Long term high dose morphine, ketamine and midazolam infusion in a child with burns

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1 Br. J. clin. Pharmac. (1990), 30, Long term high dose morphine, ketamine and midazolam infusion in a child with burns I. CEDERHOLM', M. BENGTSSON', S. BJORKMAN2, I. CHOONARA' & A. RANE3 'Department of Anaesthesiology, University Hospital, S Linkoping, and 2Hospital Pharmacy, Malmo General Hospital, S Malm6 and 3Division of Clinical Pharmacology, Akademiska Hospital, S Uppsala, Sweden The metabolism of morphine and ketamine was studied in a 14 month old child with extensive burns, who received infusions of both drugs for more than 30 days. The mean plasma clearance of morphine was 29 ml min-' kg-1 and the plasma ratios of morphine-6- glucuronide to morphine were similar to those previously reported in children. The mean plasma clearance of ketamine was 32 ml min-1 kg-' which is greater than that previously reported in older children and adults. There were no complications despite high dose long term therapy with morphine, ketamine and midazolam. Keywords children morphine ketamine burns Introduction The importance of adequate analgesia in hospitalised children is now being recognised (Choonara, 1989). Children with severe burns are a particular problem with respect to pain therapy, which is often inadequate (Perry & Heidrich, 1982). Morphine infusions in children were used initially for the management of severe cancer pain (Miser et al., 1980), but have since been shown to be effective also in the postoperative child (Bray, 1983; Dilworth & Mac- Kellar, 1987) and for pain relief and sedation in the intensive care unit (ICU). The major metabolites of morphine are morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) which are present in plasma at significantly greater concentrations than morphine itself (Sawe et al., 1983, 1985). M6G may have significant analgesic properties (Osborne et al., 1988; Shimomura et al., 1971) and we have previously reported the ability of neonates and children to form this active metabolite (Choonara et al., 1989). Ketamine has analgesic properties (Bovill & Dundee, 1971) and infusions have recently been used for pain relief (Joachimsson et al., 1986). It is commonly employed in the perioperative period and has been used extensively in burn units (Corssen & Oget, 1971; White etal., 1982). However, experience with prolonged infusions of ketamine is limited (Park etal., 1987; Shetty et al., 1986). Its major metabolite is norketamine which animal studies suggest is pharmacologically active (White et al., 1982). There have been few studies of the pharmacokinetics of ketamine in children (Cook et al., 1982; Grant et al., 1983). It is well known that thermal injury causes 'resistance' to many drugs used in anaesthetic practice (Marathe et al., 1989; Martyn, 1986; White et al., 1982) but causes of this tolerance have not been fully established. There is little information available regarding the long term administration of either morphine or ketamine to children in relation to pharmacokinetics or metabolism. Therefore, we report a case of a young child with extensive bums who received such treatment. Correspondence: Dr I. Choonara, Institute of Child Health, Alder Hey Children's Hospital, Liverpool L12 2AP 901

2 902 L Cederholm et al. Methods Case report A 14 month old girl, previously healthy and on no drugs, was admitted to the ICU because of major thermal injury. She had been involved in a car-fire, and 50% of her body surface was severely burned (36% third degree and 14% second degree). There were early signs of thermal injury in the airway due to inhalation of warm, smoky gases. The burn injuries were localized to the face, head, both arms and legs and the back. She required a tracheostomy, ventilation and a central venous line was inserted for i.v. fluid replacement. An escarotomy was done on the right arm. On day 4 early excision and autologous skin transplantation of the burned areas were performed. Cleaning and shifting of the dressings was done every second day. Additional skin transplants were carried out on three occasions. Total parenteral nutrition (glucose, aminoacids and fat) and albumin were given from day 2 (see Figure 1). Renal function was normal throughout and plasma creatinine ranged from 19 to 38,umolI -. During the time spent in the ICU there were major problems in providing satisfactory sedation and analgesia. A continuous infusion of morphine was started on the second day to ensure adequate pain relief and sedation in order to perform the ventilatory treatment and changing of wound dressings. Supplementary doses of midazolam were given, initially as a continuous infusion (dose range mg day-', days 2-26) and then intermittently up to day 44 (see Figure 1). After 9 days in the ICU the child was still in pain, despite a morphine infusion of 204 mg day-'. Therefore, a supplementary infusion of ketamine was started on the 10th day. Nevertheless the need for analgesia increased, such that morphine dosage reached a maximum of 833 mg day-' on day 28. The dosage of ketamine increased to 475 mg on the 14th day, was thereafter decreased and stopped on the 41st day. No withdrawal symptoms were seen following cessation of the sedative/analgesic drugs. Total drug doses were Annn,- - +UVV CN q 3000 _ (M 'Eoc n E go 1000 _ C o JF r-- ' 11 1 J I---',' 1r ~ - L J I. Crystalloids Albumin 40 r E -W C._ - 30[ r : ' L Morphine Ketamine Midazolam nliv Number of days in ICU Figure 1 Fluid, albumin (upper panel), morphine, ketamine and midazolam (lower panel) requirements during the initial 44 day period of treatment.

3 Short report mg of morphine over 44 days, 5222 mg of ketamine over 32 days and 2924 mg of midazolam over 42 days. The doses given on the days that blood samples were collected for drug measurement are shown in Table 1. There was insufficient plasma for the analysis of midazolam and on days 13, 36 and 40 only ketamine and norketamine were measured. The patient was ventilated artificially through the tracheostomy until day 46. A week later, a tracheobronchoscopy was performed showing a tracheomalacia. A temporary stent treatment was given and the patient was successfully decanulated 3 months after admission. Follow up at the age of 3 years showed a mentally and physically normal child, with the exceptions of the scars. Reconstructive surgery has been carried out several times in the burned areas, especially on both arms. Analytical methods Plasma concentrations of rac-morphine, M3G and M6G were measured by reversed phase ionpair high performance liquid chromatography (Svensson et al., 1982). Plasma concentrations of rac-ketamine and norketamine were measured by gas liquid chromatography (Chang & Glazko, 1972). Calculations Plasma clearance was determined by dividing the infusion rate by the steady state plasma drug concentration. All blood samples were collected after constant infusion rate for at least 24 h, by which time steady state concentrations of morphine and ketamine should have been achieved. Results The plasma concentrations of morphine, ketamine and their respective metabolites are shown in Table 1. The mean (± s.d.) plasma clearance of morphine was 29.0 (± 5.9) ml min-1 kg-'. The plasma M3G/M and M6G/M ratios were 19.1 (± 1.1) and 1.6 (± 0.1), respectively. The mean plasma clearance of ketamine was 32.1 (± 8.4) ml min-' kg-1. Discussion Burns can affect the pharmacokinetics and pharmacodynamics of many drugs (Martyn, 1986), particularly in the period immediately after injury. The plasma drug measurements made in the present case concern the period 2 weeks after initial injury and thus we cannot extrapolate our findings to patients with burns in the acute phase. A previous report suggested that morphine disposition is not altered in adults with burns (Perry & Inturrisi, 1983). The management of pain relief in children with burns is a major clinical problem (Perry & Heidrich, 1982). Ketamine infusions used in subanaesthetic doses have analgesic activity (Bovill & Dundee, 1971) but are usually given for only a short time in the immediate postoperative period (Joachimsson et al., 1986). A recent case report described the use of a ketamine infusion for 7 days in a 19 year old adult (Shetty et al., 1986). We are unaware of any reports describing the use of ketamine for longer than a week. No psychological sequelae were observed in our patient, possibly because of the co-administration of midazolam (Park et al., 1987). Grant et al. (1983) reported a greater plasma clearance of ketamine in children aged 4-9 years than in adults (16.8 and 12.6 ml min-' kg-', Table 1 Clinical details and plasma concentrations of morphine, ketamine and their metabolites Day Weight (kg) Plasma albumin (g 1-1) Morphine infusion rate (mg h1) Ketamine infusion rate (mg h-1) Plasma concentration morphine (ng ml-') , Plasma concentration M3G (ng ml-1) - 13,132 12,600 23,435 18,618 - Plasma concentration M6G (ng ml-1) 1,022 1,045 2,246 1,602 Plasma concentration ketamine (ng ml-1) Plasma concentration norketamine (ng ml-') CL morphine (ml min-' kg-) CL ketamine (ml min-' kg-1)

4 904 I. Cederholm et al. respectively). They also found greater plasma norketamine concentrations in children than in adults suggesting that the N-demethylation of ketamine to norketamine is the major metabolic pathway in children. In the present case, the plasma clearance of ketamine was considerably higher ( ml min-' kg-') but she was only 14 months old and infants often have higher clearance values than older children. This is consistent with other studies of ketamine in infants reporting a shorter half-life (Cook et al., 1982) and higher dose requirements (kg-1 body weight) (Lockhart & Nelson, 1974). The plasma clearance of morphine and the plasma M3G/M ratio (29.0 ml min-' kg-1 and 19.1 respectively) were similar to our previous findings in post-operative children (25.7 ml min-' kg-1 and 23.9, respectively) (Choonara et al., 1989). There was no evidence of saturation of glucuronidation despite the massive doses of morphine used. This is consistent with findings in adults (Sawe et al., 1983). The M3G/M6G ratio in plasma (11.7) was similar to previous values in urine in children (9.9) and neonates (10.3) (Choonara et al., 1989). This is consistent with our suggestion that the glucuronidation of morphine to M3G and M6G is controlled by the same or similar regulatory mechanisms. The normal pharmacokinetic values for morphine in this child suggest that her high morphine requirements were the result of altered pharmacodynamics. This work was supported by grants from the Swedish Medical Research Council (04X-04496) and the Swedish Cancer Society. I.C. was on an MRC Travelling Fellowship. We thank Miss S. Oliphant for typing the manuscript. References Bovill, J. G. & Dundee, J. W. (1971). Alterations in response to somatic pain associated with anaesthesia-ketamine. Br. J. Anaesth., 43, Bray, R. J. (1983). Post operative analgesia provided by morphine infusion in children. Anaesthesia, 38, Chang, T. & Glazko, A. J. (1972). A gas chromatographic assay for ketamine in human plasma. Anesthesiology, 36, Choonara, I. A. (1989). Pain relief. Arch. Dis. Child., 64, Choonara, I. A., McKay, P., Hain, R. & Rane, A. (1989). Morphine metabolism in children. Br. J. clin. Pharmac., 28, Cook, D. R., Stiller, R. & Dayton, P. (1982). Pharmacokinetics of ketamine in infants and small children. Anesthesiology, 57, A428. Corssen, G. & Oget, S. (1971). Dissociative anesthesia for the severely burned child. Anaesth. Analg., 50, Dilworth, N. M. & MacKellar, A. (1987). Pain relief for the pediatric surgical patient. J. Pediatr. Surg., 22, Grant, I. S., Nimmo, W. S., McNichol, L. R. & Clements, J. A. (1983). Ketamine disposition in children and adults. Br. J. Anaesth., 55, Joachimsson, P. O., Hedstrand, U. & Eklund, A. (1986). Low-dose ketamine infusion for analgesia during post operative ventilator treatment. Acta Anaesthesiol. Scand., 30, Lockhart, C. H. & Nelson, W. L. (1974). The relationship of ketamine requirement to age in pediatric patients. Anesthesiology, 40, Marathe, P. H., Dwersteg, J. F., Paulin, E. G., Haschke, R. H., Heimbach, D. M. & Slattery, J. T. (1989). Effect of thermal injury on the pharmacokinetics and pharmacodynamics of atracurium in humans. Anesthesiology, 70, Martyn, J. (1986). Clinical pharmacology and drug therapy in the burned patient. Anesthesiology, 65, Miser, A. W., Miser, J. S. & Clark, B. S. (1980). Continuous intravenous infusion of morphine sulfate for control of severe pain in children with terminal malignancy. J. Pediatr., 96, Osborne, R., Joel, S., Trew, D. & Slevin, M. (1988). Analgesic activity of morphine-6-glucuronide. Lancet, i, 828. Park, G. R., Manara, A. R., Mendel, L. & Bateman, P. E. (1987). Ketamine infusion. Its use as a sedative, inotrope and bronchodilator in a critically ill patient. Anaesthesia, 42, Perry, S. & Heidrich, G. (1982). Management of pain during debridement: a survey of U.S. burn units. Pain, 13, Perry, S. & Inturrisi, C. E. (1983). Analgesia and morphine disposition in burn patients. J. Burn Care Rehab., 4, Sawe, J., Kager, L., Svensson, J. 0. & Rane, A. (1985). Oral morphine in cancer patients: in vivo kinetics and in vitro hepatic glucuronidation. Br. J. clin. Pharmac., 19, Sawe, J., Svensson, J. 0. & Rane, A. (1983). Morphine metabolism in cancer patients on increasing oral doses-no evidence for autoinduction or dose dependency. Br. J. clin. Pharmac., 16, Shetty, G. K., Kelsall, P. G. & Ryan, D. W. (1986). Long term ketamine infusion. Anaesthesia, 41, Shimomura, K., Kanaat, O., Ueki, S., Ida, S., Oguri, K., Yoshimura, H. & Tsukamoto, H. (1971). Analgesic effect of morphine glucuronides. Tohaku J. exp. Med., 105, Svensson, J. O., Rane, A., Sawe, J. & Sj6qvist, F.

5 Short report 905 (1982). Determination of morphine, morphine-3- glucuronide and (tentatively) morphine-6-glucuronide in plasma and urine using ion-pair highperformance liquid chromatography. J. Chromatogr., 230, White, P. F., Way, W. L. & Trevor, A. J. (1982). Ketamine-its pharmacology and therapeutic uses. Anesthesiology, 56, (Received 14 May 1990, accepted 7 August 1990)