British Journal of Anaesthesia 1990; 65: 661-667
PHARMACOKINETICS OF PROPOFOL IN CHILDREN R. D. M. JONES, K. CHAN AND L. J. ANDREW
SUMMARY
PATIENTS AND METHODS
Twelve Chinese children, aged 4-12 yr, were studied. All patients were ASA grade I and underwent circumcision for the treatment of phimosis. The study was approved by the Faculty of Medicine Ethics Committee (University of Hong Kong) and written, informed consent was obtained from the parents. Children were excluded from the study if there was a history of asthma or allergies, previous adverse anaesthetic experience, halothane anaesthesia within the previous month, hepatic, renal, respiratory, cardiac or haematological disease, mental retardation and age less than 2 yr. Patients were premedicated with trimeprazine 3 mg kg"1 (maximum 90 mg) and atropine 0.03 mg kg"1 by mouth 2 h before operation. EMLA emulsion cream 2 g (lignocaine 25 mg g"1 and prilocaine 25 mg g"1) was applied also to the dorsum of the left hand. In the operating suite, a 24-gauge cannula was inserted into a vein underKEY WORDS lying the EMLA-pretreated area. Procaine hyAnaesthetics, intravenous:propofol. Anaesthesia: paediatric. Pharmacokinetics: propofol. children. drochloride 1 mg kg"1 was administered 15 s before induction of anaesthesia with the aqueous emulsion formulation of propofol (Diprivan) 1 Rapid recovery after general anaesthesia may be 2.5 mg kg" injected over 30 s. Time zero was an advantage in paediatric patients, particularly taken at completion of the injection. An 18-gauge those undergoing minor day-care surgery. Pro- cannula was inserted into a vein in the contrapofol seems to confer some advantage over other lateral antecubital fossa for venous sampling. available agents in this respect [1]. The phar- Thereafter, anaesthesia was maintained with the macology of propofol has been reviewed by White patient breathing spontaneously 67% nitrous [2] but, although there has been a rapid accumulation of clinical and pharmacological data, R. D . M. JONES, F.F.A.R.A.C.S., F.F.A.R.C.S., Department of there have been few reports on the pharmaco- Anaesthesiology, Room 415, Block K, Queen Mary Hospital, Pokfulam Road, Hong Kong. KELVIN CHAN, PH.D., CBIOL., kinetics of propofol in children [3, 4]. Age-related changes in body water, lean body F.I.BIOL., F.C.P., F.A.C.B., Department of Pharmacology, Chinese University of Hong Kong. L. J. ANDREW, F.F.A.R.CS., mass, regional blood flow, renal and hepatic Department of Anaesthesiology, University of Hong Kong, function [5-7] affect drug distribution, metab- Hong Kong. Accepted for Publication: May 15, 1990. Correspondence to R.D.M.J. olism and excretion [8-10]. We report the first
Downloaded from http://bja.oxfordjournals.org/ at New York University on May 30, 2015
The pharmacokinetics of propofol were studied in 12 healthy Chinese children, aged 4-12 yr, undergoing circumcision under inhalation anaesthesia. All patients received a single i. v. bolus dose of propofol 2.5 mg kg'7 and blood concentrations of propofol over the subsequent 24 h were measured using high pressure liquid chromatography with fluorimetric detection. Data were consistent with a three-compartment model with a mean (SEM) elimination half-life of 209 (29) min and total body clearance of 40.4 (3.6) mlmin'1 kg~1. The mean (SEM) apparent volume of distribution at steady state was 5.0 (2.7) litre kg-' and volume of the central compartment was 0.6 (0.1) litre kg-1. The mean (SEM) ratio of k,2.k2, was 1.4 (0.2), suggesting that, after injection of a single bolus dose in children, propofol is distributed rapidly to the shallow compartment. The mean ratio of k 3 ,:k, 0 suggests that lipophilicity constrains return of the drug to the central compartment.
phase of a series of studies investigating the pharmacokinetics of propofol in Chinese children.
662
gram [14, 17] which utilizes the method of residuals, whereby each curve is fitted with experimental data in terms of a bi-exponential or tri-exponential function. BITRI chooses the best fit such that the logarithms of squared deviation between exponential and computer values are minimized [18]. Distribution and elimination half-lives (Tf Tf 7JT), apparent central volume of distribution (F), apparent volume of distribution at steady state (V™), apparent volume of distribution in the elimination phase (V) and total body clearance (C/) were calculated using standard formulae [19]. RESULTS
On arrival in the operating suite, two of the children were awake and apparently anxiety free, seven patients were drowsy with intermittent eye opening and the remaining three children were asleep but awoke on command. Induction of anaesthesia was devoid of side effects in 50 % of patients and satisfactory in the remainder. Five episodes of semi-purposeful movement occurred, combined with breath-holding, tremor and rigidity in two patients, and one patient developed hiccup. The demographic and haemodynamic changes during induction and details of anaesthesia are shown in table I. The maximum change in heart rate and systolic arterial pressure from preinduction values during the first 5 min of the induction period was calculated. The mean maximum end-tidal carbon dioxide value recorded
TABLE I. Demographic, induction haemodynamia and anaesthetic data in the 12 children (mean (SEM) [range]) Age (yr) Weight (kg) Mean increase in heart rate from pre-induction values (beat min"1) Mean decrease in systolic arterial pressure from pre-induction values (mm Hg) Maximal end-tidal carbon dioxide recorded during anaesthesia (kPa) Anaesthesia time (min) Awakening time (min)
7.9(0.8) [4-12] 25.8(7.9) [16-39] 4.3(6.4) [ - 4 2 to +42]
- 7 . 1 (4.4) [ - 2 8 to +16]
6.8(0.3) [5.3-7.8]
28.8(1.5) [21-36] 30.5(4.0) [11-61]
Downloaded from http://bja.oxfordjournals.org/ at New York University on May 30, 2015
oxide and 1-3% halothane in oxygen via a Mapleson F ( < 25 kg) or a Mapleson A (> 25 kg) breathing system. The surgeon infiltrated each dorsal nerve at the root of the penis with 0.5 % bupivacaine 1.5 ml. On arrival in the operating suite the children were assessed and recorded as agitated or crying, aware and apparently anxiety free, drowsy, or asleep but responsive to command [11]. Induction was graded as good (absence of side effects), adequate (side effects present but not interfering with induction) and poor (side effeas severe and protracted). Evidence of excitatory phenomena on induction of anaesthesia was recorded also. During anaesthesia, all patients were monitored with an electrocardiograph, non-invasive arterial pressure cuff, pulse oximeter, capnograph and for inspired oxygen concentration (Datex, Cardiocap). After operation, the patient's coma scale [12] and a structured observation score [13] were assessed and noted at each of the blood sampling times. The awakening time (time from the discontinuation of general anaesthesia to spontaneous eye-opening) and time until the patient could identify himself were recorded also. Samples were collected for measurement of whole blood concentration of propofol at 2, 5, 10, 15, 20, 30, 45, 60, 90, 120 and 180 min and 4, 6, 8, 10, 12, 18 and 24 h. Each sample was mixed thoroughly in tubes containing lithium—heparin (Sarstedt LH/5) and stored at +4°C until assayed. Propofol concentrations in whole blood were determined by a modified liquid chromatography method [14]. Propofol in whole blood (0.5-ml samples rather than 1.0-ml samples used by Plummer [15]) and internal standard thymol, buffered with sodium dihydrogen phosphate 0.1 mol litre"1, were extracted into cyclohexane. The mobile phase consisted of 75 % (v/v) acetonitrile in distilled water containing 1 % (v/v) glacial acetic acid. A CJ8 reversed phase column (Nova-Pak), linked to a C18 pre-column was used and the eluate was measured by a fluorimetric detector with excitation and emission wavelengths set at 276 nm and 310 ran, respectively [16]. The calibration graphs were linear over the range 2-3000 ng ml"1 with coefficients of variation ranging from 1.0 to 8.0%. The between-batch coefficient of variance was 6.7 % at 50 ng ml"1 and 4.8 % at 3000 ng ml"1. The limit of detection was approximately 2 ng ml"1. Blood concentration-time profiles of propofol were analysed by the BITRI computer pro-
BRITISH JOURNAL OF ANAESTHESIA
PROPOFOL IN CHILDREN
663
TABLE II. Relationship between awakening, as assessed by coma score [10], and time after induction dose of propofol. {Mean (SEM) anaesthesia time 30.5 (5.13) min)
Time after induction (min)
PHARMACOKINETICS OF PROPOFOL IN CHILDREN R. D. M. JONES, K. CHAN AND L. J. ANDREW
SUMMARY
PATIENTS AND METHODS
Twelve Chinese children, aged 4-12 yr, were studied. All patients were ASA grade I and underwent circumcision for the treatment of phimosis. The study was approved by the Faculty of Medicine Ethics Committee (University of Hong Kong) and written, informed consent was obtained from the parents. Children were excluded from the study if there was a history of asthma or allergies, previous adverse anaesthetic experience, halothane anaesthesia within the previous month, hepatic, renal, respiratory, cardiac or haematological disease, mental retardation and age less than 2 yr. Patients were premedicated with trimeprazine 3 mg kg"1 (maximum 90 mg) and atropine 0.03 mg kg"1 by mouth 2 h before operation. EMLA emulsion cream 2 g (lignocaine 25 mg g"1 and prilocaine 25 mg g"1) was applied also to the dorsum of the left hand. In the operating suite, a 24-gauge cannula was inserted into a vein underKEY WORDS lying the EMLA-pretreated area. Procaine hyAnaesthetics, intravenous:propofol. Anaesthesia: paediatric. Pharmacokinetics: propofol. children. drochloride 1 mg kg"1 was administered 15 s before induction of anaesthesia with the aqueous emulsion formulation of propofol (Diprivan) 1 Rapid recovery after general anaesthesia may be 2.5 mg kg" injected over 30 s. Time zero was an advantage in paediatric patients, particularly taken at completion of the injection. An 18-gauge those undergoing minor day-care surgery. Pro- cannula was inserted into a vein in the contrapofol seems to confer some advantage over other lateral antecubital fossa for venous sampling. available agents in this respect [1]. The phar- Thereafter, anaesthesia was maintained with the macology of propofol has been reviewed by White patient breathing spontaneously 67% nitrous [2] but, although there has been a rapid accumulation of clinical and pharmacological data, R. D . M. JONES, F.F.A.R.A.C.S., F.F.A.R.C.S., Department of there have been few reports on the pharmaco- Anaesthesiology, Room 415, Block K, Queen Mary Hospital, Pokfulam Road, Hong Kong. KELVIN CHAN, PH.D., CBIOL., kinetics of propofol in children [3, 4]. Age-related changes in body water, lean body F.I.BIOL., F.C.P., F.A.C.B., Department of Pharmacology, Chinese University of Hong Kong. L. J. ANDREW, F.F.A.R.CS., mass, regional blood flow, renal and hepatic Department of Anaesthesiology, University of Hong Kong, function [5-7] affect drug distribution, metab- Hong Kong. Accepted for Publication: May 15, 1990. Correspondence to R.D.M.J. olism and excretion [8-10]. We report the first
Downloaded from http://bja.oxfordjournals.org/ at New York University on May 30, 2015
The pharmacokinetics of propofol were studied in 12 healthy Chinese children, aged 4-12 yr, undergoing circumcision under inhalation anaesthesia. All patients received a single i. v. bolus dose of propofol 2.5 mg kg'7 and blood concentrations of propofol over the subsequent 24 h were measured using high pressure liquid chromatography with fluorimetric detection. Data were consistent with a three-compartment model with a mean (SEM) elimination half-life of 209 (29) min and total body clearance of 40.4 (3.6) mlmin'1 kg~1. The mean (SEM) apparent volume of distribution at steady state was 5.0 (2.7) litre kg-' and volume of the central compartment was 0.6 (0.1) litre kg-1. The mean (SEM) ratio of k,2.k2, was 1.4 (0.2), suggesting that, after injection of a single bolus dose in children, propofol is distributed rapidly to the shallow compartment. The mean ratio of k 3 ,:k, 0 suggests that lipophilicity constrains return of the drug to the central compartment.
phase of a series of studies investigating the pharmacokinetics of propofol in Chinese children.
662
gram [14, 17] which utilizes the method of residuals, whereby each curve is fitted with experimental data in terms of a bi-exponential or tri-exponential function. BITRI chooses the best fit such that the logarithms of squared deviation between exponential and computer values are minimized [18]. Distribution and elimination half-lives (Tf Tf 7JT), apparent central volume of distribution (F), apparent volume of distribution at steady state (V™), apparent volume of distribution in the elimination phase (V) and total body clearance (C/) were calculated using standard formulae [19]. RESULTS
On arrival in the operating suite, two of the children were awake and apparently anxiety free, seven patients were drowsy with intermittent eye opening and the remaining three children were asleep but awoke on command. Induction of anaesthesia was devoid of side effects in 50 % of patients and satisfactory in the remainder. Five episodes of semi-purposeful movement occurred, combined with breath-holding, tremor and rigidity in two patients, and one patient developed hiccup. The demographic and haemodynamic changes during induction and details of anaesthesia are shown in table I. The maximum change in heart rate and systolic arterial pressure from preinduction values during the first 5 min of the induction period was calculated. The mean maximum end-tidal carbon dioxide value recorded
TABLE I. Demographic, induction haemodynamia and anaesthetic data in the 12 children (mean (SEM) [range]) Age (yr) Weight (kg) Mean increase in heart rate from pre-induction values (beat min"1) Mean decrease in systolic arterial pressure from pre-induction values (mm Hg) Maximal end-tidal carbon dioxide recorded during anaesthesia (kPa) Anaesthesia time (min) Awakening time (min)
7.9(0.8) [4-12] 25.8(7.9) [16-39] 4.3(6.4) [ - 4 2 to +42]
- 7 . 1 (4.4) [ - 2 8 to +16]
6.8(0.3) [5.3-7.8]
28.8(1.5) [21-36] 30.5(4.0) [11-61]
Downloaded from http://bja.oxfordjournals.org/ at New York University on May 30, 2015
oxide and 1-3% halothane in oxygen via a Mapleson F ( < 25 kg) or a Mapleson A (> 25 kg) breathing system. The surgeon infiltrated each dorsal nerve at the root of the penis with 0.5 % bupivacaine 1.5 ml. On arrival in the operating suite the children were assessed and recorded as agitated or crying, aware and apparently anxiety free, drowsy, or asleep but responsive to command [11]. Induction was graded as good (absence of side effects), adequate (side effects present but not interfering with induction) and poor (side effeas severe and protracted). Evidence of excitatory phenomena on induction of anaesthesia was recorded also. During anaesthesia, all patients were monitored with an electrocardiograph, non-invasive arterial pressure cuff, pulse oximeter, capnograph and for inspired oxygen concentration (Datex, Cardiocap). After operation, the patient's coma scale [12] and a structured observation score [13] were assessed and noted at each of the blood sampling times. The awakening time (time from the discontinuation of general anaesthesia to spontaneous eye-opening) and time until the patient could identify himself were recorded also. Samples were collected for measurement of whole blood concentration of propofol at 2, 5, 10, 15, 20, 30, 45, 60, 90, 120 and 180 min and 4, 6, 8, 10, 12, 18 and 24 h. Each sample was mixed thoroughly in tubes containing lithium—heparin (Sarstedt LH/5) and stored at +4°C until assayed. Propofol concentrations in whole blood were determined by a modified liquid chromatography method [14]. Propofol in whole blood (0.5-ml samples rather than 1.0-ml samples used by Plummer [15]) and internal standard thymol, buffered with sodium dihydrogen phosphate 0.1 mol litre"1, were extracted into cyclohexane. The mobile phase consisted of 75 % (v/v) acetonitrile in distilled water containing 1 % (v/v) glacial acetic acid. A CJ8 reversed phase column (Nova-Pak), linked to a C18 pre-column was used and the eluate was measured by a fluorimetric detector with excitation and emission wavelengths set at 276 nm and 310 ran, respectively [16]. The calibration graphs were linear over the range 2-3000 ng ml"1 with coefficients of variation ranging from 1.0 to 8.0%. The between-batch coefficient of variance was 6.7 % at 50 ng ml"1 and 4.8 % at 3000 ng ml"1. The limit of detection was approximately 2 ng ml"1. Blood concentration-time profiles of propofol were analysed by the BITRI computer pro-
BRITISH JOURNAL OF ANAESTHESIA
PROPOFOL IN CHILDREN
663
TABLE II. Relationship between awakening, as assessed by coma score [10], and time after induction dose of propofol. {Mean (SEM) anaesthesia time 30.5 (5.13) min)
Time after induction (min)
