Laryngoscopy and tracheal intubation is often accompanied by significant increases in arterial blood pressure (BP) and heart rate (HR) [1-3]. Tracheal extubation, as well as intubation, causes hypertension and tachycardia . These hemodynamic changes during extubation and emergence from anesthesia may cause dangerous increases in myocardial oxygen demand in patients with coronary arterial disease (CAD) and in those with risk factors for CAD [4,5]. A variety of drugs have been recommended for the control of these hemodynamic events, including lidocaine, esmolol, alfentanil, and fentanyl [6-9].
Diltiazem, a calcium channel blocker, has been used extensively to maintain perioperative hemodynamic stability [10,11]. This drug is effective in blunting the hemodynamic changes associated with laryngoscopy and tracheal intubation . Although the exact mechanisms whereby tracheal intubation and extubation cause hemodynamic changes remain as yet to be elucidated, they would seem to be different. Tracheal intubation produces a profound but short, uniform stimulation in the anesthetized patient. During tracheal extubation, stimulation which affects hemodynamic changes is multifactorial; e.g., pain of the wound, emergence from anesthesia, or tracheal irritation. Even if a drug is used effectively to control cardiovascular changes during tracheal intubation, its dose and timing of dosing most probably are different from those during extubation. This study was undertaken to evaluate the ability of diltiazem to attenuate cardiovascular responses to tracheal extubation. To make this assessment, we compared the effect of diltiazem with that of intravenous (IV) lidocaine, 1 mg/kg. This dose of lidocaine is shown to reduce hemodynamic changes attendant on extubation .
After obtaining institutional approval and informed consent from all patients, we studied 106 females (ASA physical status I) undergoing elective abdominal gynecologic surgery. Patients were excluded if they suffered from coexisting systemic illness and were taking cardiovascular or antihypertensive medications. The patients were randomly divided into four groups using random-number tables: Group 1, the control group, was given saline; Group 2 patients, 1 mg/kg lidocaine; Group 3 patients, 0.1 mg/kg diltiazem (Herbesser Registered Trademark; Tanabe, Osaka, Japan); and Group 4 patients received 0.2 mg/kg diltiazem. These drugs all were given 2 min before tracheal extubation invariably.
All patients were premedicated with intramuscularly atropine 0.5 mg 30 min before the induction of anesthesia. An epidural catheter was placed preoperatively, but no drugs were administered via this route until final hemodynamic data were obtained. Anesthesia was induced with 5 mg/kg thiamylal and 2 micro gram/kg fentanyl and tracheal intubation was facilitated with 0.2 mg/kg vecuronium IV. Anesthesia was maintained with 0.5%-1.5% isoflurane and 60% nitrous oxide (N2 O) in oxygen. The end-tidal partial carbon dioxide pressure (PETCO2) was maintained between 4.2 and 5.3 kPa (30 and 35 mm Hg). Peripheral arterial oxygen saturation (SpO2) and the concentration of end-tidal isoflurane were monitored throughout anesthesia (Capnomac Ultima Registered Trademark; Datex, Finland). The BP was recorded immediately before the induction of anesthesia and every 3 min during anesthesia using automated noninvasive BP monitor with printer (Pulsemate BX-5 Registered Trademark; Nippon Colin, Tokyo, Japan). The HR was monitored by electrocardiography (ECG lead II). The BP and HR were maintained between 80% and 120% of the preoperative values by increasing or decreasing the concentration of isoflurane until completion of surgery. Muscle relaxation was maintained by intermittent boluses of vecuronium (0.02 mg/kg). After surgery, isoflurane and N2 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, saline, lidocaine, or diltiazem was given IV. These medications had been prepared beforehand by an assistant, and their identities were unknown to the anesthetist. The trachea was extubated 2 min after administration of these drugs. Immediately before tracheal extubation, we confirmed that the concentration of end-tidal isoflurane had decreased to less than 0.1% and the patients could breathe spontaneously (PETCO2 < 6.7 kPa (45 mm Hg)) and open their eyes on command. The recovery from muscle relaxation was assessed by hand grip. Further more, oropharyngeal secretions were aspirated just prior to extubation. Immediately after tracheal extubation, 100% oxygen was given via a face mask for 5 min.
The BP and HR were then recorded every minute from the completion of surgery (= injection of neostigmine and atropine). The systolic BP (SBP), diastolic BP (DBP), 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 (= at the time of study medications) until 5 min after extubation were analyzed for cardiovascular changes associated with emergence from anesthesia and tracheal extubation. Peak SBP, DBP, and HR values observed during tracheal extubation and emergence from anesthesia were also recorded for the calculation of maximum percent changes. Values of SBP, DBP, and HR found immediately before the induction of anesthesia, at completion of surgery, at the time of injection of the study drugs (2 min before tracheal extubation), 1 min after these drugs (1 min before tracheal extubation), at tracheal extubation, and 1 min and 5 min after tracheal extubation were compared among the four groups and these values were also compared with baseline values (at completion of surgery) within individual study groups. The hemodynamic data were also recorded immediately after return to the ward from operating room (approximately 20 min after tracheal extubation). Anesthetists were unaware of the study treatment. The quality of tracheal extubation was evaluated using a five-point rating scale (1 = no cough or strain; 2 = very smooth, minimal coughing; 3 = moderate coughing; 4 = high degree of coughing or straining; and 5 = poor extubation, very uncomfortable) .
Data are expressed as mean +/- SEM. Statistical analysis was performed using a two-way (time and group) analysis of variance followed by Bonferroni modification of t-test for parametric data, and using the Kruskal-Wallis test and chi squared test for nonparametric (distribution) data. P < 0.05 was deemed significant.
Of 106 patients enrolled in the study, 80 completed it. Twenty-six patients were excluded from analysis of the results due to gross protocol deviations (5, 9, 5, and 7 patients in control, lidocaine, diltiazem 0.1, and diltiazem 0.2 mg/kg groups, respectively). Table 1 indicates that no statistical differences were observed among the four groups with respect to weight, age, or duration of anesthesia, or with respect to preoperative SBP, DBP, or HR.
(Figure 1 and Figure 2) show that SBP, DBP, and HR in the control group increased significantly in association with tracheal extubation. Lidocaine and diltiazem successfully attenuated these increases. Diltiazem 0.2 mg/kg had a greater inhibitory effect on the increases in SBP, DBP, and HR than did lidocaine or diltiazem 0.1 mg/kg. Alleviative effect of diltiazem 0.1 mg/kg on these variables was similar to that of lidocaine.
Lidocaine and diltiazem (0.1 and 0.2 mg/kg) significantly attenuated the maximum increases in SBP, DBP, and HR during the stimulus of tracheal extubation as compared with the control group Figure 3. The inhibitory effect was greatest in the diltiazem 0.2 mg/kg group.
A significantly smaller number of patients receiving diltiazem 0.1 mg/kg or 0.2 mg/kg experienced an SBP > 150 mm Hg and a DBP > 100 mm Hg. Furthermore, the number of patients with a HR > 110 bpm was significantly smaller in the 0.2 mg/kg diltiazem group than in the control, lidocaine, and 0.1 mg/kg diltiazem groups Table 2.
No patients suffered from laryngeal spasm after extubation. The numbers of patients who had coughed or strained were 20, 11, 20, and 20, and extubation quality scores (median (range)) were 3(2-5), 2(1-3), 3(2-5), and 3(2-5) in the control, lidocaine, diltiazem 0.1 mg/kg, and diltiazem 0.2 mg/kg groups, respectively. Lidocaine (1 mg/kg) significantly suppressed coughing and strain compared with the other three treatments. The number of patients with pruritus, nausea, vomiting, diarrhea, or laryngeal irritation, including sore throat and hoarseness, did not differ among the four groups.
No patients in the diltiazem groups developed profound hypotension [SBP < 80 mm Hg ] or bradycardia (HR < 50 bpm) severe enough to require pressor or sympathomimetic drugs during tracheal extubation or in the ward.
We were able to demonstrate that the cardiovascular changes during tracheal extubation were attenuated by a single dose (0.1 or 0.2 mg/kg) of diltiazem and this alleviative effect was similar to or stronger than that of lidocaine 1 mg/kg. During and after tracheal extubation plasma concentrations of adrenaline and noradrenaline are reported to increase . Although the precise mechanism responsible for tachycardia and hypertension after tracheal extubation is unknown, these hemodynamic changes may be associated with the release of catecholamines occurring during this stressful period. Although diltiazem at high doses (10-5 mol/L = 4.51 micro gram/mL) inhibits the release of catecholamines evoked by acetylcholine or potassium ion in cats , the drug at doses used in clinical setting (0.2-0.6 micro gram/mL) is unlikely to suppress catecholamine release. This finding suggests that the effectiveness of diltiazem in controlling BP and HR relates to its direct vasodilatory, negative chronotropic and dromotropic properties , but not to modulation of catecholamine release.
Extubation irritates airways, causing cough or strain, both of which are known to increase BP and HR. The number of patients who had coughs or strains was smaller in the lidocaine group than in the control and diltiazem (0.1 and 0.2 mg/kg) groups, being similar in these latter groups. Although diltiazem at either of the dose levels failed to alleviate laryngeal irritation, the drug successfully attenuated hemodynamic changes associated with tracheal extubation. A combination of lidocaine and diltiazem would attenuate hemodynamic changes to more tolerable levels than each drug administered alone, because the mechanisms, whereby these two drugs attenuate tachycardia and hypertension, are thought to be different. Thus, the effects of the combination of the two drugs in the same setting deserve further studies.
The rationale for use of diltiazem at these doses (0.1 and 0.2 mg/kg) in the current study was based on the following findings: 1) Diltiazem 0.1-0.2 mg/kg has been used to treat supraventricular tachycardic arrhythmia [17,18] or unstable angina ; 2) IV diltiazem, at doses of 0.09-0.23 mg/kg  or 10 mg (for 57-kg adults) , has been used to reduce abrupt circulatory changes in response to various surgical stimuli, and 3) the use of diltiazem 0.2 mg/kg is recommended to attenuate cardiovascular changes after tracheal intubation . In our preliminary study, one of four patients receiving diltiazem 0.3 mg/kg had hypotension (SBP = 71 mm Hg). Thus, the use of diltiazem 0.3 mg/kg did not seem to be justified in the current study. The onset of antihypertensive action of diltiazem (0.2 mg/kg) occurs obviously within approximately 30 s after a single IV injection, with a peak effect occurring at 1.5-2 min . The decision to give the drug 2 min prior to tracheal extubation was based on these data. This timing of administration of diltiazem was coincident with that of lidocaine in this setting. Since the duration of action of diltiazem is as short as 10 min , profound hypotension did not occur in any patient. It seems, therefore, to be one of the most appropriate drugs to attenuate the cardiovascular responses to tracheal extubation.
IV administration of the mixture of neostigmine and atropine increases HR within 1 min, the effect peaking 1-2 min after injection. The HR returns to basal values 3 min after injection and decrease further until 6 min after dosing . The degree of HR change reaches a 20% increase at 1-2 min and then a 20% decrease from the basal values for more than 30 min. It is also reported that the blood pressure decreased to less than 70% of prevalue in 3 of 32 patients. As we analyzed the hemodynamic response to tracheal extubation from 3 min after the injection of neostigmine-atropine mixture to 5 min after extubation (i.e., 10 min after injection of the mixture), the early increase in HR induced by atropine was likely to be excluded. Importantly, the subsequent decrease in HR was included in the study period. Diltiazem 0.2 or 0.3 mg/kg IV decreases the mean arterial pressure 20-40 s after administration, with a return toward basal value apparently by 3 min and complete restoration after 10 min . In the current study, the combination of neostigmine-atropine mixture and diltiazem may have suppressed the increase in HR and BP synergistically during extubation period. This possible synergistic bradycardic and hypotensive action of these drugs may be disadvantageous to patients in whom cardiac depression is undesirable. The use of other cholinesterase inhibitors (e.g., edrophonium or pyridostigmine) may have caused different results.
We studied patients in ASA physical status I without any known cardiovascular disease. This population was chosen to ensure the safety of the initial evaluation of the effects of diltiazem in this setting. Some groups studied the hemodynamic responses to tracheal extubation after coronary artery surgery in patients with CAD. The hemodynamic variables included HR, BP, cardiac index, systemic vascular resistance index, pulmonary artery pressure, plumonary artery occlusion pressure, and pulmonary vascular resistance index. One study demonstrated significant increases in all the variables . In patients with CAD, myocardial ischemia may occur during tracheal extubation [24,25], and the occurrence of intraoperative ischemia is associated with a high rate of perioperative myocardial infarction. Because the HR is a major controllable determinant of myocardial oxygen balance , the suppressive effect of diltiazem on tachycardia may justify its use in this setting. Thus, diltiazem may be effective in attenuating the cardiovascular responses to tracheal extubation in patients with CAD.
In conclusion, in ASA physical status I patients, diltiazem 0.1 or 0.2 mg/kg IV given 2 min before extubation is a simple, effective, and practical method for blunting cardiovascular responses to tracheal extubation. This suppressive effect of diltiazem was comparable to or even more potent than that of lidocaine 1 mg/kg. However, further studies are required to evaluate the advantage, beneficial effects, and safety of diltiazem in comparison with other drugs when used for the purpose of attenuating the hemodynamic changes associated with extubation in patients with CAD and cerebrovascular disease.
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