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Morphine Pharmacokinetics in Children Following Cardiac Surgery:

Effects of Disease and Inotropic Support


Ovadia Dagan, MD, Julia Klein, MSc, Desmond Bohn, MB, Geoffrey Barker, MB, and Gideon Koren, MD

The pharmacokinetics of morphine have not been previously significantly slower clearance rates (0.73 + 0.3 L/kg/h) when
studied in children following cardiac surgery for tetralogy of compared to the rest of the patients (1.5 * 0.41 L/kg/h,
Fallot (TOF) or transposition of the great arteries (TGA). P < 0.05). Because most children needing inotropic support
Morphine steady-state pharmacokinetics were studied in 21 underwent the Fontan procedure, it is conceivable that their
children undergoing repair of TOF, TGA, or atrio-ventricular cardiovascular status had a major impact on morphine metab-
septal defects (AVSD). Children with TOF or TGA had in- olism. These results suggest a 50% reduction in morphine
creased right-sided pressures with no differences between dosage in children requiring inotropic support following
the groups. Children with TOF had significantly faster clear- cardiac surgery.
ance rates of morphine (1.39 f 0.37 L/kg/h) than children Copyright Q 1993 by W.B. Saunders Company
following the Fontan procedure (0.86 f 0.31 L/kg/h,
P < 0.01). When stratifying children by their postsurgical KEY WORDS: morphine, tetralogy of Fallot, transposition of
needs for inotropic support, those needing epinephrine, great arteries
dopamine, or dobutamine at more than 10 pg/kg/min had

M IS one of the most frequently used drugs


ORPHINE arterial catheter. If sedation was indicated beyond 20 hours, it was
for postoperative analgesia. Whereas morphine administered at 30 and 40 hours postoperatively and every 24 hours
pharmacokinetics have been studied in adults, neonates, thereafter. Following discontinuation of the morphine infusion.
blood samples were drawn at 1, 3. 6, 12. and 24 hours whenever
and children following surgery, 1-Ythe disposition of the drug
possible. Mechanical ventilation was continued throughout the
in pediatric patients after cardiac surgery has not been
pharmacokinetic studies in all children except for two after
reported. It is generally agreed that the pharmacokinetics
correction of a VSD who were extubated within 5 hours. Along
of morphine in children over 5 to 6 months of age are with the collection of samples for analysis of morphine concentra-
similar to adults,, although it was recently documented tions, hemodynamic parameters were recorded including heart
that prepubertal children have faster clearance rates than rate. blood pressure, right and left atrial pressures, and central
older adolescents.12 venous pressure. Drug support and mechanical ventilation were
Cardiac surgery is often associated with changes in tissue also recorded.
perfusion and hepatic blood flow. Because morphine is Blood samples were immediately centrifuged and serum was
metabolized mainly by liver enzymes, changes in tissue stored at -20C until analyzed within 14 days. Morphine concentra-
tions were measured directly in the serum using a radioimmunoas-
perfusion and hepatic blood flow may potentially affect the
say (Coat-a-Count Diagnostic Products Corporation, Los Angeles.
disposition of the drug and hence its optimal dose schedule.
CA). The coefficient of variation of the test in the laboratory is less
Therefore, a prospective evaluation of morphine pharmaco-
than 5% and the lowest sensitivity is 1 ng/mL. The assay has
kinetics in children following cardiac surgery with normal negligible cross-reactivity with the m-6- and m-l glucoronides of
right-sided pressures and high right-sided pressures was morphine. Steady-state clearance of morphine was determined
conducted. from at least two concentration time points obtained after at least
15 hours of unchanged dose rate. Clearance rate (Cl) was calcu-
PATIENTS AND METHODS lated as the ratio between the infusion dose rate and the respective
After approval by the Human Experimentation Review Commit- mean steady-state serum concentration. Terminal elimination
tee, informed consent was obtained from all parents. Included half-life (t/l) was determined using the ADAPT computer pro-
were children between 6 months and 10 years of age following gram. Distribution volume (Vd) was calculated as cl/~,, where Kc
surgical repair of ventricular septal defects (VSD), atrio-ventricu- is the elimination constant, using the steady-state Cl value.
lar septal defects (AVSD), tetralogy of Fallot (TOF), or transposi- Comparison of pharmacokinetic values between subgroups wab
tion of the great arteries (TGA). conducted by the unpaired t-test. When more than two groups were
All patients were anesthetized with fentanyl, 10 to 30 kg/kg, in compared. the Bonferoni correction was applied. Patients were
the operating room. On admission to the intensive care unit (ICU) stratified by their primary cardiac diagnosis and by their need for
morphine infusion rates between 20 and 40 pgikglh were started inotropic support, defined as use of either epinephrine, dopamine.
using volumetric infusion pumps, with constant rates of infusion or dobutamine at rates higher than 10 hg/kg/min for at least 2
maintained for at least 20 hours. Two children required additional hours. All data are presented as mean 2 SD.
sedation, and received fentanyl, 5 kg/kg (N = l), or diazepam, 0.1
RESULTS
mgikg (N = 1). Blood samples were drawn from an indwelling
Twenty-one children were studied; 8 following the Fon-
tan procedure for TGA, 8 after correction of TOF, and 5
after either VSD or AVSD repairs. Their mean ages were
From the Divisiorz of Clinical Pharmacology, Departments of 3.4 t 2.1 years, (range, 8 months to 7 years), and 8 were
Pediatrics and Critical Care, and Research Institute, The Hospital for
girls. Children undergoing TOF correction were of similar
Sick Children, Toronto, Deparrment of Pediatrics, Pharmacology and
age to those treated with the Fontan pressure (3.4 2 2.2
Anesthesia, The University of Toronto.
and 3.8 2 2.2 years, respectively). Children with both TOF
Address reprint requests to Gideon Karen, MD, ABMT, FRCP(C),
Division of Clinical Pharmacology, The Hospital for Sick Children, and TGA had increased right-sided pressures with no
555 University Ave, Toronto, Ontario, M5G 1X8. differences between them. However. the children with TOF
Copyright 0 1993 by NB. Saunders Company had significantly faster clearance rates of morphine
1053-077019310704-0003$03.0010 (Table 1).

396 Journalof Cardiothoranc and VascularAnesthesla, Vol7. No 4 (August), 1993: pp 396.398


MORPHINE PHARMACOKINETICS IN CHILDREN 397

Table 1. Comparison Between Children Following TOF and Table 3. Morphine Pharmacokinetics
Fontan Repair
Ke (h - 1) VD (L/kg) CL (L/kg/h) t%(h)
Fontan TOF
1 0.144 10.25 1.32 6.5
RA Morphine RA Morphine 2 0.102 13.1 1.28 11.5
Patient PWSSlre ClearalICe Patient PR?SSUW CleWSlC2
3 0.066 10.3 0.76 5.5
NO. (cm HzO) (L/kg/h) NO. (cm H,Ol (L/kg/h)
4 0.097 8.3 0.78 11.5
1 10 1.32 1 12 1.42 5 0.137 4.2 0.53 5.5
2 8 1.28 2 14 1.92 6 0.0589 20.6 1.42 6.5
3 17 0.50 3 14 1.03 7 0.0706 23.2 1.92 7
4 8 0.76 4 10 1.28 8 0.0531 14.8 1.03 3.3
5 8 0.78 5 14 1.06 9 0.134 10.9 1.28 3.3
6 14 0.72 6 13 1.16 0.096 ? 0.036 12.9 + 5.9 1.15 + 0.42 6.7 5 3
7 15 0.53 7 7 2.00
NOTE. Included in this table are only children in whom samples
8 14 0.96 8 14 1.24
during the elimination phase (after cessation of morphine infusion)
Mean 11.7 & 3.7 0.86* -t 0.31 12.3 + 2.6 1.39* + 0.37
were available.
*P < 0.01.

operations or those with cancer pain. In the present study,


Nine children did not need any inotropic support, 6 mean clearance of morphine was on average 50% lower
needed up to 5 pg/kg of epinephrine (E), or 5 kg/kg/min of than in children with sickle cell disease using similar steady-
dopamine (D) or dobutamine (DB), and 6 required 10 state pharmacokinetics and an identical analytical protocol
ug/kg/min or more of D or DB and E more than 10 (2.1 f 0.69 L/kg/h in sickle disease v 1.39 2 0.37 L/kg/h in
ug/min. When stratifying children by their postsurgical cardiac patients without inotropic support and 0.86 2 0.31
needs for inotropic support, those needing E, D, or DB at
L/kg/h with inotropic support).12
the highest doses had significantly lower clearance rates of
Maturation of the metabolic pathways of morphine
morphine (0.73 t 0.3 L/kg/h) when compared to the rest
elimination occurs by 6 months of age*OJ4; there is a
of the group (1.5 2 0.41) (P < 0.05) (Table 2). Children
tendency towards a decrease in morphine clearance to-
following the Fontan procedure who needed no inotropic
wards puberty.* This study has documented a correlation
support (N = 4) had mean clearance rates of morphine of
among morphine clearance, cardiovascular status, and the
0.98 ? 0.39 L/kg/h, not significantly higher than the rest of
need for inotropic support. Because the majority of such
the Fontan cases, possibly because of the small sample size
support was needed in patients following the Fontan
of the subgroups.
procedure, it is possible that the lower clearance rates in
Adequate sedation was associated with mean serum
children undergoing this operation were caused by their
concentrations of morphine of 23.3 ? 8.4 ng/mL (range,
impaired cardiovascular status. More cases will have to be
15.2 to 40 ng/mL). Elimination half-life and distribution
studied to separate the effects of the disease entity from the
volume of morphine were determined in 9 patients and are
hemodynamic status. The identical ages of the two groups
presented in Table 3. In all cases there was a secondary
peak of the morphine concentration at 10 to 12 hours. ruled out maturation changes in morphine clearance be-
Because samples were drawn for only 24 hours after drug tween the two groups.
discontinuation, the sampling time may not be long enough This analysis reveals that high right-sided pressures
to fully characterize the elimination phase in two patients probably did not affect morphine clearance, because chil-
(no. 2 and 4, Table 3) who appear to have prolonged t%. dren with both TGA and TOF repairs had similarly high
pressures. Rather, it is conceivable that cardiac output, and
DISCUSSION the need to control it by inotropic support, had a direct
Virtually all children undergoing cardiac surgery receive effect on morphine clearance. It is believed that hepatic
morphine postoperatively during their stay in the ICU. Due blood flow, which follows changes in cardiac output, affects
to their underlying cardiac diseases and their postsurgical the clearance rate of the opioid.r5 Changes in kidney
cardiovascular status, these children cannot be assumed to function during impaired cardiac output are less likely to
handle morphine similarly to other children following affect morphine pharmacokinetics.16-s A similar obsetva-
tion has recently been made by Notterman et a1,19who
Table 2. Morphine Clearance in Children Requiring lnotropic Support found that dopamine clearance was influenced in children
Patient Morphine Clearance
by the degree of organ system function.
No/Diagnosis (L/kg/h) Drug support The threefold decrease in morphine clearance rates in
IIVSD 1.13 D. E
children with evidence of cardiovascular instability suggests
2iAVSD 0.29 D. E
that they should achieve comparable analgesia with less
3/TGA (Fontan) 0.50 D. DB, E than 50% of the regular doses. Moreover, the lower
4/TGA (Fontan) 0.76 D. E clearance rate of morphine, followed by its accumulation,
S/TGA (Fontan) 0.72 DB, E may enhance its untoward cardiovascular effects.20-22The
G/TGA (Fontan) 1 .oo D practical implication of this observation is a 50% decrease
NOTE. Drug support: D = dopamine > 10 yglkglmin. E = epineph- in the dose rate of morphine in children needing inotropic
rine > 10 wg/min. DB = dobutamine > 10 pg/kg/min. support following cardiac surgery.
398 DAGAN ET At

REFERENCES
1. Stanski DR. Greenblatt DJ, Lapas D, et al: Kinetics of 12. Robieux I. Kellner J, Copper M. et al: Analgesia in children
high-dose intravenous morphine in cardiac surgery patients. Clin with sickle cell crisis. Ped Hematol Oncol (in press)
Pharm Ther 30:629-635, 1981 13. Diagnostic Products Corporation, 5700 W 96th St, Los
2. Dahlstrom B, Bolme P, Feychting P, et al: Morphine kinetics Angeles, CA. 90045. Package Insert 1817. September 7, 1990
in children. Clin Pharm Ther 26:354-365, 1979
14. McRovie TI, Slattery JT. Lynn AM, et al: Maturation of
3. Dahlstrom B, Tamsen A. Paalzow L, et al: Patient-controlled
morphine clearance in newborns and infants. Clin Pharm Ther
analgesic therapy: IV pharmacokinetics and analgesic plasma
47: 132, 1990
concentrations of morphine. Clin Pharmacokinet 7:266-279, 1982
15. Jenkins JG. Lynn AM. Wood AE. et al: Acute hepatlc
4. Bhat R, Chari G. Gulati A, et al: Pharmacokinetics of a single
failure following cardiac operation in children. J Thorac Cardio-
dose of morphine in preterm infants during the first week of life. J
vast Surg 84:865-X71, 1982
Pediatr 117:477-481. 1990
5. McRovie Tl, Slattery JT, Lynn AM: Metabolism of morphine 16. Ball M, Moore RA, Fisher A. et al: Renal failure and the use
in early infancy. Pharmacotherapy 30:238-241,199O of morphine in intensive care. Lancet 1:784-786. 1985
6. Mercurio M. Nelli C, Gettner P, et al: Morphine pharmacoki- 17. Shelly M. Park GR: Renal failure and use of morphine m
netics in preterm newborns. Pediatr Res 25:71A. 1989 intensive care. Lancet 7:llUO. 1985
7. Chay PCW, Due BJ, Walker JS: Pharmacokinetic-pharmaco- 18. Hanks GW, Aherne GW: Morphine metabolism: Does the
dynamic relationships of morphine in neonates. Clin Pharm Ther renal hypothesis hold water? Lancet 1:221. 1985
11334-342. 1992
19. Notterman D. Greenwald B. Moran F. et al: Dopamine
8. Koren G, Butt W, Chinyanga H. et al: Postoperative mor-
clearance in critically ill infants and children: Effect of age and
phine infusion in newborn infants: Assessment of disposition
organ system dysfunction. Clin Pharm Ther 48:138-147, 1990
characteristics and safety. J Pediatr 107:963-967. 1985
20. Fennessy MR, Rattray JF: Cardiovascular ef?ects of intrave-
9. McGuinness GA, Farrington EA, Johnson GF, et al: Postop-
nous morphine in the anaesthetized rat. Eur J Pharm 14: l-8. 197 I
erative morphine requirement in newborn infants. Pediatric Res
25:224A, 1989 21. Rothbard RL. Schreiner BF, Yu NP: Hemodynamic and
10. Olkkola K, Mannuksela E, Korpela R, et al: Kinetics and respiratory effects of dezocine. ciramadol, and morphine. Clin
dynamics of postoperative intravenous morphine in children. Clin Pharm Ther 3X:84-88, 1985
Pharm Ther 44:128-136, 1988 22. Romagnoli A. Keats AS: Comparative hemodynamic effects
Il. Nahata M, Miser A, Miser J. et al: Variation in morphine of nalbuphine and morphine in patients with coronary artery
pharmacokinetics in children with cancer. Dev Pharmacol Ther disease. Cardiovascular Disease Bulletin of the Texas Heart
8:182-188, 1985 Institute 5:19-24. 1Y78

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