British Journal of Anaesthesia 1994; 73:

Transcription

1 British Journal of Anaesthesia 1994; 73: Comparison of the effects of sevoflurane and halothane on the quality of anaesthesia and serum glutathione transferase alpha and fluoride in paediatric patients T. TAIVAINEN, P. TIAINEN, O. A. MERETOJA, L. RAIHA AND P. H. ROSENBERG Summary We have compared sevoflurane and halothane anaesthesia in paediatric patients with reference to induction and recovery. We also assessed hepatocellular integrity by measurement of serum glutathione transferase alpha (GSTA) concentration and sevoflurane metabolism by serum fluoride concentration. Fifty unpremedicated 5-12-yr-old children were allocated randomly to induction of anaesthesia via a face mask with 66% nitrous oxide in oxygen and sevoflurane (up to 7%) or halothane (up to 3.5%). Anaesthesia was maintained for 1.8 h at MAC of the volatile agent. Children receiving sevoflurane had significantly faster induction and recovery variables than those receiving halothane. There was a small postanaesthetic increase in GSTA in both groups, suggesting that halothane and sevoflurane may disturb hepatocellular integrity. Serum concentrations of fluoride were significantly greater after sevoflurane than after halothane anaesthesia. There were no clinical signs or symptoms of hepatic or renal disturbance. Children tolerated sevoflurane better than halothane, which may have been because of the nonpungency of sevoflurane and the rapid psychomotor recovery after anaesthesia. (Br. J. Anaesth. 1994; 73: ) Key words Anaesthesia, paediatric. Anaesthetics volatile, halothane. Anaesthestics volatile, sevoflurane. is a new inhalation anaesthetic agent undergoing clinical investigations. It has low blood and tissue solubilities, which should provide rapid uptake and elimination [1]. Rapid emergence from sevoflurane anaesthesia has been demonstrated in adults [2, 3] and children [4-6]. In one of these paediatric studies [6], induction of anaesthesia with sevoflurane was more rapid than that of halothane. is still the major volatile anaesthetic agent used in paediatric anaesthesia because it provides smooth induction of, and emergence from, anaesthesia. In children, the incidence of halothane hepatitis is extremely rare [7]. Subclinical hepatotoxicity has been revealed in 50% of adults after halothane anaesthesia, as indicated by changes in glutathione transferase alpha (GSTA), a very sensitive marker of centrilobular liver damage [8, 9]. Studies using GSTA as an indicator of possible hepatotoxicity of halothane in children have not been published. A major metabolic product of sevoflurane is inorganic fluoride [10]. Although metabolism of halothane is significantly greater, inorganic fluoride is released in very small amounts [11]. Our aim was to compare the effects of sevoflurane and halothane anaesthesia during induction, maintenance and emergence in paediatric patients, in addition to children's subjective opinion about the anaesthesia. Our particular interest was to evaluate if subclinical hepatotoxicity occurs in children after sevoflurane or halothane anaesthesia and if potentially nephrotoxic serum concentrations of fluoride are produced by sevoflurane. Patients and methods With the approval of the Ethics Committee of the Children's Hospital, written informed consent was obtained from the parents of 50 healthy, 5-12-yrold, ASA I II children, who were undergoing elective general surgery with an anticipated duration of anaesthesia of at least 1 h and anticipated hospitalization of at least 24 h after surgery (table 1). Children were allocated randomly to two groups of 25 patients to receive either sevoflurane or halothane as the volatile anaesthetic agent. None of the children received premedication. Anaesthesia was induced via a face mask by inhalation of 66 % nitrous oxide in oxygen and 2 % sevoflurane or 1 % halothane via an open paediatric breathing system (Mapleson F) and an appropriately calibrated vaporizer (for sevoflurane, Penlon, Intermed, Abingdon, UK, and for halothane, Vapor 19, Dragerwerk AG, Lubeck, Germany). Average fresh gasflow (litre min" 1 ) was adjusted to the square root of the patient's body weight (kg) [12]. Both anaesthetic agents were introduced gradually into the breathing system every three to five breaths or more rapidly if tolerated by the patient; successive inspiratory concentrations were 2, 4, 6 and 7% for T. TAIVAINEN MD, PHD, O. A. MERETOJA, MD, PHD (Department of Anaesthesiology, Children's Hospital); P. TIAINEN, MD, L. RAIHA, RN, P. H. ROSENBERG, MD, PHD (Department of Anaesthesiology, Surgical Hospital); Helsinki University Central Hospital, FIN Helsinki, Finland. Accepted for publication: May 5, Correspondence to T.T.

2 Sevofiurane and halothane in paediatric anaesthesia 591 sevofiurane and 1, 2, 3 and 3.5% for halothane. Maximum concentrations of sevofiurane (7%) and halothane (3.5%) were considered equipotent in children aged 5 12 yr [13, 14]. These concentrations represent 2.2 MAC at steady state [15]. An i.v. cannula was inserted immediately after the end of induction and samples for baseline laboratory tests were obtained. Thereafter an infusion of Ringer's acetate solution was started. When an adequate depth of anaesthesia was achieved, the trachea was intubated without using a neuromuscular blocking agent. The lungs were ventilated mechanically using a semi-open circuit without a carbon dioxide absorbent (Servo, Siemens-Elema, Sweden). End-tidal carbon dioxide was maintained at %. Anaesthesia was maintained using 66% nitrous oxide in oxygen and inhalation of MAC of sevofiurane or halothane. In addition, increments of fentanyl1 2 ug kg" 1 were administered as needed to eliminate nociceptive responses to surgical stimuli. For neuromuscular block, vecuronium was administered when indicated clinically. Monitoring included continuous ECG, inspiratory and expiratory oxygen, sevofiurane or halothane concentration, pulse oximeter and end-tidal carbon dioxide (Capnomac Ultima, Datex, Helsinki, Finland) in addition to automated arterial pressure and nasopharyngeal temperature. In the operating theatre, arterial pressure and heart rate were recorded at 3- min intervals from 1 min before to 15 min after induction. Thereafter arterial pressure and heart rate were recorded at 5-min intervals and in the recovery room at 10-min intervals. Patients were observed by an independent observer throughout the study period from the time the patient arrived in the operating theatre until 2 h in the recovery room. Times from application of the face mask to loss of the eyelash reflex, to the end of induction (defined as unconscious child with constricted pupils and regular respirations) and to tracheal intubation were recorded. At the end of operation, the volatile anaesthetic agent and nitrous oxide were discontinued simultaneously and abruptly, and all recovery assessments were timed from this point. The trachea was extubated when spontaneous breathing was adequate. Emergence from anaesthesia was denned as opening of eyes to commands issued at 1-min intervals after cessation of the anaesthetic. Thereafter the patient was asked every 1 min to squeeze the observer's hand. In addition, times to the patient's orientation to name, age and date of birth were recorded. To evaluate the five physiological variables, motor activity, respiration, arterial pressure, skin temperature and consciousness, modified Aldrete scores (0-10 points) were measured at 10-min intervals in the recovery room. Each of these variables scored 0-2 points, for example for respiration the following scores applied: apnoea = 0, difficulties in breathing = 1, no difficulties in breathing = 2 points. A modified Trieger dot test was performed before anaesthesia and at 1,2, 4, 6 and 24 h after anaesthesia. In this simple pen and paper test, children connected as many dots as possible in 10 s with the maximum points being 52. For postoperative pain relief in the recovery room, morphine increments of 0.1 mg kg ' were administered i.v. until satisfactory analgesia was achieved. At 24 h a standardized questionnaire was used to enquire about possible side effects, acceptance of induction of anaesthesia, graded as pleasant, indifferent or unpleasant, and if the child would like to have possible future anaesthesia carried out in the same way. LABORATORY ANALYSIS Blood samples for haematology and blood chemistry were obtained at baseline and 24 h after anaesthesia. Standard laboratory methods were used for measurement of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, alkaline phosphatase (ALP) and creatinine concentrations at baseline and 24 h after anaesthesia. For measurement of serum GSTA and inorganic fluoride concentrations, blood samples (1.5 ml) were obtained in plain fluoride-free glass tubes after induction of anaesthesia (baseline), at the end of anaesthesia (0) and 1, 2, 4, 6, 24 and 48 h after anaesthesia. Blood samples were stored at + 4 C and centrifuged within 10 h. Serum was stored in plastic Eppendorf tubes at -20 C. Hepatocellular integrity was assessed with serum GSTA concentrations which were measured with a time resolved immunofluorometric assay (TR-IFMA) according to a standard assay procedure [16]. The quantitation range of the assay was ug litre" 1, corresponding to ug litre" 1 in serum (diluted 10-fold). The intraand interassay coefficients of variation were % and %, respectively. Serum concentrations of inorganic fluoride were measured by a method modified from that of Fry and Taves [17]. A fluoride selective combination electrode Orion model (Orion Research Incorporated, Boston, MA, USA) was used for measurement on Parafilm "M" (American National Can, Greenwich, CT, USA) placed on 16-mm cell culture wells. Before measurement, 200 ul of acetate buffer (acetate-naoh 1 mol litre" 1, ph 5.2, NaCl 1 mol litre" 1 ) and 10 ul of sodium fluoride 20 umol litre" 1 were added to 190 ul of serum. The sensitivity of this assay was 0.5 umol litre" 1 and the intra- and interassay coefficients of variation were % and %, respectively. STATISTICAL ANALYSIS Intergroup comparisons of anaesthesia data were performed by two-way Student's r-test for unpaired data or by Fisher's exact test. Values are expressed as mean (SD), unless otherwise indicated. Analysis of variance (ANOVA) for repeated measurements was used for testing statistical significance of the differences of the cardiovascular and laboratory variables between baseline and each time. The intergroup differences were also tested with ANOVA. Baseline concentrations of GSTA were used for measurement of the reference range of GSTA for children aged 5-12 yr. This was defined as mean + 2 SD on a logarithmic scale.

3 592 British Journal of Anaesthesia Results ANAESTHESIA DATA Patients in the two groups were comparable in sex, age, weight, duration of anaesthesia and type of surgery (table 1). Times from application of the face mask to loss of the eyelash reflex and to end of induction were significantly shorter in the sevoflurane than in the halothane group (table 2). During induction only mild side effects were seen (table 2). Systolic and diastolic arterial pressures and heart rate did not differ between groups before induction of anaesthesia. After induction, systolic and diastolic arterial pressures decreased in both groups by a mean of 20%, with no differences between groups (fig. 1). Heart rate changed less in the sevoflurane than in the halothane group at each time (P < 0.05). The dose of inhalation anaesthetic was 2.0 (0.8) MAC-h in the sevoflurane group and 2.3 (1.3) MAC-h in the halothane group (ns). Fentanyl doses of 2.3 (1.2)ugkg-' and 1.8 (1.4)ngkg"' were administered in the sevoflurane and halothane groups, respectively (ns). The trachea was extubated at 3.5 (3.4) min and 3.8 (3.0) min after discon- Table 1 Patient and clinical data (mean (SD or range) or number of patients). No significant differences between groups Sex(M/F) Age (yr) Weight (kg) Duration of anaesthesia (h) Type of surgery Orthopaedic Minor Major Superficial Urological (non-renal) Minor Major 12/ ( ) 31.0(9.6) 1.8(0.8) / ( ) 35.4(12.6) 1.8(0.9) tinuation of sevoflurane or halothane, respectively. Mild laryngospasm was observed in two children in both study groups. Times to emergence, hand squeeze on request and orientation were significantly shorter in the sevoflurane than in the halothane group (P ) (table 3). Modified Aldrete scores were significantly greater in the sevoflurane than in the halothane group for the first 30 min after anaesthesia (fig. 2). Patients in both groups performed equally in the Trieger dot test before anaesthesia (33 (10) dots in the sevoflurane group and 38 (10) dots in the halothane group). One hour after anaesthesia, children in the sevoflurane group connected significantly more Trieger dots than children in the halothane group (72 (30) % vs 42 (37)% of the preoperative test result) (P < 0.05). In the halothane group, the Trieger dot scores were significantly lower up to 6 h after anaesthesia compared with the preanaesthetic scores (P < 0.05). In the sevoflurane group, only the 1-h Trieger dot score was lower than the preanaesthetic score (fig. 3). In the recovery room, morphine doses of 0.20 (0.13) mg kg" 1 and 0.13 (0.12) mg kg" 1 were administered for postoperative pain relief in the sevoflurane and halothane groups, respectively (P < 0.05). Significantly more children who were anaesthetized with sevoflurane rated induction of anaesthesia as pleasant compared with those receiving halothane (56 % vs 20 % of patients) (P < 0.005). More children in the sevoflurane than in the halothane group said they would prefer to have another anaesthetic carried out by a similar method (76% vs 44% of patients, P < 0.005). At the 24-h follow-up, 36 % and 48 % of patients in the sevoflurane and halothane groups, respectively, expressed mild or moderate nausea (ns). Fifty percent of patients in both groups had episodes of mild or moderate vomiting during the same period (ns). Table 2 Induction and intubation times (mean (SD)) and side effects (number of patients) during induction Loss of eyelash reflex 1.0 (0.3) (min) End of induction (min) 2.4 (1.0) Excitement 2 Breath-holding Intubation (min) 4.5 (1.0) P 1.7 (0.6) < (0.9) < ns 2 ns 5.1 (1.0) ns LABORATORY DATA The reference range of GSTA for children (5-12 yr of age) in our immunoassay was \ig litre" 1, which is only slightly higher than that for adult females ( ig litre" 1 ) but lower than that for adult males ( ug litre" 1 ) [11]. The difference between the sexes in this study was not statistically significant (3.1 (1.9) ug litre" 1 vs 3.8 (2.6) ug litre" 1 for girls and boys, respectively). Baseline concentrac x*e F» Time (min) Time (min) Figure 1 Systolic ( ) and diastolic (D) arterial pressure (AP), and heart rate (HR) (#) (mean, SEM) from 1 min before ( 1) to 15 min after induction. Heart rate changed less in the sevoflurane than in the halothane group at all times. *P < 0.05 compared with the value 1 min before induction.

4 and halothane in paediatric anaesthesia l aeie i 593 Recovery oaua tmean tsd;; Extubation (min) Emergence (min) Hand squeeze (min) Orientated to Name (min) Date of birth (min) Age (min) 5- P 3.5 (3.4) 15.4(12.4) 19.5(12.3) 3.8 (3.0) 33.0(16.6) 38.4 (20.5) ns 25.2(11.5) 23.6 (9.3) 25.2(11.5) 42.8 (20.0) 41.3(23.1) 43.2 (20.2) 4- j>2- < l Time (h) Figure 4 Changes in serum glutathione transferase alpha (GSTA) concentrations (mean, SEM) from baseline values at 0, 1, 2, 4, 6, 24 and 48 h after the end of anaesthesia with sevoflurane ( ) or halothane (H)- There were no significant differences between groups. *P < 0.05 compared with prcanaesthetic controls. o o S 7 03 I Time (min) = 15 o Figure 2 Aldrete score (0-10) (mean, SEM) immediately after arrival in the recovery room (0) and 10, 20, 30, 40 and 50 min thereafter for the sevoflurane ( ) and halothane (H) groups. *P < 0.05 between groups. CD 50J t Time (h) 48 Figure 5 Serum fluoride concentrations (mean, SEM) at baseline (arrow) and at 0, 1, 2, 4, 6, 24 and 48 h after the end of anaesthesia in the sevoflurane ( ) and halothane ( ) groups. *P < 0.05, **P between groups. ) Figure 3 Trieger dot test (mean, SEM) as a percentage of the preanaesthetic control value at 1, 2, 4, 6 and 24 h after the end of anaesthesia with sevoflurane ( ) or hajothane (H). *P < 0 05 between groups; +P < 0.05 compared with preanaesthetic control in the same group. tions of GSTA exceeded the reference range in one child in the sevoflurane group (18 ug litre"1) and in two in the halothane group (17 and 10 ug litre"1)! and these were excluded from further GSTA evaluations. Differences in GSTA concentrations between the study groups were not statistically significant at any time. Baseline GSTA concentration was 2.6 (1.5) (range ) ug litre"1 in the sevoflurane group and 4.1 (2.3) ( ) ug litre"1 in the halothane group (ns). The greatest individual values were 20.9 ug litre"12 h after sevoflurane and 32.6 ug litre"1 4 h after halothane. The changes in serum GSTA concentrations from baseline are shown in figure 4. The increases at 1 and 2 h after the end of anaesthesia were statistically significant in both groups. There was a secondary increase in GSTA in four children at 48 h (two after sevoflurane: 16.4 ug litre"1, 224 ug litre"1; and two after halothane: 8.8 ug litre"1, 14.7 ug litre"1). The child with Table 4 Laboratory results (mean (SD)) for serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), bilirubin and creatinine concentrations at baseline and 24 h after anaesthesia. No within- or between-group differences ALT (iu litre"1) AST (iu litre"1) ALP (iu litre"1) Bilirubin (umol litre"1) Creatinine (umol litre"1) Baseline 24 h Baseline 24 h 16.4(9.3) 37.6 (8.6) 545 (148) 7.1 (6.4) 56.8(10.4) 16.4(9.8) 37.8(11.7) 487(139) 7.7 (7.3) 58.5 (13.2) 19.7(12.4) 35.5 (9.0) 522 (150) 4.4 (2.7) 52.6 (8.9) 19.4(12.6) 36.3 (8.5) 487(145) 9.2 (7.8) 55.5 (12.8)

5 594 British Journal of Anaesthesia a serum GSTA concentration of 224 ug litre" 1 (199 ig litre" 1 in control measurements) 48 h after sevoflurane anaesthesia was excluded. The course of anaesthesia in this particular patient was normal, the primary increase in GSTA was minimal (0.5 ug litre" 1 ), the operation was lumbar spondylodesis and sulphadiazine-trimethoprim was started for asymptomatic lower urinary tract infection on the day of operation. Symptoms of hepatic or renal disease were not observed in any patient after anaesthesia, and control samples of the four patients with secondary increases in GSTA had normal liver enzyme activities (ALT, AST and y-glutamyltransferase) and normal GSTA concentrations 3 6 months after anaesthesia. Fluoride concentrations were significantly greater in the sevoflurane group at all times (fig. 5). The greatest individual concentration was 45 umol litre" 1 1 h after anaesthesia; it decreased to 32 umol litre" 1 by 3 h. No significant changes between the sevoflurane and halothane groups were noted in ALT, AST, ALP, bilirubin or creatinine when analysed 24 h after operation (table 4). Discussion Children preferred anaesthesia with sevoflurane compared with halothane. We feel that this result is important as children are seldom asked for their views on anaesthesia. This difference probably reflects the non-pungent odour of sevoflurane. The irritant effect of sevoflurane has been shown to be less than that of halothane, enflurane or isoflurane [18]. Our study showed that induction of, and emergence from, anaesthesia were significantly faster in children receiving sevoflurane than those receiving halothane, because of the different solubility profiles of these agents. The solubility of sevoflurane in blood and tissues is significantly lower than that of halothane; blood-gas partition coefficients are 0.69 and 2.3, respectively [19, 20]. We maintained equipotent inspired concentrations of sevoflurane and halothane during induction of anaesthesia. However, because of rapid equilibration with sevoflurane, alveolar concentrations of sevoflurane increased more rapidly than those of halothane [15]. For example, 5 min after application of the face mask, alveolar concentrations were estimated to be 2.0 and 1.5 MAC, respectively. Two previous paediatric studies comparing sevoflurane and halothane failed to show any significant difference in induction times in children receiving sevoflurane or halothane via a face mask [4,5]. However, differences in induction times between these agents were demonstrated by Davis and colleagues [6] and in the present study. This may be explained by the fact that the anaesthetic agents were introduced more slowly in previous studies [4, 5] compared with our study, where the maximum concentrations of sevoflurane and halothane were always reached within 60 s. No premedication was given and thus our patients were alert and maintained breathing. Both sevoflurane and halothane provided smooth induction of anaesthesia with only few side effects. Our patients did not exhibit tachycardia or hypertension during induction of anaesthesia as occurred in other studies [21]. Desflurane, which has an even lower solubility profile (blood-gas partition coefficient of 0.42 [22]) than sevoflurane, produces very rapid induction and recovery from anaesthesia [23, 24]. However, desflurane has been shown to irritate the respiratory tract and to cause breath-holding, coughing and laryngospasm in children. Previously, isoflurane has been shown to possess the same features [25]. Even after almost 2 h of anaesthesia, the rapid washout of sevoflurane was evident by the clinical tests of recovery. Our study clearly showed that all recovery variables were significantly shorter in children anaesthetized with sevoflurane than in those anaesthetized with halothane, in accordance with data from previous studies [4-6]. The trachea was extubated within 4 min after discontinuation of the anaesthetic agent and we could find no differences in respiratory activity between groups. It has been shown that the respiratory depressant effects of halothane and sevoflurane are approximately equal [26]. Naito and Tamai [5] reported that the incidence of postoperative agitation and restlessness was more frequent after sevoflurane than after halothane anaesthesia. However, this was not observed in our patients. The high incidence of nausea and vomiting in our patients was probably caused by treatment of postoperative pain with i.v. opioids. A small increase in GSTA was observed after both halothane and sevoflurane anaesthesia. The increase in the halothane group appeared to be similar to that seen in adults after halothane anaesthesia [9]. Therefore, the same mechanisms of halothane hepatoxicity may be involved in children, although clinical hepatotoxicity after halothane anaesthesia in children is rare [7]. Hepatotoxicity after sevoflurane anaesthesia in humans has not been reported, but studies with new sensitive markers have not been published previously. We found a small, statistically significant increase in GSTA after sevoflurane, suggesting that disturbances in hepatocellular integrity may also be associated with sevoflurane anaesthesia. These results suggest that both halothane and sevoflurane may cause mild deterioration in hepatocellular integrity. It should be noted, however, that none of the other enzyme assays, or clinical signs, indicated hepatic dysfunction or toxicity in any patient. The decrease in GSTA was rapid but a secondary increase was noted in some patients in this study as has also been found elsewhere [9, 27]. The reason for the large unexpected secondary increase in one patient (224 ug litre" 1 ) was unclear. Surgical reasons seem unlikely, as the operation was not intraabdominal and there were no signs of infection after operation. hepatotoxicity could have been possible, but the primary peak was minimal and the secondary peak was delayed, which suggests mechanisms different from those involved in halothane henatotoxicity. Sulphadiazine-trimethoprim may be a probable cause of the delayed subclinical increase in GSTA, as sulphonamides are known occasionally to cause liver injury [28]. GSTA and

6 and halothane in paediatric anaesthesia 595 aminotransferase values for that patient were normal 3 months after anaesthesia. has been shown to react with carbon dioxide absorbers producing possible toxic degradation products under certain conditions [1, 29]. However, in this study this possibility was eliminated by using a semi-open system without a soda-lime carbon dioxide absorber. An increase in serum fluoride concentration during sevoflurane anaesthesia was detectable in baseline samples, obtained immediately after insertion of an i.v. cannula, that is after induction with a face mask. This is an expression of the very rapid hepatic metabolism of sevoflurane. Changes in serum fluoride concentrations were similar to those found in adults [30]. The maximum individual fluoride concentrations in the present study were detected 1 or 2 h after the end of sevoflurane anaesthesia and the greatest individual concentration (45 umol litre" 1 ) was near the assumed nephrotoxic concentration of 50 umol litre" 1 [11]. Nevertheless, the risk of nephrotoxicity is most likely small, as sevoflurane is not retained in the body for long periods and therefore the postanaesthetic decrease in serum fluoride is rapid. Indeed, there were no signs of renal problems in the present study; Kobayashi and co-workers [31] did not find any signs of nephrotoxicity in adult patients after approximately 13 h of sevoflurane anaesthesia. However, nephrotoxicity after prolonged sevoflurane inhalation has not been studied in children. Acknowledgements This study was supported by Abbott Laboratories, Abbott Park, IL, USA. We are grateful to Ms Annika Puustincn for help in laboratory analysis. References 1. 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