Subarachnoid haemorrhage (SAH) initiates a stress response with high plasma concentrations of catecholamines [1,2] and electrocardiographic (ECG) abnormalities including changes in the T-wave and ST-segment, and prolongation of the QT interval  and increased QT dispersion (QTD) . The prolongation of the QT interval and probably also increased QTD predispose patients to cardiac dysrhythmias [4-6].
In healthy subjects, the induction of anaesthesia with thiopental results in a significant prolongation of corrected QT interval (QTc), and in comparison with propofol, the changes after thiopental have been greater . On the other hand, sodium pentobarbital decreases QTD in a dose-dependent fashion . The differences of the effects of thiopental and propofol on QTD have not been studied. We compared thiopental and propofol in patients with SAH, often presenting with ECG abnormalities. Our hypothesis was that dysrhythmias during the induction of anaesthesia are more frequent in SAH patients receiving thiopental than in those receiving propofol.
The study was approved by the Hospital Ethics Committee, and patients gave informed consent. Thirty patients with non-traumatic SAH from a ruptured aneurysm of a cerebral artery in the anterior circulation not more than 3 days before the study were included. Only patients with Hunt and Hess Grades I-III  were considered as eligible. Based on earlier findings, it was estimated that 12 patients in each group were needed to show with 80% power a significant difference in QTc between thiopental and propofol.
The patients were premedicated with diazepam 5-20 mg orally 1 h before operation; and the skin of the antecubital fossa and the site for cannulation of the radial artery were covered with local anaesthetic cream (EMLA®; AstraZeneca, Södertälje, Sweden). The patients were randomized to receive either thiopental or propofol as the induction agent. In the operating theatre, an antecubital vein was cannulated and an intravenous (i.v.) infusion with Ringer's acetate solution was started. The radial artery was cannulated after local infiltration of lidocaine for invasive monitoring of arterial pressure. Five-lead ECG monitoring was started with the II and V5 leads on display and recorded continuously on paper (speed 25 mm s−1) during the study period (AS/3®; Datex-Ohmeda, Helsinki, Finland).
After baseline recordings, the patients received glycopyrrolate 0.2 mg and fentanyl 7 μg kg−1 i.v. After 20 s, the induction agent (thiopental 25 mg mL−1 or propofol 10 mg mL−1) was given at 5 mL in 15 s until the disappearance of the eyelash reflex, after which an additional 2 mL bolus of the induction agent was given. Vecuronium 0.15 mg kg−1 was given for neuromuscular blockade. The patients' lungs were ventilated with 100% oxygen aiming at mild hyperventilation. After 3 min, an additional 2 mL dose of induction agent was given, and after 20 s the trachea was intubated. If the blood pressure increased markedly during laryngoscopy or intubation, a 2 mL dose of the induction agent was given as deemed clinically necessary.
Arterial blood pressure, heart rate and saturation by pulse oximetry were recorded at baseline, immediately after the administration of vecuronium (induction) and 1, 2 and 3 min after induction; after the top-up dose of induction agent before laryngoscopy, immediately and 30 s, 1 and 2 min after tracheal intubation. The end-tidal PCO2 was recorded after the start of controlled ventilation of the lungs. A 12-lead ECG recorded on paper (50 mm s−1) was obtained at baseline after the administration of vecuronium and immediately after intubation.
The ECGs were analysed for QT interval and QTD. QT intervals were measured manually from the onset of the QRS configuration to the end of the T-wave, which was defined as a return to the T-P baseline. If U-waves were present, the QT interval was measured to the nadir of the curve between the T- and U-waves. Three consecutive cycles in each of the 12 leads were measured and used for analysis. QT time was corrected by dividing QT time (ms) by the cubic root of the RR interval (s). From the three cycles, the mean QTc was calculated. QTc dispersion was defined as the difference between the maximum and minimum QTc occurring in any of the leads in which the QT interval was measured. When the QT interval could not be measured reliably, the lead was not used in the determination of QTc dispersion. A minimum of six leads was considered as necessary for analysis. QT measurements were made by one blinded experienced author (T. R.). A dispersion of ≤70 ms [10,11] and QTc of ≤430 ms in males, and ≤450 ms in females were considered as normal. The two-lead (II, V5) continuous recording was analysed for cardiac dysrhythmias.
Normally distributed data are presented as means (SD) and were analysed with an unpaired t-test. Other results are presented as medians (25th and 75th percentiles) and extremes. Differences between the groups were analysed with a U-test or with Fisher's exact test. The differences within groups were analysed with the Wilcoxon signed rank sum test. To find the relationships between parameters, the Kendall rank correlation coefficient with continuity correction was used. P < 0.05 was considered as significant.
The data for one patient were excluded because of protocol violation (wrong dose of fentanyl). Thus, there were 29 patients in the study, of which 15 received thiopental as the induction agent and 14 received propofol. The characteristics of the patients are presented in Table 1. The median Hunt and Hess category was 2 (25th and 75th percentiles 1 and 2). The median dose of diazepam was 15 (10, 15) mg in both groups. The median dose of thiopental was 350 (300, 413) 250-450 mg, and of propofol 165 (130, 190) 110-200 mg. One patient in the propofol group received an additional bolus, and three patients in the thiopental group (ns).
The median mean arterial pressure (MAP) at baseline was 94 (82; 103) 65-113 mmHg in the thiopental group and 101 (91; 109) 78-116 mmHg in the propofol group (ns). After induction, MAP decreased by 6% in the thiopental group and by 17% in the propofol group (P < 0.05 within group; the difference between groups was not significant). After endotracheal intubation, MAP increased in both groups, but the changes did not reach statistical significance. After the induction of anaesthesia, heart rates increased in both groups. The differences between the groups were not significant at any time during the study period (Table 2).
In both groups, the ECGs of one patient were not suitable for the analysis of QTc or QTD (Table 3). In three ECGs, only five leads were suitable for the measurement of QTc and QTD, but in these the QTDs were 103, 81 and 90 ms, and were used for further analysis. In the thiopental group, the number of patients with a prolonged QTc at baseline was greater than in the propofol group, but the difference did not reach statistical significance. Only in the thiopental group did the duration of QTc increase further during the study period. The number of patients with increased QTD was greater in the propofol group than in the thiopental group after the induction and tracheal intubation. There was a negative correlation between the induction dose of thiopental and QTD after induction (P < 0.05, r = −0.416), but not with propofol (r = −0.336) (Fig. 1a, b).
Five patients in the thiopental group had cardiac dysrhythmias during the study period: two had supraventricular extrasystoles (SVES), one had a ventricular extrasystole (VES) and in one case there was a junctional rhythm. One patient had SVES before induction, but not afterwards. In the propofol group, three patients had SVES and two had VES, and in one case both SVES and VES were observed. Supraventricular tachycardia (heart rate > 100 beats min−1, no P-waves detectable) was seen in five cases in the thiopental group and in two in the propofol group (ns). No patient in either group had ventricular tachycardia. The occurrence of dysrhythmias was not related to QTc or QTD.
Induction of anaesthesia with thiopental resulted in prolongation of the rate-corrected QT interval, but in a decrease in the incidence of abnormal QTD in patients scheduled for the ligation of a ruptured cerebral aneurysm. The occurrence of cardiac dysrhythmias remained rare, and there was no difference between the thiopental and propofol groups.
ECG abnormalities after SAH were seen during the acute phase, but they can persist for up to several weeks after the bleed . The most commonly observed ECG abnormalities are depressed or elevated ST-segment, prolongation of QT interval, changes in the T-wave, and frequently present U-wave . In an earlier study, we found QTD of ≥50 ms in 19 of 26 patients with SAH, and in none of the patients presenting for ligation of an unruptured cerebral aneurysm . In the present material, the incidence of QTD of >50 ms, at the arrival in the operating room, was close to that, i.e. 15 of 27. We speculate that premedication with diazepam may have decreased the frequency of abnormal ECG findings by attenuating anxiety. The dose of diazepam varied markedly in our patients depending on the age, weight and state of anxiety of the patient, and the aim was a calm and co-operative patient. The doses of diazepam were comparable between the groups.
As a clinical routine, all patients received glycopyrrolate at the induction of anaesthesia. Of the anticholinergic drugs, atropine is known to prolong the QTc interval , but QTD is independent of heart rate changes or the reflex vagal activity . It is probable that the effects of glycopyrrolate on the ECG resemble those of atropine. In the present study, all patients were given equal doses of glycopyrrolate. Thus, the differences in the QTc and QTD between the groups are not likely to be related to the administration of an anticholinergic drug.
SAH patients are at a risk of re-rupture of their aneurysm until after its ligation, and sudden increases in blood pressure must be avoided. Laryngoscopy and tracheal intubation are followed by a haemodynamic response with increased plasma concentrations of catecholamines . Therefore, we administered to our patients a dose of fentanyl known to obtund these responses . Fentanyl does not prevent the effects of thiopental on QT interval  but may, in fact, prolong the interval . In our study, the QTc interval increased more in the thiopental group than in the propofol group, which is in agreement with the results of an earlier study in which opioids were not given at induction . The findings suggest that the changes in the QTc are not due to fentanyl, but can be accountable to the induction agent. The increased plasma concentrations of catecholamines followed by laryngoscopy and intubation may increase the afterload of the heart, and as a consequence the QTD can increase . In our patients, QTD did not increase after laryngoscopy and tracheal intubation, which can be explained by the fairly large dose of fentanyl. However, the number of patients in whom QTD was abnormally increased was similar throughout the study period in the propofol group but decreased in the thiopental group. The effects of the two drugs on the QTD have not been compared earlier, but barbiturates have been noted to decrease the QTD .
The normal rate-corrected QTD are between 20 and 50 ms , but because of poor reproducibility of the measurement (up to 35% relative error), we used 70 ms as the upper cut-off point of normal QTD [11,17]. Furthermore, the paper speed was 50 mm s−1, which is shown to result in less intra- and interobserver variability in QTD . Increased QTD has been proposed to reflect an abnormal repolarization of the myocardium, and it has been shown to correlate better with the risk of dysrhythmias than the QT interval itself [5,6]. However, the importance of an increased QTD as a prognostic marker has been challenged in a recent study on myocardial infarct survivors . In the present study, neither prolongation of the QT interval nor increased QTD were related to the occurrence of cardiac dysrhythmias. Unfortunately, there are no published studies on the incidence of cardiac dysrhythmias after induction of anaesthesia in patients with SAH to make comparisons. Manninen and colleagues noted intraoperative ECG changes in 35% of patients undergoing ligation of a cerebral aneurysm . These abnormalities also included T-wave inversion and ST-segment depression. In our study, the number of patients with either cardiac dysrhythmia, or prolongation of the QT interval, or increased QTD during the induction period accounted to 85%, and they were evenly distributed in both study groups.
Lindgren and colleagues reported a case of prolonged QT interval together with bigeminy and ventricular tachycardia in a healthy subject after thiopental induction, but in their study QTD was not measured . In the present study, we also observed prolongation of QT interval in the thiopental group, but at the same time there was a decrease in the number of patients with increased QTD. These findings are consistent with earlier observations. Anaesthesia with pentobarbital has been shown to prevent the development of torsades de pointes in in vivo models of long QT syndrome [21,22], and similarly pentobarbital was found to decrease the dispersion of repolarization . The data provided by Shimizu and colleagues indicate that there are circumstances in which prolonged QT interval may not predispose to cardiac dysrhythmia . In patients with SAH, long QTc is temporarily acquired, and by decreasing QTD, thiopental may be protective against dysrhythmias. However, greater numbers of patients are needed to study the suggested favourable effect of thiopental in this group of patients.
In conclusion, the dysrhythmias seen at the induction period were mild in nature and not related to QTc and QTD. Regardless of their different effects on QTc and QTD, thiopental and propofol are equally suitable for the induction of anaesthesia in patients with SAH.
1. Grad A, Kiauta T, Osredkar J. Effect of elevated plasma norepinephrine on electrocardiographic changes in subarachnoid hemorrhage. Stroke
2. Randell T, Tanskanen P, Scheinin M, et al.
QT dispersion after subarachnoid hemorrhage. J Neurosurg Anesthesiol
3. Lanzino G, Kongable GL, Kassell NF. Electrocardiographic abnormalities after nontraumatic subarachnoid hemorrhage. J Neurosurg Anesthesiol
4. Schwartz PJ, Wolf S. QT interval prolongation as predictor of sudden death in patients with myocardial infarction. Circulation
5. Perkiomaki JS, Huikuri HV, Koistinen JM, et al.
Heart rate variability and dispersion of QT interval in patients with vulnerability to ventricular tachycardia and ventricular fibrillation after previous myocardial infarction. J Am Coll Cardiol
6. Day CP, McComb JM, Campbell RWF. QT dispersion: an indication of arrhythmia risk in patients with long QT intervals. Br Heart J
7. Lindgren L, Yli-Hankala A, Randell T, et al.
Haemodynamic and catecholamine responses to induction of anaesthesia and tracheal intubation: comparison between propofol and thiopentone. Br J Anaesth
8. Shimizu W, McMahon B, Antzelevitch C. Sodium pentobarbital reduces transmural dispersion of repolarization and prevents torsades de pointes in models of acquired and congenital long QT syndrome. J Cardiovasc Electrophysiol
9. Hunt WE, Hess RM. Surgical risk as related to time of intervention in the repair of intracranial aneurysms. J Neurosurg
10. Higham PD, Campbell RWF. QT dispersion. Br Heart J
11. Coumel P, Maison-Blanche P, Badilini F. Dispersion of ventricular repolarization. Reality? Illusion? Significance? Circulation
12. Annila P, Yli-Hankala A, Lindgren L. Effect of atropine on the QT interval and T-wave amplitude in healthy volunteers. Br J Anaesth
13. Yee K-M, Lim PO, Ogston SA, Struthers AD. Effect of phenylephrine with and without atropine on QT dipersion in healthy normotensive men. Am J Cardiol
14. Kautto U-M. Attenuation of the circulatory response to laryngoscopy and intubation by fentanyl. Acta Anaesth Scand
15. Lindgren L, Saarnivaara L, Klemola U-M. Protection by fentanyl against cardiac dysrrythmias during induction of anaesthesia. Eur J Anaesthesiol
16. Blair JR, Pruett JK, Crumrine RS, Balser JS. Prolongation of QT interval in association with the administration of large doses of opiates. Anesthesiology
17. Kautzner J, Gang Y, Camm AJ, Malik M. Short- and long-term reproducibility of QT, QTc, and QT dispersion measurement in healthy subjects. Pacing Clin Electrophysiol
18. Van de Loo A, Arendts W, Hohnloser SH. Variability of QT dispersion measurements in the surface electrocardiogram in patients with acute myocardial infarction and in normal subjects. Am J Cardiol
19. Zabel M, Klingenheben T, Franz MR, Hohnloser SH. Assessment of QT dispersion for prediction of mortality of arrhythmic events after myocardial infarction. Results of a prospective, long-term follow-up study. Circulation
20. Manninen PH, Gelb AW, Lam AM, Moote CA, Contreras J. Perioperative monitoring of the electrocardiogram during cerebral aneurysm surgery. J Neurosurg Anesthesiol
21. Dawson AK, Leon AS, Taylor HL. Effect of pentobarbital anesthesia on vulnerability to ventricular fibrillation. Am J Physiol
22. Hunt GB, Ross BL. Comparison of effects of three anesthetic agents on induction of ventricular tachycardia in a canine model of myocardial infarction. Circulation