Pharmacokinetics and pharmacodynamics of intravenous meperidine in neonates and infants The pharinacokinetics of meperidine (pethidine) was studied in 21 infants who received a single intravenous dose of 1 mg/kg after surgery (n = 18) or during mechanical ventilation because of respiratory distress (n = 3). Eleven patients were younger than 1 week old, 10 patients were aged from 3 weeks to 5 months, and five of the patients were premature. The pharmacokinetics of meperidine varied greatly between the subjects, with a median elimination half-life of 10.7 hours (range, 3.3 to 59.4 hours), median clearance of 8.0 mUkg/min (range, 1.8 to 34.9 ml/kg/mm), median volume of the central compartment of 2.4 L/kg (range, 0.5 to 4.8 L/kg), and median steady-state volume of distribution 7.2 L/kg (range, 3.3 to 11.0). The great interindividual variability in meperidine pharmacokinetics should be taken into consideration when meperidine is administered to neonates. Although no life-threatening or serious side effects were observed in this study, appropriate care should be exercised when prescribing meperidine for this age group. (GUN PHARMACOL THER 1992;52:342-9.)

Marja-Leena Pokela, MD, Klaus T. Olkkola, MD, Maila Koivisto, MD, and Pauli Ryhanen, MD Oulu and Helsinki, Finland Meperidine (pethidine) is widely used as an analgesic agent for infants," although there is little information on its pharrnacokinetics in subjects of this age. Its disposition has been studied in neonates whose mothers have been given meperidine during labor, and its elimination half-life (tv2) immediately after birth is known to be 2 to 7 times longer in neonates than in adults because of reduced N-demethylation activity, reduced hydrolysis and conjugation rates, and a low glomerular filtration rate.'" Impaired meperidine metabolism is believed to be limited to newborns; Atwood et al.9 reported a mean elimination t1/2 of 2.3 hours in nine infants from 3 to 18 months of age, which is even less than in adults, and a correspondingly larger mean steady-state volume of distibution (Vss) (5.0 versus 4.2 L/kg). Plasma binding was 85% in infants compared with 64% in adults. From the Departments of Pediatrics and Anesthesiology, University of Oulu, Oulu, and the Department of Anesthesiology, University of Helsinki, Helsinki. Supported by the Pharmacal Research Foundation, Helsinki, the Alma ock K. A. Snellman Foundation, Oulu, the Foundation for Pediatric Research in Finland, and the Paulo Foundation, Helsinki. Received for publication March 30, 1992; accepted June 23, 1992. Repr:nt requests: Marja-Leena Pokela, MD, Department of Pediatrics, University of Oulu, SF-90220 Oulu, Finland. 13/1/40424

342

To study the effect of age on the pharmacokinetics and pharmacodynamics of meperidine, we monitored its intravenous administration to 21 infants aged from 6 hours to 5 months. Plasma meperidine concentrations were measured, and hemodynamic and ventilatory parameters and the level of analgesia were monitored up to 24 hours after its administration.

PATIENTS AND METHODS Institutional approval and informed consent from the parents were obtained to examine 21 infants undergoing surgery (n = 18) or receiving mechanical ventilation in a pediatric intensive care unit for cardiorespiratory problems (n = 3). The median gestational age was 39 weeks (range, 28 to 42 weeks), and the age at the time of the trial varied from 6 hours to 5 months: 11 patients were younger than 5 days old, 10 patients were from 3 weeks to 5 months (median, 4.3 days), and five patients were premature. Three of the patients were critically ill and needed analgesia and sedation during mechanical ventilation because of meconium aspiration syndrome, persistent fetal circulation, or severe congenital heart disease. Eighteen patients were given meperidine for pain after surgery. Details of the patients are shown in Table I. The patients undergoing surgery had received anesthesia according to our usual routine: anesthesia was in-

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Meperidine in infants

343

Table I. Clinical data on the patients Patient No.

Term (study age 1

2 3

4

Age (days)

Sex

3 wk) 10 Male 26.0 11 Male 32.0 12 Female 37.0 13 Male 54.0 14 Female 62.0 15 Male 73.0

36 40 36 38 42 40

278 318 289 326 357 356

3.1 4.7 2.3 4.5

Male

150.0

40 38

434 326

8.8 4.5

Patent ductus arteriosus

54.0

1.6

Duodenal atresia Imperforate anus Hydrocephalus Intraventricular hemorrhage Atrioventricular septal defect Down's syndrome Atrioventricular septa! defect Patent ductus arteriosus

5

6 7 8

9

Median

16

Median

Treatment procedure

Diagnosis

1.1

6.0 6.3

Tracheal suction Tracheal suction Plastic surgery Closure Anoplasty Anoplasty Ventriculoperitoneostomy Subclavopulmonary anastomosis

Preterm 17 18 19

Female Male Male

3.6 4.3 23.0

32 33 28

233 237 221

2.2

20

Male

51.0

32

275

2.4

21

Male

65.0

31

282

2.4

23.0

32

237

2.2

Median

duced with thiopental, and intubation was facilitated with pancuronium or atracurium. Anesthesia was then maintained with nitrous oxide or air in oxygen, isoflurane, and fentanyl. Neuromuscular blockade was produced by administration of nondepolarizing neuromuscular blocking agents. The mean interval from the end of the operation to the present monitoring period was 61/2 hours (range, 1/2 to 17 hours). The need for analgesia was deduced from physiologic and behavioral reactions such as facial expressions, movements of the limbs and body, vocalizations or cries, spontaneous motor activity, irritability, response to handling, and consolability, together with the measured cardiorespiratory changes.

1.9

Duodenoduodenostomy Anoplasty Ventriculoperitoneostomy

Pulmonary banding

Ligation

Plasma urea and alanine aminotransferase (ALAT) were measured at the beginning. Diuresis was measured as a routine procedure in critically sick neonates and after surgery. An intravenous bolus of mg/kg meperidine was administered over a period of minute. Heart rate, respiratory rate, oxygen saturation, arterial blood pressure, and pain reactions were monitored continuously and recorded 10 minutes before and at 15, 30, and 60 minutes and at 2, 4, 6, 8, 10, 12, 18, and 24 hours after meperidine administration. In cases of insufficient analgesia, 0.1 mg/kg morphine was given, as clinically indicated, during the meperidine concentration samples. 1

1

344 Pokela

CLIN PHARMACOL THER OCTOBER 1992

et al.

\ E

1000

1:7)

Is=

100 -

10 o

1

2

0

500

1000

1500

2500

2000

Time (min) Fig. 1. Meperidine plasma concentrations (in nanograms per milliliter) in intravenous dose of mg/kg.

21

infants after a single

1

Arterial or venous blood was sampled for the determination of meperidine at time 0 (baseline) and at 2, 10, 30, 60, 120, 180, 240, 360, 480, 600, 720, 1080, and 1440 minutes after the injection. At least nine samples were drawn from each patient, and the plasma was separated and stored at -20° C until analyzed. Assay of meperidine. Meperidine was extracted from the serum by a method modified from Mather and Tucker.m An internal standard 50 p.1 (lidocaine hydrochloride, 10 pl/m1) and 8N sodium hydroxide (100 Ill) were added to 0.5 ml serum, and the solution was extracted with diethyl ether (5 ml) for 10 minutes. After centrifugation at 3000g for 10 minutes, 4 ml of the organic phase was transferred to conical tubes and evaporated to dryness at 50° C under nitrogen. The residue was dissolved in methanol (50 11,1). The samples were analyzed by gas chromatography-mass spectrometry (Hewlett-Packard GC 5890 [HewlettPackard Company, Palo Alto, Calif.] equipped with a 12 m HP-1 fused silica capillary column and a 5791A mass selective detector). The mass spectrometry was operated in a selective ion (247, 218, 172, and 234) monitoring mode. The target ion for meperidine was 247 and that for the internal standard 234. The initial temperature was 80° C, and after 1 minute the temperature was programmed to 110° C with rate of 70° C/min and to 240° C with a rate of 15° C/min. The retention times for meperidine and lidocaine were 7.65 minutes and 8.61 minutes, respectively. The

within-day coefficient of variation in the serum standards ranged from 2.5% to 6%. The limit of detection was 2 ng/ml. Pharmacokinetic analysis. The individual plasma concentrations were fitted to the following biexponential function with the aid of a microcomputer-based nonlinear regression program' 1: 2

C(t) =

E A;

e'

1=1

in which C(t) is the plasma concentration of meperidine at time t, A, is a zero-time intercept, and a, is a

disposition rate constant. The measured concentration values were weighted equally and with the factor 1/c2. The goodness of fit was determined by the Akaike information criterion12 and by assessing the randomness of "scatter" of the actual data points about the fitted function. The initial estimates were obtained by use of an iterative curve-stripping technique." The pharmacokinetic parameterst1/2, volume of the central compartment (Vc), Vss, and clearance (CL)were calculated according to standard formulas. '4 Statistical analysis. The distributions of the variables were tested statistically for normality. The changes in hemodynamic parameters and arterial Pco2 were tested with a repeated measures ANOVA, t test, or nonparametric Wilcoxon signed-rank test for paired observations. Either Dunnett's or Bonferroni's correction was used for multiple comparisons as appropriate.

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Meperidine in infants

Table II. Pharmacokinetic parameters of infants given Patient No.

CL (ml/kg/mm)

1

345

mg/kg intravenous meperidine

V, Elimination

(1,11(g)

(LIkg)

1.9 1.5 2.2 0.5 2.0 3.6 2.0 3.2

4.5 2.0 0.5-4.5

5.2 4.4 5.0 3.7 7.2 6.9 7.9 5.6 9.2 5.6 3.7-9.2

4.1 10.2

4.6

11.0

1.5

4.9 9.7 20.5

3.0 3.2 3.8 3.1

1.5-4.6

4.9 8.0 6.6 7.6 8.7 8.3 8.0 4.9-11.0

6.6 8.2 5.7-31.7

1.8

4.8

9.4

59.4

3.2 34.9 3.5

1.5

3.3 8.8 5.7 8.8 8.8

11.9 3.3 18.9 9.2 11.9

3.3-9.4

3.3-59.4

t1/2

(hr)

Term (3 10 11

12 13

14 15 16

Median Range

10.7

6.6 11.2

9.4 6.3 11.2 16.8

4.9 13.5 10.7

4.9-16.8

vi.1)

9.1 15.6 9.7

4.1-20.5

4.0 3.1

31.7 5.7 19.3 8.2

5.9 14.4

Preterm 17 18 19

20 21

Median Range

11.3 3.5

1.8-34.9

2.4 2.1 1.1

2.1 1.1-4.8

CL, Total body clearance; Vc, volume of the central compartment; Vss, steady-state volume of distribution; t1/2, half-life.

The relationships of the pharmacokinetic parameters to body surface area were analyzed with Pearson's correlation coefficient. The differences of the pharmacokinetic parameters between the patient groups were compared with use of a Kruskal-Wallis one-way ANOVA. For data management and analysis we used the SAS computer program package (Statistical Analysis System, Inc., Cary, N.C.); p values of less than 0.05 were considered significant. The findings are expressed as median and range.

RESULTS Meperidine plasma concentrations are shown in Fig. 1. Fifteen of 21 patients had some secondary increase in meperidine concentrations between 60 and 1440 minutes after the administration of meperidine. The pharmacokinetic parameters varied greatly between the subjects (Table II). Vc, Vss, and tv2 for meperidine were not correlated with age, gestational age,

postconceptional age, weight, or body surface area (Fig. 2); however, CL was correlated with all these parameters and it was also highly significantly (p < 0.0001) correlated with body surface area after the data from patient 19 (who had a CL that was three times higher than the mean and the lowest postconceptional age) had been exluded. The pharmacokinetic parameters varied greatly in preterm infants, as well as in all age groups in the whole series. There were no differences in pharmacokinetic parameters between the patient groups. Patient No. 17 differed distinctly from the others in that meperidine CL was only 1.8 ml/kg/min and elimination ti/2 was very long at 59.4 hours. She had transitory renal failure, with an s-urea concentration of 10.3 mmol/L at the beginning of the study, and had oliguria 1 day after the operation. Diuresis and s-urea were normalized within 24 hours. Otherwise, no renal or hepatic dysfunction was observed in any of the in-

346 Pokela

GUN PHARMACOL THER

et al.

OCTOBER 1992

40

4000

30 -J

E 1--

20

4,

3000 2000

CD

.E

1000

10

2

A 000

0.1

0.2

0.3

Body surface area

0.4

0.5

B

.

00

0.1

0.2

"

0;3

04

Body surface area (m')

fml

12-

5

42-

C

00

01

0.2

0:3

04

00

05

0:1

0.2

0:3

0:4

0.5

Body surface area (m2)

Body surface area (m2)

Fig. 2. Meperidine clearance (CL, in milliliters per minute per kilogram; A) elimination half-life (t1/2, in minutes; B), central volume of distribution (Vc, in liters per kilogram; C), and steady-state volume of distribution (V, in liters per kilogram; D) related to body surface area (in square meters). CL was correlated with body surface area when patient 12, whose CL was more than three times the mean, was excluded (correlation coefficient, 0.711; p < 0.001).

fants, although patient 12 had evident cholestasis, with total bilirubin elevated to 195 mmol/L, a conjugated bilirubin fraction of 126 mmol/L and ALAT of 53 U/L. Patient 9 also had a slightly elevated ALAT level of 62 U/L. The pharmacokinetic parameters in seven critically ill patients (patients 1, 2, 3, 9, 15, 20, and 21) did not differ from the values of the others with a median tv, of 10.7 hours (range, 6.6 to 18.9 hours) versus 8.8 hours (range, 3.3 to 59.4 hours); median CL of 8.0 ml/kg/min (range, 3.5 to 11.3 ml/kg/min) versus 8.4 ml/kg/min (range, 1.8 to 34.9 ml/kg/min); median Vc of 2.1 L/kg (range, 1.1 to 4.5 L/kg) versus 3.1 L/kg (range, 1.5 to 4.8 L/kg); and median Vss of 5.7 L/kg (range, 6.6 to 18.9 L/kg) versus 7.4 L/kg (range, 3.3 to 11.0 L/kg). There were no clinically significant changes in arterial blood pressure or heart rate during or after meperidine injection (Table III). Three newborn infants with respiratory difficulties received mechanical ventilation the whole study period. Of 18 infants studied after surgery, only three were extubated in the operating room and three were extubated before the beginning of the study. Twelve of the infants were receiving routine mechanical ventilation (Baby-Bird, SIMV neona-

ventilator; Bird Products Corporation, Palm Springs, Calif.) at the beginning of the study; two of the infants were extubated within 4 hours after the administration of meperidine. None of the spontaneously breathing infants had apnea or hypoventilation that required assistance during the trial. Pco2 did not differ significantly from the baseline level when measured 2 hours (p = 0.384), 12 hours (p--- 0.650), or 24 hours (p = 0.126) after the administration of meperidine (Table III), and Pco2 in eight spontaneously breathing infants did not differ from the baseline values (p = 0.467) or values recorded for the 13 infants who received mechanical ventilation (p = 0.312). Additional morphine was given to 20 of 21 patients two to six times during the 24-hour period. tal

DISCUSSION The pharmacokinetic parameters of meperidine showed great interindividual variation in these infants. This variability has also been observed in pharmakokinetic studies with morphine,15 fentany1,16 and alfentani1.17 The tv2 of meperidine in this study varied from 3.3 to 59.4 hours, compared with the mean of 2.3 hours in infants aged 3 to 18 months and 3.3 hours in adults reported by Atwood et al.9 Our values for Vc

VOLUME 52 NUMBER 4

Meperidine in infants

Table III. Physiologic responses to Time

Baseline Median Range 5 Min Median Range 15 Min Median Range 30 Min Median Range 60 Min Median Range 120 Min Median Range 240 Min Median Range 480 Min Median Range 720 Min Median Range 24 Hours Medium Range

1

347

mg/kg meperidine (n = 21)

Heart rate (beatslmin)

Mean blood pressure (mm Hg)

Oxygen saturation (%)

pH

Pco2 (kPa)

156

62 39-95

97 79-99

7.39 7.30-7.53

4.8 3.1-6.3

7.38 7.29-7.55

4.4 2.7-6.4

7.35 7.22-7.60

3.3-6.9

7.35 7.21-7.47

5.3 2.7-6.6

107-184 159

55

97

113-188

42-97

78-99

140 109-180

52

40-84

96 83- 99

146 108-178

55 42-92

97 81-99

151

101-187

58 38-97

80-99

140 103-185

58 40-97

82-99

133

55 36-98

97 78-99

60 34-85

97 77-99

144

59

120-190

34-85

97 80-90

108-177 140

106-180

97

97

4.9

No significant changes were seen in hemodynamic or ventilatory parameters.

and Vss were slightly higher than those reported earlier for adults, but CL was approximately 50% smaller.I8 This great variability is not surprising because sick newborn infants often have multisystem illnesses, with immature hepatic and renal function and agerelated differences in body composition, organ development, and drug biotransformation mechanisms. Changes in organ blood flow and protein binding during and after surgery may also modify the disposition and effect of a drug.I9 The pharmacokinetic parameters of Vc, Vss, and

were not correlated with age, gestational age, postconceptional age, weight, or body surface area, but CL was correlated with all of these. This is fairly plausible because CL is dependent on two physiologic parameters, hepatic metabolic capacity and renal function, both of which are highly dependent on the maturation of the child.8 The composition of the body undergoes several changes during development, but these changes are slower than those in hepatic and renal function. Theoretically, the volume of distributv2

tion of lipid-soluble drugs such as meperidine is smaller in infants and young children because their bodies contain more water but very often, as in the present series, the changes observed in the volume of distribution do not seem to be related to the known changes in extracellular water2° or fat.2I The very long elimination t1/2 values for meperidine recorded in newborn infants are based on values observed in infants who have received meperidine by placental transfer during labor.6 Interestingly, some of our patients had very long t1/2 values, but none of these patients were given meperidine during the first day of life, although some were preterm infants. Meperidine is eliminated in adults mainly by hepatic metabolism, but in newborn infants significant amounts of unchanged meperidine can be found in the urine together with metabolites.8 The major metabolism pathway is hepatic N-demethylation to normeperidine followed by hydrolysis and subsequent conjugation or hydrolysis to meperidine acid, which can then undergo conjugation. High levels of normeperidine, which has a

348

CLIN PHARMACOL THER OCTOBER 1992

Pokela et al.

longer ti,,, than meperidine, may produce tremor, muscle twitches, hyperactive reflexes, and convulsions. The rate of normeperidine formation in neonates is relatively slow, but accumulation to toxic levels can occur in the presence of renal failure or after multiple doses .5 Unfortunately, normeperidine concentrations were not be measured in this study. The mean tv, appeared to be smaller in those infants who showed no rebound increase in meperidine plasma concentrations. Presumably the rebound increase was attributable to enterohepatic circulation or sequestering. When the elimination of meperidine occurred relatively rapidly, this could not be detected in the plasma concentration; thus a slow elimination of meperidine was a prerequisite for the detection of this phenomenon, which has also been described during the administration of morphine22 and fentany123 to newborn infants. Recent research has shown that even preterm newborn infants have all the anatomic and physiologic components required for the perception of pain,24 but extreme hormonal and metabolic stress responses to surgery can be prevented with adequate anesthesia and analgesia, which improve the clinical outcome.2526 Fear of opioid-induced side effects, especially ventilatory depression, has discouraged clinicians from giving adequate analgesia to infants. Opioids produce respiratory depression primarily by a direct effect on the brain-stem respiratory center-an effect that is proportional to the drug dose and is attributable to a reduction in the responsiveness of the respiratory center to carbon dioxide tension. 19 To our knowledge, only a few reports exist on the ventilatory effects of intravenous opioids in infants. Way et al.27, in a comparison of the effects of meperidine and morphine on carbon dioxide response in newborn infants undergoing circumcision, noted that both drugs suppressed the regular "sigh" in the breathing patterns of the infants. Morphine reduced the resting ventilation rate and shifted the carbon dioxide response curve downward and to the right, whereas meperidine did not alter the response to carbon dioxide. Given equal end-tidal carbon dioxide levels, morphine produced a 57% decrease in minute volume and meperidine produce a 23% decrease. Because only six of the 21 patients were breathing spontaneously during the administration of meperidine in this study, we cannot draw any conclusions regarding the respiratory effects of this drug. In conclusion, the great interindividual differences in the pharmacokinetics of meperidine must be taken into consideration when it is administered to preterm

or term newborn infants. Although no life-threatening or serious side effects were observed in this study, appropriate care should be exercised when meperidine is prescribed for this age group. We thank Pentti Arvela, PhD, for measurement of the plasma meperidine concentrations.

References Yaster M, Deshpande JK. Management of pediatric pain with opioid analgesics. J Pediatr 1988;113:421-9. Purcell-Jones G, Dormon F, Sumner E. The use of opioids in neonates. A retrospective study of 933 cases. Anaesthesia 1987;42:1316-20. Miall-Allen VM, Whitelaw AGL. Effect of pancuronium and pethidine on heart rate and blood pressure in ventilated infants. Arch Dis Child 1987;62:1179-80. Morselli PL, Rovei V. Placental transfer of pethidine and norpethidine and their pharmacokinetics in the newborn. Eur J Clin Pharmacol 1980;18:25-30. Caldwell J, Wakile LA, Notarianni Li, Smith RL, Correy G. Maternal and neonatal disposition of pethidine in childbirth-a study using quantitative gas chromatography-mass spectrometry. Life Sci 1978;22:589-96. Caldwell J, Notarianni U, Smith RL. Impaired metabolism of pethidine in the human neonate. Br J Clin Pharmacol 1978;5:362-3. Kuhnert BR, Kuhnert PM, Prochaska AL, Sokol RJ. Meperidine disposition in mother, neonate, and nonpregnant females. CLIN PHARMACOL THER 1980;27: 486-91. Boreus LO. Principles of pediatric pharmacology. New York: Churchill-Livingstone, 1982:46-152. Atwood GF, Evans MA, Harbison RD. Pharmacokinetics of meperidine in infants [Abstract]. Pediatr Res 1976;10:328. Mather LE, Tucker GT. Meperidine and other basic drugs: general method for their determination in plasma. J Pharm Sci 1974;63:306-7. Wilkinson L. Systat: the system for statistics. Evanston, Illinois: Systat Inc, 1988. Akaike H. An information criterion (AIC). Math Sci 1976;14:5-9. Dunne A. An iterative curve stripping technique for pharmacokinetic parameter estimation. J Pharm Pharmacol 1986;38:97-101. Wagner JG. Linear pharmacokinetic equations allowing direct calculation of many needed pharmacokinetic parameters from the coefficient exponents of polyexponential equations which have been fitted to the data. J Pharmacokinet Biopharm 1976;4:443-67. Bhat R, Chari G, Gulati A, Aldana 0, Velamati R. Pharmacokinetics of a single dose of morphine in preterm infants during the first week of life. J Pediatr 1990;117:477-81. Koehntop D, Rodman J, Brundage D, Hegland M.

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Pharmacokinetics of fentanyl in neonates. Anesth Ana1g 1986;65:227-32. Marlow N, Weinding AM, Van Peer A, Heykants J. Alfentanil pharmacokinetics in preterm infants. Arch Dis Child 1990;65:349-51. Verbeeck K, Branch RA, Wilkinson GR. Meperidine disposition in man: influence of urinary pH and route of administration. CLIN PHARMACOL THER 1981;30:619-28. Roberts RJ. Drug therapy in infants. Pharmacologic principles and clinical experience. Philidelphia: WB Saunders Company, 1984. Friis-Hansen B. Body water compartments in children: changes during growth and related changes in body composition. Pediatrics 1961;28:135-59. Brook CGD. Cellular growth: adipose tissue. In: Falkner F, Tanner JM, eds. Human growth, vol 2: postnatal growth. New York: Plenum Publishing, 1978:2133. Koren G, Butt W, Chinyanga H, Soldin S, Tan YK, Pape K. Postoperative morphine infusion in newborn

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infants: assessment of disposition characteristics and safety. J Pediatr 1985;107:963-7. Koehntop DE, Rodman JH, Brundage DM, Hegland MG, Buckley JJ. Pharmacokinetics of fentanyl in neonates. Anesth Analg 1986;65:227-32. Schuster A, Lenard HG. Pain in newborns and prematures: current practise and knowledge. Brain Dev 1990;12:459-65. Anand KJS, Phil D, Hickey PR. Halothane-morphine compared with high-dose sufentanil for anesthesia and postoperative analgesia in neonatal cardiac surgery. N Engl J Med 1992;326:1-9. Anand KJS, Sippel WG, Aysnley-Green A. Randomized trial of fentanyl anaesthesia in preterm babies undergoing surgery: effects on the stress response. Lancet 1987;1:243-8. Way WL, Costley EC, Way EL. Respiratory sensitivity of the newborn infant to meperidine and morphine. CLIN PHARMACOL THER 1965;6:454-61.

Correction An error occurred in Table I of the article, "Human N-acetylation genotype determination with urinary caffeine metabolites" (Kilbane AJ, Silbart LK, Manis M, Beitins IZ, Weber WW. CLIN PHARMACOL THER 1990;47:470-7). In Table I on page 474, the heading for column 2 should be [AAMUI p.g/50 p.1 of urine; the heading for column 3 should be [1U] p.g/200 p.1 of urine; and the heading for column 4 should be [IX] lig/200 ill of urine.

Pharmacokinetics and pharmacodynamics of intravenous meperidine in neonates and infants.

The pharmacokinetics of meperidine (pethidine) was studied in 21 infants who received a single intravenous dose of 1 mg/kg after surgery (n = 18) or d...
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