P&S Medical Review: August 1996, Vol.3, No.2
Vasopressin Deficiency and Hypersensitivity in Vasodilatory Shock - discovery of a new clinical syndrome

Donald W. Landry, MD, PhD

Introduction

Septic shock is a syndrome of cardiovascular collapse and multiple organ failure that afflicts 500,000 in the U.S. each year. The hallmark of septic shock is hypotension due to systemic vasodilation¹ and, in many instances, vasopressor agents must be used to maintain arterial pressure. Norepinephrine can be an effective^2,3 pressor but its action is frequently diminished in sepsis^3,4. The mortality from persistent hypotension in sepsis remains high and alternative treatments could be useful.

The mechanisms responsible for vasodilation in sepsis are the subject of intense investigation and remain to be fully elucidated. An obvious possibility is that one or more of the normal vasodilatory mechanisms are pathologically activated. In fact, we and others have shown that the hypotension of sepsis is mediated in part by the inappropriate release of endothelium-derived relaxing factor⁵ and the opening of vascular ATP-sensitive potassium channels⁶. The possibility that countervailing vasoconstrictor mechanisms might be defective in sepsis has not been well studied.

Our incidental observation of a marked pressor response to exogenous vasopressin in a patient with vasodilatory septic shock led us to examine the role of vasopressin in the hypotension of sepsis. We have discovered that baroreflex-mediated vasopressin secretion is defective in septic shock and that this defect contributes to the hypotension of sepsis⁷.

A review of the physiology of vasopressin secretion and the description of two case reports of patients with vasodilatory septic shock will illustrate the salient features of this hormone deficiency syndrome. One report describes our first observation of a marked pressor response to vasopressin in sepsis. The other describes our first observation of hypersensitivity to the pressor action of vasopressin in sepsis.

Vasopressin as the antidiuretic hormone (ADH)

Arginine vasopressin (AVP) is released from the neurohypophysis in response to plasma osmolality above a set point (Figure 1a). Just a few percent increase above this point results in a plasma AVP concentration of > 5 pg/ml. AVP binds at the kidney to the V₂-receptors of the collecting duct and thereby effects insertion of water channels into the luminal membrane. A vasopressin concentration of only 5 rg/ml is sufficient to maximally concentrate the urine (Figure 1b).

Vasopressin is also secreted in response to baroreflex stimuli. The release of vasopressin, despite plasma osmolality below the normal set point, is the major cause of hyponatremia in states of arterial underfilling. The plasma concentrations of vasopressin in the setting of volume depletion or arterial hypotension ranges over an order of magnitude higher than those associated with osmotic stimuli (Figure 1c, note the log-scale).

Vasopressin as a vasoconstrictor

Vasopressin also binds to V₁-receptors of vascular smooth muscle and courses potent vasocontriction in vivo. However, vasopressin is a most intriguing vasopressor hormone in vivo because it has little pressor activity in hemodynamically normal subjects^9-11. Similarly, patients with the syndrome of inappropriate antidiuretic hormone (SIADH) are not predisposed to hypertension¹². However, vasopressin antagonists cause marked hypotension in subjects with arterial underfilling and thus the vasoconstrictor action of vasopressin becomes important when intravascular volume or arterial pressure decreases^13-15. Nonetheless, administration of vasopressin to hypotensive or volume depleted subjects does not result in a marked pressor response, perhaps because V₁-receptors on vascular smooth muscle are already occupied by endogenous hormone released by the same baroreflex¹⁶.

Heretofore, the therapeutic administration of vasopressin as a vasoconstrictor was indicated only for hemostasis of bleeding esophageal varices in cirrhotic patients¹⁷. A continuous infusion of 0.4 U/min is typically administered and at this dose the plasma vasopressin concentration rises to supra-physiologic levels (> 500 rg/ml)¹⁸. However, the systolic arterial pressure of a cirrhotic patient generally rises only by 10 mmHg.

Case 1. Vasopressin pressor sensitivity despite catecholamine resistance

A er year old woman with a history of alcoholic cirrhosis and esophageal variceal bleeding presented with an upper gastrointestinal hemorrhage. Vasopressin was administered at 0.4 U/min upon admission and hemostasis was achieved. On HD 3, I evaluated the patient for oligoanuria in the setting of fever with leukocytosis and hypotension requiring norepinephrine. The patient's cardiac output was increased and this clinical constellation was consistent with vasodilatory septic shock (decompensated cirrhosis can give a similar hemodynamic picture).

A review of the ICU record (Figure 2a) showed that blood pressure had abruptly declined from 160 to 80 mmHg within a few minutes of a discontinuation of vasopressin on HD 2. The rapid response to withdrawal of vasopressin was consistent with its short t_1/2 (5 minutes) in plasma¹⁹. Administration of norepinephrine at doses up to 18 mg/min increased systolic arterial pressure only to ~ 95 mmHg.

The patient was returned to vasopressin at 0.4 U/min and, as shown in Figure 2b, arterial pressure increased and norepinephrine could be discontinued within 45 minutes with systolic arterial pressure maintained >120 mmHg.

Conclusions from case 1: This apparently septic patient displayed uncommon vasopressin pressor sensitivity despite catecholamine resistance. Resistance to the pressor effect of catecholamines in the setting of septic shock is well known^3,4 but this response to vasopressin in a septic patient was without precedent.

Case 2. Vasopressin hypersensitivity in septic shock

A 53 year old man presented with intractable ventricular arrhythmias and as a bridge to cardiac transplantation, right and left ventricular assist devices were placed. Over several days the patient developed fever, leukocytosis and hypotension requiring catecholamine pressors. Ventricular flows were good and the clinical impression was vasodilatory septic shock (blood cultures were eventually positive for acinetobacter cloacii).

As shown in Figure 3, during hours 0-4, arterial pressure was decreased and norepinephrine (6.4 mg/min) and epinephrine (5.0 mg/min) were administered to maintain a systolic arterial pressure (SAP) at ~ 90 mmHg. In collaboration with Drs. Howard Levin of Circulatory Physiology and Mehmet Oz of Cardiothoracic Surgery, intravenous vasopressin was started at 0.04 U/min and an immediate pressor response was noted (hour 5) while cardiac output remained stable. Because of the increase in SAP, norepinephrine and epinephrine were discontinued (hour 6). Vasopressin administration was associated with an increase in urine output from 6 cc/h to > 50 cc/h. Step-wise withdrawal of vasopressin resulted in a decrease in arterial pressure which again required norepinephrine (8.0 mg/min) to maintain SAP at 90-100 mmHg (Fig. 1, 7.5 to 14 hours). Moreover, urinary output fell to 30 cc/h. Readministration of vasopressin (hour 15) again caused a pressor response which allowed discontinuation of norepinephrine (hour 17); six hours later, the SAP was maintained ~ 105 mmHg on vasopressin alone. Urine output stabilized at > 50 cc/h.

Vasopressin infusion was tapered over the next day to ~ 0.02 U/min. As shown in Figure 4, discontinuation of the hormone resulted in hypotension but arterial pressure recovered with resumption of the infusion at 0.01 U/min.

Conclusions from case 2: This patient's response to vasopressin demonstrated several interesting characteristics. First, vasopressin and catecholamines administered together provided a more potent pressor action than either alone. This observation is consistent with their synergy in constricting of vascular smooth muscle in vitro^20,21. Second, vasopressin administered alone was an adequate pressor, in this case maintaining arterial pressure between 100-110 mmHg.

Third, urine flow rates increased significantly during the administration of vasopressin, perhaps due to improved renal perfusion as arterial pressure increased. However, increased pressure with catecholamines rarely increases urine output because the glomerular afferent arteriole is constricted and filtration falls^22. In contrast, vasopressin constricts only the glomerular efferent arteriole²³, thus maintaining glomerular filtration rate¹¹ despite a decrease in renal blood flow.

This favorable vascular selectivity pattern may account for the increased urine output with vasopressin in sepsis.

Finally, this patient unexpectedly responded to a continuous vasopressin infusion of only 0.04 U/min - one-tenth that administered to cirrhotics. This dose was intended to be subtherapeutic and a starting point for titration. Clearly, the patient manifested extraordinary vasopressin hypersensitivity.

We have observed similar responses to low dose vasopressin in over 10 septic patients, nearly half of whom no longer required catecholamine pressors. In every patient, arterial pressure rose as a consequence of increased systemic vascular resistance; cardiac output showed a small though significant decline.

Vasopressin deficiency in septic shock

The hypersensitivity of septic patients to the pressor action of vasopressin suggested the possibility of vasopressin deficiency. First consider that an infusion of 0.01 U/min would be expected to provide a plasma vasopressin concentration of only 25-30 pg/ml¹⁸. If plasma vasopressin concentrations were appropriately elevated in sepsis by baroreflex mechanisms, then occupancy of vascular smooth muscle V₁-receptors in these patients would be little changed and a marked pressor response to exogenous hormone would be unlikely. Second, hypersensitivity to exogenous hormone has been observed only in primary autonomic failure and baroreceptor deafferentation^24-26 - conditions notable for a defect in baroreflex-mediated vasopressin secretion.

Thus, we measured plasma vasopressin in a series of patients with vasodilatory septic shock requiring catecholamine pressors. The vasopressin concentration of 15 septic patients averaged 3 pg/ml, inappropriately low for the setting of shock. In contrast, a control population composed of patients with cardiogenic shock requiring catecholamine pressors showed an average plasma vasopressin of 20 pg/ml. A relative deficiency of vasopressin in sepsis appears to exacerbate the hypotension of sepsis since replacement of vasopressin to physiologically appropriate levels significantly restores vascular tone and arterial pressure.

Future directions:

Several questions arise from these observations and are the subjects of ongoing investigations.

First, what is the natural history of vasopressin deficiency in septic shock in man? Plasma vasopressin levels initially rise markedly and then decline in animals treated with endotoxin^27-29 - is this the pattern for plasma vasopressin concentrations in early septic shock in man? What is the temporal pattern for other vasoconstrictor and vasodilator hormones?

Second, what are the clinical implications of vasopressin replacement therapy in sepsis? Vasopressin replacement diminishes or eliminates the need for catecholamine pressors in many patients with septic shock - do reduced catecholamine requirements alter the morbidity and mortality of the septic shock syndrome? Is responsiveness to vasopressin a general characteristic of patients with septic shock or does responsiveness vary with the plasma concentration of the endogenous hormone or with other factors?

Third, why is baroreflex-mediated secretion of vasopressin deficient in sepsis? Endotoxin is a most potent secretogogue²⁷ and intense secretory stimuli have been shown to deplete the hypothalamus and neurohypophysis of vasopressin^30-32 - is depletion of glandular stores the mechanism for vasopressin deficiency in sepsis? Alternatively, sympathetic function appears to be impaired in septic shock³³ - could autonomic failure explain our finding?.

Beyond sepsis

Preliminary data from a small series of patients studied by Dr. Oz suggests that the vasodilatory shock noted after prolonged cardiopulmonary bypass is also highly responsive to vasopressin. A double-blinded placebo-controlled trial is now in progress to investigate this phenomenon. Similarly, the vasodilatory state noted after prolonged hemorrhagic shock (so-called irreversible shock) also proved to be highly vasopressin responsive in one patient. In each of these clinical situations, the baroreflex stimulus for vasopressin secretion is extreme and animal studies are underway to investigate the possibility of depletion of glandular stores.

Conclusion

We have discovered that a relative deficiency of vasopressin secretion to baroreflex stimuli contributes to the hypotension of sepsis and perhaps other conditions of vasodilatory shock. The pathophysiologic bases and therapeutic implications of these observations are subjects of ongoing investigation.

References

1. Parrillo JE, Parker MM, Natanson C, Suffredini AF, Danner RL, Cunnion RE, Ognibene FP. Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med 1990;113:227-42.

2. Desjars P, Pinaud M, Potel G, Tasseau F, Touze M-D. A reppraisal of norepinephrine therapy in human septic shock. Crit Care Med 1987; 15:134-37.

3. Meadows D, Edwars JD, Wilkins RG, Nightingale P. Reversal of intractable septic shock with norepinephrine therapy. Crit Care Med 1988; 16:663-66.

4. Chernow B, Roth BL. Pharmacologic manipulation of the peripheral vasculature in shock: Clinical and experimental approaches. Circ Shock 1986; 18:141-55.

5. Kilborne RG, Gross SS, Jurbran A, Adams J, Griffith OW, Levi R, Lodatao RF. N^G-methyl-L-arginine inhibits tumor necrosis factor-induced hypotension; implications for the involvement of nitric oxide. Proc Natl Acad Sci 1990;87:3629-32.

6. Landry DW, Oliver JA. The ATP-sensitive K⁺channel mediates hypotension in endotoxemia and hypoxic lactic acidosis in dog. J Clin Invest 1992;89:2071-74.

7. Landry DW, Levin HR, Gallant EM, Ashton RC Jr, Seo S, D'Alessandro DA, Oz MC and Oliver JA. Vasopressin Deficiency in Vasodilatory Septic Shock. Lancet in press.

8. Rose

9. Grollman A, Geiling EMK. The cardiovascular and metabolic reactions of man to the intramuscular injection of posterior pituitary liquid (Pituitrin), Pitressin and Pitocin. J Pharmacol & Exper Therap 1932; 46:447-60.

10. Graybiel A, Glendy RE. Circulatory effects following the intravenous administration of Pitressin in normal persons and in patients with hypertension and angina pectoris. Am Heart J 1941;21:481-89.

11. Wagner HN Jr, Braunwald E. The pressor effect of the antidiuretic principle of the posterior pituitary in orthostatic hypotension. J Clin Invest 1956;35:1412-418.

12. Padfield PL, Brown JJ, Lever, AF, Morton JJ, Robertson JIS. Blood pressure in acute and chronic vasopressin excess. New Eng. J. Med. 1981; 304:1067-70.

13. Aisenbrey GA, Handelman WA, Arnold P, Manning M, Schrier RW. Vascular effects of arginine vasopressin during fluid deprivation in the rat. J Clin Invest 1981;67:961-68.

14. Schwartz J, Reid IA. Effect of vasopressin blockade on blood pressure regulation during hemorrhage in conscious dogs. Endocrinology 1981;108(5):1778-80.

15. Schwartz J, Keil LC, Maselli J, Reid IA. Role of vasopressin in blood pressure regulation during adrenal insufficiency. Endocrinology 1983; 112(1):234-8.

16. CHF

17. Cirrhosis

18. levels

19. t 1/2 vasop.

20. Bartelstone HJ, Nasmyth PA. Vasopressin potentiation of catecholamine actions in dog, rat, cat, and rat aortic strip. Am J Physiol 1965; 208:754-62.

21. Patel KP, Schmid PG. Vasopressin inhibits sympathetic ganglionic transmission but potentiates sympathetic neuroeffector responses in hindlimb vasculature of rabbits. J Pharmacol & Exper Therap 1988; 245:779-85.

22. Edwards RM. Segmental effects of norepinephrine and angiotensin II on isolated renal microvessels. Am J Physiol 1983;244:F526-34.

23. Edwards RM, Trizna W, Kinter LB. Renal microvascular effects of vasopressin and vasopressin antagonist. Am J Physiol 1989;256:F274-78.

24. Wagner HN Jr, Braunwald E. The pressor effect of the antidiuretic principle of the posterior pituitary in orthostatic hypotension. J Clin Invest 1956;35:1412-418.

25. Mohring J, Glanzer K, Maciel Jr, JA, Dusing R, Kramer HJ, Arbogast R, Koch-Weser J. Greatly enhanced pressor responde to antidiuretic hormone in patients with impaired cardiovascular reflexes due to idiopathic orthostatic hypotension. J Cardiovasc Pharm 1980;2:367-76.

26. Montani J-P, Liard J-F, Schoun J, Mohring J. Hemodynamic effects of exogenous and endogenous vasopressin at low plasma concentrations in conscious dogs. Circ Res 1980;47:346-55.

27. Wilson MF, Brackett DJ, Hinshaw LB, Tompkins P, Archer LT, Benjamin BA. Vasopressin release during sepsis and septic shock in baboons and dogs. Surgery Gynecology & Obstetrics 1981;153:869-72.

28. Wilson MF, Brackett DJ, Tompkins P, Benjamin B, Archer LT, Hinshaw LB. Elevated plasma vasopressin concentrations during endotoxin and E. coli shock. Adv Shock Res 1981;6:15-26.

29. Brackett DJ, Schaefer CF, Tompkins P, Fagraeus L, Peters LJ, Wilson MF. Evaluation of cardiac output, total peripheral vascular resistance, and plasma concentrations of vasopressin in the conscious, unrestrained rat during endotoxemia. Circ Shock 1985;17:273-84.

30. Cooke, CR, Wall, BM, Jones GV, Presley DN, Share L. Reversible vasopressin deficiency in severe hypernatremia. Am J Kidney Diseases 1993;22(1):44-52.

31. Negro-Vilar A, Samson WK. Dehydration-induced changes in immunoreactive vasopressin levels in specific hypothalamic structures. Brain Research 1979;169:585-89.

32. Jones CW, Pickering BT. Comparison of the effects of water deprivation and sodium chloride imbibition on the hormone content of the neurohypophysis of the rat. J. Physiol 1969;203:449-58.

33. Garrard CS, Kontoyannis DA, Piepoli M. Spectral analysis of heart rate variability in the sepsis syndrome. Clin Autonomic Res 1993;3:5-13.