J. P. WEISUL, B.A.,T. F. O’DONNELL, JR., M.D., M. A. STONE, B.A., AND G. H. A. CLOWES, JR., M.D. Department of Surgery, Harvard Medical School, The Sears Laboratory, Boston City Hospital, Boston, Massachusetts 02118 Submitted for publication December 11, 1974.
The circulatory response to extensive infection is characterized by a high cardiac output and low systemic vascular resistance [3, 131.Failure of the cardiovascular system to satisfy the elevated circulatory requirement is associated with a low cardiac output, high systemic vascular resistance, low arterial pressure, lactacidemia, and progressive acidosis leading to death [3, 7, 131. Responsible factors in the development of cardiovascular decompensation include hypovolemia secondary to fluid translocation , increased pulmonary vascular resistance accompanied by right ventricular failure [ 1] and myocardial depression [ 121. The present study reports six patients with a mean arterial pressure of less than 70 mmHg associated with extensive infection in whom hemodynamic measurements were made with a Swan-Ganz catheter . Myocardial performance in the septic shock state and the results of therapy with positive inotropic agents are reported, comparing the effects of isoproterenol and glucose/potassium/insulin. Regardless of cause, the results of the clinical studies to be reported in this paper confirm the presence of severe myocardial dysfunction in the septic shock state. The evidence suggests the myocardial response to an infusion of glucose/potassium/insulin significantly exceeds that produced by isoproterenol, the inotropic Address all correspondence to: Dr. George H. A. Clowes, Department of Surgery, Boston City Hospital, Boston, Massachusetts 02118. This research was supported in part by Grant No. GM-19954-02 from the U.S. Public Health Service. Copyright o 1975by Academic Press, Inc. All rights of reproduction in any form reserved.
agent usually employed in such circumstances. METHODS Six patients admitted to the surgical service of Boston City Hospital with extensive abdominal infection and positive blood or wound cultures whose mean arterial pressure was below 70 mmHg were selected for study (Table 1). Treatment was in no way altered from that being administered by the attending surgeons except for therapeutic measures indicated by the hemodynamic measurements made in the study. A balloon-tipped, flow-directed pulmonary artery catheter was placed according to the technique of Swan and Ganz [ 171permitting measurement of pulmonary artery pressure, pulmonary wedgepressure, central venous pressure, and cardiac output by the thermodilution method . Arterial pressure was recorded through an indwelling cannula in the radial artery. Stroke work index (SWI) was calculated for the left ventricle in gram-meters per beat per m2 by the following formula: SW1 = SVI x (MAP - PWP) x 0.0144 where SVI = stroke volume index, MAP = mean arterial pressure, PWP = pulmonary wedge pressure and 0.0144 is the conversion factor. Right ventricular stroke work index was similarly calculated by employing mean pulmonary artery pressure (MPAP) and central venous pressure (CVP). Systemic vascular resistance index (SVR,) was calculated in dyne-seconds per centimeter per m2 by the following formula: SVR, = (MAP CVP) x SO.O/CI where MAP and CVP are
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TABLE 1 Clinical Information Concerning the Patients Studied in Septic Shock Patient 1 2
67 M Pelvic peritonitis after endarterectomy 71 F Upper GI bleed, subphrenic abscess, pneumonia 62 M Diverticulitis, perforated cecum, peritonitis 27 M Trauma, hepatectomy, peritonitis 48 F Cholangitis, peritonitis 49 M Gastrectomy, preitonitis, subphrenic abscess
Mixed, E. coli predominating
Died 10 days later Respiratory failure
E. coli, Proteus vulgaris
Died 3 days later
Mixed, E. coli predominating
Enterobacter cloacae Mixed, E. coli predominating
Died 13 days later Died 68 days later
as above, CI = cardiac index, and 80.0 is the conversion factor. Pulmonary vascular resistance index (PVR,) was calculated as above with substitution of MPAP and PWP. Three periods in the clinical course of each patient were defined for the present study. The first was the state of septic shock which was not responsive to intravenous administration of normal saline or Ringer’s lactate correcting fluid translocation. These fluids were infused until the central venous pressure increased without a concomitant rise in mean arterial pressure or an increase in cardiac index. The second period included positive inotropic therapy with isoproterenol infused intravenously at a rate of 2-8 pg/kg/ min until no further increase in cardiac index occurred. The third period includes the 6 hr after a lo-min infusion of glucose lg/kg, insulin 1.5 units/kg, and potassium 15 meg. Two patients were studied only during the septic shock period and after infusion of glucose/potassium/insulin. Multiple measurements during each period of study were averaged to assessthe hemodynamic status of the patient. Significance was determined with comparison of paired observations by Student’s t test. RESULTS The course of the patient presented in Fig. 1 is illustrative of the hemodynamic pattern of septic shock as well as the responses to
Acute myocardial infarction
Hepatic failure Respiratory and hepatic failure
isoproterenol and subsequent treatment with glucose/potassium/insulin. The average hemodynamic values for the six patients studied are given in Table 2.
FIG. I. The clinical course of a severely septic patient transferred to the Surgical Service with cholangitis. An exploratory iaporatomy was performed on the 6th day with decompression of the biliary system. Subsequently peritonitis developed with blood cultures positive for Enterobacter cloacae. Swan-Ganz catheterization was performed on the 2nd postoperative day. Isoproterenoi therapy was instituted with an increase in cardiac index. Glucose/potassium/insulin produced a prompt increase in cardiac index and a decrease in ventricular filling pressures. The patient died on the 10th postoperative day of hepatic failure and bleeding secondary to disseminated intravascular coagulation.
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TABLE 2 Hemodynamic Measurements in Septic Shock and the Results of Therapy with Positive Inotropic [email protected]
Septic shock (n = 6)
Isoproterenol. (n =4)
Mean arterial pressure mmHg (normal 85-95)
59.3 f 6.2
Pulmonary wedge pressure mmHg (normal 8-12)
14.6 * 3.6
Mean pulmonary art. pressure mmHg (normal 16-20)
29.0 * 5.8
Central venous pressure mmHg (normal 3-5)
14.8 + 3.7
Cardiac index liters/min/m’
1.52 f .56
73.9 f 10.0 (NV 13.0 + 2.9 (NS) 26.8 * 3.8 (NV 11.5 f 2.1 WS) 3.33 * .51 (P 0.0 5) 126 * 13 (P 0.05) 26.6 + 3.7 (NS) 5.82 f .99 (NS) 23.8 f 5.5 WS) 373 f 57 (P 0.05) 1480 f 260 (P 0.05)
Heart rate beats/min (normal 72-80)
114 f 14
Stroke volume index cc/beat/m2 (normal 30-40)
14.1 f 6.1
ventricular SWI g-m/beat/m2 (normal 8-10)
3.12 f 1.94
Left ventricular SWI g-m/beat/m2 (normal 35-45)
9.46 i 5.12
Pulmonary vascular resistance dyne-se&m/m2 (normal 260-300) Systemic vascular resistance dyne-sec/cm/m2 (normal 1600-2000)
797 -i 242 2640 k 970
Glu/Pot/In (n = 6) 77.3 f 8.0 (P 0.05) 10.1 f 3.4 (P 0.05) 26.3 i 6.5 W-3 7.5 * 2.0 (P 0.01) 5.23 f .55 (P 0.01) 112 f 14 WI 47.1 * 12.9 (P 0.01) 12.1 f 3.5 (P 0.01) 45.3 f 9.6 (P 0.01) 325 f 156 (PO.01) 1120 f 390 (P 0.05)
uP values comparing means after therapy to the septic shock state. NS = no significant difference.
In the period of septic shock, not responto adequate fluid infusion, the patients were hypotensive (MAP = 59.3 f 6.2 min Hg) and cardiac index (1.52 f 56 liter / min/m2) was very low. Mean pulmonary artery pressure, pulmonary wedge pressure, and central venous pressure were all elevated above normal. Stroke volume index (14.1 f 6.1 cc/beat/m2) was very low and both right ventricular stroke work (3.12 + 1.94 g-m/ beat/m2) and left ventricular stroke work (9.46 f 5.12 g-m/beat/m2) were also substantially reduced below normal. Systemic vascular resistance (2640 i 970 dynesec/cm/m2) and pulmonary vascular resistance (797 f 242 dyne-sec/cm/m2) were elevated, particularly the latter. Hemodynamic changes during isoproterenol infusion are also summarized in Table 2 and Figs. 2 and 3. Mean arterial pressure (73.9 f 10.0 mmHg) tended to be higher although the change was not significant. Mean pulmonary artery pressure, pulmonary wedge pressure, and central sive
venous pressure showed little change from the septic shock state. Cardiac index (3.33 + 5 lit/mm/mz) was increased 100% and heart rate (126 f 13) was significantly increased. Stroke volume index (26.6 + 3.7 cc/beat/m2), right ventricular stroke work (5.82 f. .99 g-m/beat/m2) and left ve; tricular stroke work (23.8 f 5.5 g-m/beat/ m2) increased but the change was not significant. Systemic vascular resistance (1480 f 260 dyne-sec/cm/m2) was much reduced as was pulmonary vascular resistance (373 f 57 dyne-sec/cm/m2). During the period after the administration of glucose/potassium/insulin several dramatic changes were apparent (Table 2, Figs. 2 and 3). Mean arterial pressure (77.3 f 8.0 mmHg) was significantly increased although the value was less than expected in normal man. Mean pulmonary artery pressure (26.3 f 6.5 mmHg) showed little change and both pulmonary wedge pressure (10.1 f 3.4 mmHg) and central venous pressure (7.5 & 2.0 mmHg) were significantly reduced.
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01 ILOll 1‘1Pro emI
0: shock ISlV#. C/U/l
0: Shock Isoptl.
FIG. 2. Heniodynamic abnormalities of low-output septic shock and the results of positive inotropic therapy with isoproterenol (Isopro.) and with glucose/ potassium/insulin (G/K/I) are graphically presented. Patients studied in all phases are indicated with a straight line () and the two patients studied only in the shock state and after the administration of glucose/potassium/insulin are indicated with a dotted line (-- ).
Cardiac index (5.23 f 1.55) was remarkably increased to 350% of the septic shock value. Stroke volume index (47.1 =t 12.9 cc/beat/ m2) was increased to values greater than expected in normal man. Both right ventricular stroke work (12.1 =t 3.5 g-m/beat/ m2) and left ventricular stroke work (45.3 f 9.0 g-m/beat/m2) were significantly increased to values exceeding normal man. The systemic vascular resistance (1120 f 390 dyne-sec/cm/m2) was reduced to values below normal, and the pulmonary vascular resistance (325 f 156 dyne-sec/cm/m2) was also significantly reduced. A summary of myocardial performance in the various study periods is presented in Fig. 4. While isoproterenol therapy modestly increased myocardial work at lower filling pressures, attention is drawn to the marked
FIG. 3. Stroke work and vascular resistance in lowoutput septic shock and the results of positive inotropic therapy with isoproterenol (Isopro.) and with glucose/ potassium/insulin (G/K/I). Patients studied in all phases are indicated with a straight line () and the two patients studied only in the shock state and after the administration of glucose/potassium/insulin are indicated with a dotted line (-----).
increase in both right and left ventricular stroke work after the administration of glucose/potassium/insulin. It is also of importance to note that none of the patients died in the septic shock state after the administration of glucose/potassium/insulin (Table 1). All four deaths occurred more than 3 days later as a result of other causes. DISCUSSION Two circulatory patterns exist in severe sepsis. The appropriate cardiovascular response leading to recovery consists of an elevated cardiac index, low systemic vascular resistance, and adequate perfusion as indicated by a normal or slightly elevated pH, low levels of blood lactate, and maintenance of urinary output [3, 131.Failure to maintain an elevated cardiac index defines low-output septic shock and is secondarily associated with high systemic vascular resistance, evidence of inadequate perfusion, and a mortality over 75% if prolonged for 24 hr or more [13, 16, 181.The present study
WEISUL ET AL.: MYOCARDIAL
FIG. 4. Ventricular performance in septic shock. Stroke work index vs ventricular filling pressure is shown for septic shock not responsive to fluid administration (o), during isoproterenol infusion (0) and after the administration of glucose/potassium/insulin (A). Attention is drawn to the marked increase in stroke work at lower ventricular filling pressures after glucose/potassium/insulin.
ventricular stroke work index less than 25% of normal. The systemic vascular resistance was elevated in response to the left ventricular dysfunction and inadequate cardiac output. This contrasts with the low systemic vascular resistance expected when the appropriate high-output cardiovascular response to severe infection is present [7, 131. Right ventricular performance was even more severely depressed. In the shock state central venous pressure was elevated 200% while mean pulmonary artery pressure was only slightly increased. Right ventricular stroke work was calculated to be 25% of normal entirely insufficient for the increased circulatory requirement of sepsis. The elevated central venous pressure provides evidence that right ventricular dysfunction predominates in septic shock. Increased pulmonary vascular resistance is known to accompany the pulmonary abnormalities of sepsis, and is again observed in our patients
Since severe hypovolemia, commonly associated with septic shock , was’not a factor in these patients an elevation of pulmonary vascular resistance and myocardial failure remain to be considered. Pulmonary changes including capillary further describes the hemodynamic abnor- congestion and interstitial edema accommalities associated with low-output septic pany increased pulmonary vascular resistance in septic shock [I, 81. Right venshock. The cardiac index in the patients during tricular failure secondary to the pulmonary low-output septic shock was remarkably changes may explain the cardiovascular reduced to approximately 30% of the ex- decompensation of low-output septic shock. pected normal value. This low value is even The patients demonstrate severe right-heart more dramatic in view of the elevated circu- failure consistent with this mechanism. latory requirement of sepsis. Mean arterial However, biventricular dysfunction is noted pressure was seento be low while pulmonary indicating depression of both sides of the wedge pressure was slightly elevated. The heart and not isolated right-heart failure. reflection of left atria1 pressure and subse- While right ventricular failure predominates quent left ventricular filling pressure by in septic shock, it is insufficient to explain the pulmonary wedge pressure has been ade- myocardial depression observed. quately demonstrated. Left ventricular dysA circulatory factor with a direct function is illustrated in the patients pre- depressive action on the myocardium has sented by the requirement of an elevated been postulated  although its existence filling pressure to produce a low mean has been disputed [lo]. The biventricular arterial pressure and by the calculated left dysfunction observed in this study is consis-
tent with myocardial depression. However, the precise mechanism of myocardial depression remains obscure. Several interesting hemodynamic changes occur with the administration of isoproterenol. Heart rate is increased reflecting the positive chronotropic effect of the drug. Cardiac index is increased 100%. So too is the stroke volume index indicating the positive inotropic effect of isoproterenol. Both systemic and pulmonary vascular resistance are significantly decreased secondary to increased perfusion. However, insignificant increases in right and left ventricular stroke work were present. Failure of isoproterenol to return stroke work to normal and continuing elevated ventricular filling pressures indicate that ventricular dysfunction was not corrected. This phenomenon is clearly demonstrated for both ventricles in Fig. 4. The stroke work remained low and filling pressure remained elevated. Although the physiologic basis for the decreased response to isoproterenol in low-output septic shock is not entirely clear, it is of interest to note that low-output septic shock is associated with high levels of circulatory catecholamines  and the addition of further ,&stimulation may not be appropriate. Remarkable hemodynamic changes are observed after the infusion of glucose/potassium/insulin. Mean arterial pressure was significantly increased and cardiac index was increased 3.5fold over the shock state and 80% over the values observed during isoproterenol infusion. The dramatic inotropic effect is observed in stroke volume index and right and left ventricular stroke work which are all elevated to values greater than expected for normal man. As seen in Fig. 4 there is a substantial improvement of both right and left ventricular performance at lower filling pressures. Pulmonary vascular resistance is significantly reduced, although remaining slightly elevated consistent with the pulmonary abnormalities of sepsis. Systemic vascular resistance is reduced to the low levels expected in com-
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pensated high output sepsis. It is again emphasized that none of the patients treated with glucose/potassium/insulin died in the septic shock state (Table 1). The precise mechanism of action of glucose/potassium/insulin is unknown. Glucose/potassium/insulin is believed to reduce mortality after myocardial infarction [ 151 and to protect the hypoxic myocardium . Anoxia produces myocardial loss of potassium and gain of sodium leading to loss of transmembrane action potential and myocardial contractility [ 11, 181.Failure to maintain transmembrane potential has been related to changes in the metabolism of energy production . A similar mechanism may be present in the septic shock state in which the metabolism of the myocardium itself may be altered in a fashion similar to that demonstrated in other tissues . SUMMARY Six patients with low-output septic shock were studied with Swan-Ganz pulmonary artery catheterization. The results indicate severe biventricular dysfunction. Inotropic therapy with isoproterenol produced improved ventricular performance but did not correct myocardial depression. Infusion of glucose/potassium/insulin dramatically improved myocardial performance and appeared to correct the myocardial abnormalities of low-output septic shock. REFERENCES Clowes, G. H. A., Jr., Farrington, G. H., Zuschneid, W. Circulating factors in the etiology of pulmonary insufficiency and right heart failure accompanying severe sepsis (peritonitis). Ann. Surg. 171:663, 1970 Clowes, G. H. A., Jr., O’Donnell, T. F., Jr., Ryan, N. T., and Blackburn, G. L. Energy metabolism in sepsis: Treatment based on different patterns in shock and high output stage. A&. Surg. 179:684, 1974. Clowes, G. H. A., Jr., Vucinic, M., and Weidner, M. G. Circulatory and metabolic alteration associated with survival or death in peritonitis. Ann. Surg. 163:866, 1966. Cope, O., Hopkirk, J. F., and Wight, A. Derangements imperiling the perforated ulcer patient. The
WEISUL ET AL.: MYOCARDIAL dehydration and fluid shifts. Arch. Surg. 71:669, 1965. 5. Forrester, J. S., Ganz, W., Diamond, G., et al. Thermodilution cardiac output determination with a single flow-directed catheter. Am Heart J. 83:306, 1972. 6. Groves, A. C., Griffiths, J., and Meek, R. N. Plasma catecholamines in patients with serious postoperative infection. Ann. Surg. 178:102, 1973. 7. Gunnar, R. M., Loeb, H. S., Winslow, E. J., et al. Hemodynamic measurements in bacteremia and septic shock in man. J. In&f. Dis. 128:S295, 1973. 8. Harrison, L. H., Hinshaw, L. B., Coalson, J. J., and Greenfield, L. J. Effects of E. co/i septic shock on pulmonary hemodynamics and capillary permeability. J. Thorac. Cardiovus. Surg., 61:795, 1971. 9. Henry, P. D., Sobel, B. E., and Braunwald, E. Protection of hypoxic guinea pig hearts with glucose and insulin. Am. J. Physiol. 226:309, 1974. 10. Hinshaw, L. B., Archer, L. T., Greenfield, L. J., and Guenter, C. A. Effects of endotoxin on myocardial hemodynamics, performance, and metabolism. Am. J. Physiol. 221:504, 1971. 11. Hunter, E. G., McDonald, T. F., and MacLeod, D. P. Metabolic depression and myocardial potassium. Pflugers Arch., 335:226, 1972. 12. Lefer, A. M. Blood-borne humoral factors in the
pathophysiology of circulatory shock. Circ. Rex 32:129, 1973. 13. MacLean, L. D., Mulligan, W. G., McLean, A. P. H., and Duff, J. M. Patterns of septic shock in man-A detailed study of 56 patients. Ann. Surg. 166:543, 1967. 14. MacLeod, D. P., and Prasad, K. Influence of glucose on the transmembrane action potential of papillary muscle. J. Gen. Physiol. 53:792, 1969. 15. Mittra, B. Potassium, glucose and insulin in the treatment of myocardial infarction. Lance? 2:607, 1965. 16. Shoemaker, W. C., Montgomery, E. S., Kaplan, E., and Elwyn, D. N. Physiologic patterns in surviving and non-surviving shock patients. Arch. Surg. 106:630, 1973. 17. Swan, H. J. C., Ganz, W., Forrester, J. Catheterization of the heart with use of a flow-directed balloon-tipped catheter. N. Engl. J. Med 283:447, 1970. 18. Weissler, A. M., Altschuld, R. A., Gibb, L. E. Effect of insulin on the performance and metabolism of the anoxic isolated performance and metabolism of the anoxic isolated perfused rat heart. Circ. Res. 32:108, 1973. 19. Wilson, R. F., Thal, A. P., Kindling, P. M., Hemodynamic measurements in septic shock. Arch. Surg. 91:121, 1965.