Pharmacokinetics and pharmacodynamics of cimetidine and metabolites in critically ill children

Cimetidine and antacids are the mainstays of therapy for the prophylaxis of stress-induced ulceration in critically ill children. Previous cimetidine dosing recommendations have been empiric because of a lack of knowledge about cimetidine disposition kinetics in children. Thirty children, mean age 9 +/- 3.2 years, were admitted to the study with the following primary diagnoses: closed head injury (23 patients), sepsis (four), gunshot wound (two), and bleeding gastric ulceration (one). The mean dose of cimetidine was 26 mg/kg/day, administered intravenously over 15 minutes in four divided doses. Cimetidine disposition was best described by a biphasic elimination curve with t1/2 values for cimetidine, cimetidine sulfoxide, and hydroxymethyl cimetidine of 1.39, 2.6, and 4.7 hours, respectively. Cimetidine plasma concentrations were maintained at greater than or equal to 0.5 microgram/ml for a significantly longer time in patients who received greater than or equal to 20 mg/kg/day. Most patients had a plasma cimetidine concentration below 0.5 to 1.0 microgram/ml 4 hours after infusion. The mean apparent volume of distribution and total body clearance for cimetidine were 1.23 L/kg and 10.4 ml/min/kg, respectively. A significant correlation was found between age and either apparent volume of distribution (r = 0.76, P less than 0.001) or total body clearance (r = 0.75, P less than 0.001). No significant correlation between cimetidine concentrations in either plasma or gastric juice and gastric pH could be determined. However, seven of nine patients who received only cimetidine had a gastric pH of greater than or equal to 4 at 2 hours after infusion when the plasma cimetidine concentration was greater than or equal to 1.0 or the gastric juice concentration was greater than or equal to 2.0 microgram/ml. The mean gastric pH was 2.2 at 6 hours, when plasma and gastric juice concentrations of cimetidine were greater than or equal to 1.0 microgram/ml. On the basis of our data, a cimetidine dosage of 20 to 30 mg/kg/day administered in six divided doses should provide for average steady-state plasma cimetidine concentrations of 1.3 to 2.0 micrograms/ml.     

Intravenous metronidazole in the newborn

Twenty four neonates at high risk of anaerobic sepsis were treated with intravenous metronidazole, 7.5 mg/kg, 8 hourly, for a mean period of 5 days. The highest observed concentration after the first dose (mean +/- SD) 9.6 +/- 4.0 mg/l (56.1 +/- 23.4 mumol/l) was significantly lower (P less than 0.001) than the highest observed concentration after the final dose (mean +/- SD) 19.3 +/- 8.6 mg/l (112.7 +/- 50.2 mumol/l). The overall metronidazole half life was (mean +/- SD) 23.4 +/- 13.1 hours. The half life after the first dose (mean +/- SD) 21.9 +/- 10.1 hours was not appreciably different from the half life after the final dose (mean +/- SD) 21.6 +/- 12.4 hours. The concentrations of the major metabolite of metronidazole (20396RP) also rose appreciably during treatment. No side effects of metronidazole were noted and its extended half life in neonates suggests that less frequent dosage would be appropriate.     

Efficacy of cimetidine for gastric acid suppression in pediatric patients.

The efficacy of oral cimetidine for gastric acid suppression in pediatric patients was examined in a double-blind study. Twenty-seven patients with gastroesophageal reflux-related gastrointestinal symptoms, pulmonary symptoms, or both were given randomly determined doses of cimetidine. Response was evaluated by continuous intragastric monitoring with a pH probe. Twenty-three patients were given cimetidine doses of 5,7.5, and 10 mg/kg; eight of these patients were also given additional doses of 15 mg/kg. Four patients received only 10 and 15 mg/kg, because of previous poor clinical response to the lower dosages. The onset of gastric pH greater than 4 was delayed more than 2 hours in 50% of patients with responses to the 5 mg/kg dose. Of the patients with responses to the 10 mg/kg dose, 75% had showed a rise in gastric pH greater than 4 within 2 hours. With respect to the duration of gastric acid suppression, 70% of patients receiving 5 mg/kg doses and 52% of those receiving 7.5 mg/kg doses did not have a sustained a response for more than 2 hours, whereas 75% of patients receiving 10 mg/kg doses had gastric acid suppression for longer than 2 hours. Of the patients receiving 15 mg/kg doses, 75% had a response for more than 2 hours; 50% of these patients had a response for more than 3 hours. We conclude that recommended doses of cimetidine for children may not be optimal for adequate gastric acid suppression.     

Cefotaxime and desacetylcefotaxime pharmacokinetics in very low birth weight neonates

The single-dose pharmacokinetics of cefotaxime (CTX) and desacetylcefotaxime (dCTX) after a 50.0 mg/kg intravenous dose were evaluated in 18 very low birth weight neonates (13 male; 1015.6 +/- 349.8 gm; 28.4 +/- 2.4 weeks gestational age) during the first week of life. Microanalytic high-performance liquid chromatography was used to quantitate both CTX and dCTX from serum. A two-compartment open model best characterized the disposition of CTX during a 24-hour post-dose period. The disposition of dCTX was adequately characterized by a one-compartment model. The elimination half-life, apparent steady-state volume of distribution, and total body clearance of CTX (mean +/- SEM) were 4.44 hours, 0.461 +/- 0.027 L/kg, and 0.074 +/- 0.003 L/hr/kg, respectively. Peak concentrations (mean +/- SD) of dCTX (17.96 +/- 5.54 mg/L) occurred at 0.6 to 8.3 hours (5.9 +/- 1.9 hours) after CTX administration, and the apparent elimination half-life of dCTX was 9.36 hours. Comparison of CTX and dCTX pharmacokinetic parameters between very low birth weight neonates who weighed less than 1000 gm (n = 9; 703.3 +/- 46.6 gm; 27.0 +/- 0.8 weeks gestational age) and greater than or equal to 1000 gm (n = 9; 1328.8 +/- 48.6 gm; 29.8 +/- 0.5 weeks gestational age) revealed no significant differences, but significant linear correlations were found between gestational age and weight versus CTX half-life and total body clearance. Because of the prolonged clearance of both CTX and dCTX in the very low birth weight neonate, a CTX dose of 50 mg/kg every 24 hours may provide effective serum concentrations for susceptible infections outside the central nervous system.     

Pharmacokinetics and antipruritic effects of hydroxyzine in children with atopic dermatitis

We studied the pharmacokinetics and antipruritic effects of hydroxyzine hydrochloride in 12 children, mean age 6.1 +/- 4.6 years, with severe atopic dermatitis. After a single 0.7 mg/kg orally administered dose of the drug, the mean peak serum hydroxyzine concentration of 47.4 +/- 17.3 ng/ml occurred at a mean time of 2.0 +/- 0.9 hours. The mean elimination half-life was 7.1 +/- 2.3 hours, the mean clearance rate was 32.08 +/- 11.05 ml/min/kg, and the mean apparent volume of distribution was 18.5 +/- 8.6 L/kg. The elimination half-life increased with increasing age (r = 0.83). Pruritus was significantly suppressed from 1 to 24 hours after the administration of the dose, with greater than 85% suppression from 2 to 12 hours. The only adverse effect reported was sedation. In a subsequent double-blind, crossover, multiple-dose study of 2 weeks' duration, hydroxyzine 0.7 mg/kg three times daily was as effective as hydroxyzine 1.4 mg/kg three times daily in relieving pruritus and promoting resolution of the skin lesions. The 0.7 mg/kg tid dose caused significantly less sedation than the 1.4 mg/kg tid dose.     

Pharmacokinetics of a single dose of morphine in preterm infants during the first week of life

We studied morphine pharmacokinetics after a single intravenous dose of 0.1 mg/kg in 20 newborn infants, who were born at 26 to 40 weeks of gestation and were less than 5 days of age. In the 10 infants whose gestational age was less than or equal to 30 weeks, the mean (+/- SD) distribution half-life was 50 +/- 35 minutes, elimination half-life was 10 +/- 3.7 hours, and clearance was 3.39 +/- 3.28 ml/kg/min; the corresponding values for the three term infants were 19 +/- 8 minutes, 6.7 +/- 4.6 hours, and 15.5 +/- 10 ml/kg/min, respectively. The data suggested a trend of decreasing values for distribution and elimination half-lives with increasing gestation, but a considerable degree of variation was seen. The morphine clearance rate increased as a function of gestational age at a rate of 0.9 ml/kg/min per week of gestation. Between 18% and 22% of the drug was found to be protein bound. Four hours after the dose, the drug level remained greater than or equal to 12 ng/ml in 8 of 10 infants born at greater than or equal to 31 weeks of gestation. In 8 of 10 infants born at less than or equal to 30 weeks of gestation, similar levels were maintained at 8 hours after the initial dose. We conclude that (1) there is a marked degree of variation in morphine pharmacokinetics during the neonatal period, (2) nearly 80% of the intravenously infused drug remains free, which might explain the high sensitivity to morphine in this age group, and (3) during the first week of age, adequate blood levels can be maintained by administration of morphine at 4- to 6-hour intervals in term infants and at less frequent intervals in very premature infants (less than or equal to 30 weeks of gestation).     

Intravenous nicardipine for treatment of severe hypertension in children.

OBJECTIVE: To examine the effect of intravenous nicardipine in the treatment of children with severe hypertension. METHODS: The medical records of 29 children (mean age 94 months) treated with intravenous nicardipine were retrospectively reviewed. The mean duration of severe hypertension before nicardipine use was 12.5 hours. Most (74%) patients were receiving other antihypertensive agents before nicardipine. RESULTS: The initial nicardipine dose was 0.8 +/- 0.3 microg/kg/min (mean +/- SD). The mean effective dose was 1.8 +/- 1.0 microg/kg/min (range, 0.3 to 4.0). Blood pressure control was achieved within 2.7 +/- 2.1 hours after nicardipine was started. Nicardipine treatment produced a 16% reduction in systolic blood pressure, a 23% reduction in diastolic blood pressure, and a 7% increase in heart rate. Nicardipine was effective as a single agent on 26 (84%) of 31 occasions. Adverse effects included tachycardia, flushing, palpitations, and hypotension. CONCLUSIONS: When administered in the intensive care unit setting with close patient monitoring, intravenous nicardipine effectively lowered blood pressure in children with severe hypertension. Larger prospective studies should be conducted to confirm these findings.     

Intravenously administered labetalol for treatment of hypertension in children.

Thirteen children (ages 9.2 +/- 3.7 years, mean +/- SD) received intravenous doses of labetalol, an alpha 1- and beta-adrenergic blocker, on 15 separate occasions for treatment of hypertension. In 12 of 15 episodes an initial dose of 0.55 +/- 0.34 mg/kg was given; in all 15 a continuous infusion of 0.78 +/- 0.39 mg/kg per hour was utilized for 67.3 +/- 57.1 hours. A significant decrease in systemic blood pressure occurred in all episodes (143/99.1 +/- 17.7/11.1 vs 115.6/72.4 +/- 7.7/9.5; p less than 0.01). A clinically unimportant yet statistically significant decrease in heart rate occurred during labetalol infusion (116.3 +/- 19.8 vs 107.8 +/- 11 beats/min; p less than 0.01). The episodes in children with creatinine clearances greater than 50 (n = 6) were compared with those with creatine clearances less than 20 ml/min per 1.73 m2 (n = 9); similar doses of labetalol were required for control of blood pressure. We conclude that infusion of labetalol is effective for control of blood pressure in children with hypertension, regardless of renal function.     

Use of Intravenous Amiodarone for Postoperative Junctional Ectopic Tachycardia in Children

To assess the efficacy and safety of intravenous (IV) amiodarone for the treatment of postoperative junctional ectopic tachycardia (JET) in children, we retrospectively reviewed 11 patients treated with IV amiodarone for JET between 1/92 and 2/00. Data included heart rate and hemodynamics pre- and post-amiodarone, drug dosage, duration of therapy, and effect. Success was defined as reversion to sinus rhythm or slowing to a hemodynamically stable rate. The mean heart rate prior to amiodarone was 203 bpm, and the mean systolic blood pressure was 64 mmHg. Mean IV amiodarone loading dose was 8.2 +/- 4.0 mg/kg, followed by an infusion in 7 patients at a dose of 12.9 +/- 3.9 mg/kg/day for a duration of 74.3 +/- 46.9 hours. At 1 hour post-load, mean heart rate was 147 bpm and mean systolic blood pressure was 88 mmHg for the group. Three patients were in sinus rhythm, 4 in intermittent sinus rhythm with accelerated junctional rhythm, and 4 patients solely accelerated junctional rhythm. Control of JET persisted in 9 patients. Of the two patients requiring additional treatment, both had received a 5 mg/kg load and neither was on an infusion. Five patients were paced at some point following amiodarone: four to improve hemodynamics and one for late sinus bradycardia. Side effects included hypotension with loading (1) and late sinus bradycardia (1). One patient was discharged on oral amiodarone. Intravenous amiodarone given in doses of 10 mg/kg in two 5 mg/kg increments, followed by an infusion of 10-15 mg/kg/day for 48-72 hours, appears to be safe and effective for postoperative JET in patients who fail conventional therapy or who are hemodynamically unstable. Long-term oral therapy is usually not necessary.     

Metoclopramide pharmacokinetics and pharmacodynamics in infants with gastroesophageal reflux

The pharmacokinetics and pharmacodynamics of metoclopramide oral solution were evaluated in six infants (0.9-5.4 months) with gastroesophageal reflux (GER) following the initial and 10th dose of 0.15 mg/kg administered every 6 h. Metoclopramide pharmacodynamics were assessed by pre- and post-dose comparison of esophageal pH monitoring data and clinical evaluation of improvement in GER symptoms. A significant reduction in the number of episodes of pH less than 4 for greater than 5 min and the longest episode of GER was seen between the predose and 10th dose (steady-state) evaluation periods. Four of the 6 patients had a 75% reduction in reflux time and demonstrated improvement in clinical symptoms by the 10th dose. Metoclopramide pharmacokinetics were best characterized by a one-compartment open model following the first and 10th doses. Metoclopramide serum concentrations (mean +/- SD) ranged from 56.2 +/- 23.5 to 32.7 +/- 13.2 ng/ml within a 6-h dosing interval at steady state. There were no significant differences between the first versus tenth dose values for Tmax (2.0 +/- 0.5 versus 2.2 +/- 0.4 h), Kel (0.14 +/- 0.03 versus 0.17 +/- 0.04 h-1), Vdarea (4.9 +/- 0.4 versus 4.4 +/- 0.6 L/kg), or clearance (0.66 +/- 0.16 versus 0.67 +/- 0.13 L/h/kg). The youngest subject (3.5 weeks) had a metoclopramide t 1/2 of 23.1 h following initial dose, which decreased to 10.3 h at steady-state. Care should be exercised in using the 0.15 mg/kg dose in infants less than 1 month of age as prolonged clearance may produce excessive serum concentrations.     

Oliguria and tolazoline pharmacokinetics in the newborn

Tolazoline treatment of neonates has been reported since 1965. Dosages increased from pulse doses of 1 to 2 mg/kg to continuous infusions of 10 mg/kg X h before neonatal plasma tolazoline concentrations were measured. We developed a microassay for tolazoline and determined neonatal distribution volume, 1.61 +/- 0.21 L/kg, and disposition rate constant (beta), 0.0027 +/- 0.005 min-1 (mean +/- SEM). Half-life (gamma) ranged from 1.47 to 41.25 (median = 4.43) hours and correlated inversely with urine output (x); y (h) = -0.46 + 7.63/x (mL/kg X h), r = .61, P less than .05. The highest plasma tolazoline concentration in a neonate was 20.3 mg/L. Lethal tolazoline concentrations in lambs ranged from 21.8 to 56.8 mg/L. Initial tolazoline concentrations during infusions and after 1- to 2-mg/kg pulse doses ranged from 0.35 to 2.3 mg/L and PaO2 increased greater than or equal to 15 mm Hg in 64% of 14 treatments. The average neonatal pharmacokinetics predict that each 1 mg of tolazoline HCl per kilogram pulse dose will increase the plasma concentration of tolazoline base by 0.5 mg/L. The plasma concentration should remain constant with infusion dose increments of 0.16 mg of tolazoline HCl per kilogram per hour for every 1.0-mg/kg loading dose. Tolazoline dose requirements for specific patients will vary, especially with renal dysfunction. Reduced tolazoline doses were used to treat two patients, concentrations remained constant, and PaO2 was maintained. Tolazoline doses derived from neonatal kinetics are less than current infusion doses and may avoid high concentrations.     

Continuous gastric pH measurement in young and older healthy preterm infants receiving formula and clear liquid feedings

Gastric pH was recorded with an intragastric pH electrode for 12 h in two groups of healthy, preterm infants with similar birth weights (range 1.4 to 2.0 kg). Group I infants (n = 13) were less than 7 days old and Group II infants (n = 10) were 7-15 days old. Infants were fed three formula feedings and one clear liquid feeding during the study. In Group I, mean gastric pH measured at 15-min intervals was above 4.0 for 3 h after either feeding. In Group II mean gastric pH was lower particularly after clear liquid feedings, where it remained below pH 4.0 for the entire 3-h postprandial period. The percent of monitored time at gastric pH less than 4.0 was low in Group I--15.2 +/- 4.2% and 20.6 +/- 6.4% after formula and clear liquid, respectively. The percent time was greater in Group II--42.7 +/- 8.0% and 61.9 +/- 7.3% after formula and clear liquid, respectively. In the younger preterm infant, gastric pH does not appear sufficiently low to support peptic activity.     

Dose-response relationship of doxapram in the therapy for refractory idiopathic apnea of prematurity

Eighteen infants with idiopathic apnea of prematurity refractory to therapeutic levels of aminophylline were treated with incremental doses of doxapram beginning at 0.5 mg/kg/h. Continuous recording of heart rate, thoracic impedance, and transcutaneous PO2 demonstrated that 47% of the infants satisfied objective response criteria at the lowest dose, 53% responded at 1.0 mg/kg/h, 65% at 1.5 mg/kg/h, 82% at 2.0 mg/kg/h, and 89% at the highest allowed dose of 2.5 mg/kg/h. The mean serum doxapram concentration at the response dose was 2.9 +/- 1.3 micrograms/mL, and all infants who responded had levels greater than 1.5 micrograms/mL. BP was significantly elevated at doses higher than 1.5 mg/kg/h (P less than .05). Minute ventilation significantly increased and PCO2 significantly decreased as the doxapram dosage was increased (P = .02). Terminal elimination half-life was 9.9 +/- 2.9 hours. When doxapram is used for treatment of refractory neonatal apnea the starting dosage should be no more than 0.5 mg/kg/h.     

Effects of antenatal steroids on protein metabolism in preterm infants on the first day of life

OBJECTIVE: To analyze, in an existing cohort of infants, whether antenatal administered corticosteroids influence protein metabolism in preterm infants on the first day of life. Study design Three groups of infants were studied. The mothers of 25 infants had received 2 or more doses of corticosteroids, the mothers of 5 had received 1 dose, and there was no antenatal steroid exposure for 8 infants. Within a few hours after birth, a double-tracer leucine infusion was started by intravenous and intragastric routes and continued for 5 hours while the infants received only intravenous glucose. RESULTS: The plasma alpha-keto-isocaproic acid (KIC) enrichment (mol percent excess, MPE) from the intravenous tracer was not different between infants who reveived no antenatal steroids (8.58+/-1.64), 1 dose (7.60+/-0.78), and 2 or more doses (7.61+/-1.29). From the intragastric tracer, the plasma KIC enrichment from the intragastric tracer was different among the 3 groups, 7.62+/-2.35 for 0 doses, 5.78+/-0.85 for 1 dose, and 5.53+/-1.58 for 2 or more doses of antenatal steroids.Plasma KIC enrichment from the intravenous tracer was significantly higher than from the intragastric tracer in infants who received antenatal steroids, whereas there was no difference in infants who had not received antenatal steroids. Plasma leucine enrichment showed the same results. CONCLUSIONS: Antenatal corticosteroid administration to the fetus has no effect on whole-body leucine metabolism on the first day of life. However, it is associated with an increase in splanchnic leucine uptake at birth.     

Pharmacokinetics, outcome of treatment, and toxic effects of amphotericin B and 5-fluorocytosine in neonates

To determine the pharmacokinetics of amphotericin B and 5-fluorocytosine in neonates, we measured serum concentrations at first dose and after 5 days of therapy by high-performance liquid chromatography in 13 neonates (mean birth weight 1.2 +/- 0.8 kg). The dose of amphotericin B was serially increased from 0.1 to 0.5 mg/kg/day in 10 infants but was decreased from 0.8 to 1.0 to 0.5 mg/kg/day in three infants. Amphotericin B concentrations were not detectable in infants receiving 0.1 mg/kg/day. Amphotericin B cerebrospinal fluid concentrations were 40% to 90% of serum values obtained simultaneously. Serum concentrations after oral administration of 5-fluorocytosine (dose 25 to 100 mg/kg/day) were detectable in all infants. We found extreme interindividual variability for the half-life, volume of distribution, and clearance for both drugs. Four infants had minimal elimination for both drugs between doses, a finding that correlates with rises in serum creatinine (greater than 0.4 mg/dl, 40 mumol/L) and blood urea nitrogen (greater than 10 mg/dl, 3.6 mmol/L). We recommend that the dose of amphotericin B given on the first day of treatment be greater than the usual testing dose of 0.1 mg/kg/day. We also recommend an initial 24-hour dosing interval for amphotericin B and 5-fluorocytosine. Serum drug concentrations may need to be monitored in high-risk, low birth weight infants.     

Factors influencing final/near-final height in 12 boys with central precocious puberty treated with gonadotrophin-releasing hormone agonists. Italian Study Group of Physiopathology of Puberty

Gonadotrophin-releasing hormone agonists (GnRHa) have been demonstrated as the therapy of choice for central precocious puberty (CPP). Few studies have provided male patients' adult height data. In our multicenter study we evaluated long-term effects of different GnRHa preparations and final/near-final height (FH) in 12 boys with CPP and analyzed the factors influencing FH. Patients' mean chronological age at the time of diagnosis was 7.6 +/- 0.9 yr. Three patients were treated only with triptorelin at a mean dose of 90 microg/kg i.m. every 28 days. Nine patients initially received buserelin (at a mean initial dose of 53.4 microg/kg/day i.n. divided into 3-6 equal doses) or buserelin (at a mean dose of 36.7 microg/kg/day s.c.) and were subsequently switched to triptorelin. The GnRHa therapy was continued for 4.1 +/- 0.6 yr (range 2.9-5.4). The mean predicted adult height increased from 169.9 +/- 4.2 cm at diagnosis to 180.7 +/- 6.0 cm at the end of treatment. Mean FH was 176.1 +/- 6.1 cm (170.1-190.7), corresponding to mean SDS(CA) 0.4 +/- 0.8 (-0.6/2.5), mean SDSBA 0.2 +/- 0.9 (-0.6/2.4) and mean corrected SDS for target height of 0.4 +/- 0.6 (-0.8/1.2). Multiple regression analysis revealed that FH was mainly influenced by target height and height at discontinuation of GnRHa therapy. The present data indicate that GnRHa therapy significantly improves growth prognosis in boys with CPP and fully restores genetic height potential.     

Acute metabolic effects of human growth hormone on 15N-nitrogen balance in patients with thalassaemia as compared to patients with other types of short stature

The acute response to various doses of human growth hormone (hGH) was determined in short patients with thalassaemia and compared to that in patients with classic growth hormone deficiency and Turner's syndrome. Nitrogen balance was analyzed using the stable isotope 15N. While patients with growth hormone deficiency responded with a marked nitrogen retention (+2.9 +/- 0.4 to +6.1 +/- 0.6 mg 15N/kg) to small doses of hGH (2 x 3 IU/m2), those with Turner's syndrome had a higher basal balance, but responded much less (+3.1 +/- 0.7 to +3.7 +/- 1.8 mg 15N/kg). They required a double dose of hGH (2 x 6 IU/m2) to achieve a significant retention (+4.1 +/- 1.0 to +7.1 +/- 0.4 mg 15N/kg). The thalassaemic patients responded still less than the patients with Turner's syndrome to 2 x 6 IU/m2 (+7.7 +/- 0.3 to +8.0 +/- 0.4 mg 15N/kg), and even hGH doses up to 2 x 12 IU/m2 had little effect, indicating a relative resistance to hGH. In conclusion, no or little effect is to be expected from long-term hGH treatment at low doses in thalassaemic patients. When it is decided to treat these patients, the dose should be about 4 times higher than a regular replacement dose in growth hormone deficiency.     

Interactive ventilatory effects of two respiratory stimulants, caffeine and doxapram, in newborn lambs.

Caffeine and doxapram are two respiratory stimulants used in the treatment of apnea in newborns. When used concurrently, these drugs may produce interactive effects on the control of breathing in the newborn. The ventilatory effects of these drugs, given alone or together, were measured during 150 min of drug infusion in two groups of awake lambs 2-5 days old. The first group (n = 5) received a caffeine loading dose of 10 mg/kg followed by a maintenance dose of 0.1 mg/kg/h and incremental doses of doxapram: 0.25, 0.5, 1.25 and 2.5 mg/kg/30 min. The second group (n = 5) received a doxapram loading dose of 5.5 mg/kg followed by a maintenance dose of 1 mg/kg/h and incremental doses of caffeine: 2.5, 5.0, 7.5 and 10.0 mg/kg/30 min. In the first group, ventilation increased after the caffeine loading dose from 566 +/- 55 to 680 +/- 74 ml/kg/min (plasma caffeine = 14.7 +/- 1.6 mg/l) and progressively increased with the addition of incremental doses of doxapram up to 1,000 +/- 108 ml/kg/min at 2.5 mg/kg of doxapram (p less than 0.001 compared to baseline and caffeine loading dose). In contrast, in the second group, the doxapram loading dose markedly increased ventilation from 582 +/- 50 to 936 +/- 75 (p less than 0.002 and p less than 0.04 compared to caffeine loading dose) at plasma doxapram of 5.3 +/- 0.8 mg/l, but incremental doses of caffeine had no effects. We conclude that doxapram exerts a brisk and powerful respiratory stimulant effect and produces an additional dose-dependent ventilatory response when added to caffeine.     

Metoclopramide in gastroesophageal reflux of infancy

This study examined the effect of metoclopramide on lower esophageal sphincter (LES) pressure, and frequency and duration of reflux episodes in 28 children (mean age (+/- SD) 9 +/- 11 months) referred for evaluation of gastroesophageal reflux (GER). Esophageal manometry was performed before and after one intravenous dose of metoclopramide (0.125 mg/kg), and esophageal pH was monitored over a 24-hour baseline period, followed by oral metoclopramide therapy (0.125 mg/kg four times a day, for 24 hours.) During pH monitoring, patients received diet for age and were kept in the prone position with the head elevated 45 degrees while sleeping. Eight patients entered a 6-month double-blind, placebo-controlled trial of metoclopramide. Metoclopramide significantly (P = 0.04) increased end-expiratory LES pressure, from 14.9 +/- 7.5 mm Hg to 18.6 +/- 6.8 mm Hg. However, there was a significant (P less than 0.05) increase in the number of reflux episodes/24 hours, and no significant change in percentage of time pH was less than 4, number of episodes lasting greater than 5 minutes, or the longest episode of reflux between the 24-hour baseline and M periods. LES pressure did not correlate well with any of these measurements (r = 0.2). In the controlled trial, the three patients receiving metoclopramide, but none of those receiving placebo, were withdrawn by their parents because of exacerbation of GER symptoms and marked irritability (P = 0.01). In the placebo group, symptoms improved in four infants, but did not change in one. The use of metoclopramide in the treatment of GER of infancy needs to be reconsidered.     

Pharmacokinetic profile of caffeine in the premature newborn infant with apnea.

The pharmacokinetic profile of caffeine was studied in 32 premature newborn infants with apnea: 12 following a single intravenous dose; 3 after a single oral dose; 7 during treatment with an initial empirical (high) maintenance dose schedule; and 10 during treatment with a revised (lower) dose schedule. Mean (+/- SE) AV d, t 1/2, ke1, and clearance following a single intravenous dose were 0.916 +/- 0.070 1/kg, 102.9 +/- 17.9 hours, 0.009 +/- 0.001/hours and 8.9 +/- 1.5 ml/kg/hour, respectively. Rapid absorption was noted with plasma concentrations of 6 to 10 mg/l achieved within 30 minutes to two hours following an oral dose of 10 mg/kg. Cpss of caffeine in infants given a high empirical dose (11.2 +/- 1.5 mg/kg/day) ranged from 22.5 to 84.2 mg/l (mean = 45.3) whereas a dose schedule based on kinetic data (2.5 mg/kg/day) yielded plasma concentrations ranging from 7.4 to 19.4 mg/l (mean = 13.7). We suggest a loading dose of 10 mg/kg intravenously or orally followed by a daily maintenance dose of 2.5 mg/kg/day administered as a single dose for the treatment and prevention of neonatal apnea.