework of a 7-day IGF-I generation test. Blood samples were collected on day 1 (D1; pre-dose) and on day 8 (D8; post 7 doses) of GH therapy. All subjects received GH for 12 months at 0.05 mg/kg/day. Serum IGF-I was measured by radioimmunometric assay. Normative historic data from healthy children and those with idiopathic short stature were used for comparison. RESULTS: Sixteen subjects (age 2-13 years) with creatinine clearances of between 25 and 75 ml/min/1.73 m(2) were enrolled. Annualized height velocity for all subjects was 10.3 ± 1.1 cm/year (mean ± standard deviation), with an annual change in height Z score of 0.7 ± 1.0. No correlation was found between the generated serum IGF-I levels (D8 - D1) and creatinine clearances, and with changes in height Z scores. Serum IGF-I levels on D1 and D8 in CKD subjects were lower than normative data, but with adequate IGF-I generation on D8. CONCLUSIONS: Children with CKD were able to respond to GH therapy with both growth and an increase in serum IGF-I levels, but the IGF-I generation test was not a good predictor of growth response in this cohort.

The association between abnormal birth history and growth in children with CKD.

BACKGROUND AND OBJECTIVES: Poor linear growth is a well described complication of chronic kidney disease (CKD). This study evaluated whether abnormal birth history defined by low birth weight (LBW; <2500 g), prematurity (gestational age <36 weeks), small for gestational age (SGA; birth weight <10th percentile for gestational age), or intensive care unit (ICU) at birth were risk factors for poor growth outcomes in children with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Growth outcomes were quantified by age-sex-specific height and weight z-scores during 1393 visits from 426 participants of the Chronic Kidney Disease in Children Study, an observational cohort of children with CKD. Median baseline GFR was 42.9 ml/min per 1.73 m(2), 21% had a glomerular diagnosis, and 52% had CKD for ≥ 90% of their lifetime. RESULTS: A high prevalence of LBW (17%), SGA (14%), prematurity (12%), and ICU after delivery (40%) was observed. Multivariate analyses demonstrated a negative effect of LBW (-0.43 ± 0.14; P < 0.01 for height and -0.37 ± 0.16; P = 0.02 for weight) and of SGA (-0.29 ± 0.16; P = 0.07 for height and -0.41 ± 0.19; P = 0.03 for weight) on current height and weight. In children with glomerular versus nonglomerular diagnoses, the effect of SGA (-1.08 versus -0.18; P = 0.029) on attained weight was more pronounced in children with a glomerular diagnosis. CONCLUSIONS: LBW and SGA are novel risk factors for short stature and lower weight percentiles in children with mild to moderate CKD independent of kidney function.

Mandatory pre-suit mediation: local malpractice reform benefiting patients and healthcare providers.

The Florida Patient Safety and Pre-Suit Mediation Program (FLPSMP) was implemented as a pilot program to provide patients of healthcare providers and facilities associated with the University of Florida Health Science Center with timely and fair compensation when injured and to combat rising healthcare legal liability expenses. Prior to filing a formal lawsuit, participants of the FLPSMP join in a confidential and nonbinding pre-suit mediation conducted by a neutral third-party mediator. The process fosters confidential and candid communication between doctors and patients, saving thousands of dollars in legal expenses for both patients and providers.

Innovative teaching for health law: a case study of a hospital medical malpractice lawsuit simulation.

In this article we describe a case study of a learning exercise for healthcare management students to more effectively understand how the legal process impacts healthcare organizations and healthcare professionals. Through a semester-long mock trial, we illustrate how healthcare executives can better understand and prepare their employees, their organization, and fellow administrators for the financial, emotional, and time investment that a lawsuit requires. Students participate as a member of the plaintiff team, defendant team, or juror in a simulated lawsuit brought by a patient against a hospital. We explain how students who participate in the simulated lawsuit gain a better understanding of difficult legal principles discussed throughout the course. We further indicate how the mock trial simulation may support achievement of current Commission on Accreditation of Healthcare Management Education (CAMHE) criteria. Next, we highlight how the mock trial allowed students to put into practice many of the health law principles discussed in class through role playing the different stages of medical malpractice trial. The article concludes with examples of how a simulated mock trial may also provide similar interdisciplinary educational, performance improvement, and cost saving benefits to healthcare professionals and their organizations.

Treatment of primary hyperoxaluria type 1 with sequential liver and kidney transplants from the same living donor.

Alanine-glyoxalate aminotransferase deficiency occurs in patients with primary hyperoxaluria type 1. Increased hepatic oxalate production leads to high urine concentrations of glycolate and oxalate. Calcium oxalate nephrolithiasis and nephrocalcinosis occur, and renal function progressively declines until patients develop end-stage renal disease. Renal transplantation alone is inadequate therapy because the primary enzyme deficiency remains. We report what we believe to be the second-youngest recipient to undergo successful sequential liver and kidney transplantation from a single living-related donor for treatment of primary hyperoxaluria type 1. We also discuss the changes in this patient's serum oxalate levels after transplantation.

Is the extrapolated adult dose of fosinopril safe and effective in treating hypertensive children?

We evaluated the efficacy, safety, and dose-response relationship of fosinopril in children aged 6 to 16 years with hypertension or high-normal blood pressure with an associated medical condition requiring treatment. The study was a prospective, double-blind, placebo-controlled trial conducted in 78 clinical sites in the United States, Russia, and Israel. There were 4 phases: a screening phase of 10 days maximum, a 4-week dose-response phase, a placebo withdrawal phase of 2 weeks maximum, and a 52-week open-label safety phase. The primary objective of the dose-response phase was to determine whether low (0.1 mg/kg), medium (0.3 mg/kg), or high (0.6 mg/kg) doses of fosinopril based on established adult dosing affect trough seated systolic blood pressure. During the dose-response phase, all 3 doses were equally effective in lowering systolic blood pressure. During the placebo withdrawal phase, there was an adjusted mean systolic blood pressure increase of 5.2 mm Hg for the placebo group and 1.5 mm Hg for the fosinopril group, a net withdrawal effect of 3.7 mm Hg (P=0.013). Fosinopril was well tolerated; serious adverse events occurred infrequently and were generally not attributed to fosinopril. Because children appear to be more sensitive to lower doses of fosinopril than adults, starting doses for children should be < or =0.1 mg/kg.