Low systemic vascular resistance during cardiac surgery: Case reports, brief review, and management with angiotensin II

CASE REPORTS

Low Systemic Vascular Resistance During Cardiac Surgery: Case Reports, Brief Review, and Management With Angiotensin II Upendra Thaker,

MD, Vincent

Geary, MB, FFARCSI,

C

LINICIANS HAVE observed patients who, despite having an adequate cardiac output (CO), develop profound hypotension subsequent to separation from hypothermic cardiopulmonary bypass (CPB). The hypotension is associated with a low systemic vascular resistance (SVR), which may be refractory to traditional a-adrenergic agonist therapy. Two cases are described in which such a low SVR state was successfully treated using a non-a-agonist vasopressor, angiotensin. CASE

REPORTS

Case I A 68-year-old man with insulin-dependent diabetes and severe peripheral vascular disease was admitted for lower limb revascularization. Preoperative cardiac status was evaluated because of a significant history of angina, and coronary angiography showed severe two-vessel disease with impaired left ventricular function. The patient was scheduled for elective coronary artery bypass grafting. Preoperative medical therapy consisted of nifedipine, nitroglycerin patch, and captopril, which were continued until the morning of surgery. The patient was premeditated with morphine, phenobarbital, and diazepam. In the operating room, radial and pulmonary arterial catheters were placed before induction. Anesthesia was induced with fentanyl, 80 pg/kg, and pancuronium, 0.15 mg/kg, was used to facilitate intubation and muscle relaxation. Mechanical ventilation was started with 100% 0,, and PaCO, was maintained at 35 to 45 mm Hg. His pre-CPB course was uneventful and he maintained a stable hemodynamic profile. CPB was initiated uneventfully and the patient was cooled to 28OC rectally and hemodiluted to a hematocrit of 22%. Thirty minutes after beginning CPB, maintenance of adequate perfusion pressure became difficult despite bypass flows of 3 L/min/m2. A

From the Department of Anesthesiology. Albany Medical Center Hospital, Albany, NY. Address reprint requests to Farhan Sheikh, MB, Department of Anesthesiology, Albany Medical Center Hospital, New Scotland Ave. Albany, NY 12208. o 1990 by W.B. Saunders Company. 0888-6296/90/0403-0012$03.00/0

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Paul Chalmers,

MD, and Farhan Sheikh, MB

phenylephrine infusion was begun, and despite rapidly increasing the infusion rate, maintaining a perfusion pressure in excess of 40 mm Hg through the hypothermic CPB period was difficult. Upon rewarming, perfusion pressure decreased further, and became refractory to phenylephrine; consequently, a norepinephrine infusion was substituted with some improvement. Separation from CPB was attempted with atria1 pacing, dopamine, 5 pg/kg/min, and a norepinephrine infusion. Despite increasing the dose of norepinephrine to 3 pg/kg/min, the mean arterial pressure (MAP) remained at 40 to 45 mm Hg with a CO of 8 L/min and SVR about 300 dyne - s - cm-r. Central pressures were checked through the aortic cannula and found to correlate with the radial arterial pressure. The patient was returned to CPB and further attempts at treating the hypotension were made. Intravenous (IV) bolus doses of epinephrine, norepinephrine, and calcium chloride were administered, yet the perfusion pressure remained at 30 to 40 mm Hg. At this point, an angiotensin infusion was initiated at 6 Ng/min, and within minutes, an increase in the perfusion pressure from 45 to 50 mm Hg was seen. At this time, an intra-aortic balloon pump (IABP) was also inserted in an attempt to augment coronary perfusion. Having achieved a perfusion pressure of 50 mm Hg, a second attempt at separation from CPB was made. The patient was successfully weaned from CPB with a CO of 4.8 L/min, MAP of 56 mm Hg, and SVR of 800 dyne - s . cmm5.Over the next 30 minutes, the MAP continued to improve (70 to 75 mm Hg) after administration of dopamine, 5 pg/kg/min, angiotensin, 6 rg/min, and IABP at 1:l. Anticoagulation was reversed with protamine, surgical closure was achieved, and the hemodynamically stable patient was transferred to the intensive care unit. Over the next 24 hours, the intra-aortic balloon counterpulsation was gradually reduced and the pump was removed on the second postoperative day. The angiotensin infusion was also gradually reduced and discontinued. The patient subsequently made an uneventful recovery and was discharged from the intensive care unit.

Case 2 A Ill-year-old man with a recent extensive anterior wall myocardial infarction, complicated by left ventricular failure, was initially treated with tissue plasminogen activator and subsequently anticoagulated with coumadin. He had persistent postinfarction angina with left ventricular dysfunction, which was treated with captopril, and he was referred for angiography. During the procedure, a critical left ostial stenosis was found. His ejection fraction was estimated at

Journal of Cardiorhoracic Anesthesia,

Vol4,

No 3

(June),

1990:

pp 360-363

TREATMENT OF A LOW SVR WITH ANGIOTENSIN

The patient decompensated during the procedure, necessitating the insertion of an IABP with subsequent stabilization. Surgery was delayed until anticoagulation was reversed with fresh frozen plasma and vitamin K. All monitoring catheters, including a pulmonary artery catheter, were placed in situ when the patient arrived in the operating room. Immediately before induction, further decompensation occurred, as evidenced by a decrease in MAP to 60 mm Hg and an increase in the pulmonary capillary wedge pressure (PCWP) to 30 mm Hg. A dopamine infusion, 5 pg/kg/min, was immediately started, followed by an epinephrine infusion, 4 rg/min, resulting in an improvement in the MAP and reduction of the PCWP to 18 mm Hg. Induction of anesthesia with fentanyl and vecuronium, and subsequent tracheal intubation were well tolerated. PaCO, was maintained at 35 to 45 mm Hg with controlled ventilation, using an F,O, of 1.O. The patient remained stable during the pre-CPB period on dopamine and epinephrine therapy and the IABP. CPB was initiated, and the patient was cooled to 28OC rectally and hemodiluted to a hematocrit of 25%. Immediately after cooling, the patient required large doses of phenylephrine to maintain a perfusion pressure of 40 mm Hg, despite adequate pump flows. During rewarming, perfusion pressures decreased further, despite an increasing phenylephrine dose; consequently, norepinephrine was substituted. The infusion rate was rapidly increased to 3 pg/kg/min, with only marginal improvement. At this point, an angiotensin infusion was initiated at 7 pg/min, with immediate improvement in the perfusion pressure. A loading dose of amrinone, 3 mg/kg, was administered while the patient was on CPB, followed by an infusion at 10 pg/kg/min for inotropic support. Subsequent to this, the angiotensin infusion was titrated to maintain a perfusion pressure of 60 mm Hg, and the patient was successfully separated from CPB. Over the next 24 hours the angiotensin infusion was gradually decreased and discontinued, and the patient remained hemodynamically stable. Before discharge from the intensive care unit, he developed clinical evidence of sepsis. Despite appropriate antibiotic therapy and aggressive cardiovascular support, including the reintroduction of angiotensin, the patient succumbed to fulminant overwhelming sepsis on the fourth postoperative day. 0.25.

DISCUSSION

Systemic resistance is dependent on vascular and nonvascular factors. Vascular factors considered important include vessel caliber, number of conducting vessels, vessel length, and precapillary shunting. Of these, the major component of vascular resistance is offered by the arterioles and is determined by arteriolar tone, which in turn is regulated by the neuroendocrine system. Nonvascular determinants include temperature, packed cell volume, red cell rheology, plasma viscosity, and CO or pump flow rate.’ Upon initiation of conventional CPB using hemodilution and total body hypothermia, the initial response is a decrease in the SVR, which is

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clinically manifested by decreased perfusion pressure. The major component responsible for this change is an acute reduction in plasma viscosity. Reduced vascular tone is also contributive, possibly because of factors such as histamine release, and the initial effect of a large volume of anoxic and cold priming solution on the peripheral vasculature.2 Subsequently, with continuation of hypothermic CPB, the majority of patients respond with a gradual increase in the SVR. The evidence to date suggests that this is because of increased vascular tone, the etiology of which is multifactorial with the sympatho-adrenal and the renin-angiotensin systems being major components.3-7 De Leeuws et al8 reported significant increases in renin and angiotensin levels from before induction of anesthesia until initiation of CPB. During CPB, their levels initially decreased briefly with a subsequent marked increase that continued into the postoperative period.8 Taylor et aL6 using an angiotensinconverting enzyme inhibitor, were able to completely blunt the SVR changes in dogs undergoing CPB. These investigators suggest that the renin-angiotensin system may play a more predominant role than the adrenergic system in SVR changes in the perioperative period. On the other hand, Turton et al9 and Hine et al,” in their investigations, emphasized the role of catecholamines. Elevated norepinephrine levels may be particularly significant in patients who develop hypertension after cardiac surgery. Elevated serotonin and arginine vasopressin levels may also contribute to the increasing SVR associated with CPB.” Although an increased SVR is usually observed following routine cardiac surgery, it has been observed clinically that some patients develop a profoundly low SVR that can be refractory to conventional vasopressor therapy. It has been the authors’ clinical observation that such a low SVR state is most likely to occur in patients who have sustained an extensive perioperative myocardial infarction, have severe peripheral vascular disease, or are septic. Prolonged CPB time seems to be a common denominator for the development of low SVR. Although the pathophysiological basis for the development of low SVR is unknown, models of chronic sepsis have shown that a derangement in the sympathoadre-

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nal system can occur. It has been shown that in chronic sepsis and during shock, a,-adrenergic receptors become down-regulated, leading to diminished vascular responsiveness to norepinephrine.12 There is also a depression of peripheral vascular adrenergic action by endotoxin (lipopolysaccharide [LPS]). Endotoxin-mediated complement activation via the alternative pathway with subsequent anaphylatoxin release is thought to produce some of the hemodynamic sequelae of gram-negative septic shock.i3 Endotoxin levels have been shown to increase significantly during nonpulsatile CPB.14 This endotoxin is thought to originate from the gastrointestinal tract as a consequence of splanchnic stasis and bowel wall ischemia.” This may partly explain the development of a low SVR in some patients during or shortly after CPB. Some patients requiring cardiac surgery may already have a marked stress response as a consequence of myocardial infarction or refractory angina with subsequent elevated plasma catecholamines. Catecholamine levels may become further elevated in response to CPB.3,7 It is possible that in such a situation, catecholamine stores may become depleted and lead to reduced vascular tone in the post-CPB period. Current receptor theory suggests that the cu,-adrenergic receptor is intimately related to a calcium channel in the vascular smooth muscle. Conformational change of the receptor leads to opening of the calcium channel with subsequent influx of calcium ions.12 Increased intracellular calcium leads to activation of actin-myosin fibrils causing contraction of the vascular smooth muscle. Recent work suggests that the activation of a series of second messengers by increased intracellular calcium may be important in the normal function of vascular smooth muscle.16 It is possible that receptor down-regulation or insensitivity may in part be the result of impairment or uncoupling of the receptor from the calcium channel or dysfunction of the second messenger system. Goldberg et al” were able to virtually abolish the vasoconstrictor action of arginine-vasopressin, norepinephrine, and angiotensin II in rats using verapamil and nifedipine. Chernow and RothI reversed hypotension in the adrenergic unresponsive rat endotoxemia model using a calcium channel agonist (BAY K8644). The clinical implications and therapeutic possibilities of this work remain to be demonstrated.

THAKER ET AL

Concomitant drug therapy may also play a role in the development of a low SVR state. This may be the case in patients on the antiarrhythmic agent amiodarone. Lieberman et al’* reported a number of patients taking this drug who developed profound hypotension in association with CPB, proving refractory to conventional vasopressor therapy. Angiotensin-converting enzymeinhibitor therapy with captopril in hypertensive rats diminishes vascular responsiveness to norepinephrine.19 Both cases reported here were being treated with captopril preoperatively. This may have contributed to the development of the low SVR state. Anesthetic techniques using highdose narcotics have been associated with increased fluid and vasopressor requirement.20 Such a technique was used in both cases, and this may also have been a contributing factor. Both cases described here developed low SVR states, and despite aggressive cu-adrenergic therapy continued to have poor vascular tone. Because there was a need for an alternative vasopressor, angiotensin was chosen. Angiotensin II, a naturally occurring octapeptide produced as a result of an enzymatic cascade, is one of the most potent vasoconstrictors known.21 A commercial preparation of angiotensin II (valineS-angiotensin II amide [Hypertensin, Ciba, Summit, NJ]) has been available since 1957. Although there are reports of its use in treatment of shock-like states in the early 196Os, there are no recent reports of its use.22T23In the cases described here, an infusion of 2.5 mg/250 mL of 0.9% saline was titrated to effect. Although angiotensin II produces widespread arteriolar constriction, the exact mechanism of action is unknown. The common mechanism resulting in vascular smooth muscle contraction may be the calcium channel, which is closely associated with the a-adrenergic receptor. It is thought that other vasopressors may act through separate receptors modulating the calcium channel, leading to vascular smooth muscle contraction and increased vascular tone. In summary, the successful use of an angiotensin II infusion in the management of refractory low SVR states in patients undergoing hypothermic CPB is described. It is suggested that in situations in which cu-adrenergic therapy is ineffective, angiotensin may prove to be a valuable alternative.

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