Clinical and laboratory observations Pharmacokinetics of Iorazepam in critically ill neonates with seizures C a t h e r i n e A. M c D e r m o t t , DO,* A l i c e L. Kowalczyk, PharmD,** Eugene R. Schnitzler, MD, Henry H. M a n g u r t e n , MD, Keith A. Rodvold, PharmD, a n d Seymour Metrick, MD From the Department of Pediatrics, Divisions of Neonatology and Pediatric Neurology, Lutheran General Children's Medical Center, and the Department of Pharmacy, Lutheran General Hospital, Park Ridge, illinois;and the Clinical Pharmacokinetics Laboratory, University of Illinois,Chicago Pharmacokinetic data were e v a l u a t e d in I0 term neonates with seizures after intravenous administration of Iorazepam, 0.05 m g / k g or 0.4 m g / k g . All seizure activity ceased, with no adverse effects. Pharmacokinetic d a t a revealed a decreased volume of distribution and clearance, and a prolonged half-life in comparison with data from older children and adults. These findings are consistent with physiologic differences in the neonate. (J PEDIATR1992;120:479"83)

Lorazepam is a benzodiazepine with potent anticonvulsant activity. Clinical reports have demonstrated the effectiveness of lorazepam in the management of status epilepticus in adults and older children. 1-3 Laeey et al. 2 treated 31 children, aged 2 through 18 years, in status epilepticus and found an 84% response rate. Our group previously conducted a pilot study of lorazepam in seven infants with hypoxic-isehemic eneephalopathy and seizures refractory to phenobarbital and phenytoin4; cessation or reduction of clinical seizure activity occurred in all seven patients, some of whom also had a resolution of seizures electrographically. Supported in part by a grant from the Park Ridge Health Foundation, Park Ridge, Ill. Presented in part at the Cleveland Clinic International Epilepsy Symposium,Cleveland,Ohio, May 1988, and at the Annual Meeting of the American Collegeof Clinical Pharmacy, San Francisco, Calif., August 1990. Submitted for publication Nov. 14, 1990; accepted Oct. 21, 1991. Reprint requests: Henry H. Mangurten, MD, Divisionof Neonatology, Lutheran General Hospital, 1775 Dempster St., Park Ridge, IL 60068. *Now at Children's Hospital of San Francisco,San Francisco, Calif. **Now at Hospital for Sick Children, Toronto, Ontario, Canada.

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The neonate has decreased hepatic enzyme activity, particularly conjugation and hydroxylation,5 and the activity of these enzymes is further impaired in the sick, asphyxiated neonate. We therefore postulated that the metabolism of 10razepam would differ considerably from that in older pediatric and adult patients. The purpose of this investigation was to characterize the pharmacokinetics of lorazepam in neonates and to evaluate further the efficacy and safety of lorazepam in critically ill neonates with seizures. METHODS

Study population. The study population was composed of 10 neonates admitted to the neonatal intensive care unit at Lutheran General Children's Medical Center between JanAUC Area under the concentration-time curve CL Systemicclearance CSF Cerebrospinalfluid TV2 Elimination half-life VDarea Volumeof distribution uary 1987 and August 1988. The research protocol was approved by the institutional review board of the hospital. Written informed consent was obtained from a parent or guardian of each neonate. All neonates were -->37 weeks of gestational age, with birth weights >2500 gin. All neonates had asphyxia neona-

479

480

Clinical and laboratory observations

torum according to the low Apgar scores (median 5-minute score = 4), and all required resuscitation at the time of delivery. Beginning 1 to 18 hours after birth, clinical features that were consistent with hypoxic-ischemic encephalopathy developed in every neonate. None of the neonates had dysmorphism or congenital anomalies. All neonates were examined and treated for presumptive sepsis, but all cultures of blood and cerebrospinal fluid showed no bacterial growth. All neonates had clinically documented seizures of multifoeal clonic and subtle types during the first 48 hours. The cause of the seizures was believed to be hypoxic-ischemic encephalopathy; however, two neonates had an intraventricular hemorrhage, and one neonate had a right parietal intracerebral hemorrhage. Before the administration of lorazepam, all neonates had complete blood cell counts, platelet counts, and blood chemistry studies (SMA 20; Technicon Instruments Corp., Tarrytown, N.Y.) performed. Blood gas values were monitored as dictated by the clinical conditions. Those patients who received phenobarbital and phenytoin had serum levels of these drugs measured. Drug administration. Initial treatment of four neonates consisted of appropriate intravenouslyadministered loading doses of phenobarbital and phenytoin sodium, each at 20 mg/kg per dose. In one neonate the initial treatment consisted of phenobarbital only. The therapeutic serum concentrations of phenobarbital (15 to 45 rag/L) were documented in all five of the infants. Therapeutic serum concentrations of phenytoin (10 to 20 mg/L) were documented in three of four neonates. Neonates were enrolled in the study when seizures persisted after loading doses of these drugs. All patients received a single dose of lorazepam given intravenously for 1 to 2 minutes. Five received lorazepam as initial treatment for seizure activity. Four were given a single dose of lorazepam, 0.05 mg/kg. On the basis of reports in the literature, 3 the dose was subsequently increased to 0.1 mg/kg in the other six infants in an attempt to improve seizure control. N o infant received a second dose of lorazepam. The pharmacokinetic study described below was carried out during the first 72 hours after the administration of lorazepam. Clinical measures. The following clinical data were collected and monitored: (1) vital signs, including blood pressure, up to 24 hours after lorazepam administration and (2) serial observations (evaluation of level of activity and consciousness, tone, posture, and brain-stem reflexes) and descriptions of seizure activity. Electroencephalograms were obtained within 24 hours of admission for all patients; for two neonates, 24-hour eightchannel ambulatory electroencephalograms were obtained. Either computed tomography of the brain or cranial ultrasonography was performed for all patients.

The Journal of Pediatrics March 1992

Blood sampling and laboratory analysis. Serial blood samples were collected at thc end of the infusion and at 0.5, 1, 12, 24, and 48 hours after the end of the infusion. An additional blood sample was obtained at 72 hours from seven patients. The exact time of blood collection was recorded and used in the pharmacokinetic analysis. Blood samples were drawn from heel puncture, umbilical vessels, or peripheral veins. After sample collection serum was separated and stored at - 2 0 ~ C until assayed. Assay of lorazepam was performed by a gas chromatography method with electron capture detection devcloped at MEDTOX Laboratories (St. Paul, Minn.). A method similar to that described by Bradshaw et al. 6 was used, but the chromatograph consisted of a Hewlett-Packard model 5860 (Hcwlctt-Packard Co., Palo Alto, Calif.) fitted with a capillary column, with 3-methyl-clonazepam as the internal standard. The standard curve ranged from 50 to 300 ng/ml, with assay linearity established through 500 ng/ml. The sensitivity of the assay was 1 ng/ml of serum. The respective intraday and intcrday coefficients of variation for control samples were less than 5% and 8.5%, respectively. Pharmacokinetic and statistical analysis. Peak serum concentration was determined directly from the individual observed lorazepam serum concentration-time plots. The area under the concentration-time curve from zero to the time of the last serum concentration was estimated by the linear trapezoidal method. The area from the last time point to infinity was determined by dividing the last measured serum concentration by the patient's elimination rate constant. The latter was determined by nonlinear least-squares regression of the terminal log-linear portion (the final three or four concentrations) of the serum concentration-time curve. The elimination half-life was estimated by dividing the elimination rate constant into the natural logarithm of 2. Systemic clearance and apparcnt volume of distribution were estimated as follows: Dose CL = A u c Dose VDarea Ke • AUC where "Dose" is the administered dose of lorazepam, and Ke is the elimination rate constant. Where appropriate, pharmacokinetic parameters were normalized to total body weight. Pharmacokinetic parameters were compared in neonates who remained free of seizures versus those who had seizure recurrence. A Mann-Whitney U test was used to test for differences in dose, peak serum concentration, AUC, T1/2, VDarea, and CL. Pharmacokinetic parameters were also compared in neonates receiving lorazepam alone versus neonates receiving lorazepam and other anticonvulsants. A Mann-Whitney tJ test was similarly used to test for dif-

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481

Table. Relevant patient demographic characteristics and pharmacokinetic parameters

Patient NO. 1 2 3 4 5 6 7 8 9 10

Gestational age (wk) 37 37.5 41 40 40 40 39 41 40.5 40

Mean 39.6 SD 1.4 C,,~ax,Peak serumconcentration.

Weight (gm) 2590 2660 4100 2650 2810 3700 3545 3040 3560 3960 3261.5 576.6

Dose (/zg/kg)

Cmax (ng/ml)

AUC (/Lg-hr/ml)

CL (ml/min/kg)

TI.,~ (hr)

VDarea (L/kg)

50 50 50 50 100 100 100 100 100 100

358 97.5 764 118.4 435 701 144 94.9 120 95

13,011.6 5,839.5 2,946.2 8,369.0 4,395.5 6,348.3 10,673.1 5,385.6 4,580.7 6,384.2

0.064 0.143 0.283 0.100 0.379 0.263 0.156 0.309 0.354 0.261

24.6 47.8 24.3 50.1 17.9 30.8 73.0 48.4 37.6 47.6

0.14 0.59 0.59 0.43 0.59 0.70 0.99 1.30 1.18 1.08

292.8 260.8

6,793.4 3,071.5

0.232 0.110

40.2 16.5

0.76 0.37

80.0 25.8

ferences in AUC, TIA, VDarea, and CL between the two groups. Linear least-squares regression was used to evaluate the relationships between demographic characteristics and pharmacokinetic parameters, including an analysis of variance for linearity. The level of significance accepted for statistical evaluation was p ~ 0.05. RESULTS Clinical observations. Administration of a single dose of lorazepam resulted in termination of seizure activity within 5 minutes in all 10 neonates. Four neonates receiving concurrent anticonvulsanttherapy with both phenobarbital and phenytoin had no further seizures; the remaining six had recurrence of clinical seizures at a mean.time of 6.5 hours (range 3 to 19 hours) after lorazepam administration. Vital signs (temperature, blood pressure, and pulse rate), blood chemistry values, and renal and hepatic function remained stable in all infants. No deterioration of respiratory or cardiovascular status was observed; the patients did not require increased respiratory support. All electroencephalograms obtained within 24 hours showed abnormalities, demonstrating background suppression, disorganization, and focal or multifocal epileptogenic activity. Computed tomography demonstrated evidence of diffuse cerebral ischemia and secondary edema in six neonates; two had intraventricular hemorrhage, and one had frontoparietal parenchymal hemorrhage. Pharmacokineties. After intravenous administration of a single dose of lorazepam, serum concentrations varied considerably. The Table lists the Single-dose pharmacokinetic parameters for intravenouslyadministered lorazepam in the 10 individual neonates. The mean TI/2was 40.2 hours (range 17.9 to 73.0 hours), the total apparent VDarea was 0.76 L/kg (range 0.14 to 1.30 L/kg), and the lorazepam CL was 0.232

ml/min per kilogram (range 0.064 to 0.379 ml/min per kilogram). Despite the wide interpatient variability, there were no significant differences in drug concentrations or other pharmacokinetic measurements between neonates who remained free of seizures and those who had seizure recurrence. The mean pharmacokinetic parameters in neonates who remained seizure free versus those with seizure recurrence were as follows: dose, 83.33 versus 75.00 #g/kg; peak serum concentration, 186.5 versus 363.7 ng/ml; AUC, 6247.03 versus 7157.57 #g-hr/ml; T1/2, 40.84 versus 39~79 hours; VDarea, 0.67 versus 0.82 L/kg; and CL, 0.221 versus 0.240 ml/min per kilogram. Additionally, lorazepam pharmacokinetic parameters did not significantlydiffer between neonates receiving lorazepam alone and those receiving lorazepam and other anticonvulsants. The mean values for pharmacokinetic parameters in neonates receiving lorazepam alone versus those receiving lorazepam and other anticonvulsants were as follows: AUC, 7511 versus 6074 #g-hr/ml; TV2, 38.06 versus 42.36 hours; VDarea, 0.720 versus 0.796 L/kg; and CL, 0.226 versus 0.238 ml/min per kilogram. Lorazepam CL was found to correlate with gestational age (r = 0.74; p = 0.015) (Figure). The statistical significance of these results is limited by the small number of patients in each of the sample groups. DISCUSSION Lorazepam is a lipophilic drug that has a large VDa~a of approximately 1.3 L/kg in adults. 7 Our patients had a slightly smaller VDa~o~ of 0.76 L/kg, consistent with the lower percentage of adipose tissue in the neonatal population. Biotransformation of lorazepam occurs primarily via conjugation in the liver to an inactive glucuronide, which is then excreted in the urine by glomerular filtration.8 In the neonatal period the enzymatic activity of the glucuronida-

482

Clinical and laboratory observations

The Journal of Pediatrics March 1992

0.5E

0.4-

0.30.20.1 0.0 36

3'7

3'8

GESTATIONAL

3'9

40 AGE

4'I

42

(weeks)

Figure. Relationship between lorazepam CL and gestational age in 10 patients (clearance data for patients 6 and 10 were virtually identical).

tion pathway is decreased 5 relative to that in adults, resulting in a prolonged lorazepam T1/2 and decreased CL. In the 10 neonates studied, the mean TV2 was 40.2 hours, significantly greater t h a n that reported in adults (12.9 hours) 7 and older children (10.5 hours). 9 Lorazepam CL was 0.232 versus 1.21 m l / m i n per kilogram reported in adults 7 and 1.3 m l / m i n per kilogram in children, 9 consistent with the decreased hepatic enzyme activity in neonates. The pharmacokinetic findings in our study also may be influenced by alterations in protein binding in the neonate; however, we did not evaluate lorazepam protein binding. Other anticonvulsants did not significantly affect the pharmacokinetics of lorazepam in the neonatal population that we studied. All patients responded clinically to administration of lorazepam with cessation of seizure activity. Those patients who remained free of seizures also had received phenobarbital and phenytoin in addition to lorazepam. Seizures recurred in five patients who received lorazepam alone and in one patient who received lorazepam and phenobarbital. However, the study design limited the administration of lorazepam to a single dose. In view of these constraints and the wide interpatient variability in lorazepam serum concentrations, we were unable to establish a relationship between pharmacokinetics and clinical effects. This may also be attributable to lorazepam's action at central nervous system receptor sites. In addition, this may reflect the underlying severity of the seizure disorder in our study population. The concentration of lorazepam in brain tissue is an important determinant of its clinical effect. Other studies 1~ 11 have failed to correlate C S F concentrations with total lorazepam serum concentration. Concentrations of lorazepam in the C S F were found to be proportional to the unbound or free concentration of the drug 1~ 11; only unbound lorazepam enters the brain. If the concentrations in the brain are proportional to C S F

concentrations,12 the concentration of free lorazepam in the serum may correlate with the concentration at the site of action 1~ and to clinical efficacy. We did not measure free lorazepam concentrations. In the severely asphyxiated neonate it is difficult to sort out or isolate the influence of hypoxemia on the hepatic metabolism of lorazepam; therefore our pharmacokinetic findings may not apply to the neonatal population in general. However, only one of our patients had significantly elevated serum transaminase values. Our data support our hypothesis that the pharmacokinetics of lorazepam in the neonate differ considerably from those in older children and adults; we found a prolonged TI/2, decreased CL, and decreased VDarea. These findings are consistent with the physiologic differences present in the neonate. Lorazepam produced no appreciable adverse effects in this small neonatal population. Our earlier pilot study, 4 as well as other reports, 1, 2, l~, 14 generally describe a high safety profile for intravenously administered lorazepam. The results of our study are preliminary because of the small sample size, but we believe that our data are useful in beginning to establish a safe and effective dose of lorazepam in neonates. REFERENCES

1. Leppik IE, Derivan AT, Homan RW, et al. Double-blind study of lorazepam and diazepam in status epilepticus. JAMA 1983;249:1452-4. 2. Lacey D J, Singer WD, Horwitz S J, Gilmore H. Lorazepam therapy of status epilepticus in children and adolescents. J PEDIATg 1986;108:771-4. 3. Crawford TO, Mitchell WG, Snodgrass SR. Lorazepam in childhood status epilepticus and serial seizures: effectiveness and tachyphylaxis. Neurology 1987;37:190-5. 4. Deshmukh A, Wittert W, Schnitzler E, Mangurten HH. Lorazepam in the treatment of refractory neonatal seizures: a pilot study. Am J Dis Child 1986;140:1042-4. 5. Morselli PL, Franco-Morselli R, Bossi L. Clinical pharmacokinetics in newborns and infants. Age-related differences and therapeutic implications. Clin Pharmacokinet 1980;5:485527. 6. Bradshaw EG, Ali AA, Mulley BA, Rye RM. Plasma concentrations and clinical effect of lorazepam after oral administration. Br J Anaesth 1981;53:517-2l. 7. Greenblatt D J, Shader RI, Franke K, et al. Pharmacokinetics and bioavailability of intravenous, intramuscular, and oral lorazepam in humans. J Pharm Sci 1979;68:57-63. 8. Elliot HW. Metabolism of lorazepam. Br J Anaesth 1976; 48:1017-23. 9. Relling MV, Mulhern RK, Dodge RK, et al. Lorazepam pharmacodynamics and pharmacokinetics in children. J PEDIATe 1989;114:641-6. 10. Ochs HR, Busse J, Greenblatt DJ, Divoll Allen M. Entry of lorazepam into cerebrospinal fluid. Br J Clin Pharmacol 1980;10:405-6. 11. Aaltonen L, Kanto J, Salo M. Cerebrospinal fluid concentra-

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tions and serum protein binding of lorazepam and its conjugate. Acta Pharmacol Toxicol 1980;46:156-8. 12. Ramsay RE, Hammond E J, Perchalski R J, Wilder BJ. Brain uptake of phenytoin, phenobarbital, and diazepam. Arch Neurol 1979;36:535-9. 1979;36:535-9.

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13. Maloley PA, Gal P, Mize R, Weaver RL, Ransom J L Lorazepam dosing in neonates. DICP 1990;24:326-7. 14. Walker WE, Homan RW, Vasko MR. Lorazepam in status epilepticus. Ann Neurol 1979;67:207-13.

Treatment of aggressive cytomegalovirus retinitis with ganciclovir in combination with foscarnet in a child infected with human immunodeficiency virus Karina M. Butler, MB,BCH,MRCPI,Marc D. De Smet, MD, FRCSC, Robert N. Husson, MD, Brigitta Mueller, MD, Kallanna Manjunath, MD, Karen Montrella, RN, CPNP, Gay!e Lovato, RN, MS, Paul Jarosinski, PD, Robert B. Nussenblatt, MD, and Philip A. Pizzo, MD From the Pediatric Branch, Clinical Oncology Program, National Cancer Institute, and the Laboratory of Immunology, National Eye Institute, National Institutes for Health, Bethesda, Maryland, the Pharmacy Department, Clinical Center, and the Albany Medical Center, Albany, New York

Ganciclovir and foscarnet are both effective for cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome, but the benefits of either agent given alone are limited. A child infected with human immunodeficiency virus who had cytomegalovirus retinitis that progressed despite treatment with either agent alone received the combination of ganciclovir and foscarnet. This treatment resulted in a sustained clinical response. (J PEDIATR1992;120: 483-6)

Cytomegalovirus retinitis results in vision loss in 10% to 20% of adults and a smaller, albeit undefined, proportion of children with acquired immunodeficiency syndrome. Untreated, C M V retinitis usually progresses within 1 month and can result in total retinal destruction within 6 months.1 Ganciclovir is the current standard treatment for C M V retinitis, but disease ultimately progresses in most cases. 24 Foscarnet has just been approved for the treatment o f C M V retinitis. As with ganciclovir, however, relapse has been observed both after the discontinuation of foscarnet therapy and in patients receiving maintenance therapy. 5-8 The combination of ganciclovir and foscarnet has been shown to be superior to either agent alone in inhibiting cellular infection by C M V , both in vitro 9, 10 and in an animal model system. 9 In this report we describe the course of a

Submitted for publication Aug. 16, 1991; accepted Oct. 11, 1991. Reprint requests: Karina M. Butler, MB, BCh, Pediatric Branch, National Cancer Institute, National Institutes of Health, Building 10, Room 13N240, Bethesda, MD 20892. 9/26/34282

patient in whom this combination was successfully employed. CASE R E P O R T A 5.6-year-old white girl with vertically acquired Centers for Disease Control class P-2 human immunodeficiency virus infection CMV ddI

ELISA HIV

Cytomegalovirus Dideoxyinosine Enzyme-linked immunosorbent assay Human immunodeficiency virus

was enrolled in phases I/II of a trial of dideoxyinosine in 1989.11 Hepatomegaly was first noted in October 1988. During the next months additional problems included thrush, onychomycosis, intermittent diarrhea with weight loss, Norwegian Scabies, and an episode of interstitial pneumonia, diagnosed presumptively and treated as Pneumocytis carinii pneumonia. Her HIV infection was diagnosed on the basis of HIV antibody detection by ELISA and Western blot test~ In August 1989 treatment with ddI was commenced at a dose of 540 mg/m 2 per day, given orally in three divided doses every 8 hours. Laboratory test results were remarkable only for the presence of hypergammaglobulinemia (serum IgG