Esmolol resistance during anesthesia for thoracoscopically assisted coronary artery bypass grafting

Esmolol Resistance During Anesthesia for Thoracoscopically Assisted Coronary Artery Bypass Grafting Lian Kah -fi, MBBS, MMED, Keng Fatt Cheong, MBBS, MMED, and Fun Gee Chen, MBBS, MMED, FANZCA HORACOSCOPIC HARVESTING of the left internal mammary artery (LIMA) followed by a minimal anterior thoracotomy to perform the distal anastomosis for isolated left anterior descending artery (LAD) stenosis was first described by Benetti and Ballester. 1 This technique is an attractive alternative to conventional coronary artery bypass grafting (CABG) and percutaneous transluminal coronary angioplasty (PTCA) for the treatment of single-vessel stenosis. Like other minimally invasive techniques,2 it has the advantage of allowing the use of the LIMA with its superior long-term graft patency rates 3 without the greater morbidity of conventional CABG. Esmolol, a short-acting selective [31-antagonist, is used to slow the heart rate with the aim of providing an acceptable surgical field for the surgeon to perform the distal anastomosis. However, in contrast to other reports of successful reduction of the heart rate with the use of esmolol,4,5 the authors experienced marked esmolol resistance, resulting in failure to achieve a slow heart rate in spite of exceeding the manufacturer's maximum recommended dose. The first two patients, both of whom showed esmolol resistance during CABG with the use of thoracoscopy, are presented.

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CASE REPORTS Case 1

A 43-year-old, 73-kg man with a history of smoking and controlled hypertension presented with stable angina. Coronary angiogram revealed 75% proximal LAD stenosis and good left ventricular function. A successful PTCA reduced his stenosis to 10%. A repeated angiogram performed 4 months later for recurrence of angina revealed restenosis to 70% of the previously dilated site. He was offered a repeat PTCA, but opted for a thoracoscopically assisted CABG. Preoperative assessment was normal. He was continued on his usual doses of nifedipine, 10 mg three times daily, and dipyridamole, 50 mg three times daily, and was premedicated with oral midazolam, 7.5 mg. In the operating room under local anesthesia, a 14-G intravenous (IV) catheter was inserted into his right forearm, a 20-G arterial catheter into the left radial artery, and a triple-lumen central venous pressure catheter into the right internal jugular vein. External defibrillation pads were used. Anesthesia was induced with propofol, 200 mg IV, and fentanyl, 500 ~tg. Intubation with a double-lumen 39-F left Bronchocath endobronchial tube (Mallinckrodt Laboratories, Athlone, Ireland) was facilitated by succinylcholine, 150 rag. The patient was placed in the right lateral decubitus position, 30 ° from the horizontal, with the left arm above the head. One-lung ventilation was initiated using an air-oxygen mixture with a fraction of inspired oxygen of 0.6, achieving a pulse oximetry reading of 97% to 100%. The duration of one-lung ventilation was 2.5 hours. Anesthesia was maintained with propofol, 6 mg/kg/h; vecuronium, 6 mg/h; and morphine, 15 mg. Fentanyl, 1,000 pg, was administered intermittently in response to hemodynamic changes. Journal o f Cardiothoracic and Vascular Anesthesia,

Harvesting of the LIMA was performed as the first stage. Thoracoscopic ports were inserted into the third to sixth intercostal spaces for the thoracoscope, grasping and cutting instruments, and a fanned lung retractor. The LIMA pedicle was examined for suitability through a 10-cm limited anterior thoracotomy over the fourth intercostal space. The second stage involved anastomosis of the LIMA to the LAD, and was facilitated by slowing the heart with 1V esmolol. To maintain organ perfusion, the patient was started on normothermic percutaneous (femorofemoral) cardiopulmonary support (PCPS) with full heparinization (300 IU/kg of bovine heparin) to a cardiac index of 1.4 to 1.7 L/min/m2. A Sarns centrifugal pump (3M; Ann Arbor, MI), together with 28-F venous and 20-F arterial cannulae, were used. Boluses of midazolam, 2 mg IV, and morphine, 4 rag, were administered before bypass and the patient was started on IV nitroglycerin (NTG), 1 ~tg/kg/min. There was difficulty in slowing the heart rate during PCPS. Esmolol was used at the maximum recommended dose of 300 ~tg/kg/min by infusion, plus boluses of 30 to 50 mg (total dose, 1.4 g) (Fig 1). The heart rate initially decreased transiently in response to both the initiation of the infusion and the boluses of esmolol, but each time this was quickly replaced by a persistent sinus tachycardia. In view of this, increments of labetalol and verapamil totaling 100 mg and 10 rag, respectively, were added. Unexpectedly, the heart rate instead increased from 85 to 110 beats/rain while the mean arterial pressure decreased from 70 to 60 mmI-Ig. Despite the rapid heart rate, the anastomosis was successfully completed. Total PCPS time was 70 minutes. Urine output during PCPS was 450 mL. The patient was weaned off PCPS with dopamine, 10 ~tg/kg/min IV. Total operative and anesthesia time was 7 hours. He was extubated 4 hours postoperatively in the intensive care unit, discharged to the ward on the I st postoperative day (POD), ambulated on the 2nd POD, and was discharged to home on the 4th POD. Repeated angiogram 1 week later showed good flow from the LIMA to the LAD. Case 2

A 58-year-old, 67-kg man with a history of hypertension presented with exertional angina for 6 months. Angiogram revealed a sclerotic 90% LAD stenosis not amenable to PTCA and normal left ventricular contractility. Preoperative findings were normal. He was continued on his usual dose of atenolol, 50 mg, and premedicated with oral midazolam, 7.5 rag, and tramadol, 50 mg. The venous, arterial, and central venous pressure catheters were inserted under local

From the Department of Anaesthesia, National University Hospital, Singapore. Address reprint requests to Lian Kah Ti, MBBS, MMED, Department of Anaesthesia, National University Hospital, 5, Lower Kent Ridge Rd, Singapore 119074. Copyright @ 1998 by W..B.Saunders Company 1053-0770/98/1203-001558.00/0 Key words: coronary artery bypass grafting, thoracoscopy, esmolol

Vo112,No 3 (June), 1998:pp 317-320

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off PCPS without inotropes. Total operation time was 8 hours. The patient was extubated on the operating table, discharged to the ward on the 2nd POD, and was discharged to home on the 4th POD.

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Fig 1. Heart rate and esmolol dose during PCPS. Case 1: The dose of esmolol is the sum of the bolus doses and the background infusion averaged out over lO-minute blocks. Because of the transient nature of the initial bradycardic responses to esmolol, these could not be reflected in the figure. (--), heart rate; ([]}, esmolol dose.

anesthesia. He was induced with propofol, 100 mg IV; midazolam, 3 mg; fentanyl, 100 pg; morphine, 10 mg; and was paralyzed with vecuronium, 10 nag. He was inmbated with a double-lumen 37-F left Bronchocath endobronchial tube, and had a transesophageal echocardiogram (TEE) probe inserted. Defibrillator pads were placed, and the patient was positioned in the 30 ° right lateral decubitus position. Anesthesia was maintained with isoflurane, 0.5% in 100% oxygen. Midazolam, 7 rag; morphine, 20 mg; vecuronium boluses for paralysis; and NTG infusion of 0.3 }ag/kg/min were administered throughout the operation. The LIMA was harvested thoracoscopically with the left lung collapsed and then checked for suitability through a limited anterior thoracotomy. Normothermic PCPS with full heparinization was started, achieving a cardiac index of 2.0 L/min/m 2. Attempts to slow the heart for the purpose of anastomosis were unsuccessful despite an esmolol infusion, 400 vg/kg/min IV, with boluses of 30 to 50 mg (total dose, 2.4 g) (Fig 2). As with case 1, the patient had transient responses to esmolol, but these were soon replaced by sinus tachycardia. In view of this, propranolol, 0.4 mg, and labetalol, 10 rag, were administered. The heart rate instead increased from 60 to 80 beats/min and the mean blood pressure decreased, requiring support with boluses of metaraminol totaling 5 mg to maintain a mean blood pressure of 70 mmHg. Despite these problems, the anastomosis of the LIMA to the LAD was completed within the PCPS time of 54 minutes. There was no evidence of ischemia on the electrocardiogram or TEE. Urine output during PCPS was 280 mL. The patient was weaned

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Fig 2. Heart rate and esmolol dose during PCPS. Case 2: The dose of esmolol is the sum of the bolus doses and the background infusion averaged out over lO-minute blocks. Because of the transient nature of the initial bradycardic responses to esmolol, these could not be reflected in the figure, (--), heart rate; ([]), esmolol dose.

The authors have presented the results of their initial anesthetic experience with two patients who underwent CABG surgery with the use of thoracoscopy and minithoracotomy. The benefit of this surgical approach is to avoid the complications associated with stemotomy 6 and cardiac arrest 7 used during the usual CABG procedure. Whereas cardiac arrest used during the usual CABG operations presents the optimal operative field, anastomosis during the authors' cases was to be facilitated by slowing the heart rate pharmacologically. Esmolol is the ideal agent, with its selective [31-blocking activity and short duration of action that allows titration of effects, 8 and it has been successfully used by others. 4,5 In contrast, the authors' patients developed esmolol resistance. They were given 1.4 g and 2.4 g of esmolol, respectively, which was much higher than the recommended dosage range, but their heart rates still increased. There is little in the literature to explain this phenomenon. Esmolol resistance was previously described with the use of atrial-aorta cardiopulmonary bypass (CPB) and a cardiopulmonary assist device, although the investigators did not attempt to elucidate the cause) Because esmolol resistance is only seen when CPB or cardiopulmonary assist devices are used, it would appear that the use of PCPS was the cause of this phenomenon. The use of PCPS in these patients gave the authors a greater margin of safety. It has the beneficial effect of reducing cardiac work, 1° improving oxidative metabolism in selective myocardial segments while reducing infarct size and ischemic damage after revascularization of an acute coronary occlusion in pigs, 11,12 and improving organ perfusion. Furthermore, PCPS does not cause any change in heart rate) ° However, PCPS does not efficiently unload the left ventricle or increase coronary perfusion pressure,13 raising the possibility of increased sympathetic output secondary to myocardial ischemia. There were no changes on the electrocardiogram and no wall motion abnormalities on the TEE, which was used for early detection of ischemia in these patients. PCPS also does not provide pulsatile flow. It is well documented that continuous flow is associated with a greater stress response than pulsatile flow, resulting in higher catecholamine levels. 14 Perhaps this may be a contributory factor to esmolol resistance. Another explanation is that of the catecholamine surge associated with bypass. This surge has been attributed to aortic cross-clamping and hypothermic cardiac arrest, 15 although these did not occur in the authors' patients. The use of PCPS decreases venous return and pulmonary pressures, which may lead to a reduction in the discharge of low- pressure baroreceptors in the heart and pulmonary vasculature, resulting in reflex tachycardia. 16 The decrease in pulse pressure and lack of pulsatility may also reduce stimulation of the aortic and carotid sinus baroreceptors, because baroreceptors react to both the pulse pressure and the rate of pressure change in addition to mean pressure. 16 These physiologic responses may have overwhelmed the attempted [3-blockade.

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It was also postulated that other unknown mechanisms may provide an explanation. It is possible that the esmolol administered was diluted by the prime of the PCPS circuit, which consisted of Hartmann's solution, 1,250 mL; mannitol 20%, 250 mL; sodium bicarbonate 8.4%, 60 mL; and bovine heparin, 5,000 1U, for a total volume of 1,560 mL. This is unlikely because the high doses of esmolol administered should still produce a high plasma concentration of esmolol, even after dilution. Absorption of drugs by the bypass components, primarily the membrane oxygenator, is a potential source of an unexpectedly low plasma concentration of these drugs during bypass. This phenomenon has occurred with a variety of drugs, including fentanyl, 17 NTG, 18 propofol, 19 and isoflurane. 2° However, this does not appear to occur with esmolol. Jacobs et al 2I showed that there was no difference between esmolol concentrations measured from the inflow and outflow ports of the membrane oxygenator in their series of patients undergoing CPB. Another postulation is that it may be because of the intrinsic sympathetic activity associated with [3-blockers. Although esmolol has little or no intrinsic sympathetic activity at recommended doses, 8 it may show it at the doses used by the authors. A further postulation is that it may be caused by activation of [33-adrenergic receptors by circulating catecholamines. In animal studies, [33-receptor activation resulted in a chronotropic response. 22 Esmolol, a selective [31-blocker, does not block [33. Although light anesthesia may be a cause of tachycardia, it is believed that it is highly unlikely in these patients given the anesthetic techniques used. Certainly these patients did not suffer any recall of the surgery. Other considerations with the attempt at inducing a slower heart rate revolve around the negative inotropic effect of esmolol. Although esmolol has salutary effects on myocardial preservation, 23 weaning off bypass would be an area of potential concern given the large doses of esmolol used. Fortunately, there was little evidence of residual effect in either of these

patients. Other areas of concern with the use of high-dose esmolol are hyperkalemia 24 and methanol toxicity, 9 although these are less likely to be of clinical significance. The authors' patients' serum potassium levels remained within normal limits throughout the entire perioperative period. The authors are unable to determine the exact cause of the esmolol resistance. The solution may be to increase the dose of esmolol used or to add calcium channel blockers 25 or adenosine. Adenosine has been successfully used in conjunction with esmolol for minimally invasive coronary artery bypass surgery, although without the use of percutaneous cardiopulmonary support. 2 The response to an adenosine bolus is transient bradycardia, which is followed by a sinus tachycardia that is secondary to an increase in plasma catecholamines and sympathetic n e r v e t r a f f i c . 26 It is therefore uncertain if the use of adenosine would have succeeded in reducing the tachycardia in these patients. The authors believe that avoiding PCPS altogether is the answer, 4,5 but at the risk of myocardial ischemia and an inadequate cardiac output, especially during cardiac manipulation. Irrespective of the anesthetic technique chosen, it has to be tailored to offer adequate depth of anesthesia, yet provide a rapid emergence with the possibility of early extubation either on the operating table as with the second case, or soon after in the intensive care unit to maximize the benefits offered by this surgical technique.

SUMMARY

The anesthetic technique for two patients who underwent thoracoscopic harvesting of the LIMA followed by a minithoracotomy for surgical myocardial revascularization of isolated LAD artery stenosis is reported. Both patients unexpectedly showed esmolol resistance during anastomosis of the LIMA to the LAD artery. However, excellent graft patency, early extubation, and rapid recoveries were achieved.

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15. Reves JG, Karp RB, Buttner EE, et al: Neuronal and adrenomedullary catecholamine release in response to cardiopulmonary bypass in man. Circulation 66:49-55, 1980 16. Eckberg DL, Slight P: Human baroreflexes in health and disease. Oxford, Great Britain, Oxford University Press, 1992, pp 123-215 17. Skacel M, Knott C, Reynolds E Aps C: Extracorporeal circuit sequestration of fentanyl and alfentanil. Br J Anaesth 58:947-949, 1986 18. Booth BP, Henderson M, Milne B, et al: Sequestration of glyceryl trinitrate (nitroglycerin) by cardiopulmonary bypass oxygenators. AnesthAnalg 72:493-497, 1991 19. Hynynen M, Hammar6n E, Rosenberg PH: Propofol sequestration within the extracorporeal circuit. Can J Anaesth 41:583-588, 1994 20. Hickey S, Gaylor JDS, Kenny GNC: In vitro uptake and elimination of isoflurane by different membrane oxygenators. J Cardiothorac Vasc Anesth 10:352-355, 1996 21. Jacobs JR, Croughwell ND, Goodman DK, et al: Effect of

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hypothermia and sampling site on blood esmolol concentrations. J Clin Pharmacol 33:360-365, 1993 22. Goldberg DE, FrishmanWH: Beta3-adrenergic agonists and their effects on the cardiovascular, bronchopulmonary, immune, and central nervous systems, in: Beta3-Adrenergic Agonism: A New Concept in Human Pharmacotherapy. New York, NY, Futura, 1995, pp 139-156 23. Cork RC, Kramer TH, Dreishmeier B, et al: The effect of esmolol given during cardiopulmonary bypass. Anesth Analg 80:28-40, 1995 24. Antrobus JH, Doolan LA, Bethune DW: Hyperkalemia and myocardial atonia following cardioselective beta-blockade. J Cardiothorac Vase Anesth 7:76-78, 1993 25. Kyritsis A, Douraki T, Giannopoulos N, et al: Calcium channel blocker administration improves operative conditions in beating heart coronary artery bypass grafting. Br J Anaesth 74S2:40(A78), 1995 26. Carom AJ, Garratt CJ: Adenosine and supraventricular tachycardia. N Eng J Med 325:1621-1629, 1991