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June 1998
Clearance of morphine in postoperative infants during intravenous infusion: The influence of age and surgery.
Lynn A, Nespeca MK, Bratton SL, Strauss SG, Shen DD; Anesth Analg 1998; 86: 958-63.
[ see abstract below ]
In April 1997, I reviewed two
articles on the pharmacology of drugs commonly used in neonates, fentanyl (Wilson
AS, et al. Anesth Analg 1997;84:315-8) and bupivacaine (Larsson
BA, et al. Anesth Analg 1997;84:501-5). Additional information regarding
morphine pharmacokinetics was recently published by Dr. Anne Lynn and her colleagues
at the University of Washington.
The question in this study arose from the investigators' previous observations that the respiratory effects of morphine administered by continuous infusion were related to plasma morphine concentrations ([M]) (concentrations < 20 ng/mL were associated with minimal changes in ventilation) and not to age. In order to extend their investigations to analgesic requirements and respiratory effects in spontaneously breathing infants, they needed to know what infusion rates are most likely result in plasma [M] of 20 ng/mL. Determination of accurate morphine clearance values was necessary to predict a specific concentration.
The investigators measured plasma [M] and its active metabolite morphine-6-glucuronide (M-6-G) during continuous steady state morphine infusion in 26 healthy term infants, aged 1 day to just over 1 year. All infants had had major non-cardiac surgery not requiring postoperative mechanical ventilation. Morphine clearance increased with age (R2 = 0.64 by linear regression analysis) and was equal to or greater than reported adult values by two months of age. Drug clearance was consistently higher in these infants than in those reported previously who had undergone cardiac surgery with or without cardiopulmonary bypass (infants requiring inotropic support had even lower clearances). M-6-G concentrations were stable and measurable in all infants.
Infusion Rates (mg/kg/h) to Achieve Steady State [M] * 20 ng/mL
| Age |
Cardiac Surgery |
Non-Cardiac Surgery |
| 1 - 30 days |
5 |
10 |
| 1 - 3 months |
15 |
20 |
| 3 - 6 months |
20 |
25 |
Unlike fentanyl and bupivacaine, the effects of which depend on protein binding as well as on hepatic metabolism and renal excretion, morphine is less protein-bound. Binding is lower in infants than in adults (22% vs. 35%, McRorie TI, Lynn AM et al, Am J Dis Child. 1992; 146:972-6) and remains substantially unchanged during the first two years of life. The developmental maturation of a1-acid glycoprotein is thus less important for this drug.
Return to the Current Literature Review Front Page, or read the abstract:
ABSTRACT
We analyzed morphine clearance values in infants receiving the drug by continuous i.v. infusion for analgesia after surgery, because we found lower steady-state morphine concentrations than we expected from our previous studies.
Infants received morphine after a loading dose of 0.05 mg/kg and continuous infusion calculated to reach a steady-state concentration of 20 ng/mL. Blood was sampled twice on Postoperative Day 1 at times separated by at least 2 h, and morphine and morphine-6-glucuronide (M-6-G) concentrations were determined by high-performance liquid chromatography. Clearance of morphine was calculated as infusion rate divided by the steady-state morphine concentration. Morphine given to 26 infants by continuous i.v. infusion after major noncardiac surgery has rapidly increasing clearance values, >from a median value of 9.2 mL x min(-1) x kg(-1) in infants 1-7 days old, 25.3 in infants 31-90 days old, and 31.0 in infants 91-180 days old to 48.9 in infants 180-380 days old. Adult clearance values are reached by 1 mo of age, more quickly than in infants of the same age previously studied who received morphine after cardiac surgeries. M-6-G was measured in all infants.
The ratio of M-6-G to morphine concentrations was 1.9-2.1 in these infants, which is lower than ratios reported in older infants or adults by others, but higher than those reported in newborns. Infants with normal cardiovascular systems undergoing surgery clear morphine more efficiently than infants of the same age undergoing cardiac surgery.
Implications: Morphine removal >from the body is slow in newborns but increases to reach adult values in the first months of life. Calculating the clearance of morphine from blood samples drawn during continuous i.v. infusions after surgery shows that this maturation occurs more quickly in infants undergoing noncardiac surgery (by 1-3 mo of age) than in those receiving morphine after cardiac surgery (by 6-12 mo of age).
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