Correlation between age and plasma level/dosage ratio for phenobarbital in infants and children.

123 plasma concentration measurements of phenobarbital were obtained from 82 children (2 months - 6 1/2 years old) at steady-state conditions. The plasma level/dosage ratio has been found to have a highly significant correlation with the age of the patient both for dosage in mg/kg and in mg/m2. The ratio increases with the increase in the age of the patient at a rate which is greater for dosages expressed on the basis of body weight. Moreover, at least for body weight related dosages, this increase is relatively high in the first year of life, becoming less marked after. Practical indications are given about the required dosage of phenobarbital in different groups of ages from 2 months to 6 1/2 years. It is recommended however to regularly measure the plasma level of the drug in infants and children treated for long periods of time.     

Influence of salivary Ph on the correlation between salivary and plasma levels of phenobarbital in the neonatal period

The influence of salivary pH on the estimate of blood barbiturates obtained by measuring phenobarbital on saliva at newborn age.     

Electrolyte and glucose concentration in plasma and cerebrospinal fluid measured parallel in pathologic newborn infants.

Cerebrospinal fluid and plasma sodium, potassium, chloride, calcium and glucose concentration were measured parallel in 14 pathological newborn babies of gestational age and birthweight of 36.3 +/- 4.3 wks and 2410 +/- 890 g, respectively, at the age of 37.8 +/- 4.4 wks postconceptionally. Whilst potassium, calcium and glucose level is much lower in the cerebrospinal fluid than in the plasma, similar sodium and higher chloride concentration was found in the cerebrospinal fluid. The significant positive correlation between plasma and cerebrospinal fluid glucose and sodium levels proves the lack of a functioning barrier for these compounds. On the other hand, cerebrospinal potassium level varied within a narrow range, independently of the plasma-concentration and the maturity of the studied babies. Pathophysiological implications of the results are further discussed in short.     

The effect of phenobarbital on asphyxia in the newborn monkey.

This study characterizes the circulatory changes associated with asphyxia in the newborn monkey and examines the effect of phenobarbital on asphyxia. The time to last gasp and duration of total asphyxia as well as heart rate at the start of resuscitation were the same in the phenobarbital-treated and untreated infants. Initial cardiac output was the same in both groups; there was a profound drop in cardiac output with asphyxia which was the same in both groups. Organs which preferentially receive a greater percentage of cardiac output during asphyxia are heart, total brain, and adrenal glands. Organs receiving a decreased percentage of cardiac output during asphyxia are kidneys, liver, and gastrointestinal tract. Cerebral hemisphere flow as a percentage of cardiac output is maintained during asphyxia, whereas paleoencephalon flow as a percentage of cardiac output increases significantly. These data confirm the circulatory redistribution of cardiac output in response to asphyxia described previously in the monkey fetus. The treated infants did not show the prolongation of time to last gasp reported in the monkey fetus; the dose of phenobarbital we used, although adequate to produce sedation, may have been too low to demonstrate the protective effect.     

Plasma concentrations of phenobarbital in the treatment of seizures in newborns.

The plasma concentration of phenobarbital given as anticonvulsive treatment in the newborn period has been followed in 18 infants. With constant daily doses, the drug accummulated for at least 5 days. After intramuscular injection of a single dose, 90% of the peak concentration was reached within 4 hours in 8 of the 10 infants. The peak concentration (in mug/ml) approximately equalled 1.3 x the dose (in mg/kg). Absorption after oral administration was less reliable. In 12 of the infants the clinical course allowed attempts to evaluate the anticonvulsive effect of phenobarbital. In 4 cases the convulsions continued. In those 8 infants where phenobarbital seemed to be effective, the approximate range of phenobarbital concentration when convulsions ceased was 12-30 mug/ml. Phenobarbital half-life ranged between 59 and 182 hours. In some infants the rate of phenobarbital disappearance from the plasma varied considerably from day to day. The pathological conditions causing seizures probably influence the distribution, metabolism and excretion of the drug. For the often seriously ill infants with convulsions it is therefore difficult to construct rational maintenance dose schedules, and optimal dosage must be based on repeated determinations of the plasma concentration.     

Cerebrospinal fluid and plasma levels of vitamin C in children

Vitamin C (ascorbic acid) levels in cerebrospinal fluid (CSF) and plasma from 67 children, in whom lumbar puncture had to be performed for medical reasons, are reported in this preliminary paper. 14 children of this group show normal CSF laboratory values and serve as controls. Vitamin C concentrations in CSF of controls are on average 2.5-3-times higher (30.1 +/- 6.3 mg/l) than the pertaining values in their plasma (12.2 +/- 4.9 mg/l). Significant differences are exhibited by premature and term babies, which have up to 16-times higher values of vitamin C in CSF than in plasma. Furthermore CSF vitamin C is 4-5 times higher in premature babies than in schoolchildren of our group (118.2 +/- 65.9 versus 28.3 +/- 3.0 mg/l). Another interesting finding in this study is a significant decrease of CSF vitamin C in cases of acute purulent meningitis (12.3 +/- 4.8 versus 30.1 +/- 6.3 mg/l, p less than 0.05). These results, in connection with reports about high vitamin C concentrations in brain tissue, particularly in prematures, make one suspect important functions of this vitamin in physiological and pathological mechanisms in the central nervous system.     

Side effects of phenobarbital in toddlers; behavioral and cognitive aspects.

Cognitive and behavioral effects of phenobarbital in toddlers were assessed in a randomized, placebo-controlled study of patients who had had a febrile seizure. There were no significant differences in IQ (Binet or Bayley Scales) between placebo and phenobarbital groups after eight to 12 months of therapy. However, detrimental effects of phenobarbital were found in memory, for which serum level influenced scores, and in comprehension, in that length of treatment time affected performance. Hyperactivity was not seen. Behavioral changes, reported by parents, were increased fussiness and a characteristic disturbance of sleep. These changes varied in severity and were classified as transient, dose related, or unacceptable. After 12 months in the study, most parents could not distinguish between phenobarbital and placebo. Our data suggest that although most toddlers do not have major side effects from phenobarbital therapy when treated for a year, serum levels and length of time on phenobarbital should be kept at a minimum to reduce negative cognitive and behavioral effects.     

Exchange transfusion treatment in a newborn with phenobarbital intoxication.

A comatose, 14-day-old boy was referred to our emergency department (ED) after an overdose of phenobarbital, which was used for the treatment of long-standing jaundice. Plasma phenobarbital concentration was 112.4 microg/ml before treatment. One hour after giving albium transfusion, an exchange transfusion, which took about 45 minutes, was performed. Volume of exchange was 400 ml (volume of exchange (ml) = 2 x 85 ml/kg). After the exchange transfusion, the phenobarbital concentration decreased to 50.84 microg/ml. At clinical and laboratory follow-up, the patient recovered fully. This case suggests that exchange transfusion is an effective and successful treatment for phenobarbital intoxication in newborn.     

Death in an adolescent following an overdose of acetaminophen and phenobarbital.

A 13-year-old epileptic girl took an overdose of acetaminophen (Tylenol) and phenobarbital. Hepatic encephalopathy developed and the patient died eight days later. Necropsy revealed extensive centrilobular necrosis of the liver, degeneration of the renal distal tubules, and infarcted and demyelinated foci throughout the white matter of the cerebral cortex. Electron microscopy of intact hepatocytes showed a proliferation of both smooth and rough endoplasmic reticulum consistent with enzyme induction from phenobarbital. To our knowledge, this is the first reported death in a child in the United States as a result of acetaminophen and should alert physicians to an expected increase in acetaminophen toxicity as the drug becomes more widely available.     

Absorption of phenobarbital after the intramuscular administration of single doses in infants.

Blood concentrations of phenobarbital, following an intramuscular administration of a single large dose of approximately 10 mg/kg, were studied in 39 infants. A rapid rise was obtained with a mean concentration of 9.30 mug/ml at 30 minutes, 12.76 mug/ml at 90 minutes, and a mean peak concentration of 13.28 mug/ml, which was reached in most cases within 2 hours of injection or less. Cerebrospinal fluid values in 13 patients averaged half the blood phenobarbital concentrations.     

Age-dependent differences in the relationship between plasma and brain extracellular fluid concentrations of magnesium after MgSO4 infusions in miniswine.

Magnesium is a potential neuroprotective agent in the treatment of head injury and ischemia whose efficacy is likely determined by increases in brain extracellular fluid (ECF) magnesium, which in turn depends on its concentration in plasma. The objectives of this study were to: 1) examine the effects of increasing plasma magnesium concentration ([Mg]plasma) to 4-6 mM on brain ECF magnesium concentration ([Mg]ECF) and 2) determine whether maturational changes occur in the transfer of magnesium into brain ECF for newborn and more mature (approximately 1 month old) miniswine. Increases in [Mg]plasma by systemic administration of MgSO4 resulted in similar maximal elevations in brain [Mg]ECF for both age groups (193+/-76% versus 253+/-106% of control for newborn and 1-month-old miniswine, respectively). Calculations of half-lives (t1/2) for the increase and decrease in magnesium concentration (t1/2 uptake and t1/2 clearance) were used to characterize magnesium kinetics in plasma and brain ECF. Plasma magnesium uptake was shorter in 1-month-old (t1/2 = 11.1+/-0.9 min) compared with newborns (12.9+/-1.7 min, p < 0.05). The faster increase in [Mg]plasma probably contributed to a faster uptake of brain [Mg]ECF in 1-month-old compared with newborn swine (t1/2 uptake = 27.9+/-12.8 versus 46.0+/-20.9 min, respectively, p < 0.05). Although plasma magnesium clearance was shorter in 1-month-old swine compared with newborn (t1/2 = 34.3+/-7.0 versus 74.7+/-33.7 min, respectively, p < 0.05), the clearance of magnesium from the brain ECF was similar for each age group. Reductions in blood pressure and heart rate occurred during hypermagnesemia and were similar in each age group. This study shows that acute elevations in [Mg]plasma to 4-6 mM result in similar relative increases in brain [Mg]ECF for both newborn and 1-month-old miniswine. However, there are maturational differences, as demonstrated by the faster rate of magnesium uptake into the ECF observed in the older miniswine.     

Brain vasoactive effects of phenobarbital during hypertension and hypoxia in newborn pigs.

Phenobarbital in anticonvulsant concentrations has been shown to lower cerebral blood flow (CBF) during hypertension and to reduce the incidence of intraventricular hemorrhage in newborn beagles after hypertensive insult. We proposed that hypoxic dilatation of brain blood vessels might alter the effect of phenobarbital (PBS) on blood flow during hypertension. Thus, in 14 control and nine PBS-treated 1- to 2-d-old newborn piglets, the radio-active microsphere technique was used to determine CBF during 1) steady state (SS), 2) hypertension (HT), and 3) HT plus hypoxia of 5 min duration. In seven controls and in four PBS-treated piglets, CBF was also determined during recovery from hypoxia. PBS was infused after SS in a 20-mg/kg dose, and serum levels were obtained 30 min later. Blood pressures were not significantly different between groups when compared during SS, HT, hypoxia, and recovery. Similarly, pH, PO2, and PCO2 were not significantly different between groups when compared during normoxia and hypoxia, and hematocrits were maintained by transfusions after reference sample withdrawals. CBF in control animals increased significantly during HT and remained significantly higher than SS values throughout the 5 min of hypoxia and into the recovery period. In PBS-treated piglets, however, there was no significant increase in CBF during HT. Blood flows also stayed at SS levels during HT plus 5 min hypoxia and recovery from hypoxia. Thus, in newborn piglets, PBS lowered CBF during HT. Furthermore, this blood flow lowering effect persisted during hypoxia, preventing compensatory increases in CBF that might have otherwise occurred.(ABSTRACT TRUNCATED AT 250 WORDS)