Toyoko S. Yamashita

Iron overload in Africa. Interaction between a gene and dietary iron content.

BACKGROUND AND METHODS In contrast to hemochromatosis, which in white populations is inherited through a gene linked to the HLA locus, iron overload in sub-Saharan Africa is believed to result solely from increased dietary iron derived from traditional home-brewed beer. To examine the hypothesis that African iron overload also involves a genetic factor, we used likelihood analysis to test for an interaction between a gene (the hypothesized iron-loading locus) and an environmental factor (increased dietary iron) that determines transferrin saturation and unsaturated iron-binding capacity. We studied 236 members of 36 African families chosen because they contained index subjects with iron overload. Linkage to the HLA region was tested with use of lod scores. RESULTS In the index subjects, increased iron was present in both hepatocytes and cells of the mononuclear-phagocyte system. Among family members with increased dietary iron due to the consumption of traditional beer, transferrin saturation in serum was distributed bimodally, with 56 normal values (less than 60 percent saturation) and 44 elevated values; the mean serum ferritin concentration was five times higher in the subjects with elevated transferrin saturation (P less than 0.005). The pedigree analysis provided evidence of both a genetic effect (P less than 0.005) and an effect of increased dietary iron (P less than 0.005) on transferrin saturation and unsaturated iron-binding capacity. In the most likely model, increased dietary iron raised the mean transferrin saturation from 30 to 81 percent and lowered the mean unsaturated iron-binding capacity from 38 to 13 mumol per liter in subjects heterozygous for the iron-loading locus. The hypothesis of tight linkage to HLA was rejected. CONCLUSIONS Iron overload in Africa may be caused by an interaction between the amount of dietary iron and a gene distinct from any HLA-linked gene.

Optimal sedation of mechanically ventilated pediatric critical care patients.

Objective: To derive a target range of optimal sedation for the COMFORT Scale and to prospectively test that target range against intensivist assessment of adequacy of sedation. Design: Serial prospective agreement cohort studies. Setting: Twelve‐bed pediatric intensive care unit in an urban academic teaching hospital. Patients: Eighty‐five mechanically ventilated children (aged 0 to 102 months). Interventions: Three serial prospective studies comparing simultaneous, independent ratings conducted by trained observers using an objective scale and intensive care physicians using global assessment. The initial study was designed to derive the target range. The second study was conducted to verify that target range in a second population. The third study was added to evaluate relative variability in methods used in the second study. Measurements and Main Results: Adequacy of sedation using visual analog scale and descriptive ratings or the COMFORT Scale (a previously validated behaviorally anchored scale to rate eight behavioral or physiologic dimensions of distress). The first study comprised 100 observations. Groups of patients described by the intensivist as inadequately sedated, optimally sedated, and excessively sedated had different mean COMFORT scores (30.5 ± 0.7 vs. 22.9 ± 5.8 vs. 14.3 ± 0.7, respectively, p < .05). The target range of optimal sedation was defined as COMFORT scores of 17 to 26. The second study verified the target range prospectively in a second group of 96 observations. The COMFORT score was strongly associated with the sedation adequacy rating by the intensivist (p < .001; r2 = .662). COMFORT scores accurately predicted the patient assignment to adequacy of sedation categories by the intensivist in 66.1% of observations. Discrepancy between physicians occurred in 38.5% of 16 paired physician ratings in the second study. In the third study, 120 observations comparing paired COMFORT scores to paired physician ratings of the same subjects demonstrated significantly less variability in COMFORT assessment of adequacy of sedation. COMFORT scores were similarly unbiased (1.1% vs. 0.22%) but more precise (8.0% vs. 16.7%) than intensivist ratings (p < .025). Conclusion: Adequacy of sedation is measured more consistently by observers using the COMFORT Scale than by intensivist global assessment. (Crit Care Med 1994; 22:163‐170)

Relationship of prenatal cocaine exposure and maternal postpartum psychological distress to child developmental outcome

Maternal cocaine use during pregnancy can affect the infant directly through toxic effects or indirectly through cocaines influence on maternal psychological status. We followed 160 cocaine exposed and 56 nonexposed infants and their mothers identified at birth through interview and/or urine screen. Although cocaine exposure defined the groups, infant exposure to alcohol, marijuana, and tobacco was allowed to vary. Infants were 99% African American and poor. All mothers completed the Brief Symptom Inventory (BSI) and infants were given the Bayley Scales of Mental (MDI) and Motor (PDI) Development at a mean corrected age of 17 +/- 8 months. Both MDIs (94 +/- 17 vs. 103 +/- 16) and PDIs (101 +/- 16 vs. 108 +/- 12) were lower for cocaine exposed infants. Psychological distress was greater in cocaine using mothers. Hierarchical multiple regression was used to assess the relative effects of gestational age, maternal psychological distress, and cocaine and polydrug exposure on infant outcomes. Both psychological distress and cocaine and alcohol exposure predicted lower MDIs after controlling for prematurity. Neither psychological distress nor alcohol exposure predicted motor outcome, while cocaine had a significant effect. Tobacco and marijuana exposure were unrelated to outcome. These findings provide further support for direct effects of cocaine and alcohol on infant development as well as highlight the need for studies to document maternal psychological factors, which may increase child risk for poorer outcomes.

High-Dose Pyridoxine and Magnesium Administration in Children with Autistic Disorder: An Absence of Salutary Effects in a Double-Blind, Placebo-Controlled Study

Several reports have described salutary effects such as decreased physical aggression and improved social responsiveness being associated with the administration of high doses of pyridoxine and magnesium (HDPM) in open-labeled and controlled studies of patients with autism. Despite this fact, this intervention remains controversial. A 10-week double-blind, placebo-controlled trial was undertaken to examine both the efficacy and safety of HDPM in autism. Twelve patients were enrolled, and 10 patients (mean age 6 years 3 months) were able to complete the study. HDPM at an average dose of 638.9 mg of pyridoxine and 216.3 mg of magnesium oxide was ineffective in ameliorating autistic behaviors as assessed by the Childrens Psychiatric Rating Scale (CPRS), the Clinical Global Impression Scale, and the NIMH Global Obsessive Compulsive Scale. Furthermore, no clinically significant side effects were noted during HDPM administration. A trend for a transient change on the CPRS was found that was possibly due to a placebo response. This study raises doubts about the clinical effectiveness of HDPM in autistic disorder.

Preschool language outcomes of children with history of bronchopulmonary dysplasia and very low birth weight.

A prospective follow-up of very low birth weight (VLBW) infants with and without bronchopulmonary dysplasia (BPD) and term control infants was conducted. The effects of BPD and VLBW on speech-language development and specific language impairment at 3 years of age were investigated, controlling for the effects of sociodemographic and other medical risk factors. Groups were compared on cognitive and speech-language outcomes using the Battelle Language and Bayley Mental Scales of Infant Development. Children with a history of BPD had lower receptive language skills than VLBW children without BPD, who in turn had lower receptive skills than term children. Children with a history of BPD also had lower expressive skills than the two comparison groups, whereas VLBW children without BPD did not differ in expressive language from term children. When IQ score was controlled, children with BPD demonstrated specific language impairment in receptive language. The presence of patent ductus arteriosis (PDA) was the best predictor of language deficits and the combined occurrence of PDA and BPD resulted in differentially lower language scores. Neurologic complications, low socioeconomic status, and minority race were also significant predictors of language delay. The findings emphasize the importance of considering both medical and sociodemographic factors in evaluating the risk of VLBW infants for poorer speech-language outcomes.

SOCIAL SUPPORT, PSYCHOLOGICAL DISTRESS, AND PARENTING STRAINS IN MOTHERS OF VERY LOW BIRTHWEIGHT INFANTS

This study investigated maternal psychological distress, perceptions of social supports, and parenting strains after the birth of a very low birthweight (VLBW) infant. Compared to mothers of term infants, mothers of VLBW infants had significantly higher incidence of psychological distress during the neonatal period, but did not differ from mothers of term infants in their feelings of role restriction, parenting competence, or social supports. Lower general social support predicted high distress levels, but only for mothers of VLBW infants. Mothers with a low sense of parenting competence, but support from spouse/partners reported lower maternal distress.

A pharmacokinetically based propofol dosing strategy for sedation of the critically ill, mechanically ventilated pediatric patient.

OBJECTIVE To assess the pharmacokinetics and pharmacodynamics of propofol sedation of critically ill, mechanically ventilated infants and children. DESIGN A prospective clinical study. SETTING A pediatric intensive care unit (ICU) in a university hospital. PATIENTS Clinically stable, mechanically ventilated pediatric patients were enrolled into our study after residual sedative effects from previous sedative therapy dissipated and the need for continued sedation therapy was defined. Patients were generally enrolled just before extubation. INTERVENTIONS A stepwise propofol dose escalation scheme was used to determine the steady-state propofol dose necessary to achieve optimal sedation, as defined by the COMFORT scale, a validated scoring system which reliably and reproducibly quantifies a pediatric patients level of distress. When in need of continued sedation, study patients received an initial propofol loading dose of 2.5 mg/kg and were immediately started on a continuous propofol infusion of 2.5 mg/kg/hr. The propofol infusion rate was adjusted and repeat loading doses were administered, if needed, using a coordinated dosing scheme to maintain optimal sedation for a 4-hr steady-state period. After 4 hrs of optimal sedation, the propofol infusion was discontinued and simultaneous blood sampling and COMFORT scores were obtained until the patient recovered. Additional blood samples were obtained up to 24 hrs after stopping the infusion and analyzed for propofol concentration by high-performance liquid chromatography. MEASUREMENTS AND MAIN RESULTS Twenty-nine patients were enrolled into this study. One patient was withdrawn from this study because of an acute decrease in blood pressure occurring with the first propofol loading dose; 28 patients completed the study. All patients were sedated immediately after the first 2.5-mg/kg propofol loading dose. Eight patients were adequately sedated with the starting propofol dose regimen, whereas five patients required downward dose adjustment and 11 patients required dosage increases to achieve optimal sedation. Four patients failed to achieve adequate sedation after five dose escalations and the drug was stopped. Recovery from sedation (COMFORT score of > or = 27) after stopping the propofol infusion was rapid, averaging 15.5 mins in 23 of 24 evaluable patients. In 13 patients who were extubated after stopping the propofol infusion, the time to extubation was also rapid, averaging 44.5 mins. Determination of the blood propofol concentration at the time of recovery from propofol sedation was possible in 15 patients. The blood propofol concentration was variable, ranging between 0.262 to 2.638 mg/L but < or = 1 mg/L in 13 of 15 patients. Similarly, tremendous variation was observed in propofol pharmacokinetics. Propofol disposition was best characterized by a three-compartment model with initial rapid distribution into a small central compartment, V1, and two larger compartments, V2 and V3, which are two-and 20-fold greater in volume, respectively, than V1. Redistribution from V2 and V3 into V1 was much slower than ingress, underscoring the importance of the propofol concentration in V1 as reflective of the drugs sedative effect. Propofol was well tolerated. Two patients experienced an acute decrease in blood pressure which resolved without treatment. CONCLUSIONS We conclude that a descending propofol dosing strategy, which maintains the propofol concentration constant in the central compartment (V1) while drug accumulates in V2 and V3 to intercompartmental steady-state, is necessary for effective propofol sedation in the pediatric ICU. Our proposed dosing scheme to achieve and maintain the blood propofol concentration of 1 mg/L would appear effective for sedation of most clinically stable, mechanically ventilated pediatric patients.

Single-dose pharmacokinetics of piperacillin and tazobactam in infants and children.

The pharmacokinetics of piperacillin and tazobactam were assessed after single-dose administration to 47 infants and children. Study subjects ranging in age from 2 months to 12 years were randomized to receive one of two different doses of a piperacillin-tazobactam combination (8:1): a low dose (n = 23) of 50 and 6.25 mg of piperacillin and tazobactam per kg of body weight, respectively, or a high dose (n = 24) of 100 and 12.5 mg, respectively. The pharmacokinetic behavior of tazobactam was very similar to that observed for piperacillin, supporting the use of these two agents in a fixed-dose combination. No differences in the pharmacokinetics of piperacillin or tazobactam were observed between the two doses administered. The elimination parameters half-life and total body clearance decreased and increased, respectively, with increasing age, whereas volume parameters (volume of distribution and steady-state volume of distribution) remained relatively constant for both compounds. The primary metabolite of tazobactam, metabolite M1, was measurable in the plasma of 18 of the 47 study subjects; 17 of these 18 subjects received the high doses. More than 70% of the administered piperacillin and tazobactam doses were excreted unchanged in the urine over a 6-h collection period. These data combined with the known in vitro susceptibilities of a broad range of pediatric bacterial pathogens indicate that a dose of 100 mg of piperacillin and 12.5 of mg tazobactam per kg of body weight administered as a fixed-dose combination every 6 to 8 h would be appropriate to initiate clinical efficacy studies in infants and children for the treatment of systemic infections arising outside of the central nervous system. Images

Feeding interactions in infants with very low birth weight and bronchopulmonary dysplasia

Infants with very low birth weight (VLBW) are at increased risk for feeding disorders that can affect growth and development. One hundred and forty one mother-infant pairs were compared [55 with infants with high medical risk due to infant VLBW and bronchopulmonary dysplasia (BPD), 34 VLBW without BPD, and 52 term infants] on operationally defined measures of feeding behaviors and maternal self-report of depression and anxiety. Mothers of VLBW infants with and without BPD spent more time prompting their infants to feed when their infants engaged in nonfeeding behavior. Despite increased maternal efforts, infants with BPD took in less formula, spent less time sucking, and spent a greater proportion of time nonfeeding. VLBW infants without BPD were equivalent to term infants in percentage of time sucking and in volume of formula ingested and were more likely to take in higher calories than infants with BPD. Mothers of VLBW infants with and without BPD were also more likely to report clinically significant symptoms of depression and anxiety than mothers of term infants. Because mothers of VLBW infants who were more depressed or anxious were less likely to verbally prompt their infants to eat, maternal psychological symptoms should be considered in assessing interactions of VLBW mother-infant dyads.

Colonization with antibiotic-resistant gram-negative organisms in a pediatric intensive care unit.

OBJECTIVE To measure the prevalence of colonization with antibiotic-resistant Gram-negative organisms and its association with potential risk factors, including antibiotic exposure, in a pediatric intensive care unit (ICU). DESIGN Prospective, observational study. SETTING A 16-bed tertiary care pediatric ICU. PATIENTS All children admitted to the pediatric ICU for > 24 hrs over a 5-month period. MEASUREMENTS AND MAIN RESULTS Two hundred ninety-six patients, approximately half of all patients admitted to the ICU, were enrolled in the study; 236 patients had sufficient data collected for analysis and were prospectively examined for nasopharyngeal and gastrointestinal colonization by antibiotic-resistant Gram-negative organisms (ceftazidime minimal inhibitory concentration of > 16 micrograms/mL, or tobramycin minimal inhibitory concentration > 8 micrograms/mL). Association between colonization and potential predisposing factors including demographics, diagnosis, Pediatric Risk of Mortality (PRISM) score, invasive instrumentation, and prior ICU antibiotic exposure was assessed. More than 20% of patients were found to be colonized with an antibiotic-resistant Gram-negative organism. Examination of the timing of colonization indicated that more than half were identified within 72 hrs of admision. Colonization was associated by unadjusted analysis to prior ICU antibiotic exposure, as well as by factors associated with the severity of illness (PRISM score and invasive instrumentation) and young age. However, when the independence of these factors was tested by logistic regression, prior antibiotic exposure was no longer associated with resistant organism colonization. CONCLUSIONS These data suggest that antibiotic-resistant Gram-negative organisms are a significant risk to intensively III children and that in many instances, they are imported into the unit or rapidly acquired from environmental reservoirs. Since risk factors for colonization are multiple, policies confined to antibiotic utilization within the ICU may have fixed, and possibly limited, benefit in their control.