Low-molecular-weight heparin in thrombotic disease in children and adolescents

PURPOSE: The use of unfractionated heparin (UFH) in children is problematic. In adults, subcutaneous low-molecular-weight heparin (LMWH) is as effective as UFH in the treatment of thrombosis. Because pediatric data are limited, the authors studied the use of enoxaparin in children. PATIENTS AND METHODS: Nineteen children (ages 18 days to 19 years; median age, 40 months) with indications for thrombosis treatment or prophylaxis were studied. Six patients (median age, 33 months), treated on a protocol that included pharmacokinetic studies, initially received enoxaparin 1 mg/kg subcutaneously every 12 hours; doses then were adjusted until target plasma levels of 0.5 to 1.2 anti-Xa U/mL were achieved. The records of 13 additional patients treated with enoxaparin off study were reviewed. RESULTS: In the first six patients, enoxaparin pharmacokinetics was found to be similar to that in adults; once targeted levels were achieved, these remained stable. Among all 19 subjects, 14 had treatment of active thrombosis and 5 underwent thrombosis prophylaxis. For treatment of thrombosis, enoxaparin 1 mg/kg initially was administered subcutaneously every 12 hours. Target anti-Xa levels were achieved with 0.55 to 1.5 mg/kg every 12 hours (mean, 0.98 mg/kg; median, 1.0 mg/kg) in 1 to 7 days (median, 1 day). All patients in the treatment group had clinical improvement within 2 to 5 days, and 12 had follow-up radiological studies that confirmed this. For prophylaxis, enoxaparin was given at 1 mg/kg subcutaneously every 24 hours. No new thrombi were clinically evident in this group. There was no major bleeding with enoxaparin; one patient had transient mild mucosal oozing. CONCLUSION: In this limited population, enoxaparin seems to be a safe, effective, and convenient alternative to UFH in children and adolescents. The adult therapeutic target range of 0.5 to 1.2 anti-Xa U/mL is readily achievable with a starting dose of 1 mg/kg every 12 hours in most children. Initial close monitoring with plasma anti-Xa activity should be done and doses adjusted to achieve target range, particularly in neonates. In the population of this study, enoxaparin seems as effective as UFH in the period immediately thrombotic episode. These results should be confirmed in the ongoing randomized trial comparing LMWH with UFH in children.     

Use of low molecular mass heparin (enoxaparin) in newborn infants: a prospective cohort study of 62 patients

OBJECTIVE: To detail low molecular mass heparin (enoxaparin) use in the first few months of life. DESIGN: Prospective, consecutive cohort of unselected newborn infants. METHODS: Newborn infants were divided into groups by gestational age, underlying condition, hepatic and renal function, thrombocytopenia, and prothrombin time (PT/INR). Groups were analysed with respect to many aspects of enoxaparin treatment using multivariate methods. RESULTS: Sixty two newborn infants received enoxaparin representing 5.39 treatment years. Thromboembolic events (TEs) occurred predominantly in the lower and upper venous system in the presence of indwelling catheters (69%). Preterm infants required longer than full term infants to achieve an anti-(factor Xa) level in the target range (six versus two days). Preterm infants required higher doses of enoxaparin than full term infants to maintain anti-(factor Xa) levels in the target range (2.1 v 1.7 mg/kg/12 h). Infants with congenital heart disease (CHD) required less enoxaparin than those without CHD to maintain an anti-(factor Xa) level in the target range (1.7 v 2.1 mg/kg/12 h). Impaired renal and liver function influenced the number of dose changes needed (three versus one a month). Complete or partial resolution of TE was accomplished in 59% of newborn infants. Four infants developed major bleeds (1.2% per patient year). Recurrent TE and clot extension occurred in three infants (0.9% per patient year). CONCLUSIONS: Preterm infants are more difficult to treat with enoxaparin than full term infants. Enoxaparin appears to be an alternative to treatment with standard heparin or no treatment.     

Experience with intravenous enoxaparin in critically ill infants and children

OBJECTIVE: Subcutaneous administration of enoxaparin is often difficult in special populations, such as premature infants and critically ill children with severe edema. The difficulty achieving adequate anticoagulation in these patients has led to the employment of intravenous enoxaparin in some cases. However, little pharmacodynamic data are available for determining the appropriate dosing and monitoring (by anti-Factor Xa levels) of intravenous enoxaparin. The objective of this study is to report our experience with the use of intravenous enoxaparin in pediatric patients in the intensive care unit. DESIGN: Retrospective review of medical records. SETTING: Single institution pediatric intensive care unit. PATIENTS: All pediatric patients receiving intravenous enoxaparin in the pediatric intensive care unit at Children's Medical Center Dallas between April 1, 2005 and March 31, 2006 were identified using hospital pharmacy records. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Seven patients were identified as having received intravenous enoxaparin while in the intensive care unit. Higher anti-Xa levels were found at 1-2 hrs after administration of intravenous enoxaparin rather than at the 4-6 hrs documented with subcutaneous administration and these levels decreased substantially 6-8 hrs after an intravenous dose. Mean therapeutic dose for children <1 yr of age was 2.40 mg/kg/dose (+/-sd 0.58). For children > or =1 yr of age, the mean therapeutic dose was 1.11 mg/kg/dose (+/-sd 0.13). The mean prophylactic dose for the two children was 0.93 mg/kg/dose (+/-sd 0.43). CONCLUSIONS: Our data show that the pharmacodynamics of intravenous administration is different from subcutaneous administration and deserves further study.     

Adverse effects of meperidine, promethazine, and chlorpromazine for sedation in pediatric patients

A combination of meperidine (M) 25 mg/ml, promethazine (P) 6.5 mg/ml, and chlorpromazine (C) 6.5 mg/ml is widely used to produce sedation in pediatric patients. A dose of MPC 0.1 ml/kg is recommended for cardiac catheterization, but no specific guidelines for dosing or frequency of monitoring have been established for patients undergoing other types of procedures. The adverse effects of MPC were studied prospectively in 95 patients undergoing various procedures. MPC was given parenterally at a dose of 0.07-0.11 ml/kg. Four patients developed respiratory depression. In these patients, the lowest respiratory rate ranged from 12 to 20 per minute. The lowest pulse rate ranged from 92 to 102 per minute. Three patients had received recommended or lower than recommended doses of MPC. One who received MPC 0.07 ml/kg developed respiratory arrest within 30 minutes; another required naloxone, and all recovered within 10 hours. These cases suggest the need for frequent monitoring and specific dosing guidelines for MPC use in pediatric patients.     

Low-dose tissue plasminogen activator thrombolysis in children

PURPOSE: To compare results of low-dose tissue plasminogen activator (TPA) in children with arterial and venous thrombi relative to standard published dosing. METHODS: Subjects consisted of all consecutive children with objectively confirmed thrombi for whom TPA thrombolysis was clinically ordered by the authors. Initial dosing used published standard dose (0.1-0.5 mg/kg per hour). With experience, a low-dose regimen (0.01-0.06 mg/kg per hour) was given in an attempt to derive a minimal effective dose. RESULTS: Thirty-five children were treated with TPA. Either standard or low-dose infusions of TPA resulted in complete thrombolysis of 28 of 29 (97%) acute thrombi, while all 6 chronic thrombi had a partial response. In contrast to the recommended adult-derived dosages of 0.1 to 0.5 mg/kg per hour, the authors found that initial doses of less than 0.01 mg/kg per hour were effective in 12 of 17 patients with acute thrombosis. Neonates required 0.06 mg/kg per hour. Route of administration (local or systemic) did not affect efficacy. Major bleeding occurred in only one extremely preterm infant. Minor bleeding, primarily oozing at intravenous sites, occurred in 27% of children during TPA infusions. Prophylactic unfractionated or low-molecular-weight heparin was infused concomitant with TPA in 42% of the children and did not increase the risk of bleeding. CONCLUSIONS: TPA in very low doses appears to be safe and effective for thrombolysis of acute thromboses in most children, given appropriate patient selection.     

Individualizing gentamicin dosage in patients with cystic fibrosis: limitations to pharmacokinetic approach

Gentamicin serum concentrations were measured in 15 children and seven adults with cystic fibrosis and in eight children with other diseases. Potentially toxic trough concentrations occurred in three of the first nine patients studied, in whom the dose and a 4-hour dosing interval were prescribed on the basis of one-compartment pharmacokinetic calculations (Sawchuck-Zaske method). In contrast, final concentrations were within the accepted target ranges for the remaining 13 patients with cystic fibrosis, in whom the dose and interval were adjusted empirically on the basis of a single pair of "peak" and trough values. The mean +/- SD final dosage required to achieve target concentrations was 13.8 +/- 2.9 mg/kg/d for children and 11.8 +/- 1.1 mg/kg/d for adults (P greater than 0.05), generally divided into four doses at 6-hour intervals. Mean half-life and incremental increase in serum concentration from previous trough to subsequent "peak," an indirect measurement of volume of distribution, were not significantly different between children or adults with cystic fibrosis and pediatric control subjects; there was little interpatient variability in these values. Thus the high dosage requirements were related more to the higher target concentrations than to altered pharmacokinetic disposition in patients with cystic fibrosis. We conclude that the initial dose of gentamicin to achieve a peak of 8 to 12 micrograms/mL and a trough of less than 2.0 micrograms/mL in patients with cystic fibrosis should be 3 mg/kg administered every 6 hours in children and every eight hours in adults. Subsequent dosage adjustment should be made on the basis of a pair of peak and trough serum concentration measurements obtained after the fifth dose. Dosing intervals in this patient population generally should be no shorter than every 6 hours, even if the initial trough concentration is less than 1 microgram/mL.     

Fluctuations of anti-Xa concentrations during maintenance enoxaparin therapy for neonatal thrombosis

Aim: To evaluate fluctuations in anti‐Xa concentrations in infants treated with enoxaparin for thrombosis and describe clinical outcomes. Methods: A retrospective chart review was performed on infants treated with enoxaparin in the Neonatal Intensive Care Unit, and data on enoxaparin doses, anti‐Xa concentrations, clinical characteristics and outcomes were abstracted. Results: Our cohort (n = 26) had a median gestation of 36 (range, 23–41) weeks, birthweight of 2522 (510–3912) grams and 5‐min Apgar score of 8(4–9). Fifteen (57.7%) infants were males. Thromboses was diagnosed at a median age of 22 (range, 1–97) days; enoxaparin was initiated at 27.5 (range, 4–98) days at a mean (SD) dose of 1.4 (0.3) mg/kg every 12 h. Therapeutic anti‐Xa concentrations (0.5–1 U/mL) were achieved at a mean (SD) dose of 2.1 (0.6) mg/kg at 12.5 (12.2) days of treatment. Of the 143 anti‐Xa concentrations, 39 (27%) were within the therapeutic range. During maintenance therapy following initial therapeutic anti‐Xa concentration, 40% concentrations were therapeutic. Minor bleeding was noted in four infants and intracranial bleed in one infant; four infants died. During treatment, thrombocytopenia, renal and hepatic impairment during treatment were noted in 7, 2 and 4 infants, respectively. Clot resolution was observed in 21 (81%) infants. Conclusions: Anti‐Xa concentrations fluctuate during maintenance enoxaparin therapy, with therapeutic levels being achieved only sporadically in young infants. Despite this, enoxaparin appears efficacious in thrombosis resolution. Further studies on the impact of stringent control of concentrations on outcomes in this population are warranted.     

Failure of nasogastric omeprazole suspension in pediatric intensive care patients.

OBJECTIVES: To determine the efficacy of nasogastric administration of omeprazole suspension in raising the gastric pH >4 in critically ill pediatric patients and to determine the most appropriate dosing regimen for this indication. DESIGN: Open-label pharmacodynamic study. SETTING: Twenty-six bed tertiary-care pediatric intensive care unit. PATIENTS: Mechanically ventilated children aged 1-18 yrs with an additional risk factor for stress ulcer formation. INTERVENTIONS: Continuous gastric pH monitoring was performed during administration and dose titration of omeprazole suspension to achieve the goal of gastric pH >4 for greater than 75% of the dosing interval. MEASUREMENTS AND MAIN RESULTS: Data were collected from 18 patients. Subjects were categorized based on the pharmacologic response to nasogastric administration of 1 mg/kg omeprazole suspension (maximum 20 mg) as rapid (n = 9), late (n = 5), and nonresponders (n = 4). Rapid responders required 0.72 mg/kg per day omeprazole suspension to achieve adequate gastric pH elevation for stress ulcer prophylaxis. Late responders required 1.58 mg/kg per day. Nonresponders did not achieve adequate elevation of gastric pH for stress ulcer prophylaxis. CONCLUSIONS: Nasogastric administration of omeprazole suspension has variable efficacy in critically ill pediatric patients. Half of the studied subjects either required significant dose titrations to achieve gastric acid suppression or did not respond to nasogastric administration of omeprazole suspension.     

Omeprozole therapy in pediatric patients after liver and intestinal transplantation

BACKGROUND: Proton pump inhibitors such as omeprazole are increasingly used to prevent stress-related gastric bleeding in critically ill patients. In this investigation, the acid-suppressive potency of omeprazole was assessed in one at-risk group, pediatric patients undergoing liver or intestinal transplantation, or both. METHODS: Twenty-two patients ranging in age from 0.9 to 108 months (23.8 +/- 6.5) underwent isolated liver (n = 10) or intestinal (11 with composite liver allografts) transplantation. Omeprazole was delivered in bicarbonate suspension through a nasogastric tube. Therapy was started after surgery at 0.5 mg/kg every 12 hours. Gastric pH monitoring was performed approximately 2 days later. RESULTS: For the entire group, mean gastric pH equaled 6.1 +/- 0.3, the same in recipients of isolated liver and intestinal allografts. Twelve of the 22 patients demonstrated a discontinuous omeprazole effect, that is, dissipation of acid reduction before the next dose. Five of the 12 patients with discontinuous omeprazole effect had mean gastric pH of less than 5 (3.9 +/- 0.4). In 4 of these 5, the omeprazole dosing interval was shortened to every 8 or every 6 hours, resulting in an increase in mean pH to 6.6 +/- 0.2 ( P < 0.01). In the remaining 10 of 22 patients, acid suppression was uninterrupted until the next dose. No patient experienced bleeding attributable to gastric erosion. CONCLUSION: Omeprazole suspended in sodium bicarbonate is an effective acid-suppressing agent in pediatric recipients of liver or intestinal transplant, or both. A dosage of 0.5 mg/kg every 12 hours is sufficient for most patients, but dosing every 6 to 8 hours is required to assure maximal acid suppression in all.     

Vancomycin pharmacokinetics in premature infants

Vancomycin pharmacokinetics were studied in nine premature infants. Infants weighing less than 1,000 gm had significantly larger volumes of drug distribution and consequently longer drug half-lives than larger premature infants, regardless of postconceptual or actual age. These differences alter the vancomycin dosing recommendations in these two groups of premature infants. We recommend initial dosage regimens consisting of a loading dose of vancomycin of 25 mg/kg followed by doses of 15 mg/kg every 12 hours for infants with weights less than 1,000 gm. Infants weighing over 1,000 gm should receive 10 mg/kg every 12 hours, with a loading dose of 12.5 mg/kg. Serum vancomycin concentration should be monitored, however, for final optimization of therapy.     

Optimal dose of acetaminophen in children

Acetaminophen is an antipyretic and analgesic drug frequently prescribed in children. Unlike aspirin, the recommended doses for acetaminophen are different in France (20-30 mg/kg/24 h) and in the USA (65 mg/kg/24 h). The authors reviewed literature data, looking for the scientific basis of these recommendations in children. The antipyretic effect of a 7-20 mg/kg single oral dose was demonstrated versus placebo. A dose-effect relationship was established: 20 mg/kg as a single oral dose was more effective than 10 mg/kg while 5 mg/kg had little antipyretic effect. More than 10 mg/kg were required to keep on average the temperature 1.5 degrees C below the starting point for 6 hours. There was no significant difference regarding the antipyretic effects of a single 10-15 mg/kg dose using suppositories or oral suspension, although there was a greater consistency of response with the oral suspension. There was no significant difference concerning the antipyretic effect between a 10-15 mg/kg acetaminophen oral dose and the same dose of aspirin. The analgesic effect of a single 10-15 mg/kg oral dose was also demonstrated versus placebo in children. Plasma concentrations between 4 and 18 mg/l seem appropriate to obtain an antipyretic effect. Half-life is 1-3.5 h. Based on these data different dose regimens including an initial loading dose have been proposed. The simplest one is as follows: 25 mg/kg loading dose and 12.5 mg/kg every 6 h as maintenance dose.     

Pharmacokinetics and tolerance of zidovudine in preterm infants

OBJECTIVE: To determine zidovudine pharmacokinetics and tolerance in premature human human immunodeficiency virus-exposed infants. STUDY DESIGN: Pediatric AIDS Clinical Trials Group Study 331 was a multicentered prospective, open-label study of the use of zidovudine in premature infants. Thirty-eight infants <35 weeks' gestational age (GA) were studied while receiving zidovudine 1.5 mg/kg every 12 hours until 2 weeks of age, then 2.0 mg/kg every 8 hours until 6 weeks of age. Population pharmacokinetics were evaluated at 1, 2, and 4 weeks' postnatal age; zidovudine doses were adjusted to maintain troughs <3 microM. RESULTS: Zidovudine clearance was lower than reported in term infants at similar postnatal ages. Nine premature infants required dose reduction because of high levels (7/19 <30 weeks' and 2/19 >/=30 weeks' GA). Postnatal age, GA, serum creatinine, and furosemide use independently predicted zidovudine clearance. Zidovudine was generally well tolerated in this high-risk population. CONCLUSIONS: Zidovudine clearance is greatly reduced in premature infants. We recommend the following zidovudine dosing schedule in this population: 1.5 mg/kg (intravenous) or 2.0 mg/kg (oral) every 12 hours increased to every 8 hours at 2 weeks of age (>/=30 weeks' GA) or at 4 weeks (<30 weeks' GA).     

TRAUMATIC OPTIC NEUROPATHY COMPLICATING COMBINED IDIOPATHIC THROMBOCYTOPENIA AND NEUTROPENIA

High-dose Busulfan in combination chemotherapy has been used commonly for hematopoietic stem cell transplantation. It crosses the blood-brain barrier and could cause seizure. Benzodiazepines have been used as anticonvulsant prophylaxis. This is a prospective study using oral lorazepam together with busulfan-based conditioning regimen in 30 children undergoing hematopoietic stem cell transplantation. The dose of lorazepam used ranged from 0.017 to 0.039 mg/kg (median = 0.026 mg/kg) per dose. None of the patients developed seizure while receiving oral lorazepam or within 72 hours of the last dose of Busulfan. Oral lorazepam was tolerated by the patients, but all patients needed dose reduction due to some adverse effects. In the authors’ experience, oral lorazepam is a useful anticonvulsant prophylaxis for children receiving high-dose busulfan.     

Safety and pharmacokinetics of fluconazole in children with neoplastic diseases

To evaluate the safety, tolerance, and pharmacokinetics of fluconazole in children with neoplastic diseases, we studied fluconazole in 26 children, aged 5 to 15 years, with normal renal function who were receiving treatment for cancer. The patients received fluconazole, 2, 4, or 8 mg/kg per day for 7 days intravenously for a 2-hour period. Patients had no nausea or vomiting related to fluconazole; three patients had an asymptomatic rise in hepatic aminotransferase values after four to six doses (one patient at 2 mg/kg per day and two patients at 8 mg/kg per day), which returned to normal within 2 weeks after discontinuation of the drug. Fluconazole showed linear first-order kinetics over the dosage range tested and during multiple dosing. After the first dose, mean clearance was 22.8 +/- 2.3 ml/min, volume of distribution 0.87 +/- 0.06 L/kg, and terminal elimination half-life 16.8 +/- 1.1 hours. Similarly, after the last dose, clearance was 19.4 +/- 1.3 ml/min, volume of distribution 0.84 +/- 0.04 L/kg, and terminal elimination half-life 18.1 +/- 1.2 hours. Patients receiving their first fluconazole dose of 8 mg/kg achieved peak serum levels of 9.5 +/- 0.4 microgram/ml and trough levels of 2.7 +/- 0.5 microgram/ml 24 hours later, and an area under the serum concentration-time curve from time zero to infinity of 186 +/- 16 micrograms.hr per milliliter. Renal clearance of fluconazole was 65% +/- 5% of total clearance and demonstrated the predominantly renal excretion of this drug. We suggest that the shorter serum half-life and the higher frequency of aminotransferase elevations in comparison with those of adults warrant careful investigation of fluconazole in controlled clinical trials.     

Hepatic failure despite early acetylcysteine following large acetaminophen-diphenhydramine overdose

We describe the case of a patient with massive acetaminophen-diphenhydramine overdose and a 4-hour serum acetaminophen concentration of 653 μg/mL. The patient was treated with acetylcysteine 5 hours after ingestion. Because of a persistently elevated serum acetaminophen level of 413 μg/mL 45 hours after ingestion, a medical toxicologist recommended that the patient be treated with a second bolus of acetylcysteine (150 mg/kg followed by 12.5 mg/kg per hour for 4 hours, then 6.25 mg/kg per hour). On hospital day 3, she developed hepatic failure despite early treatment. Her transaminase levels and hepatic synthetic function began to improve on hospital day 6, and acetylcysteine was discontinued on hospital day 10. In cases of massive acetaminophen overdose, standard acetylcysteine dosing may not be adequate. We suggest that elevated serum acetaminophen concentrations at the end of a standard 20-hour acetylcysteine infusion should be discussed with the local poison center.     

Antipyretic treatment in young children with fever: acetaminophen, ibuprofen, or both alternating in a randomized, double-blind study

OBJECTIVE: To compare the antipyretic benefit of acetaminophen or ibuprofen monotherapy with an alternating regimen of both drugs in young children aged 6 to 36 months. DESIGN: Randomized, double-blind, parallel-group trial. SETTING: Three primary pediatric community ambulatory centers in central Israel. PARTICIPANTS: A total of 464 children aged 6 to 36 months with fever. INTERVENTION: Infants were assigned to receive either acetaminophen (12.5 mg/kg per dose every 6 hours) (n = 154) or ibuprofen (5 mg/kg per dose every 8 hours) (n = 155) or to receive alternating acetaminophen and ibuprofen (every 4 hours) (n = 155) for 3 days after a loading dose. MAIN OUTCOME MEASURES: Temperature, stress score, amount of antipyretic received, total days that the infant or caregiver was absent from day care or work, respectively, at the 3-day time point, recurrence of fever, and number of emergency department visits. RESULTS: The group given the alternating regimen was characterized by a lower mean temperature, more rapid reduction of fever, receiving less antipyretic medication, less stress, and less absenteeism from day care as compared with the other groups; all of the differences were statistically significant (P< .001). None of the regimens were associated with a significantly higher number of emergency department visits (P = .65) or serious long-term complications (P = .66). The drug used for initial loading had no effect on outcome in any of the groups. CONCLUSIONS: An alternating treatment regimen of acetaminophen (12.5 mg/kg per dose) and ibuprofen (5 mg/kg per dose) every 4 hours for 3 days, regardless of the initial loading medication, is more effective than monotherapy in lowering fever in infants and children.     

Treatment of cerebral malaria in African children by intravenous quinine: comparison of a loading dose regimen to a regimen without a loading dose]

OBJECTIVE: To compare in a randomized study the efficacy and the toxicity of the new WHO intravenous quinine treatment of cerebral malaria including a loading dose regimen to a regimen without loading dose. PATIENTS AND METHODS: Seventy-two children eight months to 15 years of age with cerebral malaria were included. Quinine formiate was administered to a group of 35 patients in an initial loading dose of 20 mg salt/kg (equivalent to 17.5 mg/kg of the base) in 10 mL/kg of 5% glucose over four hours, followed eight hours later by a maintenance dose quinine of 10 mg salt/kg (equivalent to 8.7 mg/kg of the base) dissolved in 15 mL/kg of 5% glucose over and every 12 hours. The second group of 37 patients received intravenous quinine 15 mg salt/kg (13.1 mg of base) dissolved in 15 mL/kg of 5% glucose infused over 6 to 8 hours, every 12 hours. In both groups this treatment was continued until the patient could swallow, then quinine tablets were given to complete seven days treatment. The assessment of cardiovascular side effects was made by an ECG at admission, the 4th hour, the 24th hour and at the end of treatment for each patient. RESULTS: Coma mean durations were similar in the two groups: 35.5 +/- 17.8 hours and 28.6 +/- 14.4 hours respectively for the loading dose group and the group without loading dose. The two groups were comparable also for the decrease evolution of parasitemia. Case-fatality rates were also similar: 95% of healing at the 72nd hour and a lethality rate between 5 and 6% in the two groups. But a significant increase of the body temperature was noted between the 51st and the 63rd hour in the group without loading dose. No significant cardiovascular toxicity was noticed in the two groups. The mean cost of the loading dose regimen was less than that of the second regimen. CONCLUSION: The loading dose regimen of quinine is well tolerated and it seemed slightly more effective than the regimen without loading dose. In cases of contra-indications (patients who recently received quinine, mefloquine or halofantrine), regimens without loading dose, which remains effective, should be used.     

Intravenous ketamine infusion as an adjuvant to morphine in a 2-year-old with severe cancer pain from metastatic neuroblastoma

A 2.8-year-old female patient (11.6 kg) was admitted to the hospital for uncontrolled pain and swelling in the left leg relating to a metastatic neuroblastoma. Initially, her pain was managed with oral morphine 2 mg (approx. 0.2 mg/kg) every 4 hours. Because she was quite somnolent but still in significant pain, analgesia was then changed to methadone 1 mg orally every 6 hours (approximately 0.1 mg/kg/dose) and was eventually increased over 36 hours to 2 mg every 6 hours (approximately 0.2 mg/kg/dose). She received oral methadone 0.6 mg (approximately 0.05 mg/kg) every 4 hours as needed for breakthrough pain. She continued to have severe pain and experienced side effects, including respiratory depression, sedation, visual hallucinations, and vomiting. An intravenous ketamine infusion was started at 100 microg/kg/hour. Regular opioid administration was ceased, but she was given intravenous morphine 0.5 to 0.75 mg for breakthrough pain. She required only zero to three doses of breakthrough morphine per day, initially. After starting the ketamine infusion, her pain control improved and her symptoms of opioid toxicity abated. She was more alert and able to partake in limited activities. As a result of pain from progressive disease, the ketamine infusion was increased to 200 microg/kg/hour after 6 days with positive results. Her condition continued to deteriorate. An intravenous morphine infusion was initiated 2 weeks after starting the ketamine infusion and was eventually increased to 50 microg/kg/hour. One week later, she died with reasonable pain control. This case illustrates the use of ketamine as an effective analgesic in an adjuvant setting in a pediatric patient with advanced poorly controlled cancer pain. Ketamine not only eased the child's suffering while preserving life but also improved her quality of life by maintaining the child's ability to communicate and engage in activities.     

Effect of practical timing of dosage on theophylline blood levels in asthmatic children treated with choline theophyllinate.

Two dosage schedules, 8 mg/kg per dose daily and 10 mg/kg per dose tds of choline theophyllinate were evaluated in asthmatic children. The times of the doses were considered the most practical for use outside hospital. Theophylline levels were measured 2 hours after each dose and were satisfactory in both schedules. The levels before the first dose of the day were, however, unsatisfactory. We emphasis the desirability of measuring blood levels in any patient receiving a theophylline compound.     

Tissue plasminogen activator for the treatment of thromboembolism in infants and children

We report our experience with the use of tissue plasminogen activator to treat 12 infants and children with various thromboembolic states after conventional thrombolytic agents had failed. The dosage range was between 0.1 to 0.5 mg/kg per hour. Complete clot dissolution occurred in seven cases after 2 hours to 3 days of therapy. Partial clot dissolution and clinical improvement were noted in another four patients. Bleeding complications were noted in 6 of the 12 patients and included bruising, oozing from various venipuncture sites, and bleeding; these complications were controlled by clinically available means. In all cases with bleeding the dose rate was in the higher range (0.46 to 0.50 mg/kg per hour). In one patient, restlessness, agitation, and screaming were noted during administration of tissue plasminogen activator and when it was reinstituted. We conclude that tissue plasminogen activator is effective in inducing clot lysis in children. Because the effective dose appears to overlap with those causing bleeding, we recommend that a dose of 0.1 mg/kg per hour be started and increased gradually if clot dissolution does not occur, with close monitoring for bleeding.