Intraoperative Use of Bolws Doses of Esmolol to Treat Tachycardia Dan D. Kanitz, MD,* Thomas J. Ebert, MD, PhD,t John P. Kampine, MD, PhD$ Ijepartment and

of‘ Anesthesiology,

VA Medical

A randomized, determine

Center,

‘l-he

Milwaukee,

double-blind,

parullel,

the safety and efficacy

Medical (College of Wisconsin, WI.

placebo-controlled

of intravenow

study was conducted

to

(IV) bolus administration of esmolol

in treating intraoierat& tachycardia in patients undergoing noncardiac general surgevy. Forty-eight ASA II-IV patients were randomized into three equal groups to receive either placebo, esmolol 50 mg, or esmolol I00 mg. Premedicatiovt, (lov azepam,) und anesthetic induction techniques (thiopental sodium and succinylcho-

*Research

Fellow in Anesthesiology

tAssociate Physiology

Protessor

$Prof’essor

and Chairman,

of Anesthesiology

and

Anesthesiology

Address reprint requests to Dr. Ebert at the Department of’ Anesthesiology (1 12A), VA Medical Center, 5000 W. National Avenue, Milwaukee, WI 53295, IJSA. Received for publication November 29, 1989; revised manuscript accepted for publication ,January 23, 1990.

line) wpre identical between groups. A@ roximately 20 minutes ufter intubation, during isofluranelN,OiO, maintenance anesthesia, patients with systolic pr~.~surp (SBP) ?I IO rnmHg were advanced into a lo-minute study drug period if one of two conditions were met: (1) heart rate (HR) was ~9.5 beatslminute, or (2) an increase in HR of >20% above preinduction baseline occurred. After two consecutive recordings of HR and blood pressure (BP), the study drug (or placebo) was injected. HR was recorded every 30 seconds and BP was recorded every minute during the ensuing lo-minute period. Compared to placebo responses, HR was significantly reduced with both doses of esmolol within 1 minute of bolus injection and remained below placebo levels for 5 minutes after 50 mg of esmolol and for 9.5 minutes after 100 mg of esmolol. There were, however, only minor differences among groups with respect to SBP, diastolic blood pressure (DBP), and mean blood pressure (MBP) changes. Conclusion: Bolus administration of esmolol can produce a rapid reduction of HR with relatively few adverse effects in an unhealthy surgical population. This rapid effect reduces the potential for myocardial insult during surgical stress and affords the anesthesiologist a window of opportunity to administer more gradually acting anesthetic supplements to assist in overriding the stress response.

Keywords: 0 1990 Butterworth-Heinemann

238

J. Clin. Anesth.,

tachycardia; vol. 2, July/August

1990

blockade; anesthesia.

Beta

blood

pressure:

esmolol;

heart

rate;

Em0101 blunts response to surgical stress: Kanitz et al.

Introduction The myocardial oxygen supply and demand ratio of the human heart is adversely influenced by hypertension and tachycardia. These cardiovascular changes often occur in the anesthetized patient when surgical stimuli are sufficient to overcome analgesic levels of IV and inhaled anesthetic agents. Tachycardia appears to be more often associated with myocardial ischemia than does hypertension.1-4 Slogoff and Keats’ observed that the incidence of ischemia during coronary artery bypass graft (CABG) surgery was significantly higher in patients who developed tachycardia (> 100 beats/minute) before and during anesthesia. Thomson and Putnins’ noted that ischemic episodes occurred in anesthetized patients undergoing CABG procedures when HR increased 28% to 57% above control. The occurrence of intraoperative ischemia has been associated with a higher rate of perioperative myocardial infarction. 1 One promising approach to diminish the risk of myocardial insult during periods of augmented sympathetic drive to the heart would be to administer beta-adrenergic antagonists. The recently introduced water-soluble, cardioselective, and ultrashort-acting beta blocker esmolol has a rapid effect of slowing HR after IV administration and a short duration of action (alpha distribution half-life = 2 minutes; beta elimination half-life = 9 minutes).5-7 This pharmacokinetic profile may be ideal for attenuating transient cardiovascular responses to acute noxious surgical or anesthesia stimuli. This study evaluates the effectiveness of IV bolus doses of esmolol (50 mg or 100 mg) in the treatment of tachycardia resulting from acute increases in intraoperative surgical stimulation.

Materials and Methods Forty-eight patients who were scheduled for noncardisc surgery under general anesthesia (ASA II-IV) were entered into a prestudy evaluation period during which a medical history and electrocardiogram (EKG) were obtained and a physical examination was performed. Of these 48 patients, 6 had previous myocardial infarctions, 12 were treated hypertensives, and 19 had mild to moderate obstructive pulmonary disease. Patients with A-V conduction block greater than first degree, congestive heart failure, cardiac arrhythmia, or severe bronchial asthma were excluded. After informed consent was obtained, patients were randomly assigned a number that corresponded to one of three treatment groups: placebo, esmolol dose 50

mg, or esmolol dose 100 mg. Each group consisted of 16 patients. This study was approved by the institutions’ Human Research Review Committees. All patients were premeditated 30 to 60 minutes before induction of anesthesia with 1 to 2 mg of oral lorazepam. Three preinduction measurements of HR and BP were obtained. All patients received similar anesthetic induction agents, which consisted of thiopental sodium (4 to 5 mgikg) and succinylcholine (1 .O to 1.5 mgikg). After satisfactory establishment of the airway, sustained muscle paralysis was accomplished with pancuronium. Maintenance anesthesia was then initiated with isoflurane (0.5% to 1.0%) and nitrous oxide (60%) in oxygen (40%). The concentrations of maintenance agents were similar in all groups. Patients became eligible for this study during the intraoperative period beginning at least 20 minutes after the start of maintenance anesthesia and up to about 20 minutes prior to the end of surgery and reversal of neuromuscular blockade. Patients with an SBP of ~110 mmHg were advanced into the study drug injection period if each of two sets of vital sign measurements obtained over 1 minute showed one of the following: (1) HR ~-9.5 beats/minute or (2) an increase in HR of 20% or more above the average preinduction measurement. This increase in HR was typically in response to a sudden profound surgical stimulation, such as deep incision or retraction. The study drug was injected over 15 seconds, and the patient’s HR and BP were recorded for the next 10 minutes. HR was recorded every 30 seconds and BP every 60 seconds. The inspired anesthetic concentration was held constant, and no other anesthetic agents were given during the lo-minute study drug injection period unless (1) HR decreased below 50 beats/minute or exceeded 120 beats/minute; (2) SBP was ~90 mmHg or >160 mmHg; and/or (3) ischemic changes were noted on the EKG or ST segment monitor. Mean arterial pressure (MAP) was derived (MAP = ‘L&BP + */IDBP). Data were compared with repeated measures of analysis of variance (ANOVA) and least squares testing to determine group differences between time points during the study period. Statistical differences were noted if p values were less than 0.05.

Results Demographic namic data are hemodynamics study data and cation. There

data and prestudy (ward) hemodysummarized in Table 1. Preinduction did not differ significantly from pretherefore were omitted for simplifiwere no differences in hemodynamic

J. Clin. Anesth.,

vol. 2, July/August

1990

239

0

I .

.

+*cu

t

with respect W SBl’ or DBI’ responses. So patient developed EKG evidence of’ ischrmia. Of‘ the 32 patients who were randomized to receive esmofof, onlv one had an adverse cardiovascular response. ‘1% patient became hypotensive (SBP = 6X mmHg) and bradycardic (HK = 46 beats/minute) 6 minutes af’ter a 50 lng bofus of esmofof given in response to a HK of’ 102 beats/minute and a SBP of 160 mmHg. Full recovery was achieved within 2 minutes af’ter 10 mg of‘ ephedrine was administered. Three placebo-treated subjects required medical intervention to assist in lowering HK or BP; hemodynamic data recorded af’ter initiating the intervention were not included in subsequent analyses.

Discussion ‘I’his study determined the safety and ef‘ficacy of’ esmolof as an IV bofus in treating intraoperative tachyundergoing noncardiac general cardia in patients surgery. Bofus dosing of’ esmofof instead of’ a continuous infusion was studied for three reasons: (1) the convenience of’ this mode of’ administration, (2) noxious surgical stimuli are often transient and usually do not require the sustained intervention of a continuous esmofof inf‘usion, and (3) the effective bofus dose of’ esmofof that will produce clinically important reductions of’ HR during anesthesia is stiff undetermined.x ‘I‘his study demonstrated that a single IV bolus of either 50 mg or 100 mg of‘ esmofof is et‘f’ective in attenuating the HK increases secondary to acute increases in intraoperative surgical stress. Both doses of esmofof resulted in significant reductions of’ HR compared to placebo administration. The 100 mg dose of esmofof significantly decreased these variables to a greater extent and for a longer period of time than the 50 mg dose, but no consistent significant dif’f’erences were tound to exist between the two esmofof treatment groups for SBP, DBP, and MAP. The mean percent changes in SBP, DBP, and MAP were slightly lower f’offowing each dose of’ esmolof, but there were only a f’ew time points that achieved statistical signif’icance when compared to placebo response. Of those patients who received esmofof, only one experienced an adverse eff‘ect. ‘I-his patient had been receiving cfonidine therapy for hypertension control and became hypotensive (SBP = 6X mmHg) and bradycardic (HR = 46 beats/minute) after a 50 mg bofus dose of esmofol. ‘2’his situation was easily corrected by 10 mg of ephedrine IV. Continuous infusions of esmofof are effective in controlling hemodynamic responses to intubation and

illtraoperativc surgical stress. hlellkhaus (31(I/.: LISII~~ a tlia/epaiii-parlc~rroiliu~ii induction, clenionstratetl that esmofof attrnuatecf HR responses to intubation with as little as 100 ~glkgimin of esmolof. Gold (J/ ~1.” dcmonst rated that patients receiving esmofol at 300 pg/kg per minutt had a significantly lower HR throughout a ketaminr induction and intubation Wquence t ban those in a placebo group. In a studv 111 Kol-tYla~” ut (/I., ‘I’ patients received a 500 ~glkgimin loading dose of’ esniolol fi)r 4 minutes before thiopental sodium induction and 200 Fg/kg/min fin. 6 additional minutes during intubation. In general. HR was signif’icantfv lower in the esmolof than in the pf;tcebo group. ‘IL effectiveness of intraoperative esmolof infusions in preventing HR increases in response to surgical stimulation during aortocoronary byljass surgerv also has been demonstrated.“,‘~ (iold r/ 01. ’’ report& that an 80 mg bofus of’ esmofof f’offowed b\ a 12 mgimin infusion iI1 isoflurane-anesthetized p;;Gents was effective in treating intraoperativr tachbcardia. ‘I‘his regimen did not lower BP, \\hich is in accordance with the findings of’the present research. .-\lthough ~lu~ne~-o~~s methods are used to attenuate the heniodynamic responses to acute stresstuf surgical stimulation, the approach of‘brief‘antagonisrn of’ beta adt-enoi-eceptors seems quite appropriate in light of’ recent reports that ischemia is more f’requentli associated with tat-hycardia (HR above 100 beats/millUW) than with hypertension. I2 ’ Several investigaCors have denionstrated 1hat ischemic episodes (detected by EK(;) arc’ stronglv correlated with HK increases during c~oronar\’ arter1’ i~rvasc~i~farization.‘~ ’1 111 one report, ( there \~a5 no statistical association hetweril ischemia and either hvprrtension or rate prrssuix product. ‘fhese findings suggest tflat tachycardia ma) impose more stress on the heart than do increases in BP. ‘l-his finding may he due to the dual et‘fkct of’ tachycardia to increase myocardiaf 0, consumption while shortening the time for ef’f’ective coronary flow. In the present study, esmofol ef‘f’ectively diminished tachycardia during surgical stress without signiflcantfy lowering DBP. In addition, esmofof appears to produce less myocardial depression than propranolol when compared at equivalent chronotropic tiose~.‘~~‘~~ ‘1‘0 the extent that esmofol lengthens diastofe, preserves DBP, and may maintain a normal lef‘t ventricular end-diastolic volume, it is likely that coronary artery pertusion is well maintained if’ not improve;{ when esmolof is administered during hypertensive and tachycardic states. An IV bofus dose of esmofof appears to be safe and eflective fin- use during anesthesia to prevent increases in HK secondary to acute increases in surgical stress. Esmofol’s ultrashort duration of’action and imj. Clin. Anesth., vol. 2, July/August

1990

241

Original Contributions proved

cardioselectivity

currently drugs. patient

IV

until

for further

distinct

beta-adrenergic

Because of the one on chronic clonidine

be recommended patients

confer

available

adverse therapy,

similarly evaluation

treated

advantages

over

antagonist experience esmolol

in a cannot

hypertensive

is performed.

1. Slogoff S, Keats A: Does perioperative myocardial ischemia lead to postoperative myocardial infarction? Anesthesiology 1985;62: 107-14. I, Putnins C: Adverse effects of pancuronium 2. Thomson during high-dose fentanyl anesthesia for coronary artery bypass grafting. AnesthesioZo