1 Department of Anaesthesiology, University Hospital Hamburg-Eppendorf, Martinistraße 52, D-20246 Hamburg, Germany. 2 Department of Surgery, Asklepios Westklinikum Hamburg, Suurheid 20, D-22559 Hamburg, Germany
Corresponding author. E-mail: gerbershagen@uke.uni-hamburg.de
Accepted for publication: April 10, 2003
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Abstract |
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Methods and results. DOI 1 mg kg1 was administered three times at 40-min intervals to five MHS and five MHN anaesthetized pigs. Body temperature, heart rate, muscle tone, arterial carbon dioxide pressure (PaCO2), pH and creatine kinase concentrations were measured. The clinical occurrence of MH was defined by PaCO2 above 70 mm Hg and an increase in body temperature of more than 2 °C. Intragroup differences were analysed with the Friedman test as an overall non-parametric ANOVA and, in case of significance, with the Wilcoxon test. Intergroup comparisons were performed with the MannWhitney U-test (statistical significance P<0.05). MHS and MHN pigs developed muscle fasciculations, significant increases in body temperature and PaCO2 and a significant decrease in pH after the administration of DOI. These changes were comparable in both groups until the third dose of DOI, when in MHS pigs heart rate and PaCO2 rose significantly and pH fell significantly compared with MHN pigs. All MHS pigs fulfilled the MH criteria. Body temperature increased by more than 2 °C in all MHN pigs and PaCO2 exceeded 70 mm Hg in two. Thus, two MHN pigs fulfilled the criteria of MH.
Conclusions. The comparability of the clinical presentation following DOI administration in MHS and MHN animals and the order of the development of MH-like symptoms favour the hypothesis of a central serotonergic overstimulation, leading to a serotonin syndrome.
Br J Anaesth 2003; 91: 2814
Keywords: agonists serotenergic, DOI; anaesthetics volatile, halothane; analeptics, caffeine; complications, malignant hyperthermia; complications, serotonin syndrome
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Introduction |
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This study was designed to identify the in vivo effects of DOI on anaesthetized MHS and MH normal (MHN) pigs. In this experimental setting, a hallucinogen-induced stress reaction is excluded by anaesthesia to enable differentiation between MH and serotonin syndrome.
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Methods and results |
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Mechanical ventilation was adjusted to maintain PaCO2 at 40 (SD 2) mm Hg until the experiment started. Once a steady state was achieved for 30 min, baseline values for all variables were recorded. Three doses of DOI 1 mg kg1 i.v. were administered at 40-min intervals. Variables were measured every 10 min. After completion of all tests the animals were killed by i.v. magnesium chloride.
Statistical analysis was performed using SPSS® 10.0 (SPSS Inc., USA). Data are presented as medians and ranges. As an overall non-parametric ANOVA, the Friedman test for the analysis of intragroup variations was used. In cases of significance, we compared the baseline values with each time point using the Wilcoxon test. The intergroup analysis was performed with the non-parametric MannWhitney U-test. P<0.05 indicated statistical significance.
The median body temperature in MHS pigs before the first dose of DOI was 36.6 (range 35.838.5) °C. The temperature increased to 37.7 (36.939.6) °C 40 min after the first dose of DOI, 38.9 (38.342.1) °C 40 min after the second dose and 41.5 (40.241.9) °C 40 min after the last dose. MHN animals had a baseline body temperature of 37.8 (35.739.1) °C. The temperature increased to 38.7 (36.539.7) °C 40 min after the first dose of DOI, 39.6 (37.640.7) °C 40 min after the second dose and 40.3 (38.141.5) °C 40 min after the last dose. Statistical analysis showed a significant temperature increase in the MHS and MHN groups, but no significant intergroup variations.
PaCO2 increased significantly in both groups (Fig. 1) but there was a significant difference between the two groups only after the third dose of DOI.
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In the MHS pigs, heart rate rose significantly from the baseline value of 60 (5594) beats min1 to 66 (6191) beats min1 after the first DOI dose, 85 (65205) beats min1 after the second dose and 115 (87174) beats min1 after the third dose. In contrast, no significant changes in heart rate occurred in MHN pigs. After 120 min, however, a significant difference in heart rate was found between the groups.
Non-significant but higher baseline creatine kinase concentrations were measured in MHS pigs (median 7.7 u litre1, range 5.518.9 u litre1) compared with MHN pigs (4.8 u litre1, 4.28.1 u litre1). In both groups, the cumulative challenge of DOI exerted only slight effects on creatine kinase activity. Both MHS and MHN pigs developed skeletal muscle fasciculations. Muscle rigidity was not observed, however.
All MHS pigs fulfilled the MH criteria during the experiment. Body temperature increased by more than 2 °C in all MHN pigs and PaCO2 exceeded 70 mm Hg in two MHN animals. Thus, two MHN pigs fulfilled the criteria of MH.
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Comment |
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Our in vivo experiments did not show an unequivocal difference in the defined MH criteria in the study groups. Fasciculations and comparable increases in temperature, PaCO2 and a decline in pH were monitored after the first and second challenge of DOI in both groups of pigs. However, differences in heart rate, pH and PaCO2 between MHS and MHN did not occur until the third dose of DOI.
The predictive value of our study may be reduced because the two groups of pigs had significantly different weights. (There was no difference in age.) The weight difference could possibly explain the lower resting temperature in MHS compared with MHN pigs. In addition, a lower body temperature might be an MH-protective factor in pigs.
The results of the present study are in contrast to the typical course of MH in susceptible swine. Furthermore, the well-known trigger substances cannot induce MH in normal animals. It is notable that Löscher and colleagues5 described MH crises in conscious pigs at a lower concentration of DOI (0.8 mg kg1). Thus, it is tempting to speculate that different mechanisms are responsible for the induction of MH by 5HT2A agonists and known MH trigger agents. The prolonged onset of clinical signs and symptoms, with similarity in the course of temperature, PaCO2 and pH in the two groups of pigs is in accordance with a serotonin syndrome.10 Consequently, DOI does not seem to be a direct MH triggering agent in vivo in swine. However, 5HT2A receptor agonists might secondarily trigger a porcine stress syndrome in conscious swine by inducing central psychotic alterations, which could be prevented by anaesthesia.
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Acknowledgements |
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References |
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2 Cook DR, Brandom BW. Enflurane, halothane, and isoflurane inhibit removal of 5-hydroxytryptamine from the pulmonary circulation. Anesth Analg 1982; 61: 6715[Abstract]
3 Hede AR, Berglund BG, Post C. Trichloroethylene and halothane inhibit uptake and metabolism of 5-hydroxytryptamine in rat lung slices. Pharmacol Toxicol 1987; 61: 1914[ISI][Medline]
4 Dalsgaard-Nielsen J, Gormsen J. Effects of halothane on platelet function. Thromb Haemost 1980; 44: 1435[ISI][Medline]
5 Löscher W, Witte U, Fredow G, Ganter M, Bickhardt K. Pharmacodynamic effects of serotonin (5-HT) receptor ligands in pigs: stimulation of 5-HT2 receptors induces malignant hyperthermia. Naunyn Schmiedebergs Arch Pharmacol 1990; 341: 48393[ISI][Medline]
6 Lucke JN, Hall GM, Lister D. Porcine malignant hyperthermia. I: Metabolic and physiological changes. Br J Anaesth 1976; 48: 297304[Abstract]
7 Wedel DJ, Gammel SA, Milde JH, Iaizzo PA. Delayed onset of malignant hyperthermia induced by isoflurane and desflurane compared with halothane in susceptible swine. Anesthesiology 1993; 78: 113844[ISI][Medline]
8 Iaizzo PA, Wedel DJ. Response to succinylcholine in porcine malignant hyperthermia. Anesth Analg 1994; 79: 14351[Abstract]
9 Gronert GA. Malignant hyperthermia. Anesthesiology 1980; 53: 395423[ISI][Medline]
10 Wappler F, Fiege M, Steinfath M. The role of the serotonin (5-HT) system in malignant hyperthermia. In: Schulte am Esch J, Scholz J, Wappler F, eds. Malignant Hyperthermia. Lengerich: Pabst, 2000; 17689