Pharmacodynamics Bill A. Falinski,

of Pentamorphone During Bypass Grafting in Humans

MD, Peter S. Sebel,

L

ARGE DOSES OF potent opioids are frequently administered as the predominant anesthetic in patients undergoing myocardial revascularization surgery. Fentanyl and sufentanil, the most widely used, produce minimal cardiac depression and decrease hemodynamic responses to noxious stimuli.” Even high doses of opioids may not provide complete anesthesia.’ Frequently, adjuvant drugs are needed to provide amnesia and to control somatic and autonomic reflexes. Furthermore, anesthetic induction with fentanyl or sufentanil may be associated with hypotension and bradycardia, as well as chest wall rigidity, which may compromise ventilation and increase pulmonary artery pressure.xg The ideal cardiac anesthetic remains to be discovered. Pentamorphone (14-B-N-Pentylamino morphinonc) is a synthetic morphinone derivative that is structurally similar to oxymorphone and hydromorphone and more potent than fentanyl. Ho et al administered pentamorphone to dogs who had received thiopental as a basal anesthetic.“’ After pentamorphone infusion, the animals did not respond to tail clamping. Although the initial pentamorphonc dose decreased mean arterial pressure (MAP), heart rate (HR) and cardiac output (CO) by 50% or more, increasing the dose 14-fold did not result in further cardiac depression. Absence of responsiveness to tail clamping persisted for the duration of the study, 4 hours after the infusion was complete. It is believed the initial cardiac depression occurred because the baseline variables reflected a hyperdynamic state in lightly anesthetized animals, and it is concluded pentamorphone merited further investigation as an anesthetic.“’

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by a grant from Anaquest,

Meeting of the

Antonio, Address

Emory Inc.,

InternationalAnesthesia

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TX, 1991. reprint requests and correspondence

MD, Department of Anesthesiology, Crawford Atlanta, GA 30365. Copyright 0 1992 by W.B. Saunders Company 1053.077019210602-0009$03.OOfO 168

University School

Research

Artery

MD, Carl C. Hug, Jr, MD, PhD, and Alan Klochany,

Pentamorphone is a new, highly potent opioid reported to have minimal cardiovascular effects in humans and a high therapeutic index in animals. Pentamorphone was injected intravenously (IV) as the sole anesthetic in 10 patients with left ventricular ejection fractions greater than 0.35 who were undergoing elective coronary artery bypass grafting (CABG). After premeditation with lorazepam, 40 pglkg, and establishment of hemodynamic monitoring, pentamorphone was infused at a rate of 2 pg/kg/min until unconsciousness occurred (5.1 f 1.6 pgl kg). Anesthetic induction was accompanied by an average 30% decrease in systolic, diastolic, and mean arterial pressure (MAP), a 19% decrease in heart rate (HR), but no change in cardiac output (CO) or pulmonary artery occlusion pressure. Five patients had a MAP less than

From the Department of Anesthesiology, of Medicine, Atlanta, GA.

Coronary

to Bill A. Falinski, W. Long Hospital,

Journalof

MD

60 mm Hg after induction. Following incision, blood pressure, pulmonary artery occlusion pressure, and CO were unchanged from baseline but HR remained significantly lower. Despite additional pentamorphone (total dose 9.6 f 1.8 pg/ kg), 6 patients required thiopental and/or enflurane to control hypertension intraoperatively. When pentamorphone is used as the sole IV anesthetic in lorazepampremeditated patients with normal or mildly impaired ventricular function, there is a high incidence of hypotension during induction, and poor control of hemodynamic responses to stimulation. Pentamorphone, 10 pg/kg, does not seem to offer any significant advantage over opioids currently used for anesthesia in patients undergoing CABG. Copyright c 1992 by W. B. Saunders Company

Glass ct al first reported the pharmacodynamics of pentamorphonc in human volunteers.” Doses of 0.48 pg/kg provided analgesia lasting more than I hour with no effect on HR, blood pressure (BP), or plasma histamine concentration. In adults undergoing elective general surgical procedures under balanced anesthesia with nitrous oxide,” Ii patients rccciving pentamorphone required less thiopcntal to produce unconsciousness and less isofluranc to control hcmodynamic responses than patients receiving fentanyl.“.” During induction. there were no signilicant differences in BP or HR between patients receiving fentanyl or pentamorphonc. In the present study, pentamorphone was used as the sole intravenous anesthetic in patients undergoing coronary artery bypass grafting (CABS). The ability of pentamorphone to induce anesthesia, suppress somatic and autonomic responses to stimulation. and maintain hemodynamic stability was evaluated. MATERIALS

AND METHODS

After obtaining institutional review board approval and informed patient consent, 10 ASA Class IV patients scheduled for elective CABG were studied. Patients who had cardiovascular instability or a left ventricular ejection fraction (LVEF) less than 35% were not eligible for the study. On the day of surgery, patients received lorazepam, 40 pg/kg. and their usual morning cardiac medications, except for diuretics, 60 minutes before arriving in the operating room. Radial and pulmonary artery catheters were inserted and electrocardiographic (ECG) electrodes were attached. The respective pressures and ECG leads II and V, were monitored and continuously recorded. After a 5-minute rest period, baseline measurements of systolic (SBP), diastolic (DBP). MAP, HR, pulmonary artery pressures (PAP), pulmonary artery occlusion pressure (PAOP), and CO were obtained. Patients were given vecuronium, 1 mg, and breathed 100% 0, by face mask. Three minutes later, pentamorphone was infused at a rate of 2 pg/kg/min until the eyelash reflex was lost and the patient did not respond to name or to a tap on the forehead. At that time. the infusion was stopped, succinylcholine, 1.5 mgikg, was given, and the trachea intubated. The lungs of the patients were ventilated with 100% 0, at a minute ventilation sufficient to maintain end-tidal CO2 between 30 and 40 mm Hg. Additional pentamorphone was given if there were signs of inadequate anesthesia: movement, tearing, increases in HR of

Cardiothoraoc

and VascularAnesthes!a,

Vol6, No 2 (April), 1992: pp 168-172

PENTAMORPHONE

PHARMACODYNAMICS

169

DURING CABG

mire than 15 beatsimin above baseline, increases in MAP greater than 15%, or a SBP greater than 150 mm Hg. The first two patients received two supplemental doses, each dose equal to one-tenth the induction dose. Seven subsequent patients received two supplemental doses, each equal to one-half the induction dose. One patient received an additional dose 1.5 times the induction dose. If anesthesia remained inadequate, thiopental, 0.5 to 1.5 mgikg, was administered for rapid control of anesthetic depth. Enflurane, in 0.25% increments, was administered for further control if necessary. To assess the incidence of somatic response, no additional neuromuscular blocking agent was given unless the patient’s muscle tone interfered with surgical dissection before cardiopulmonaly bypass (CPB). Hypotension on induction was initially treated with intravenous (IV) fluid and laryngoscopy. If the MAP remained less than 65 mm Hg after intubation, phenylephrine, 50 to 100 p,g, was administered by IV. PAOP and thermodilution CO (mean of two within 10%) were measured and recorded every minute for the first 20 minutes following induction of anesthesia, and then every 5 minutes until heparinization. The study was terminated when heparin was given. The data are reported as the mean ? standard deviation. Statistical analysis was by one-way repeated measures analysis of variance and modified t-test (Bonferroni). A P value less than 0.05 was considered significant. RESULTS

The study included 9 men and 1 woman, mean age 61.8 ? 5.7 years (range, 53 to 70) weighing 83.3 I+_9.7 kg (range, 73 to 100). Four patients had a history of myocardial infarction, but none had significant left ventricular (LV) dysfunction. All 10 patients were receiving calcium entry blocking drugs, 8 were treated with nitrates, and 5 with P-adrenergic antagonists. The time from the start of anesthetic induction until heparinization averaged 79.5 ? 27.8 minutes. Loss of consciousness occurred after a mean dose of 5.1 * 1.6 pgikg of pentamorphone. The time required to induce anesthesia averaged 137 ? 60.5 seconds. Six patients lost consciousness in 2 minutes or less. Three patients developed chest wall rigidity during induction. All patients demonstrated signs of light anesthesia and received additional pentamorphone. Seven patients needed supplemental pentamorphone before incision. Supplements averaged 4.5 * 2.1 pgikg. The mean time from the start of induction to the first supplemental dose was 28.9 +- 16.8 minutes. Another dose was required 33.9 2 12.5 minutes following induction. Surgical incision was made 35.6 2 6.5 minutes after the start of induction. All 10 patients demonstrated somatic activity; usually patients grimaced, opened their eyes or moved their hands in response to stimulation. Six patients required adjuvant drugs to control intraoperative hypertension. Four patients required the administration of thiopental (averaging 1.5 mg/kg) and enflurane. Two patients received enflurane but no thiopental. The concentration of enflurane ranged from 0.25% to 1.6% and the duration of administration varied from 17 to 123 minutes. Patients requiring enflurane received an average of 0.38 2 0.36 MAC hours. Four patients required vecuronium before heparinization. Three patients who did not need a nondepolarizing muscle relaxant received enflurane. In three patients, satisfactory operating conditions were achieved without vecuronium or enflurane.

SBP, DBP, and MAP decreased significantly following induction (Fig 1). Five patients had a MAP of less than 60 mm Hg. Two patients received multiple doses of phenylephrine for a total dosage of 150 and 200 kg, as well as a phenylephrine infusion, to maintain a MAP of greater than 65 mm Hg. One patient received three incremental doses of phenylephrine for a total dosage of 450 kg, a phenylephrine infusion, and atropine, 1.6 mg, in divided doses. In the other two hypotensive patients, BP increased during laryngoscopy and no vasopressor was injected. The BPS increased after tracheal intubation, although the SBP and MAP remained significantly less than baseline until the start of electrocautery. One patient’s BP increased from 85140 mm Hg after induction to 159/95 mm Hg at the time of electrocautery. He received thiopental, 100 mg, enflurane 1.0% to 1.6%, and a nitroprusside infusion to restore the BP to control levels. The HR slowed after induction (Fig 2). There was a small, clinically insignificant increase in HR after intubation. One patient’s HR rose from 54 to 69 beatsimin, but no other patient’s HR increased more than 7 beats/min. During preparations for the start of surgery, patients typically showed signs of inadequate anesthesia and received additional pentamorphone. The HR then decreased and remained significantly lower after incision, sternotomy, and electrocautery. Despite the fluctuation in BP and HR, there was no change in CO or PAOP (Fig 3). Two patients who became hypotensive during induction developed increases in PAOP from 12 to 16 mm Hg and from 8 to 15 mm Hg after intubation. No ischemic changes were noted on the ECG, but the elevated pressures were lowered by a nitroglycerin infusion. All patients were successfully weaned from CPB on the initial attempt and survived their operation. There were no perioperative myocardial infarctions, and none of the patients recalled any perioperative events when questioned directly after surgery. DISCUSSION

This study determined the dose of pentamorphone quired to produce unconsciousness and evaluated

rethe

Fig 1. Effects of pentamorphone on blood pressure at eight time periods following baseline: after induction (induct), at the time of intubation (intub), within 3 minutes after intubation (postintub], after incision (incis), at the time of first electrocautery (taut), after stemotomy (sternot), and at the time of heparinization (heparin). Data are mean + SD. ?? P < 0.05 versus baseline.

FALINSKI

Fig 2. Effects of pentamorphone on heart rata at eight time periods following baseline: after induction (induct), at the time of intubation (intub), within 3 minutes after intubation (postintub), after incision (incis), at the time of first electrocautery (taut), after sternotomy (sternot), and at the time of heparinization (heparin). Data are mean 2 SD. ?? f < 0.05 versus baseline.

ability of pentamorphone to maintain cardiovascular stability and control somatic responses in patients undergoing CABG. No direct comparison with fentanyl or sufentanil was intended. However, the pharmacodynamics of highdose fentanyl and sufentanil during CABG have been well described.‘.’ Because the drugs used for premeditation influence the hemodynamic responses during induction with high doses of fentanyl,’ it is important to compare these data with the studies in which patients receiving high-dose opioids for myocardial revascularization have had a benzodiazepine as a sedative premeditation.‘.’ When pentamorphone was infused at a rate of 2 kgikgl min, unconsciousness occurred after a mean of 5.1 kg/kg had been administered. This suggests that in humans pentamorphone is 5 to 6 times more potent than fentanyl: and 0.8 times as potent as sufentanil.2.6 The patients lost consciousness 2.3 minutes after the start of the pentamorphone infusion. de Lange et al, using a continuous infusion, reported the time to unresponsiveness was 4.6 minutes with fentanyl and 1.3 minutes with sufentanil.’ However, they selected rates of opioid infusion (fentanyl, 400 pg/min, and sufentanil, 300 pg/min) designed to minimize chest wall rigidity and not to provide similar relative doses of opioids. It seems reasonable to conclude that when equipotent amounts of fentanyl, sufentanil, or pentamorphone are given, the induction time would be similar.h

Fig 3. PAOP and CO at eight time periods following baseline: after induction (induct), at the time of intubation (intub), within 3 minutes after intubation (postintub), after incision (incis), at the time of first electrocautery (taut), after stemotomy (sternot), and at the time of P < heparinization (heparin). (0) PAOP; (m) CO. Data are mean f SD. ?? 0.05 versus baseline.

tT AI

Pentamorphone infusion did not maintain a stable hcmodynamic state during induction. The average SBP, DBP. and MAP decreased, and the MAP after induction averaged 62 mm Hg. Half of the patients experienced at least transient episodes of hypotension during induction, which could have jeopardized myocardial perfusion. Two patient5 developed elevations in PAOP. which may have been caused by ischemia. In patients who were premeditated with lorazepam, the induction of anesthesia with either fentanyl or sufentanil rarely produces hypotension to the degree observed with pentamorphone (Table I).‘.‘.” Previous studies have shown the average decrease in BP with fentanyl or sufentanil is less than 15% from baseline, approximately half the decline the present study patients experienced. Although CO was maintained, pentamorphone also decreased HR to a greater degree than might have been expected with fentanyl or sufentanil. The results may have been influenced by other medications the patients received during the perianesthetic period. The patients of de Lange et al were given atropine, 0.1 mg/ 15 kg intramuscularly (IM), 30 minutes before arrival in the operating room, and pancuronium, 0.02 mgikg, IV. 2 minutes before induction? IM atropine and small doses of IV pancuronium have minimal hemodynamic effects, probably too small to fully account for the differences observed. The use of succinylcholine, a muscle relaxant with muscarinic cardiac properties, must also be considered. In previous studies of cardiac patients premeditated with lorazepam receiving fentanyl or sufentanil for induction, the use of succinylcholine,*,h pancuronium,‘.5.7 or atracurium’ to facilitate intubation was associated with similar hemodynamic changes. The release of histamine or an immediate hypersensitivity reaction might also result in sudden hypotension. Histamine levels were not measured, but lower doses of pcntamorphone do not cause histamine release.” Oxymorphone. another morphinan, has not been shown to release histamine from human skin mast cells.‘” Furthermore, no patients experienced flushing, erythema, wheezing, or decreases in pulmonary compliance. It may be argued that the described technique of intermittent doses of pentamorphone may not have produced sufficient blood levels to block hypertensive responses at the times of stimulation. This is unlikely because 7 of 10 patients had received supplemental pentamorphone just before incision; the second supplemental dose of pentamorphone was needed an average of only 5 minutes after the first. Two of three patients who did not receive additional pentamorphone before incision had required phenylephrine to treat hypotension during induction. Furthermore, Ho et al found that dogs who received pentamorphone, 350 ugikg, infused over 140 minutes, remained unresponsive to tail clamp at least 4 hours after the pentamorphone infusion had been completed.“’ Similarly, the total dose of pentamorphone, 9.6 pg/kg, may have been inadequate. Based on the results, this pentamorphone dose is approximately equal to 50 pg/kg of

PENTAMORPHONE

PHARMACODYNAMICS

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DURING CABG

Table 1. Comparison With Other Opioid Studies Maximum SBP

DBP

MAP

Change From Base Line HR

SW

SV

Pentamorphone (Data from current study)

-31%

-29%

-31%

-19%

+15%

-33%

Sebel et al’ Fentanyl

-10%

0

- 1%

-12%

+12%

Thompson et al’ -13%

-7%

-6%

-11%

-10%

--4%

Fentanyl

-13%

-10%

-11%

-5%

-15%

+22%

Sufentanil

-14%

-11%

-11%

+6%

fl4%

-26%

Fentanyl Howie et aI3

de Lange et al6 Fentanyl

-13%

-

-13%

-10%

+a%

--9%

Sufentanil

-11%

-

-12%

-10%

+2%

--7%

-4%

-

-5%

-6%

f2%

-12%

-5%

-

de Lange et al2 Sufentanil

-

Sebel and Bovil’ Sufentanil

-15%

-7%

--9%

NOTE. The results of maximum changes in SEP. DBP, MAP, HR. stroke volume (SV), and systemic vascular resistance (SVR) after the induction of anesthesia with pentamorphone

compared with similarly premeditated

patients receiving either fentanyl or sufentanil. (0, no change; -,

data not

reported.)

fentanyl or 8 pg/kg of sufentanil. Philbin et al examined the ability of high doses of fentanyl and sufentanil to suppress perioperative hyperdynamic episodes and found no evidence of a dose-response relationship despite increasing the dose of fentanyl from 50 to 100 kg/kg or sufentanil from 10 to 40 ug/kg plus an infusion of 0.2 pg/kg/min.” The present study defined a pentamorphone dose that produces unconsciousness; further studies are necessary to determine an “anesthetic” dose of pentamorphone, should one exist.‘5.‘”The decrease in BP observed during induction with pentamorphone did not change CO. This suggests that the primary cardiovascular effect of pentamorphone is arterial vasodilation. Despite decreases in vascular resistance, PAOP did not change after pentamorphone. This may be explained by two mechanisms. The initial therapy for hypotension was rapid fluid infusion, which helped maintain preload. Furthermore, the increased PAOP in two patients may have resulted from ischemia-induced decreases in LV compliance, producing a higher PAOP despite a decreased LV end-diastolic volume. Succinylcholine was used to provide muscle relaxation during intubation. The patients were not paralyzed intraoperatively unless it became surgically necessary, and it was believed that the patient was unconscious, Although this may not represent the usual clinical practice, it is important

that the patient retain the ability to move in response to noxious stimulation. Although reflex somatic movements do not always indicate awareness, deeper levels of anesthesia are required to block reflex movement than to produce unconsciousness.” Despite a 100% incidence of minor movements in response to stimulation, none of the patients recalled intraoperative events when questioned afterwards. Whether this is because of the pentamorphone, lorazepam premeditation, thiopental, enflurane, or the other anesthetics administered intraoperatively after the termination of the study is impossible to judge. Although pentamorphone, 5.1 *g/kg, produced unconsciousness in lorazepam-premeditated patients, the induction of anesthesia commonly resulted in significant hypotension despite an unchanged CO. Additional pentamorphone, 4.5 ug/kg, did not reliably block the hypertensive response to stimulation. Therefore, pentamorphone, up to 10 ug/kg, administered as the sole IV anesthetic in lorazepampremeditated patients undergoing CABG, provided no advantages over fentanyl or sufentanil.

ACKNOWLEDGMENT The authors thank Angela Farmer, Marina Banks for their expert secretarial

Kathleen Mainland, assistance.

and

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in 5th

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PS, Camporesi

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pentamorphone in humans: A potent IX\\ opiate. ,\nealh ,411;tl: 68:302-307. 10x’) 1.2. Lowdon JD. Sehcl PS. Murphy MR: Pentamorphonc 111 balanced anesthesia: Comparison with fentanyl. Anesthesio1o.q 71 :A225, 1989 13. Howie MB, Duarte JA, Rypel GD, et al: Pentamorphonr cs fentanyl in balanced anesthesia during general surgery. Anrsth Analg72:Sl13. 1991 14. Hermens JM. Ebertz JM, Hanifin JM, et al: Comparison ot histamine release in human skin mast cells by morphine, fentanyl and oxymorphone. Anesthesiology 62:124-l 29, 1985 1.5. Philbin DM, Rosow CE, Schneider RC, et al: Fentanyl and sufentanil anesthesia revisited: How much is enough‘? Anesthesiology 73:5-l I. 1990 16. Hug CC Jr: Does opioid “anesthesia” exist’? Anesthesiology 73: l-4. I9YO