JOURNAL

OF SURGICAL

Vasodilator

25, 180-183 (1978)

RESEARCH

Therapy

in Clinical

FRANK B. CERRA, M.D., Department

Sepsis with Low Output

JAMES HASSETT,

M.D.,

AND

JOHN

H.

of Surgery, State University of New York at Buffalo, and the Bufialo 100 High Street, Buffalo, New York 14203

Syndrome1

SIEGEL,

M.D.

General Hospital;

Submitted for publication November 7, 1977

Vasoactive nitrate compounds have been employed clinically for many years. Their more recent applications have been in critically ill man with cardiogenic states resulting from myocardial infarction, intractable congestive heart failure, or hypertensive crisis [3]. The physiologic response patterns in patients with gram-negative sepsis and septic shock have been characterized. With severe sepsis, a physiologic response state characterized by high cardiac output (CO), low total peripheral resistance (TPR), narrowed arteriovenous oxygen saturation difference (A-VOz), and low oxygen consumption is frequently found. The physiologic treatment of this state usually consists of maximized volume expansion and inotropic support [5]. In spite of this therapy, some patients develop myocardial depression and proceed into a severe cardiogenic state that carries a very high mortality. The present report is a prospective evaluation of the application of vasodilator therapy to such a group of patients. MATERIALS

AND METHODS

Eight patients, 45 to 65 years old, presented to the surgical intensive care unit with gram-negative septicemia and septic shock. The sources of sepsis were identified as acute small bowel fistulas [3], colonic perforations [2], duodenal stump blowout [ 11, and biliary tract sepsis [2]. They all received volume resuscitation with colloid and 1 Supported by Grant HL 15676 from the National Heart and Lung Institute. 0022-4804/78/0252-0180$01.00/0 Copyright 0 1978 by Academic F’ress, Inc. All rights of reproduction in any form reserved.

crystalloid; antibiotics (clindamycin-aminoglycoside or chloromycetin-aminoglycoside); respiratory support; methylprednisolone (30 mg/kg) as a single bolus; and appropriate surgical intervention. Longitudinal physiologic assessment consisted of intraluminal arterial pressure, right atria1 pressure (RAP), pulmonary capillary wedge pressure (PCWP), urine output, and computerized analysis of cardiogreen dye dilution curves and physiologic state classification [5]. All eight patients initially demonstrated a high cardiac output (9 liters/min), low total peripheral resistence (~800 dyne-cm x lo+), narrowed arteriovenous oxygen saturation difference ((3 .O vol%), and a low oxygen consumption index (< 125 ml/m*). They then progressed into a cardiogenic state. None of the eight patients had acute renal failure or electrocardiographic evidence of acute myocardial infarction. All had maximized volume expansion as judged by RAP, PCWP, and cardiogreen dye dilution analysis; were on digoxin (0.125 to 0.25 mg/day); and were receiving isoproterenol (0.5 to 1.0 pg/min) and dopamine (4 to 10 pglkglmin). In spite of this regimen, the cardiogenic state persisted (Table 1). Cardiac index fell to < 1.5 liters/min/m*; TPR rose to >3000 dyne-cm x 10m5;oxygen consumption index fell to (100 m1/m2; RAP increased to >l 1 mm Hg; and a state of marked myocardial contractility depression developed with tm >lO sec. The tm value is an index of contractility derived from the cardiogreen dye dilution curve [5]. Nitroglycerine paste was then topically applied (12 to 18 mg = 0.5 to

180

CERRA, HASSETT, AND SIEGEL: VASODILATOR

181

THERAPY

TABLE 1 PHYSIOLOGIC INDEXESBEFOREANDAFTERNITROGLYCERINEPASTE

Index RAP (mm Hg) CI (liters/min m2) tm (set) TPR (dyne-cm x 10m5) A-VO, (~01%) O2 consumption (ml/m*)

Pre-N-P 11 k 1.27 t 17 ” 3773 2 7.4 k 91 2

Post-N-P

3.0 0.31 9.7 916 2.1 14

5.7 k 2.5 * 8.8 2 1507 k 5.0 f 114 +

I.7 1.0 6.3 322 1.0 23

(N-P) P

0.05 0.01 0.05 0.01 0.02 0.02

n Cardiac mixing time, an index of contractility [5].

1.5 in., q.4.h.) Complete physiologic assessment was performed 3 hr after initial application and the dosage was readjusted until the maximum effect was obtained. RESULTS

All eight patients had a significant physiologic response, summarized in Table 1 (with the P values for the paired t statistics,) and in Fig. 1. Total peripheral resistence fell 63%; RAP fell 40%; cardiac index increased 100%; the oxygen consumption index rose 30%; and there was a significant improvement in contractility as reflected by the tm value. One patient with a colonic perforation expired after an acute myocardial infarction during the nitroglycerine paste therapy. The seven other patients all survived the initial septic insult. Two other patients subsequently expired, one 4 weeks later from pneumonia and one 3 weeks later from recurrent sepsis. Five of the eight patients (63%) left the hospital and are currently doing well. DISCUSSION

Five of eight surgical patients with gramnegative sepsis and a low output state that was refractory to volume expansion and inotropic support were successfully managed with the addition of nitroglycerine paste to the treatment regimen. One complication, that of acute myocardial infarction, occurred during the paste application. Although nitrates have been used for

many years for their circulatory effects, their precise mechanisms of action continue to be debated and investigated. Studies on patients with a normal cardiovascular status indicate a profound effect on venous compliance with pooling of the vascular volume in the venous circuit [2,6,7]. Investigations in patients with hypertensive crisis or myocardial infarction shock with elevated PCWP indicate a primary effect on afterload by a reduction in total peripheral resistence [3]. The documented changes in cardiac output following nitrate administration are variable and seem to be dependent on the existing valve status, preload (RAP or PCWP), afterload (TPR), and contractility status and reserve of the myocardium [l, 2, 4, 71. The application of nitrate compounds to clinical sepsis is a new application. The patients under study all progressed from a high cardiac output, low TPR status to a low CO, high TPR status with severe myocardial contractility depression and a marked reduction in oxygen consumption. Preload was maximized by volume expansion; contractility was supported with inotropic agents. Nitroglycerine paste was then applied. Its primary mode of action in that setting was an afterload reduction (decreased TPR). Coincident with this was a need for more volume expansion. In spite of these maneuvers, there was also a significant fall in RAP. This phenomenon would seem to imply that an effect on venous capacitance was also occurring. The net result was a marked improvement in cardiac output and oxygen

182

JOURNAL

OF SURGICAL

RESEARCH:

VOL. 25, NO. 2. AUGUST

1978

Cl Lhnin/m*

tm

me

Pz.01

PZ.05

FIG. 1. Physiologic changes following nitroglycerine paste application (12 to 18 mg = 0.5 to 1.5 in., q.4.h.) in clinical sepsis with the low output syndrome that is refractory to volume expansion and inotropic support.

CERRA, HASSETT, AND SIEGEL: VASODILATOR

consumption and an absolute salvage rate of 63%. Because of the profound effect on TPR, appropriate monitoring, such as with PCWP and cardiac output determinations, is an essential and integral part of the management regimen. In the setting of an acute care unit, vasodilator therapy is an accepted and effective method of managing hypertensive crisis, myocardial infarction shock, and refractory congestive heart failure. The results obtained in gram-negative septicemia that progresses into a cardiogenic physiologic response indicate that vasodilator therapy is a very useful adjuvant in the management of this often catastrophic situation. SUMMARY

Eight patients presented with gram-negative speticemia and septic shock. After appropriate medical and surgical therapy, they underwent a transition from a high cardiac output, low TPR state into a low cardiac, high TPR state with a significant fall in oxygen consumption. This state was refractory to maximized volume expansion and inotropic support. Vasodilator therapy with nitroglycerine paste was initiated along with intense, longitudinal physiologic assessment. All patients had a significant fall in TPR, rise in cardiac output, improvement in contractility,

THERAPY

183

and increase in oxygen consumption. Five of the eight patients survived. Vasodilator therapy with nitroglycerine paste is an effective mode of treating the often catastrophic complication of myocardial decompensation in gram-negative septic shock. REFERENCES 1. Bernstein, L., Friesinger, G. C., Lichtlen, P. R., and Ross, R. S. The effect of nitroglycerine on the systemic and coronary circulation in man and dogs. Circulation 33: 107, 1966. 2. Ferrer, M. I., Bradley, S. E., Wheeler, H. O., Enson, Y., Preisig, R., Brickner, P. W., Conroy, R. J., and Harvey, R. M. Some effects of nitroglycerine upon the splancanic pulmonary and systemic circulations. Circulation 33: 357, 1966. 3. Forrester, J. S., da Luz, P. L., and Chatterjee, K. Peripheral vasodilators in low cardiac output states. Sup. C/in. North Amer. 55: 542, 1975. 4. Rowe, G. C., Chelius, C. J., Afonso, S., Gurtner, H. P., and Crumpton, C. W. Systemic and coronary hemodynamic effects of erythrol tetranitrate. J. Clin. Invest. 40: 1217, 1961. 5. Siegel, J. H., Goldwyn, R. M., and Friedman, H. P. Patterns and process in the evolution of human septic shock. Surgery 70: 232, 1971. 6. Wegira, R., Nickerson, T. L., Case, R. B., and Holland, J. F. Effect of nitroglycerine on the cardiovascular system of normal persons. Amer. J. Med. 10: 414, 1951.

7. Williams, J. F., Glick, G., and Braunwald, E. Studies on cardiac dimensions in intact unanesthetized man. Circulation 32: 767, 1965.

Vasodilator therapy in clinical sepsis with low output syndrome.

JOURNAL OF SURGICAL Vasodilator 25, 180-183 (1978) RESEARCH Therapy in Clinical FRANK B. CERRA, M.D., Department Sepsis with Low Output JAMES...
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