Mikawa, Katsuya MD; Nishina, Kahoru MD; Takao, Yumiko MD; Shiga, Makoto MD; Maekawa, Nobuhiro MD; Obara, Hidefumi MD
Tracheal extubation often provokes hypertension and tachycardia, as does tracheal intubation . These cardiovascular changes during extubation and emergence from anesthesia may lead to myocardial ischemia in patients with coronary arterial disease [1,2]. A variety of drugs have been used to control these hemodynamic events, including lidocaine, esmolol, alfentanil, fentanyl, and diltiazem [1,3-7]. We have recently shown that verapamil attenuates the cardiovascular responses to tracheal extubation  and that the efficacy of verapamil is superior to that of diltiazem. Many types of stimuli during tracheal extubation are likely to affect these complications, including those during emergence from anesthesia and laryngeal irritation. Because the pharmacological mechanisms for control of the hemodynamic changes during tracheal extubation are thought to differ between verapamil and lidocaine, the concomitant use of these drugs may mutually enhance the prophylactic effects of each drug alone for this purpose. To test this hypothesis, we compared the efficacy of verapamil, lidocaine, and a verapamil/lidocaine combination for the attenuation of hypertensive and tachycardic responses to tracheal extubation and emergence from anesthesia. To make this assessment, we used verapamil (0.1 mg/kg) and lidocaine (1 mg/kg) as prophylaxis. The doses of these drugs are effective for this purpose [3,8,9].
We studied adult 100 patients (ASA physical status I) undergoing elective minor gynecological or urological surgery, after institutional approval and informed consent. Patients suffering from coexisting systemic illness and those taking cardiovascular or antihypertensive medications were excluded. The patients were randomly divided into four groups (n = 25 for each group) using the envelope method: Group S = saline group (control), Group V = 0.1 mg/kg verapamil (Vasolan[registered sign]; Eisai, Japan) group, Group L = 1 mg/kg lidocaine group, and Group V-L = 0.1 mg/kg verapamil plus 1 mg/kg lidocaine group. These drugs were all given intravenously (IV) 2 min before tracheal extubation. The optimal timing of verapamil and/or lidocaine injections (2 min before extubation) has been described elsewhere [3,8,9]. Figure 1 and Table 1 give the study protocol and the patients' profiles, respectively.
All patients were premedicated with intramuscular atropine (0.5 mg) 30 min before the induction of anesthesia. An epidural catheter was placed preoperatively to allow the control of postoperative pain, but no drugs were administered via this route until the final hemodynamic data were obtained. Anesthesia was induced with thiopental 5 mg/kg and fentanyl 2 micro g/kg, and tracheal intubation was facilitated with 0.2 mg/kg vecuronium IV. Anesthesia was maintained with 1.0%-2.0% sevoflurane and 60% nitrous oxide (N2 O) in oxygen. The end-tidal partial carbon dioxide pressure (PETCO2) was maintained at 4.2-5.6 kPa (32-42 mm Hg). Peripheral arterial oxygen saturation (SpO2) and the concentration of end-tidal sevoflurane were monitored throughout the period of anesthesia. The arterial pressure (AP) was recorded immediately before the induction of anesthesia and every 2.5 min during anesthesia using an automated noninvasive AP monitor with printer. The heart rate (HR) was monitored by electrocardiography (EKG lead II). The AP and HR were maintained between 80% and 120% of the preoperative values by increasing or decreasing the concentration of sevoflurane until the completion of surgery. Muscle relaxation was maintained by intermittent boluses of vecuronium (0.02 mg/kg). After surgery, sevoflurane and N (2) O were discontinued, and residual muscle relaxation was reversed with neostigmine 0.05 mg/kg and atropine 0.02 mg/kg IV. Three minutes later, two doses of saline (Group S), verapamil and saline (Group V), lidocaine and saline (Group L), or verapamil and lidocaine (Group V-L) were given IV. These medications had been prepared before hand in equivalent volume by an assistant, and their identities were unknown to the anesthetist. The trachea was extubated 2 min after administration of the study drugs. Immediately before tracheal extubation, we confirmed that the concentration of end-tidal sevoflurane had decreased to 0.1% or less and that the patients were able to breathe spontaneously (Petco2 < 6.5 kPa [49 mm Hg]) and open their eyes on command. The recovery from muscle relaxation was assessed by hand grip. Oropharyngeal secretions were aspirated immediately before extubation. Immediately after tracheal extubation, 100% oxygen was given via a face mask for 5 min.
The AP and HR were then recorded every minute from the end of surgery (i.e., injection of neostigmine-atropine mixture). The systolic AP (SAP), diastolic AP (DAP), and HR measured at the end of surgery served as baseline values. Hemodynamic data obtained from 3 min after the injection of neostigmine-atropine mixture (i.e., at the time of study medications) until 5 min after extubation were analyzed to determine cardiovascular changes associated with emergence from anesthesia and tracheal extubation. Peak SAP, DAP, and HR values observed during tracheal extubation were also recorded for the calculation of maximum percent changes. Values for SAP, DAP, and HR found immediately before the induction of anesthesia (preoperative hemodynamics), at the end of surgery, at the time of injection of the study drugs (2 min before tracheal extubation), 1 min after these medications (1 min before tracheal extubation), at tracheal extubation, and 1 min and 5 min after tracheal extubation were compared among the four groups. These values were also compared with baseline values within individual study groups. The quality of tracheal extubation was evaluated using a 5-point rating scale: 1 = no coughing or straining, 2 = very smooth, minimal coughing, 3 = moderate coughing, 4 = marked coughing or straining, and 5 = poor extubation, very uncomfortable . The anesthetists and observers were unaware of the study treatment. The hemodynamic data were also recorded immediately after the patient's return to the ward from the operating room (approximately 20 min after tracheal extubation). The HR was continuously monitored using EKG, and AP was measured every 5 min using an automated sphygmomanometer for 2 h postoperatively on the ward.
Data were expressed as means +/- sem. Statistical analysis was performed using a two-way (time and group) analysis of variance followed by Bonferroni's modification of the t-test for parametric data, and using the Kruskal-Wallis test and Fisher's exact test for nonparametric (distribution) data. We used commercial statistical software (StatView 4.11 and super-ANOVA; Abacus Concepts, Inc., Berkeley, CA). P < 0.05 was deemed significant.
Of the 128 patients enrolled, 100 completed the study. Twenty-eight patients were excluded from analysis of the results because of gross protocol deviations (8, 5, 11, and 4 patients in Groups S, V, L, and V-L, respectively). There were no significant differences among the four groups with respect to gender, age, weight, duration of anesthesia or operation, types of surgery, or preoperative SAP, DAP, or HR values (Table 1).
The SAP, DAP, and HR values in the control group increased in association with tracheal extubation (Figure 2, Figure 3, and Figure 4). Both verapamil 0.1 mg/kg and lidocaine 1 mg/kg successfully attenuated these increases. The suppressive effect of verapamil was greater than that of lidocaine. The concurrent use of the two drugs minimized the increases (Figure 2, Figure 3, and Figure 4). Maximal increases in SAP, DAP, and HR values were attenuated by verapamil or lidocaine (Table 2). Maximal percent changes in the hemodynamics were the least in Group V-L.
There were no Group V-L patients in whom SAP or DAP increased more than 20% over baseline (i.e., at the end of surgery) (Table 2). The number of patients in whom HR increased more than 20% over baseline was smaller in the two verapamil-treated groups (Groups V and V-L) than in the lidocaine-alone group (Group L). Similar number of patients in Groups S and L experienced more than 20% increases in hemodynamics.
No patients suffered from laryngeal spasm after extubation. The numbers of patients who had coughed or strained were 25, 25, 14, and 16 in Groups S, V, L, and V-L, respectively (P = 0.0001 for Group S versus Groups L and V-L, and P = 0.0008 for Group V vs Groups L and V-L). The extubation quality scores [median (range)] were 3 (2-5), 3 (2-5), 2 (1-4), and 2 (1-3) in Groups S, V, L, and V-L, respectively (P = 0.0009, 00012, 0.0003, and 0.0002 for Group S versus Group L, Group S versus Group V-L, Group V versus Group L, and Group V versus Group V-L, respectively). The administration of lidocaine (in Groups L and V-L) significantly suppressed coughing and strain compared with the other nontreatment regimens. The number of patients with pruritus, nausea, vomiting, diarrhea, or laryngeal irritation, including sore throat and hoarseness, was similar among the four groups.
Although one patient in the control group had transient bigeminy lasting approximately 10 s, no ventricular arrhythmia was observed in the other treatment groups. None of the patients who received verapamil (alone or plus lidocaine) developed profound hypotension [SAP <80 mm Hg ], bradycardia (HR <50 bpm), or sinoatrial or atrioventricular block severe enough to require pressor or sympathomimetic drugs during or after tracheal extubation or in the ward.
In the current study, we have confirmed that the cardiovascular changes during tracheal extubation were blunted by verapamil 0.1 mg/kg and by lidocaine 1 mg/kg. We have also found that the combination of verapamil and lidocaine at these doses attenuated the hemodynamic events more effectively than did either medication alone.
Although the precise mechanism responsible for the cardiovascular changes during tracheal extubation remains to be elucidated, multifactorial stimuli during tracheal extubation, including wound pain, emergence from anesthesia, and tracheal irritation, are involved in the events. The beneficial effect of lidocaine on the hemodynamic sequences may be due, in part, to direct cardiac depression and peripheral vasodilation. Extubation irritates airways and causes cough, which is known to produce hypertension and tachycardia. IV lidocaine suppresses the cough reflex [11,12]. As in previous reports, the number of patients in the current study who experienced coughs was less in the lidocaine-treated groups than in the group treated with verapamil alone. Attenuation of the activity in afferent C fibers from the larynx may contribute to this successful intervention . Verapamil, which has a potent local anesthetic activity, failed to attenuate laryngeal irritation. This calcium channel blocker is thought to control hypertension and tachycardia by its direct vasodilatory and negative chronotropic and dromotropic properties . Because verapamil is highly protein-bound (90%), concomitant use of lidocaine is likely to increase the pharmacologically active unbound portion of verapamil , resulting in an elevation of free concentrations of verapamil. Lidocaine may have enhanced the suppressive effect of verapamil on the hemodynamic complications during tracheal extubation through this mechanism. Plasma concentrations of adrenaline and noradrenaline increase during this stressful period . The IV infusion of lidocaine inhibits hypertensive and tachycardic responses to tracheal extubation . However, the lidocaine infusion reportedly failed to inhibit the general sympathetic response to extubation as assessed by increased plasma catecholamine concentrations . At doses used in the clinical setting (0.1-0.3 micro g/mL), verapamil is also unlikely to suppress catecholamine release, inconsistent with an in vitro study .
Myocardial ischemia may occur during tracheal extubation in patients with coronary arterial disease [19,20]. The occurrence of perioperative myocardial ischemia during anesthesia is associated with postoperative myocardial infarction [21,22]. Because HR is a major controllable determinant of myocardial oxygen balance , satisfactory suppression of tachycardic response to tracheal extubation with verapamillidocaine combination may be beneficial to patients with coronary arterial disease.
The administration of an atropine-neostigmine mixture for the reversal of residual muscle blockade increases HR within one minute, with the peak effect (20% increase) occurring one to two minutes after injection. The HR returns to baseline values three minutes after injection . These phenomena are probably caused by a more rapid onset of atropine compared with neostigmine. Verapamil plus lidocaine given three minutes after the atropine-neostigmine mixture in the current study probably had no effect on the reversal-induced tachycardia. A further study with differing timings, doses, and/or modes of the administration of verapamil and lidocaine should be conducted. The HR continues to decrease below the baseline until six minutes after the administration of the atropine-neostigmine mixture and subsequently shows a 20% decrease from the baseline for more than 30 minutes . A single IV injection of verapamil decreases the mean AP 20 seconds after administration, with a return toward basal values by four minutes . Thus, neostigmine may intensify the effects of the verapamil/lidocaine combination on hemodynamics during the extubation period. In the current study, none of the patients who received the combination of verapamil and lidocaine sustained bradycardia or hypotension sufficient to require pressor or sympathomimetic drugs after extubation. However, this possibly enhanced hypotensive action of neostigmine, verapamil, and lidocaine may be disadvantageous to patients in whom cardiac depression is undesirable (e.g., those with congestive heart failure because of hypertension). In this setting, administering verapamil or lidocaine alone may be more suitable than the combination. The benefit to risk ratio of the combined method for these patients warrants further study.
In conclusion, we have shown that a combination of verapamil 0.1 mg/kg and lidocaine 1 mg/kg injected IV two minutes before extubation is a simple, effective, and practical prophylactic method for suppressing the hypertensive and tachycardic responses to tracheal extubation, and this beneficial effect is superior to that of each drug alone.
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