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Vasopressin is a nonapeptide synthesised in the hypothalamus and released upon stimulations such as hyperosmolality, hypotension and hypovolaemia. In acute shock states serum vasopressin levels increase rapidly and decrease in prolonged septic shock. The administration of vasopressin in healthy subjects has little effect, whereas in vasodilatory shock it increases the mean arterial pressure through V1 receptors and decreases the cardiac output. Vasopressin stimulates the V2 receptors in the kidney leading to reabsorption of water through aquaporin 2. However, in vasodilatory shock the antidiuretic effects are overcome by the effect vasopressin has on the kidneys: improvement of renal blood flow leading to water excretion. Twenty-four studies on the use of vasopressin in patients with vasodilatory shock are reviewed. They show that vasopressin potentiates norepinephrine effects, increases blood pressure significantly in patients with vasodilatory shock and may improve renal function. Side effects ranging from ischaemic skin lesions to possible intestinal ischaemia should not be underestimated. Above a dose of 0.04 U/min it may lead to cardiac arrest. Effects on mortality cannot be interpreted from these studies. Broad clinical use should await controlled trials to clarify its effects on clinical outcomes such as organ failure and mortality. I N T R O D U C T I O N In intensive care medicine vasopressin is reserved for patients with severe vasodilatory shock who are already receiving norepinephrine and still have hypotension, although it is used with the greatest caution because of the possible side effects. In this review the physiology of vasopressin and its effects in vitro and in animal models are discussed. Thereafter a discussion is presented of the literature on studies with vasopressin treatment in patients with septic shock or vasodilatory shock of other origin. The goal of this review is to provide some insight into the current place of vasopressin in patients with vasodilatory shock. P H Y S I O L O G Y A N D E F F E C T S O F V A S O P R E S S I N Production and release of vasopressin Vasopressin is a nonapeptide, which is synthesised in magnocellular neurons of the paraventricular and supraoptic nuclei in the hypothalamus. Its production depends on vasopressin gene (chromosome 20p13) transcription, which increases on either hypertonic conditions, hypotension or hypovolaemia. From the magnocellular neurons the prohormone of vasopressin, consisting of vasopressin, vasopressin-associated neurophysin and a glycopeptide, is transported down long axons to the pars nervosa of the posterior pituitary where it is stored in granules. After stimulation, a generated action potential causes a calcium influx, followed by neurosecretory granule movement and release of vasopressin from the complex molecule with neurophysin and glycopeptide. The granules fuse with the cell membrane and extrude its contents into the perivascular space and the posterior pituitary capillary system. The pituicytes surrounding axon terminals in the posterior © 2005 Van Zuiden Communications B.V. All rights reserved. R E V I E W Vasopressin: physiology and clinical use in patients with vasodilatory shock: a review D.T. den Ouden, A.E. Meinders Department of General Internal Medicine, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, the Netherlands, e-mail: D.T.den_Ouden@lumc.nl, corresponding author pituitary remove an immediate barrier between the axons and the perivascular space by retracting, thus facilitating diffusion of peptides into capillaries. Control of hormone synthesis resides at the level of transcription; after transcription the mRNA is increased and vasopressin released. The axonal transport is a regulated process linked to vasopressin synthesis, as shown in rat models. Vasopressin release is mainly stimulated by hyperosmolality and hypotension or hypovolaemia, as well as acidosis, pain, hypoxia, hypercapnia and vomiting. Low central venous pressure alone in for instance slightly dehydrated people is not a trigger for releasing vasopressin; at least a 10% reduction in circulating volume is necessary to release vasopressin. The amount of vasopressin stored is enough for several days; however it appears that during prolonged shock states the amount stored does not meet the amount of vasopressin required. In both animals and humans in shock, the vasopressin levels first rise to supranormal levels and then decrease as the shock state persists. Three reasons can be found for this: firstly the depletion of neurohypophyseal stores of vasopressin, secondly autonomic insufficiency or high concentrations of norepinephrine which both have a central inhibitory effect on vasopressin release and thirdly the nitric oxide inhibiting vasopressin production. MRI scans have shown, in both animals and humans, that a decreased vasopressin production accounts for at least some part of the vasopressin shortage. In patients with septic shock and inappropriately low vasopressin levels, brain MRIs performed to exclude brain damage for other reasons showed a depletion of vasopressin stores in the posterior pituitary. Also, in animal studies prolonged and intense stimulation of vasopressin release by dehydration or salt loading produced a depletion of stored hormone in the posterior pituitary. Vasopressin is rapidly metabolised by liver and kidney vasopressinases and has a half-life of 10 to 35 minutes. Normal vasopressin levels are 0.5 to 5 pg/ml in overnight fasted, hydrated humans. Water deprivation increases plasma osmolality and raises vasopressin to 10 pg/ml, whereas in acute shock states the level rises to 100 to 1000 pg/ml (dogs, monkeys) and decreases in prolonged septic shock to ±3.1 pg/ml in humans. Gradual recovery of the vasopressin stores in the pituitary occurs over several days. Vasopressin acts on the different vasopressin receptors: the V1 receptor, mainly causing vasoconstriction, the V2 receptor, regulating the water balance, and the V3 receptor, which stimulates corticotropin (ACTH). This subject will be discussed in more depth in following paragraphs. Baroreflex and vasopressin There has been much research about the exact trigger that releases the (high) amounts of vasopressin in response to circulatory failure. Plasma vasopressin does not increase in severe hypovolaemia until it causes a steep fall in the arterial pressure. The evidence suggests that it is the sudden unloading of arterial baroreceptors that triggers the surge in vasopressin secretion. These high pressure arterial baroreceptors are located in the carotid sinus and aortic arch. Low-pressure volume receptors are present in the atria and pulmonary venous system. Afferent signals from these receptors are carried from the chest to the brain stem through cranial nerves IX and X to the hypothalamus. It has been established that vasopressin release is higher if the tonic inhibitory baroreceptor input is diminished or absent. This is the case in animal laboratory studies in which baroreflex denervation was performed and in septic shock, where the baroreflex system is diminished or even abolished. The administration of vasopressin in healthy animals with intact baroreflex receptors produced stable mean arterial blood pressure (MAP), lower cardiac output (CO) and higher peripheral resistance, whereas baroreflex denervated animals showed a remarkable increase in MAP and stable CO at low vasopressin concentrations (0.017 U/kg) and remained stable until much higher infusion rates of vasopressin. These experiments led to the theory that baroreceptors and volume receptors normally inhibit magnocellular neurons and that absence of this counterregulation results in the release of vasopressin. A rise in vasopressin levels does not disrupt osmoregulation because hypotension increases the plasma osmolality-vasopressin relationship so that higher plasma vasopressin levels are required to maintain normal osmolality. There is, however, animal experimental research that says that baroreceptor denervation produces a state of heightened osmotic sensitivity for vasopressin neurons with evidence for increased central vasopressin release to both direct and peripheral hypertonic saline stimulation. Blood pressure and vasopressin Vasopressin has a vasoconstricting effect by four known mechanisms: activation of V1 vascular receptors, modulation of ATP-sensitive K-channels (KATP), modulation of nitric oxide and potentiation of adrenergic and other vasoconstrictor agents. The effect of vasopressin through V1 receptors is mediated by the phosphotidylinositol pathway. In vitro, the action of vasopressin on different types of vessels varies with the particular type or location of the vessel by heterogeneity of the V1 receptor. Under normal circumstances, vasopressin generally induces an endothelium-independent contraction of the vessels by acting on the smooth muscle myocyctes and potentiates the norepinephrine effect. In intracerebral arterioles of rats, increasing concentrations of vasopressin appeared to induce a triphasic response of vasodilatation, vasoconstriction and vasodilatation. The vasodilatation was endothelium dependent, whereas the constriction was not. Den Ouden, et al. Physiology and clinical use in patients with vasodilatory shock. J A N U A R Y 2 0 0 5 , V O L . 6 3 , N O . 1