INSIGHTS INTO SUCCINYLCHOLINE-INDUCED HYPOTENSION AND MALIGNANT HYPERTHERMIA IN SUSCEPTIBLE SWINE

Abstract

S383 INTRODUCTION: Administration of succinylcholine (SCH), a depolarizing muscle relaxant, to swine susceptible to malignant hyperthermia (MH) causes immediate, severe arterial hypotension, and fulminant episodes of MH. [1] However, it was previously reported that these responses could not be prevented by pretreatment with clinical doses of pancuronium. [1] The aims of our study were to gain new insights into the genotype-phenotype association underlying these SCH responses. METHODS: The in vivo effects of SCH were contrasted between swine with the MH mutation (n=10) and normal animals (n=6). Parameters studied included: ECG, heart rate, invasive blood pressure (BP), pulmonary artery (PA), central venous, left and right ventricular pressures (CVP, LVP, RVP), cardiac output (CO), endtidal CO2, axilla, esophageal, PA and liver temperatures and arterial blood gases. After a control period (PaCO2 40 +/- 2 mmHg, temperature 38 +/- 0.5 [inverted exclamation mark]C), SCH, 2 mg/kg was given i.v. and all parameters were measured for 15 min. To potentially alter the phenotypic responses various pretreatments were given to MH swine: 1) ranitidine and diphenhydramine (n=1), 2) dantrolene (n=2), 3) atropine (n=1), and 4) supra-clinical doses of vecuronium (n=3). In addition, responses of femoral artery vascular rings and whole isolated hearts isolated from both genotypes were studied in vitro. The femoral arteries were prepared without removing the endothelium and at 37 [inverted exclamation mark]C, the effects of SCH, 0.06 mM, on isometric tension was recorded. The hearts were removed using a standard cardioplegic procedure and then function was re-initiated in a four chamber working mode. Subsequently, the effects of SCH on left and right ventricular pressures, and contractility were analyzed. Statistics were performed using repeated measures ANOVA and Bonferroni multiple comparison post test. RESULTS: In vivo, SCH caused significant, early onset and severe decreases in BP, CO, LVP, and LV contractility in MH swine but not in normals: subsequently episodes of MH occurred in susceptible animals. Pretreatment with either antihistamines or atropine did not prevent either of these responses. Therapeutic doses of dantrolene prevented MH, but not the SCH-induced hypotension. In contrast, supra-clinical doses of vecuronium prevented both the hypotension and MH. In vitro, SCH was found to have no differential effects on either responses in the vascular rings or isolated hearts between the genotypes. DISCUSSION: Severe hypotension occurs before muscle hypermetabolism in swine with the MH genotype. Associated with this hypotensive reaction are changes in cardiac performance. However, in vitro neither in the functional hearts nor vascular rings did SCH induce differential response between the genotypes. Thus, the cardiovascular responses are likely of secondar origin relative to primary defects within the skeletal muscles. Our observations that only supra-clinical pretreatment doses of vecuronium prevented the systemic hypotension and MH episodes may suggest that SCH effects on both junctional and extrajunctional acetylcholine (ACH) receptors ultimately causes all phenotypic responses (cardiovascular and skeletal muscular). It was previously reported that extrajunctional ACH are upregulated in swine with this MH mutation. [2] In conclusion, SCH-induced hypotension in swine with the MH mutation is due to activation of nicotinic receptors: complete blockage of these receptors will also prevent the initiation of MH.