Physiology of Vasopressin Relevant to Management of Septic Shock

doi:10.1378/chest.120.3.989

Chest

Volume 120, Issue 3, September 2001, Pages 989-1002

https://doi.org/10.1378/chest.120.3.989 Get rights and content

Abstract

Vasopressin is emerging as a rational therapy for the hemodynamic support of septic shock and vasodilatory shock due to systemic inflammatory response syndrome. The goal of this review is to understand the physiology of vasopressin relevant to septic shock in order to maximize its safety and efficacy in clinical trials and in subsequent therapeutic use. Vasopressin is both a vasopressor and an antidiuretic hormone. It also has hemostatic, GI, and thermoregulatory effects, and is an adrenocorticotropic hormone secretagogue. Vasopressin is released from the axonal terminals of magnocellular neurons in the hypothalamus. Vasopressin mediates vasoconstriction via V1-receptor activation on vascular smooth muscle and mediates its antidiuretic effect via V2-receptor activation in the renal collecting duct system. In addition, vasopressin, at low plasma concentrations, mediates vasodilation in coronary, cerebral, and pulmonary arterial circulations. Septic shock causes first a transient early increase in blood vasopressin concentrations that decrease later in septic shock to very low levels compared to other causes of hypotension. Vasopressin infusion of 0.01 to 0.04 U/min in patients with septic shock increases plasma vasopressin levels to those observed in patients with hypotension from other causes, such as cardiogenic shock. Increased vasopressin levels are associated with a lesser need for other vasopressors. Urinary output may increase, and pulmonary vascular resistance may decrease. Infusions of > 0.04 U/min may lead to adverse, likely vasoconstriction-mediated events. Because clinical studies have been relatively small, focused on physiologic end points, and because of potential adverse effects of vasopressin, clinical use of vasopressin should await a randomized controlled trial of its effects on clinical outcomes such as organ failure and mortality.

Section snippets

History

Vasopressin is essential for survival as attested to by its teleologic persistence. The oxytocin-vasopressin superfamily is found in both vertebrates and invertebrates with a conserved nonapeptide structure. Therefore, the ancestral gene encoding the precursor protein predates the divergence of the two groups about 700 million years ago.⁴

Oliver and Schafer⁵ in 1895 first observed the vasopressor effect of pituitary extract, attributed to the posterior lobe.⁶ More than 10 years later, the

Structure and Synthesis

Vasopressin is a nonapeptide with a disulfide bridge between two cysteine amino acids.¹³ Vasopressin is synthesized as a large prohormone in magnocellular neurons located in the paraventricular and supraoptic nuclei of the hypothalamus.¹⁴ The hormone and neurohypophysin, an axonal carrier protein, then migrate via the supraoptic-hypophyseal tract to the axonal terminals of the magnocellular neurons, located in the pars nervosa of the posterior pituitary, where vasopressin is stored in granules.

Effects of Vasopressin

Vasopressin has multiple physiologic effects. Its most well-known effects are suggested by its two names. Vasopressin is a direct vasoconstrictor of the systemic vasculature mediated by V1 receptors. Also known as ADH, one of the primary functions of vasopressin is osmoregulation and maintenance of normovolemia mediated by V2 receptors in the kidney. However, vasopressin has many other physiologic functions. Importantly, vasopressin also vasodilates some vascular beds at certain concentrations,

Vasopressin in Septic Shock and SIRS

We have reviewed the human trials of low-dose vasopressin in septic shock and other forms of vasodilatory shock (Table 6). There is evidence for both a deficiency and an exquisite sensitivity to vasopressin, which has mechanistic and therapeutic implications.

Most forms of hypotension are associated with appropriately high levels of vasopressin.²⁹⁵⁴¹²⁵¹²⁶ Landry et al¹ observed that some patients with advanced vasodilatory septic shock had inappropriately low plasma levels of vasopressin. Plasma

Mechanisms of Vasopressin Deficiency in Septic Shock and SIRS

The mechanisms of vasopressin deficiency in patients with vasodilatory shock are not known. Landry and coworkers¹ showed that increased metabolism or clearance of vasopressin is not a mechanism of the low vasopressin levels in patients with septic shock. The potential mechanisms of vasopressin deficiency include (1) depletion of pituitary stores of vasopressin after exhaustive release of vasopressin in early septic shock, (2) autonomic dysfunction in patients with septic shock,⁵⁶⁵⁷ and (3)

Conclusions and Recommendations

Vasopressin deficiency may contribute to the refractory hypotension of late, refractory septic shock. Infusion of vasopressin increases plasma levels to values found during comparable degrees of hypotension from other causes, such as cardiogenic shock. Vasopressin infusion causes a pressor response and a sparing of conventional exogenous catecholamines.

In “physiologic” doses (ie, 0.01 to 0.04 U/min yielding plasma levels of 20 to 30 pg/mL), vasopressin is synergistic with exogenous

Acknowledgment

The authors thank Diane Minshall for the illustrations (Fig 1, 2).

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Optimizing Vasopressin Use and Initiation Timing in Septic Shock: A Narrative Review
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This review discusses the rationale for vasopressin use, summarizes the results of clinical trials evaluating vasopressin, and focuses on the timing of vasopressin initiation to provide clinicians guidance for optimal adjunctive vasopressin initiation in patients with septic shock.
Patients with septic shock require vasoactive agents to restore adequate tissue perfusion. After norepinephrine, vasopressin is the suggested second-line adjunctive agent in patients with persistent inadequate mean arterial pressure. Vasopressin use in practice is heterogeneous likely because of inconsistent clinical trial findings, the lack of specific recommendations for when it should be used, and the high drug acquisition cost. Despite these limitations, vasopressin has demonstrated price inelastic demand, and its use in the United States has continued to increase. However, questions remain regarding optimal vasopressin use in patients with septic shock, particularly regarding patient selection and the timing of vasopressin initiation.
Experimental studies evaluating the initiation timing of vasopressin in patients with septic shock are limited, and recent observational studies have revealed an association between vasopressin initiation at lower norepinephrine-equivalent doses or lower lactate concentrations and lower mortality.
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Septic shock is a leading cause of death in intensive care units (ICUs), with short-term mortality rates of 35–40%. Vasopressin (AVP) is a second-line vasoactive agent for septic shock, and recent studies suggest that early AVP use can be beneficial. However, differences between early initiation of AVP combined with norepinephrine (NE) and nonearly AVP with NE are unclear. A retrospective cohort research was designed to explore the effects of early AVP initiation versus nonearly AVP initiation.
This retrospective single-center cohort study included adult patients with septic shock from the MIMIC (Medical Information Mart for Intensive Care)-IV database. According to whether AVP was used early in the ICU (intensive care unit), patients were assigned to the early- (within 6 h of septic shock onset) and non-early-AVP (at least 6 h after septic shock onset) groups. The primary outcome was 28-day mortality. The secondary outcomes were ICU and hospital mortality, the numbers of vasopressor-free and ventilation-free days at 28 days, ICU length of stay (LOS), hospital LOS, sequential organ failure assessment (SOFA) score on days 2 and 3, and renal replacement therapy (RRT) use on days 2 and 3. Univariate and multivariate cox proportional-hazards regression, propensity-score matching were used to analyze the differences between the groups.
The study included 531 patients with septic shock: 331 (62.5%) in the early-AVP group and 200 (37.5%) in the non-early-AVP group. For 1:1 matching, 158 patients in the early-AVP group were matched with the same number of patients with nonearly AVP. Regarding the primary outcome, there was no significant difference between the early- and non-early-AVP groups in 28-day mortality (hazard ratio [HR] = 0.91, 95% confidence interval [CI] = 0.68–1.24). For the secondary outcomes, there were no differences between the early- and non-early-AVP groups in ICU mortality (HR = 0.95, 95% CI = 0.67–1.35), hospital mortality (HR = 0.95, 95% CI = 0.69–1.31), the numbers of vasopressor-free and ventilation-free days at 28 days, ICU LOS, hospital LOS, SOFA score on days 2 and 3, and RRT use on days 2 and 3.
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We retrospectively collected COVID19 ECMO patients' (from July 6, 2020, to November 30, 2021) data from the electronic medical records. By examining urine output, urine osmolality (if applicable), plasma sodium level, and plasma osmolality, we set DI diagnosis. We described the clinical course of DI episodes and compared baseline characteristics between patients who developed DI and those who did not.
Out of 37 patients, 12 had 18 episodes of DI. These patients were 7 years younger and had lower severity scores (APACHE-II and SOFA). Mortality difference was not seen between groups. 17 episodes occurred after vasopressin discontinuation; 14 episodes were treated with vasopressin reinstitution. DI lasted for a median of 21 h, with a median increase of 14 mEq/L of sodium.
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View all citing articles on Scopus

: Dr. Walley is a BC Lung Association/St. Paul’s Hospital Foundation Scientist.

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Chest

Critical Care ReviewsPhysiology of Vasopressin Relevant to Management of Septic Shock

Abstract

Section snippets

History

Structure and Synthesis

Effects of Vasopressin

Vasopressin in Septic Shock and SIRS

Mechanisms of Vasopressin Deficiency in Septic Shock and SIRS

Conclusions and Recommendations

Acknowledgment

J Biol Chem

Prog Neurobiol

Front Neuroendocrinol

Endocrinol Metab Clin North Am

Kidney Int

Front Neuroendocrinol

Comp Biochem Physiol A

Front Neuroendocrinol

Brain Res

Thorac Cardiovasc Surg

Am J Med

J Biol Chem

Regul Pept

Neuropeptides

Am J Med

Gastrointest Endosc

J Vasc Surg

Kidney Int

Am J Med Sci

Eur J Pharmacol

Vasopressin deficiency contributes to the vasodilation of septic shock

Circulation

Vasopressin pressor hypersensitivity in vasodilatory septic shock

Crit Care Med

Selected treatment strategies for septic shock based on proposed mechanisms of pathogenesis

Ann Intern Med

Man and the chimaera: selective versus neutral oxytocin evolution

Adv Exp Med Biol

On the physiological action of extracts of the pituitary body and certain other glandular organs

J Physiol (Lond)

The physiological effects of the hypophysis cerebri and infundibular body

J Exp Med

Diabete insipido ed opoterapia

Gazz Osped Clin

Die nierenwirkung von hypophysenextrakten beim menshen

Berl Klin Wochenscgr

The secretion of urine as studied on the isolated kidney

Proc R Soc London (Biol)

Pharmacology and clinical perspectives of vasopressin antagonists

Pharmacol Rev

A synthetic preparation possessing biological properties associated with arginine-vasopressin

J Am Chem Soc

Structural bases of vasopressin/oxytocin receptor function

J Endocrinol

Distribution of oxytocin and vasopressin in the rat supraoptic and paraventricular nucleus

J Endocrinol

Osmoregulation of vasopressin neurons: a synergy of intrinsic and synaptic processes

Prog Brain Res

Central nervous system mediators of vasopressin release

Physiol Rev

Osmotic and nonosmotic control of vasopressin release

Am J Physiol

Acidemia stimulates ACTH, vasopressin, and heart rate responses in fetal sheep

Am J Physiol

Influence of volume changes on osmolality-vasopressin relationships in conscious dogs

Am J Physiol

Osmotic control of vasopressin function

Control of release of vasopressin by neuroendocrine reflexes

Q J Exp Physiol

Renin and vasopressin responses to graded reductions in atrial pressure in conscious dogs

Am J Physiol

Effects of separate and concurrent osmotic and volume stimuli on plasma ADH in sheep

Am J Physiol

The effects of hypotension and hypovolaemia on the liberation of vasopressin during hemorrhage in the unanaesthetized monkey (Macaca mulatta)

Pflugers Arch Eur J Physiol

Cardiac and arterial baroreceptor influences in release of vasopressin and renin during hemorrhage

Am J Physiol

Response of vasopressin and norepinephrine to lower body negative pressure in humans

Am J Physiol

Critical Care Reviews
Physiology of Vasopressin Relevant to Management of Septic Shock

α₁-Adrenergic receptor activation depolarizes rat supraoptic neurosecretory neurons in vitro