Opiate-induced respiratory depression in pediatric patients.

OBJECTIVE: To describe 15 pediatric patients with opiate-induced respiratory depression. DESIGN: In-house adverse drug reaction (ADR) report forms were reviewed to identify any patients with suspected opiate-induced respiratory depression. Case review was then performed. SETTING: Large pediatric teaching hospital with regional specialties. PATIENTS: Fifteen patients aged 2 days to 17 years (median 14 mo). MAIN OUTCOME MEASURES: Respiratory depression resulting in apnea, hypoxia, cyanosis, reduced respiratory rate, or the need for naloxone following or during opiate administration was recorded. RESULTS: Fifteen patients experienced some degree of respiratory depression over the 3 years of surveillance. Treatment included naloxone (12 patients), admission to the pediatric intensive care unit (8), ventilation (5), and reduction in dosage (1). Predisposing factors for respiratory depression included an age of less than 1 year, excessive dosage, concurrent medical problems, concurrent drugs, and medication errors. CONCLUSIONS: Opiate-induced respiratory depression in pediatric patients occurs infrequently, but may have serious consequences. Opiates are potent analgesics that children require and should receive. Safe use of opiates in pediatric patients, however, depends on the dosage, route and method of administration, consideration of any predisposing factors, and adequate monitoring. This article highlights some of the problems with opiate use in children and gives some recommendations on how these problems may be prevented.

Therapeutic drug monitoring of anticonvulsants. State of the art.

There is considerable interindividual variation in the relationship between control of seizures and the serum anticonvulsant concentration. The minimum effective serum concentration is dependent on the type and severity of the epilepsy, and varies from patient to patient. The therapeutic range should be used as a guide to adjust the dose in order to further improve seizure control or reduce toxicity; the latter is more likely with higher serum concentrations, but can also be present when concentrations are low. A request for the serum concentration of an anticonvulsant should be made only for good clinical reasons, and an interpretation of that concentration can only be made if all the relevant clinical details are available. Indications for the measurement of serum anticonvulsant concentrations include poor seizure control, toxicity, suspected gross noncompliance, status epilepticus and seizure control, toxicity, suspected gross noncompliance, status epilepticus and the elapse of 2 to 4 weeks after the initiation of therapy. Additional drug therapy, pregnancy or illness may alter drug disposition in a well controlled patient and therapeutic drug monitoring may, therefore, help to prevent seizures secondary to these changes. The measurement of anticonvulsants in saliva as opposed to serum may be of benefit in some patients.

Morphine metabolism in children.

1. The metabolism of morphine was studied in 12 children and nine premature neonates on a continuous infusion of morphine (10-360 micrograms kg-1 h-1). 2. The mean plasma clearance of morphine was significantly higher in children than neonates (25.7 and 4.7 ml min-1 kg-1, respectively) (P less than 0.01). 3. All the neonates and children had detectable concentrations of morphine-3-glucuronide (M3G) in plasma. All the children and five neonates had detectable concentrations of morphine-6-glucuronide (M6G) in plasma or urine. 4. The M3G/morphine ratios in plasma and urine, and M6G/morphine ratios in urine were significantly higher in children than neonates (P less than 0.01), suggesting that morphine glucuronidation capacity is enhanced after the neonatal period. 5. There was no difference in the M3G/M6G ratio in children and neonates, indicating a parallel development of both glucuronidation pathways.

Plasma vitamin K1 concentrations in cystic fibrosis.

Plasma concentrations of vitamin K1 were similar in 37 patients with cystic fibrosis (median 46 ng/l) and 16 controls (49 ng/l). The plasma concentrations were lower than those previously described in adults, but higher than in neonates. There was no association between an increase in prothrombin time and vitamin K1 plasma concentration.

Low dose prednisolone in nephrotic syndrome.

Sixteen patients with steroid responsive nephrotic syndrome were treated on 29 separate occasions with a low dose of prednisolone (30 mg/m2/day). All went into remission within 14 days. The duration of remission in the six patients who had had previous relapses treated with a higher dose of prednisolone was similar.

Relapse of Hodgkin's disease with anaemia and weight loss.

Two children previously treated for Hodgkin's disease had relapse associated with anaemia and weight loss but no other abnormal clinical findings. It was not possible to confirm the diagnosis by bone marrow aspirate or trephine and in each case laparotomy was required in order to establish a histological diagnosis.

Accidental actinomycin D overdosage in man, a case report.

Although actinomycin D is a relatively old cytotoxic agent, relatively little is known about its toxicity in man in comparison with some of the newer cytotoxic agents that have been extensively investigated. We wish to describe a case where an overdose of actinomycin D was inadvertently administered.

The relationship between inhibition of vitamin K1 2,3-epoxide reductase and reduction of clotting factor activity with warfarin.

1 The effect of low dose steady state warfarin (0.2 mg and 1 mg daily) on clotting factor activity and vitamin K1 metabolism was studied in seven healthy volunteers. 2 Steady state plasma warfarin concentrations were 41-99 ng ml-1 for the 0.2 mg dose and 157-292 ng ml-1 for the 1 mg dose. 3 There was a significant prolongation of the mean prothrombin time (0.9 s) after 1 mg warfarin daily, but no significant change in prothrombin time after 0.2 mg warfarin daily. There was no significant change in individual clotting factor activity (II, VII, IX or X) with either dose of warfarin. 4 Following the administration of a pharmacological dose of vitamin K1 (10 mg), all seven volunteers had detectable levels of vitamin K1 2,3-epoxide with both doses of warfarin (Cpmax 31-409 ng ml-1). 5 Both the Cpmax and the AUC for vitamin K1 2,3-epoxide were significantly greater on 1 mg of warfarin daily than 0.2 mg daily (P less than 0.01). 6 The apparent dissociation between inhibition of vitamin K1 2,3-epoxide reductase and reduction of clotting factor activity, produced by warfarin, may reflect the insensitivity of functional clotting factor assays to a small reduction in clotting factor concentration.

Prescribing habits for children with acute gastroenteritis: a comparison over 5 years.

Prescriptions for children with acute gastroenteritis, requiring hospital admission were compared for the first 3 months of 1980 and 1985. Thirty-three children were identified in 1980 compared with 30 in 1985. Of these, 20 were prescribed a total of 46 drugs by their general practitioners in 1980 compared with 12 and 15 respectively in 1985. Although general practitioners still prescribed more medicines than did hospital doctors the improvement over 5 years was statistically significant (P less than 0.05).

Enantiomers of warfarin and vitamin K1 metabolism.

The effect of the individual enantiomers of warfarin at steady state (1 mg daily) was investigated in five healthy volunteers. Both enantiomers produced a significant increase in prothrombin time, but the increase with S warfarin (1.8 +/- 0.8 s, mean +/- s.d.) was greater than with R warfarin (1.0 +/- 0.3 s), despite lower steady state plasma concentrations of S warfarin, due to its more rapid clearance. Following the administration of vitamin K1, the maximum plasma concentration and area under the plasma concentration time curve values for the metabolite vitamin K1 2,3-epoxide were greater after S warfarin than after R warfarin. The greater anticoagulant potency of S warfarin is reflected by a greater degree of inhibition of vitamin K1 epoxide reductase.

Stereoselective interaction between the R enantiomer of warfarin and cimetidine.

The stereoselectivity of the pharmacokinetic interaction between warfarin and cimetidine was investigated in eight healthy volunteers. The warfarin enantiomers were given separately as single doses (15 mg) alone and during chronic administration of cimetidine (1 g day-1). Cimetidine did not interact with S warfarin but there was an interaction with the R enantiomer of warfarin. Cimetidine caused a significant increase in the mean plasma half-life of R warfarin (from 47.8 h to 57.8 h) and a significant decrease in its mean plasma clearance (from 2.3 to 1.7 ml h-1 kg-1) (P less than 0.02). Administration of a pharmacological dose of vitamin K1 together with the enantiomers of warfarin was necessary clinically and resulted in elevation of vitamin K1 2,3-epoxide concentrations, which were similar in each case.

Abnormal vitamin K metabolism in the presence of normal clotting factor activity in factory workers exposed to 4-hydroxycoumarins.

The case histories of two patients exposed to the novel anticoagulants brodifacoum and difenacoum are reported. Abnormal vitamin K1 metabolism, as indicated by elevated vitamin K1 2,3-epoxide plasma concentrations after i.v. administration of vitamin K1, could be detected for more than 18 months after exposure to the anticoagulants. There was a marked prolongation of prothrombin time (greater than 50 s) in both cases, at the time of exposure. However, subsequent haematological investigations (prothrombin time and vitamin K-dependent clotting factor activity) have been shown to be normal in both cases for at least 18 months. These cases confirm the long-acting nature of brodifacoum and difenacoum and present an apparent dissociation between the effect of coumarin anticoagulants on vitamin K1 metabolism and clotting factor activity.

Vitamin K1 metabolism in relation to pharmacodynamic response in anticoagulated patients.

The disposition of, and pharmacological response to, a single intravenous dose of vitamin K1 (10 mg) was studied in eleven patients on daily warfarin therapy. The pharmacokinetics of vitamin K1 in patients were similar to those reported previously in healthy volunteers, terminal half-life 1.7 h. All patients had been taking warfarin for at least 3 months. Steady state warfarin plasma concentrations ranged from 0.5 to 1.4 micrograms ml-1. Prothrombin complex activity ranged from 15 to 28.5%. There was considerable inter-individual variation in pharmacodynamic response as expressed by prothrombin complex activity (PCA) and Factor VII. The maximum values for PCA and Factor VII were reached at 24-96 h and 24-48 h, respectively, after the administration of vitamin K1. Vitamin K1 (10 mg) has a long duration of action (greater than 168 h) in terms of clotting factor synthesis in patients on steady state warfarin. All the patients on warfarin had measurable levels (CPmax 0.3-1.2 micrograms ml-1) of vitamin K1 2, 3-epoxide. There was a significant correlation between the pharmacodynamic response as expressed by change in % PCA and the AUC for vitamin K1 2,3-epoxide (P less than 0.05).