PEDIATRICS Vol. 121 No. 4 April 2008, pp. e844-e849 (doi:10.1542/10.1542/peds.2007-1987)
ARTICLE |
Elevated Morphine Concentrations in Neonates Treated With Morphine and Prolonged Hypothermia for Hypoxic Ischemic Encephalopathy
a First Department of Paediatrics, Semmelweis University, Budapest, Hungary
b Research Group of Paediatrics and Nephrology, Hungarian Academy of Sciences, Budapest, Hungary
c Division of Clinical Sciences, Hammersmith Campus, Imperial College London, United Kingdom
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ABSTRACT |
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 TOP ABSTRACT PATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVES. Asphyxia and hypothermia may modify drug pharmacokinetics. We investigated whether analgesia with morphine in neonates with hypoxic ischemic encephalopathy undergoing prolonged moderate systemic hypothermia resulted in elevated serum morphine concentrations compared with normothermic infants.
PATIENTS AND METHODS. Infants from 1 center participating in a multicenter randomized study of moderate whole-body hypothermia after perinatal asphyxia (the Total Body Hypothermia Study) were randomly selected for treatment with hypothermia (n = 10) or for standard care on normothermia (n = 6). Hypothermia (33°C to 34°C) was started before 6 hours of age and maintained for 72 hours. All of the infants were treated with a continuous infusion of morphine-hydrochloride, with the rate adjusted according to clinical status. Serum morphine concentrations were determined at 6, 12, 24, 48, and 72 hours after birth.
RESULTS. Serum morphine concentrations at 24 to 72 hours after birth were (median [range]) 292 ng/mL (137–767 ng/mL) in the hypothermia-treated infants and 206 ng/mL (88–327 ng/mL) in the infants on normothermia, despite similar morphine infusion rates and cumulative doses. Morphine concentrations correlated with morphine infusion rate, cumulative dose, and treatment with hypothermia. Serum morphine concentrations reached a steady state after 24 hours in the normothermic infants but continued to increase throughout the assessment period in the hypothermia group. Morphine clearance was low in both groups: (median [range]) morphine clearance estimated from area under the curve was 0.69 mL/min per kg (0.58–1.21 mL/min per kg) in hypothermic group and 0.89 mL/min per kg (0.65–1.33 mL/min per kg) in infants on normothermia. Serum morphine concentrations >300 nL/mL occurred more often in the hypothermia group and when the morphine infusion rate was >10 µg/kg per h.
CONCLUSIONS. Infants with hypoxic ischemic encephalopathy have reduced morphine clearance and elevated serum morphine concentrations when morphine infusion rates are based on clinical state. Potentially toxic serum concentrations of morphine may occur with moderate hypothermia and infusion rates >10 µg/kg per h.
Key Words: asphyxia • hypothermia • morphine • neonate
Abbreviations: HIE—hypoxic-ischemic encephalopathy • TOBY—Total Body Hypothermia • AUC—area under the curve • M3G—morphine-3-glucoronide
Hypoxic-ischemic encephalopathy (HIE) is a major cause of mortality and long-term morbidity in term infants. Treatment is currently limited to supportive intensive care, but efforts have been made to develop more effective therapies. Prolonged systemic hypothermia is a promising new approach for reducing brain damage in neonates. Two large clinical trials have demonstrated that prolonged cooling of either the head or the whole body of neonates with HIE is safe and associated with reduced short-term mortality and morbidity of 
18 months of age.1,2 Other randomized trials of moderate therapeutic hypothermia are currently underway.3–5
The induction and maintenance of hypothermia may be stressful for the patient, which may counteract the benefits of hypothermia. Thoresen et al6 demonstrated in piglets that the neuroprotective effect of hypothermia is abolished in the absence of adequate analgesia. Therefore, it is considered important to maintain adequate sedation and analgesia during hypothermia. The protocol of the Total Body Hypothermia (TOBY) Study (Whole Body Hypothermia for the Treatment of Perinatal Asphyxial Encephalopathy, ISRCTN 89547571) recommends routine treatment with morphine for all infants in the study who required ventilation or showed signs of distress,3 and this is also a common practice in our unit.
Hypothermia influences cellular functions, especially the rate of enzymatic processes. In mammals, cerebral metabolism is reduced by 7% when the body temperature is lowered by 1°C.7,8 Data obtained in adults indicate that even short-term hypothermia may have an effect on the metabolism of major analgesics and other drugs.9–11 No data are available for neonates concerning the impact of hypothermia on the pharmacokinetics of morphine. However, Thoresen et al12 reported that the half-life of phenobarbitone in neonates with HIE treated with hypothermia is double that of normothermic infants. The abnormal liver and renal function that often occurs after asphyxia is also likely to alter drug metabolism and excretion.13
The aim of our observational study, therefore, was to investigate whether morphine pharmacokinetics are altered during prolonged moderate systemic hypothermia in asphyxiated neonates, resulting in excessively high morphine concentrations compared with infants kept at normothermia; this would be important information for clinicians wishing to provide hypothermia.
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PATIENTS AND METHODS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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All 16 of the term neonates with HIE who were enrolled into the multinational TOBY Study of moderate systemic hypothermia after asphyxia from our center were studied. The infants were admitted between January 2005 and February 2006 to the regional neonatal care unit at the Semmelweis University First Department of Pediatrics. Before treatment, each patient's parents provided informed consent to participate in this study. The study was approved by the national Ethical Committee for Medical Research.
Infants were evaluated according to a 3-step eligibility system based on clinical and neurologic criteria as used in the TOBY Study.3 Infants were enrolled within 6 hours of birth if each of the following criteria was fulfilled: (1) infants were 
36 weeks’ gestation with 1 of the following: (a) Apgar score of 5 at 10 minutes after birth; (b) continued need for resuscitation, including endotracheal or mask ventilation, at 10 minutes after birth; (c) acidosis defined as pH <7.0 and/or base deficit 16 mmol/L in umbilical cord blood sample or any blood sample within 60 minutes of birth (arterial or venous blood); (2) moderate-to-severe encephalopathy consisted of altered state of consciousness (irritability, lethargy, stupor, or coma) and 1 of the following: (a) hypotonia, (b) abnormal reflexes including oculomotor or pupillary abnormalities, (c) an absent or weak suck, or (d) clinical seizures; and (3) 30 minutes duration of amplitude-integrated electroencephalogram recording showed moderately abnormal or suppressed background amplitude-integrated electroencephalogram activity or seizures.
Patient allocation was by central telephone randomization provided by the National Perinatal Epidemiology Unit (Oxford, United Kingdom). Infants allocated to treatment with standard intensive care and hypothermia were cooled to a rectal temperature of 33°C to 34°C for 72 hours, called the hypothermia group (n = 10). Hypothermia was maintained by using a cooling mattress (Tecotherm, Munich, Germany). Infants allocated to the control group (normothermia; n = 6) were treated with standard intensive care on normothermia (37°C ± 0.2°C). In both groups, rectal temperatures were monitored continuously and recorded each hour for the 72-hour intervention period. Routine laboratory measurements of liver enzymes, renal function, blood cell count, and coagulation parameters were performed daily.
Both groups were treated with the same regimen, except for the hypothermia. All of the infants received morphine-hydrochloride (Biogal-Teva, Budapest, Hungary), as a single loading dose of 50 to 150 µg/kg of body weight before 6 hours of age, followed by continuous infusion at 5 to 30 µg/kg per h. The maintenance dose was adjusted according to physical signs and symptoms of discomfort, such as excessive movement, irritability, or tachycardia. Continuous morphine infusions were stopped after 72 hours or earlier if the infant was extubated and was not distressed. Seizures were controlled with phenobarbital in both groups (starting dose: 20 µg/kg; maintenance dose: 5–10 mg/kg per d). If the infant remained agitated or seizures persisted, a single dose of midazolam (0.1–0.2 mg/kg) was administered. The daily cumulative doses of morphine and other drugs were recorded. We assessed the severity of encephalopathy during the first 24 hours of age by Sarnat score14 and again at 4 days of age by using the TOBY protocol3 modified encephalopathy score.15 Cardiovascular instability was defined as mean arterial blood pressure <40 mm Hg and was treated with a single or repeated dose of saline (10–20 mL/kg). If hypotension persisted, dobutamine (5–20 µg/kg per min), dopamine (2–10 µg/kg per min), or norepinephrine (0.1–0.3 µg/kg per min) was administered.
Venous blood samples were collected at 6, 12, 24, 48, and 72 hours after birth. Blood (0.5 mL) was centrifuged, and sera were separated and stored at –80°C until morphine concentrations were measured. Serum morphine concentrations were determined with an enzyme-linked immunosorbent assay (Opiates Reagent Pack, Abbott Diagnostics, Abbott Park, IL). The assay uses a stored 6-point calibration curve, and it is linear within the concentration range of 50 and 1000 ng/mL. Control tests were conducted before the analysis of morphine concentrations. The coefficient of variation of the control tests was 10%.
We calculated the area under the curve (AUC) of the serum morphine concentrations and calculated clearance by dividing the total morphine administered by the AUC. Serum morphine concentrations were considered to reach a steady state when the difference between measurements at successive time points was <15%.16 If morphine concentrations reached a steady state, we also estimated clearance by dividing the infusion rate by the steady-state serum morphine concentration.
A 2-tailed t test was used to compare means of normally distributed continuous data, and we used the Mann-Whitney U and Kruskal-Wallis tests for nonparametric data. Categorical data were compared with Fisher's exact test. Correlation of the serum morphine concentrations with the morphine infusion rate and treatment with hypothermia was computed by multiple regression analysis. SPSS 12, Apache Software Foundation (SPSS Inc, Chicago, IL), was used for statistical analysis. A P value of <.05 was considered significant.
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RESULTS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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The clinical characteristics of the infants in the hypothermia and normothermia groups were similar (Table 1). The clinical course during the neonatal period was also similar in the 2 groups: all 10 survived in the hypothermia group, and 5 of 6 survived in the normothermia group; 4 hypothermia infants and 3 normothermia infants developed seizures. The numbers of days ventilated were (mean [SD]) 6 (1.6) in the hypothermia and 4 (2.0) in normothermia group, and the days to oral feeding were 8 (1.3) and 8 (3.5) in the hypothermia and normothermia groups. Nine infants in the hypothermia group and 4 infants in the normothermia group received cardiovascular support with fluid bolus and/or inotropes. The duration of receiving cardiovascular support was 77.4 hours (9.6 hours) in the hypothermia group and 41.8 hours (15.9 hours) in normothermia group (P = .09). No infant developed a cardiac arrhythmia or severe hypotension (blood pressure: <30 mm Hg). The median (range) encephalopathy score at age 4 days was 8.5 (3.0–12.0) in the hypothermia group and 5.5 (0.0–15.0) in the normothermia group (P = .26). The laboratory parameters were similar for the 2 groups (Table 2).
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The median (range) of start of cooling was 4.0 hours (3.3–5.3 hours) after birth, and the mean (SD) rectal temperature in the cooled infants was 33.4°C (0.65°C) during hypothermia and 36.7°C (0.33°C) for infants on normothermia. Similar cumulative morphine doses were administered in the hypothermia and normothermia groups (median: 0.58 mg/kg per h; range: 0.31–1.87 mg/kg per h vs median: 0.60 mg/kg per h; range: 0.40–1.08 mg/kg per h; P > .1); the median (range) infusion rate was 10 µ/kg per h (4–30 µg/kg per h) in the hypothermia group and 10 µg/kg per h (5–20 µg/kg per h) in the normothermia group (P > .1). Infants in the hypothermia group received more morphine at 72 hours than the normothermia group, but the difference was not significant (Table 3). The doses of phenobarbitone and midazolam were also similar during the intervention period.
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Serum morphine concentrations were not available for 1 infant (hypothermia) at 12 hours, for 1 infant (hypothermia) at 48 hours, and for 3 infants (hypothermia) at 72 hours. In 1 infant, hypothermia treatment with morphine was only started at 24 hours, and in another infant normothermia treatment was stopped at 48 hours. Therefore, 70 samples were used for the analysis of serum morphine concentrations.
Serum morphine concentrations in the infants treated with hypothermia were higher than in the normothermia group. The morphine concentrations at 24 to 72 hours after birth were (median [range]) 292 ng/mL (137–767 ng/mL) in the hypothermia group and 206 ng/mL (88–327 ng/mL) in the normothermia group (P = .014), although there was no difference in the morphine infusion rates (P = .56) or cumulative morphine doses between the groups (P = .083). The AUC for serum morphine concentrations over the entire observation period was (mean [SD]) 18 608 ng/h per mL (8384 ng/h per mL) in the hypothermia group and 12 135 ng/h per mL (3481 ng/h per mL) in the normothermia group (P = .051).
Serum morphine concentrations reached a steady state after 24 hours in the normothermia infants, but they continued to increase in the hypothermia group (Table 3). At the 72nd postnatal hour, serum morphine concentrations for the 7 infants in the hypothermia group and 6 infants in the normothermia group were (mean [SD]) 373 ng/mL (125 ng/mL) vs 222 ng/mL (73 ng/mL; P .02; Fig. 1).
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Serum morphine concentrations >300 ng/mL occurred in 13 of 42 samples from the hypothermia group and 2 of 28 samples from infants on normothermia (P
.025) and in 10 of 25 samples obtained when the morphine infusion rate was >10 µg/kg per h compared with 4 of 45 samples at 10 µg/kg per h (P .01). Multiple regression analysis indicated that the morphine infusion rate and treatment with hypothermia (assessed as a continuous variable) strongly influenced serum morphine concentrations with little evidence of collinearity (adjusted r2 = 0.527; infusion rate: r = 0.663; P < .0001; hypothermia r = 0.441; P = .004; variance inflation factor: 1.015; Fig 2). Similar results were obtained when the analysis was repeated with the cumulative dose replacing the infusion rate (cumulative dose r = 0.646; P < .0001; hypothermia r = 0.264; P = .017).
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Median (range) morphine clearance estimated from the AUC for infants with measurements available at each time point was 0.69 mL/min per kg (0.58–1.21 mL/5–1.33 mL/min per kg) in infants on normothermia (n = 5; P = .21). Steady-state morphine clearance (estimated at 48 hours) was 0.89 mL/min per kg (0.34–1.99 mL/min per kg) in the normothermia group but could not be calculated in the hypothermia group because a steady state was not reached.
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DISCUSSION |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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We found that neonates with hypoxic ischemic encephalopathy receiving commonly used rates of morphine infusion for 72 hours developed high serum morphine concentrations. Infants treated with moderate systemic hypothermia attained higher and potentially toxic concentrations of morphine compared with normothermic infants, despite receiving similar cumulative morphine doses.
Some studies have examined the pharmacokinetics and pharmacodynamics of morphine in neonates but none after HIE.16–18 Morphine clearance correlates moderately with gestational age and birth weight, but there is considerable variability between infants, and pharmacodynamics is highly variable, so that dosage is often based on clinical response rather than a fixed regime. In our study we applied a commonly used regimen for morphine administration and altered the dose according to clinical assessment of distress. Although the median morphine infusion rate was 10 µg/kg per h, some infants received 30 µg/kg per h on some occasions. It is possible that difficulty in assessing the clinical need for sedation or analgesia in the presence of HIE and treatment with hypothermia resulted in some infants receiving excessive treatment with morphine.
Mean morphine concentration required to produce adequate analgesia in healthy term infants is said to be 
125 ng/mL.18 In our study, the median morphine concentrations in both groups of infants were >200 ng/mL, which is much higher than was observed in nonasphyxiated infants receiving greater morphine infusion rates.16,19,20 Morphine concentrations >300 ng/mL are generally regarded as likely to be toxic and may be associated with adverse cardiorespiratory events, but even lower doses may alter gut motility.16,18 We found that that morphine concentration exceeded 300 ng/mL in several infants who were treated with hypothermia or when the morphine infusion rates were >10 µg/kg per h. This finding suggests that asphyxiated infants treated with moderate systemic hypothermia and morphine for analgesia or sedation are at risk of morphine toxicity when the morphine dose is titrated according to clinical state. We did not observe major complications, such as severe hypotension,21 that could be ascribed to morphine toxicity. However, the hypothermia group had longer ventilatory requirements, longer need for cardiovascular support, and a worse encephalopathy score at 4 days of age, although none of these differences were statistically significant. It is conceivable that these observations were related to the higher morphine concentrations in the infants with hypothermia, but we did not explore these findings additional because of the small group sizes.
Morphine pharmacokinetics has not been studied previously in infants during hypothermia. In this study we were only able to carry out a limited pharmacokinetic analysis of morphine because of logistic and clinical difficulties: most infants had poor urine output for several hours. The morphine infusion rate was altered often according to the clinical state, and it was inappropriate to obtain more frequent blood samples for pharmacokinetic studies, considering the infants’ clinical condition. Because infants in the hypothermia group did not reach steady-state morphine concentrations, we estimated morphine clearance in 2 ways: by using the AUC concentrations in both groups and also from the steady-state morphine concentrations in the normothermic group. The clearance estimated by each method was very similar.
The study infants had lower estimated morphine clearance than is reported for nonasphyxiated infants.16,19,20 Moderate or severe asphyxia is often associated with multiorgan dysfunction, including hepatic impairment, which is likely to influence metabolism and clearance of morphine.13 As expected, we observed elevation of hepatic enzymes and alterations in other laboratory parameters that reflect acute cellular necrosis and tissue dysfunction, and this probably accounts for low clearance values observed in this study. However, we found that these parameters were equal or less severely abnormal in the hypothermia group (Table 2), which we have reported in more detail elsewhere.22 This suggested that hypothermia had an independent effect on the serum morphine concentrations, and this was confirmed on multiple regression analysis.
The most likely explanation for the higher morphine concentrations in infants treated with hypothermia compared with those on normothermia is the effect of temperature on drug metabolism. The activity of hepatic drug metabolizing enzymes is strongly impaired at lower temperatures, although no data are available about the kinetic properties of the enzyme (UDP-glucuronosyltransferase) responsible for morphine glucuronidation.23 Although there was no significant difference in estimated morphine clearance between the 2 groups, hypothermia may have reduced hepatic metabolism throughout the 72-hour observation period, whereas hepatic metabolism recovered over the observation period in the normothermia group. This could explain the continued rise in serum morphine concentrations during the observation period in the hypothermia group, whereas normothermia infants reached steady-state concentrations at 48 to 72 hours.
A limitation of our study is that we were unable to measure morphine metabolites. The measurement of the 2 metabolites of morphine, morphine-3-glucoronide (M3G) and morphine-6-glucoronide, requires high-performance liquid chromatography, which was not available to us. Morphine-6-glucoronid, a potent analgesic, was not detected in the plasma of any neonate in 1 study, and only low concentrations were detected in another study, but M3G levels can be detected in neonates.16,18 The morphine assay used in this study has some cross-reaction with M3G, which might have inflated our serum morphine measurements but would not explain our observation of increased serum morphine concentrations with cooling. The assay is regularly used by hospital laboratories, and, therefore, our findings are relevant to clinical practice.
If the therapeutic efficacy of moderate systemic hypothermia is confirmed by the ongoing studies and on longer follow-up, hypothermia will probably become a part of the standard therapy for HIE. Current reports suggest that hypothermia is a safe technique without obvious adverse effects in neonates with HIE.1,2 However, our study and that of Thoresen et al,12 suggest that hypothermia may result in elevated serum concentrations of morphine and phenobarbitone with undetermined clinical significance. Although no clinical evidence of toxicity was observed in the published large randomized trials of hypothermia, adverse drug-related effects may be difficult to distinguish from those of the underlying severe illness and may be missed if hypothermia becomes standard treatment after HIE, when routine observations may be less rigorous than in the clinical trials.
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CONCLUSIONS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Clinicians wishing to treat infants with HIE with morphine analgesia or sedation adjusted according to clinical state should be aware of the likelihood of elevated serum morphine concentrations. Morphine concentrations are likely to be further elevated and potentially toxic during treatment with hypothermia, and clinicians should consider monitoring drug concentrations. Our results highlight the need to investigate the effect of prolonged hypothermia and HIE on the pharmacokinetics and pharmacodynamics of commonly used drugs that are potentially toxic.
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FOOTNOTES |
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Accepted Sep 21, 2007.
Address correspondence to Anikó Róka, MD, First Department of Paediatrics, Semmelweis University, 1083 Budapest Bókay Str 53, Hungary. E-mail: aniko.roka{at}gmail.com
The authors have indicated they have no financial relationships relevant to this article to disclose.
All authors have approved the submission of this article and take full responsibility for its contents.
| What's Known on This Subject Data obtained in adults indicate that even short-term hypothermia may have an effect on the metabolism of major analgesics and other drugs. No data are available for neonates concerning the impact of hypothermia on the pharmacokinetics of morphine.
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| What This Study Adds The aim of our observational study, therefore, was to investigate whether morphine pharmacokinetics are altered during prolonged moderate systemic hypothermia in asphyxiated neonates, resulting in excessively high morphine concentrations compared with infants kept at normothermia; this would be important information for clinicians wishing to provide hypothermia.
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