Introduction

Vasopressin was first characterized in 1895 by Oliver and Schaefer [1], who recognized that neurohypophyseal extracts had potent vasoconstrictive effects. Three decades later, it was renamed antidiuretic hormone based on its effects on the distal tubule of the kidney. Until recently, its utility for vasoconstriction outside of variceal hemorrhage and hepatorenal syndrome has been largely forgotten [2, 3, 4, 5]. Recent inclusion of vasopressin in the American Heart Association Adult Cardiac Life Support Guidelines [6] has caused a “rediscovery” of its vasopressor effects and a new role in cardiac arrest. Vasopressin is also useful for the treatment of septic shock, however few clinicians are aware of its mechanism of action or the data supporting its use.

Vasopressin under normal conditions

Synthesis and metabolism

Vasopressin is a nonapeptide with a molecular mass of 1084 Daltons. (Fig. 1) It is strongly basic (isoelectric point pH 10.9) due to the amidation of three carboxyl groups and its biologic activity is readily destroyed by oxidation or reduction of its disulfide bond. Prepro-vasopressin is encoded by the 2.5 kb vasopressin-neurophysin II gene on the long arm of chromosome 20 (20p13) [7, 8]. Pro-vasopressin is generated by the removal of the signal peptide from prepro-vasopressin and glycosylation in magnocellular neurons in the hypothalamus. Vasopressin precursors migrate along neuronal axons that terminate in the posterior hypophysis. (Fig. 2) Additional post-translational processing of pro-vasopressin occurs within neurosecretory vesicles yielding vasopressin and neurophysin, which are secreted from axon terminals in the posterior pituitary.

Fig. 1
figure 1

The amino acid sequence of the nonapeptide vasopressin

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Fig. 2
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Central neural pathways important in vasopressin synthesis and release. Vasopressin is synthesized in the cell bodies of magnocellular neurons located in the paraventricular nuclei within the hypothalamus and released into the bloodstream after migration via the supraoptic-posterior hypophyseal tract

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Most newly synthesized vasopressin is stored intracellularly, only 10–20% of the total hormonal pool within the posterior pituitary can be readily released. The time from synthesis to release of the hormone into the systemic circulation is about 1.5 h [9]. Once secreted into the circulation, vasopressin is accompanied, but not bound, by its carrier protein, neurophysin II, which does not appear to have any independent biological activity. The plasma half-life of vasopressin is short, about 5–15 m. Thus, plasma concentrations [normal: 1 pg/ml (10–12  m)] reflect recent release of active hormone. Clearance occurs through vasopressinases in the liver and kidneys and is concentration independent. Vasopressin is also found in large quantities in platelets. Accordingly, vasopressin concentration in platelet-rich plasma is approximately five- to six-fold higher than in platelet-depleted plasma.

Mechanisms of action

Vasopressin has several important physiological functions including water retention by the kidneys and constriction of vascular smooth muscle (Table 1). Vasopressin exerts its effects via interaction with a family of membrane-bound G protein-coupled vasopressin-specific receptors, V1 and V2. The V1 receptors are located on vascular smooth muscle cells whereas V2 receptors are on the basolateral surface of cells of the distal convoluted tubules and medullary collecting ducts. There are also V3 receptors that are located on the anterior hypophysis and pancreatic islet cells, in the latter they play a role in insulin secretion [10].

Table 1 Antidiuretic versus vasoconstrictive effects of vasopressin
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While both receptors function via activation of guanosine triphosphate-binding proteins, their second messengers are different [11]. V1 receptor-ligand interactions lead to activation of phospholipase C, which promotes hydrolysis of phosphatidylinositol-(4,5)-biphosphate and the formation of inositol (1,4,5)-triphosphate and diacylglycerol (Fig. 3). Inositol (1,4,5)-triphosphate (IP3) acts as a second messenger that interacts with its own receptor on the endoplasmic reticulum promoting mobilization of calcium from intracellular stores and, thereby, leading to vascular smooth muscle contraction [11]. The V2 receptor is coupled to adenyl cyclase, which produces cAMP (cyclic adenosine monophosphate). Subsequent activation of cAMP-dependent protein kinases (PK) such as PKA causes recruitment of water channel proteins (aquaporin-2 [AQP2], a member of AQP family proteins) from cytoplasmic vesicles into the luminal membrane of the renal tubule, thereby increasing permeability of the luminal cell membrane to water [12]. Vasopressin may also increase translocation of AQP2 to the membrane and opening of individual water channels [13]. Once APQ2s are recruited, the bulk of water flow across the collecting tubule proceeds through epithelial cells rather than via intracellular junctional complexes [14, 15].

Fig. 3
figure 3

Mechanisms of action of vasopressin at the cellular level. Both V1 and V2 vasopressin receptors are G protein-coupled receptors. A Stimulation of V1 receptor by vasopressin leads to dissociation of Gq. The α-subunit of Gq then stimulates PLCβ, which promotes hydrolysis of PIP2, leading to increase in the levels of DAG and IP3 intracellularly. The IP3 acts on its specific receptor (IP3R) on the endoplasmic reticulum membrane promoting release of calcium from intracellular stores. B Interaction of vasopressin with its V2 receptor causes dissociation of Gs into its subunits, among which the α-subunit stimulates adenyl cyclase. Activation of adenyl cyclase leads to an increase in cAMP, which then activates PKA and the insertion of the pre-synthesized water channel (AQP2) into membrane. AQP-2 aquaporin-2, DAG diacylglycerol, GTP guanosine triphosphate, GDP guanosine diphosphate, IP3 inositol (1,4,5)-triphosphate, IP3R inositol (1,4,5)-triphosphate receptor, PIP2 phosphatidylinositol (4,5)-biphosphate, PKA protein kinase Α, PLCβ phospholipase Cβ, V1 V1 vasopressin receptor, V2 V2 vasopressin receptor

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Vascular bed dependent functions

In addition to its antidiuretic action, vasopressin has functions that depend on the sensitivity of a vascular bed to vasopressin; most notable of these are its effects on the systemic and pulmonary circulation.

Systemic circulation

On a molar basis, vasopressin is a more potent vasoconstrictor than angiotensin II or norepinephrine [16]. Vasopressin constricts systemic arteries via V1 receptors in a dose-dependent fashion. However, exogenous vasopressin has negligible vasopressor activity in healthy individuals, nor are patients with the syndrome of inappropriate antidiuretic hormone predisposed to hypertension [17, 18, 19]. The overall effect of vasopressin on systemic blood pressure is minimal at normal plasma concentrations, as vasoconstriction is generally counteracted by baroreceptor-mediated reduction in cardiac output [20]. Although, similar baroreflex-mediated effects offset the rise in blood pressure with other vasopressors, it is more pronounced with vasopressin [21].

The difference in pressor response between vasopressin and other vasopressors may reflect a centrally mediated effect via activation of brain V1 receptors causing a leftward shift of the heart rate-arterial pressure baroreflex response [21, 22, 23, 24, 25, 26]. The site involved in the modulation of the baroreflex control of heart rate by vasopressin appears to be area postrema, where there is high expression of V1 receptors [21, 26, 27, 28]. In contrast to vasopressin, catecholamines do not have an effect on area postrema and therefore do not cause a similar degree of baroreflex response [21, 27]. Accordingly, a supra-physiologic dose of vasopressin (approximately 50 times the normal) is usually required to cause significant increases in mean arterial blood pressure in normal animals and humans [29, 30].

While in vitro and animal studies show an increase in intracellular calcium concentration and inotropic effect after stimulation of myocardial V1 receptors [31, 32], vasopressin may have net negative inotropic and chronotropic effects due to increased vagal and decreased sympathetic tone as well as decreased coronary blood flow (a consequence of coronary vasoconstriction) when circulating levels of vasopressin are high [33].

The degree of vasoconstriction by vasopressin differs among vascular beds [34, 35]. Vasopressin is more potent in skin, skeletal muscle, adipose tissue and pancreas than in mesenteric, coronary and cerebral circulations [33, 36]. Diminished vasoconstrictor effect in coronary and cerebral circulations may be due to the paradoxical release of nitric oxide (NO) by vasopressin in these vascular beds [37]. Recently, a small study of intrabrachial administration of vasopressin reported a dose-dependent biphasic change (vasoconstriction followed by vasodilation) of forearm blood vessels in humans [38]. Sustained infusion was associated with preservation of the vasodilatory effect, which was presumed to be mediated by NO, however, tachyphylaxis to the constrictive effects of vasopressin was noted. The receptor subtype responsible for vasodilation is uncertain, however the V2 receptor agonist, 1-desamino[8-D-arginine]vasopressin (DDAVP) decreases peripheral vascular resistance and causes facial flushing in humans and peripheral vasodilation in dogs. Similarly, inhibition of V2 receptors hinders the vasodilatory response of the renal afferent arteriole to vasopressin [39, 40]. Alternately, it has been suggested that endothelial oxytocin receptors may mediate vasopressin-induced NO production and vasodilation [41].

The effect of vasopressin on splanchnic perfusion is controversial. While earlier studies reported reduced mesenteric perfusion even at physiologic concentrations (as low as 10 pg/ml) [42, 43, 44, 45, 46, 47], more recent data using a vasopressin analog in endotoxemic animals suggest otherwise [48]. This discrepancy may be attributed to differences in volume status between studies. Asfar and colleagues challenged endotoxic animals with fluids prior to administration of the V1 specific analog, terlipressin [48]. Vasopressin increased systemic blood pressure without affecting gastrointestinal hemodynamics in fluid-challenged animals. These results suggest that maintenance of normal intravascular volume prevents vasopressin-induced reductions in splanchnic perfusion.

A similar discrepancy about the effects of vasopressin on gastrointestinal perfusion has been observed in human studies. Paralleling the results of the most recent animal study [48], Dünser and colleagues reported an improvement in gastrointestinal mucosal perfusion (assessed by gastric tonometry) in patients with septic shock during combined vasopressin and norepinephrine infusion compared to norepinephrine alone [49]. The differences between this study and earlier studies may be due to the use of higher concentrations and bolus application of vasopressin in earlier investigations [50].

Pulmonary circulation

Vasopressin vasodilates the pulmonary circulation decreasing pulmonary vascular resistance and pressure under both normal and hypoxic conditions as a consequence of V1 receptor-mediated release of NO from endothelial cells [41, 51, 52, 53]. Pulmonary artery vasodilation occurs with low concentrations of vasopressin [54]. Pulmonary vascular resistance does increase when extremely high levels of plasma vasopressin are achieved (>300 pg/ml) [55]. Unlike other vasoactive agents, such as epinephrine [56], vasopressin does not appear to alter ventilation perfusion relationships [57] in patients who undergo cardiopulmonary resuscitation, thus, this finding may not be relevant in the setting of vasodilatory shock.

Other functions

Vasopressin acts within the central nervous system to lower body temperature and facilitate memory consolidation and retrieval [58, 59]. It also heightens hypothalamic sensitivity to corticotropin-releasing hormone, thereby increasing adrenocorticotropic hormone (ACTH) release and cortisol production [60, 61]. This effect is likely carried out through NO and cGMP (cyclic guanosine monophosphate) via central V3 receptors, which were previously thought to be V1 receptor subtypes [62]. Vasopressin does not appear to affect oxytocin release [63].

Activation of V1 receptors by high levels of vasopressin leads to platelet aggregation [39, 64]. Extra-renal V2 receptors appear to mediate the release of several coagulation factors (Factor VIIIc, and von Willebrand factor) in response to the administration of DDAVP, which is a selective V2-agonist (antidiuretic/vasoconstrictive ratio 4000:1) [65, 66]. It has been suggested, but not proven, that DDAVP decreases peripheral vascular resistance and, consequently, systemic blood pressure and increases plasma renin activity via vascular V2 receptors [67], although such receptors remain to be identified on endothelial cells.

Regulation of secretion

Vasopressin secretion is regulated by both serum osmolality (osmoregulation) and blood pressure (baroregulation) and is released in response to a variety of stimuli (hemorrhage, hypoxia, hypertonic saline) in normal humans and animals. (Table 2) Both in normal humans and experimental animals, vasopressin release is attenuated or eliminated by pretreatment with glucocorticoids [68]. This downregulation of vasopressin release is mediated by a direct effect of glucocorticoids on the hypothalamus and/or neurohypophysis [69]. Vasopressin and corticotropin-releasing hormone co-localize in neurohypophyseal parvocellular neurons projecting to the median eminence and the neurohypophyseal portal blood supply of the anterior pituitary. Levels of both vasopressin and corticotropin-releasing hormone in these neurons are inversely related to plasma glucocorticoid levels. However, vasopressin appears to be considerably less sensitive to negative feedback than the corticotropin-releasing factor-ACTH system. Since neurohypophyseal vasopressin is involved in the control of ACTH secretion, it is likely that the modulation of neurohypophyseal vasopressin by glucocorticoids is part of the overall regulation of ACTH secretion.

Table 2 Factors important in vasopressin release
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Under normal conditions, vasopressin secretion is regulated primarily by changes in plasma osmolality [70, 71] (Fig. 4). In healthy adults, the osmotic threshold for vasopressin secretion ranges from 275 to 290 mosmol/kg (average about 280 mosmol/kg). When plasma osmolality is less than 280 mosmol/kg, plasma vasopressin levels range from 0.5 to 2 pg/ml (less than 4 pg/ml) [72]. In general, a 1 mosmol/kg rise in plasma osmolality should increase plasma vasopressin levels by 0.38 pg/ml and urinary osmolality by 100 mosmol/kg [13, 73, 74]. Maximally to suppress plasma vasopressin (<0.25 pg/ml) and maximally dilute the urine (<100 mosmol/kg), total body water needs to increase only by 2% (5.6 mosmol/kg). In contrast, a 2% decrease in total body water will result in doubling the plasma vasopressin level (i.e., from 1 to 2 pg/ml). Maximal urine concentration is achieved at a plasma osmolality of about 290–292 mosmol/kg and a plasma vasopressin level of 5–6 pg/ml. As a rule of thumb, a 1 pg/ml rise in plasma vasopressin increases urine osmolality by about 200 mosmol/kg.

Fig. 4
figure 4

Changes in plasma vasopressin level with rise in osmolality

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Intravascular volume-mediated regulation of vasopressin release is regulated by baroreceptors in the left atrium, carotid sinus and aortic arch [73]. However, the minimal effect of small changes in blood volume and pressure on vasopressin secretion contrasts sharply with the extraordinary sensitivity of the osmoregulatory system. Under resting conditions or when stretched, baroreceptors inhibit vasopressin secretion. Decreased activity due to low blood pressure decreases baroreceptor neuronal output and results in the release of vasopressin from the hypothalamus. Atrial baroreceptors respond to smaller changes in blood volume than do arterial receptors and likely play a dominant role in eliciting vasopressin secretion [73, 75, 76]. This is particularly true for left atrial baroreceptors, which are more sensitive than those in the right atrium [13, 73].

There is an exponential inverse relationship between plasma vasopressin levels and the percent decline in mean arterial pressure in the setting of acute hypotension [13]. Small reductions in blood pressure (5–10% from baseline) usually have little or no effect on plasma vasopressin whereas a 20–30% drop results in hormone levels several fold higher than those required to produce maximal antidiuresis. Vasopressin response to acute reductions in blood volume is not well defined but appears to be quantitatively and qualitatively similar to the response to blood pressure [77, 78, 79]. Volume depletion in both experimental animals and humans produces little elevation in plasma vasopressin levels until the blood volume decreases by more than 8–10% [73, 80]. Further volume depletion results in exponential increases in plasma vasopressin levels. For example, a 10–15% fall in effective blood volume usually doubles hormone levels, whereas a 20% decline results in 20–30 fold increases in serum vasopressin levels. While less is known about the influence of acute elevations in blood volume or pressure, both appear to suppress vasopressin secretion [81].

In animals, reduction of left atrial pressure decreases the osmotic threshold and increases the sensitivity for osmotic release of vasopressin. In contrast, high left atrial pressure raises the threshold and dampens the sensitivity of osmoregulation [13, 73]. Fluid loading can suppress vasopressin secretion even in the presence of hyponatremia [13, 73] Changes in the osmotic set point in response to volume-mediated stimuli can be abolished by opioid antagonists [13, 73].

Due to interdependence between the osmo- and baro-regulation of vasopressin secretion, under conditions of moderate hypovolemia osmoregulation is preserved and renal water excretion is maintained, albeit at a lower plasma osmolality [70, 71, 82, 83]. As hypovolemia worsens, plasma vasopressin concentrations reach extremely high values and baroregulation overrides osmoregulation. In the elderly, osmoreceptor sensitivity is enhanced whereas baroregulation is blunted.

Vasopressin during septic shock

Pathophysiology of septic shock

Septic shock is characterized by physiologically inappropriate vasodilation leading to organ hypoperfusion despite adequate fluid resuscitation [84]. The mechanisms of hypotension during septic shock are multifactorial and include relative hypovolemia, ineffective intravascular volume and myocardial dysfunction. Blood return to the right ventricle is typically diminished because of relative hypovolemia due to a combination of loss of intravascular volume from capillary leak and increased venous capacitance. Blood return to the left ventricle is also compromised due to increased pulmonary vascular resistance.

Excessive vasodilation during septic shock occurs despite increased catecholamine levels and activation of the renin-angiotensin-aldosterone system [85, 86, 87, 88]. Hyposensitivity of α-adrenergic receptors to catecholamines due to tissue hypoxia and acidosis also contributes to vasodilation.

The membrane potential of arterial smooth muscle cells is regulated by adenosine triphosphate (ATP) sensitive K+-channels, which are important regulators of arterial tone [89, 90]. The opening of K+-channels closes voltage-dependent Ca2+-channels, decreasing intracellular calcium levels leading to smooth muscle relaxation and vasodilation [91]. Septic shock is associated with activation of these K+-ATP channels [89, 90]. Activation of the inducible form of NO synthase and deficiency of vasopressin also contribute to the vasodilation of septic shock.

Current management

In addition to identification of the nidus infection, judicious fluid administration to compensate for effective hypovolemia due to vasodilation is an important early step in the resuscitation of patients with septic shock [92]. This is an especially salient concern because absolute hypovolemia may develop as intravascular volume loss due to “third spacing” from capillary leak and increased insensible losses are common during sepsis. However, the assessment of volume status and adequacy of the fluid resuscitation is challenging and often based on clinical grounds. Therefore, it is not unusual to “under-resuscitate” these patients. In fact, Rivers et al. reported that the requirement for adequate fluid resuscitation in septic shock is frequently more than 5 L of crystalloids when invasive monitoring techniques are utilized [92].

Persistent hypotension with evidence of organ hypoperfusion despite volume resuscitation necessitates vasopressor agents. Vasopressors such as dopamine, norepinephrine, phenylephrine and epinephrine, alone or in combination, are typically used to treat septic shock. In some patients, these agents prove ineffective in maintaining adequate organ perfusion due to attenuated vasopressor response [93, 94, 95]. Similarly, there is a decreased response to the potent endogenous vasopressors, endothelin-1 and angiotensin II [96]. Differences in responsiveness to catecholamines among individuals are commonly observed and may represent differences of volume status, duration of septic shock (late versus early), phenotypic variations in responsiveness to endotoxin and other inflammatory mediators, and possibly downregulation and/or impairment of catecholamine receptors [94, 97, 98]. While numerous studies report the attributes of vasopressor regimens for the treatment of hypotension, it is important to bear in mind that there are no data that convincingly demonstrate a survival benefit with the use of any particular catecholamine or combination of catecholamines in septic shock.

Vasopressin physiology during septic shock

Two unique attributes of vasopressin make it well suited for the management of septic shock: (1) there often exists a relative deficiency of vasopressin and (2) the sensitivity of the systemic circulation to vasopressin during septic shock is increased (Table 3).

Table 3 Rationale for low dose vasopressin in the management of septic shock
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Vasopressin is important in maintaining arterial blood pressure during hypotension. Indeed, most forms of shock are associated with appropriately high levels of vasopressin (Fig. 5). Vasoconstrictive properties of vasopressin are important, especially when intravascular volume or arterial blood pressure is threatened as inhibition of V1 receptors causes marked hypotension in subjects with arterial underfilling [16, 17, 29]. The primary stimulus for vasopressin release in hypotensive states is baroreceptor-mediated [99]. It is noteworthy that exogenous vasopressin does not result in a marked pressor response when administered to volume-depleted, hypotensive patients, perhaps because the V1 receptors on vascular smooth muscle are already occupied by endogenous hormone [23, 100, 101].

Fig. 5
figure 5

Plasma vasopressin level in normal, healthy individuals and patients with septic shock (early versus late shock) and other types of vasodilatory shock. Vasopressin levels during late phase of septic shock are lower compared to early septic shock

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Endotoxin stimulates vasopressin release directly, independent of baroreceptor activity [102]. Experimental endotoxemia is associated with a prompt rise in vasopressin levels as early as 15 min after its administration [45, 103]. In addition, acute phase cytokines [i.e. interleukin-1β (IL-1β), IL-6, tumor necrosis-α] enhance vasopressin production [104, 105, 106].

Plasma vasopressin levels demonstrate a biphasic pattern during septic shock, in both animals and humans, that is characterized by a significant rise in early septic shock. Conversely, vasopressin levels in late septic shock are inappropriately low for the degree of hypotension. This decline begins as early as 6 h after the diagnosis of septic shock and results in relative deficiency within 36 h [107] In a recent study by Sharshar et al., all patients were noted to have levels below 10 pg/ml within 24 h of the diagnosis of septic shock [107]. It is noteworthy that this relative deficiency contributes to diminished vasoconstriction (10–100 pg/ml) but does not affect antidiuretic action (0–7 pg/ml).

Low vasopressin levels are most likely due to impaired vasopressin secretion, rather than increased metabolism as vasopressinase levels remain undetectable during established septic shock [90, 108]. A single study of three patients reported undetectable plasma vasopressinase levels, which were attributed to renal and hepatic dysfunction commonly seen in septic patients [108]. Proposed mechanisms for reduced serum vasopressin during sepsis include the exhaustion of pituitary stores caused in response to baroreceptor-mediated release, autonomic dysfunction, inhibitory effects of increased norepinephrine and increased release of NO in the posterior pituitary, (which may downregulate vasopressin production) [90, 109, 110]. In fact, sepsis may lead to hypothalamic dysfunction/failure and NO mediated reductions of vasopressin [111].

The other unique attribute of vasopressin is increased sensitivity to its vasoconstrictive effects during septic shock [110]. Although the precise mechanism of this marked sensitivity to vasopressin during septic shock is not known at this time, it is probably multifactorial. Low plasma concentrations of vasopressin during septic shock make its V1 receptors available for binding by exogenously administered hormone. In contrast, exogenous catecholamines must compete for receptor-binding sites with endogenous catecholamines, which already occupy these receptors and lead to receptor desensitization/downregulation. Alternately, increased sensitivity may result from altered baroreflexes during septic shock. Loss of autonomic nervous regulation has been reported in hyperdynamic states such as septic shock and portal hypertension [112, 113]. There is a dissociated cardiovascular response to vasopressin in states of dysautonomia preventing the negative inotropic effect that normally offsets its vasopressor effect [23, 114]. Conceivably, sepsis may alter V1 receptor response in area postrema and alter the normal baroreflex response.

Another explanation for increased sensitivity to the pressor effects of vasopressin may be alterations in receptor expression and/or signal transduction. Interestingly, increased response to vasopressin during sepsis appears to occur in the face of decreased vasopressin receptor density [115, 116]. In fact, in both in vitro and in vivo models, sepsis reduces vasopressin receptor levels [115, 116]. This effect was dependent on NO in vitro [115] and mediated by pro-inflammatory cytokines in an NO-independent manner in vivo [116]. In these models, sepsis did not alter downstream receptor signaling systems (G proteins, IP3) [115].

Other factors contributing to increased sensitivity to vasopressin include potentiation of the vasoconstrictive effects of catecholamines [117] and vasopressin-mediated direct inactivation of K+-ATP channels in a dose-dependent manner [118]. Vasopressin enhances the sensitivity of the vasculature to the effects of catecholamines, potentiating the contractile effect of catecholamines, electrical stimulation and KCl in the arteries [119, 120, 121]. This effect is most likely mediated by prostaglandins as it can be inhibited by cortisol and lithium. Vasopressin also stimulates synthesis of the most potent vasopressor known, endothelin-I [122, 123]. Vasopressin’s effect on K+-ATP channels is particularly interesting as these channels are important regulators of arterial tone and play a key role in the pathogenesis of septic shock and probably in decreased responsiveness to catecholamines [89, 90, 124]. Vasopressin also attenuates endotoxin and IL-1β-stimulated generation of NO [120, 125] and directly decreases intracellular concentrations of cGMP, the second messenger of NO [126, 127]. In the setting of persistent lactic acidosis, cGMP levels are high and likely contribute to the peripheral vasodilation and subsequent persistent hypotension during septic shock. Whatever the cause, heightened sensitivity probably compensates for decreased serum levels and reduced receptor density during septic shock.

The presence and contribution of adrenal insufficiency and the need for steroid therapy in septic shock are unresolved controversies. Vasopressin may provide another favorable effect by increasing cortisol levels. Pharmacologic doses of vasopressin in animals and humans induce a prompt rise in plasma cortisol levels. Theoretically, depressed levels of vasopressin may be a contributor to the relative adrenal insufficiency found in some patients with septic shock.

Differences between vasopressin and other vasopressors

There are myriad differences between vasopressin and catecholamines. While catecholamines show vasopressor effects through α-adrenergic receptors, vasopressin acts on V1 receptors located on the vascular endothelium (Table 4). There is decreased vasopressor activity to catecholamines during septic shock [88, 93, 94, 128, 129], whereas there is increased sensitivity of V1 receptors during septic shock. Furthermore, the pressor effects of vasopressin are preserved during hypoxia and acidosis [130], while there is resistance to α-adrenergic catecholamines.

Table 4 Differences between low-dose vasopressin and catecholamines as a vasopressor
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Another important difference between vasopressin and catecholamines is extrarenal V2 receptor-mediated vasodilation in selected vascular beds [40, 131]. Vasodilation occurs at low concentrations and appears to be NO-mediated [51, 54]. Interestingly, arteries of the circle of Willis are more sensitive to the vasodilatory effects of vasopressin than other intracranial and extracranial arteries [132].

Vasopressin also differs from catecholamines in terms of its effects on the kidneys. Besides its antidiuretic effects and osmoregulatory properties, vasopressin causes a paradoxical diuretic effect in patients with hepatorenal syndrome, congestive heart failure [133] and early septic shock (<24 h) [134]. Proposed mechanisms of this diuretic effect include relative resistance of renal vasculature to the vasoconstrictive effects of vasopressin [135], downregulation of V2 receptors [136], NO-mediated afferent arteriolar vasodilation [137, 138] and oxytocin receptor-activated natriuresis. At low doses, vasopressin causes efferent arteriolar vasoconstriction with relatively little effect on afferent arteriole (NO-mediated) [137, 138], thereby increasing renal perfusion pressure [138]. Vasopressin also releases atrial natriuretic peptide [139], which may be an indirect mechanism of its diuretic effect. It is not clear whether increased urine output is due to an improvement in renal function, as the creatinine does not change.

Like catecholamines, higher doses of vasopressin (>0.04 U/min) cause a dose-dependent fall in renal blood flow, glomerular filtration rate and sodium excretion [140, 141]. Afferent arteriole and medullary vessels appear to be the most sensitive parts of the renal vasculature. A V1 receptor antagonist can block the vasoconstrictor action of vasopressin on the afferent arteriole. Interestingly, even norepinephrine-induced vasoconstriction of the afferent arteriole can be abolished by treatment with vasopressin if the V1 receptor is blocked.

Clinical evidence for the use of vasopressin in septic shock

Despite available experimental data and increased enthusiasm for vasopressin in the management of septic shock, there are no clinical data to suggest any superiority (i.e., outcome benefits) over conventional pressors for the treatment of septic shock. Available studies about vasopressin in the management of septic shock consist of case series [110, 142], retrospective analyses [134, 143] and several small, randomized, controlled trials [49, 144, 145, 146]. Similar to vasopressin, terlipressin, a vasopressin analog, has also been shown to improve hemodynamics during septic shock in a case series [147] (Table 5). Vasopressin is effective in restoring blood pressure, decreasing the need for catecholamines in septic shock and also other forms of vasodilatory shock, such as late phase hemorrhagic shock [148], post-cardiotomy [143, 149, 150, 151, 152, 153], post left-ventricular assist device placement [154], solid organ transplantation [155, 156, 157] and milrinone-induced hypotension [158] (Table 6).

Table 5 Studies about vasopressin use in septic shock
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Table 6 Studies about vasopressin use in other forms of vasodilatory shock
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In all case series and randomized clinical trials, vasopressin has been shown to improve systemic blood pressure without significant adverse effects on cardiac function or pulmonary hemodynamics [49, 110, 134, 142, 143, 144, 145]. In some studies there was improvement in cardiac output [143, 153, 159, 160], probably due to the decreased use of norepinephrine, attenuation of endotoxin and IL-1β stimulated generation of NO [120], and increased intracellular calcium in myocardial cells [31, 32]. In some patients with septic shock, after hemodynamic stability had been achieved with vasopressin, attempts to discontinue it were unsuccessful [145]. A combination of vasopressin and norepinephrine appears to be more effective than norepinephrine alone in treating hemodynamic instability during vasodilatory shock [49].

Despite a growing body of evidence for the use of vasopressin in patients who remain hypotensive despite escalating doses of catecholamines, no data is available about its role as a first-line vasopressor. Given that earlier achievement of a normal hemodynamic status may improve outcome in septic shock [92], it would make sense to administer vasopressin early in the disease before refractory hypotension develops, to prevent end-organ damage. Doing so may allow diminution of the amounts of other vasopressors, which could potentially forestall development of insensitivity to catecholamines. However, lack of clinical evidence on its use early in the course of disease along with no proof of outcome benefit render it too premature to make such recommendations at this point.

Vasopressin dose during septic shock

Exogenous vasopressin can generate plasma concentrations similar to that expected for a particular degree of hypotension and causes a marked pressor response provided intravascular volume is adequate [110]. Infusion of vasopressin at 0.01 U/min raises plasma vasopressin levels to approximately 30 pg/ml, which are slightly higher than the levels reported in patients with cardiogenic shock (about 23 pg/ml) [29, 110]. Raising the infusion rate to 0.04 U/min increases plasma levels to 100 pg/ml [29, 110], which is substantially higher than the levels found during cardiogenic shock [110] and the degree of hypotension [161, 162]. Similarly, studies of low-dose vasopressin (0.01–0.04 U/min) in septic shock can also produce plasma levels that are appropriate for the degree of hypotension.

Volume-resuscitated, septic patients usually respond to vasopressin with a rise in blood pressure. However, there remain several unanswered questions, such as which criteria should be used for titration of the vasopressin dose in order to get optimal benefits from the treatment, what should be the target blood pressure and its role (or perhaps relative contraindication) in low output septic shock. It is also not clear whether vasopressin infusion should be started at a specific dose (i.e., 0.01 U/min) and titrated according to the hemodynamic response, as in the case of conventional vasopressors. It is also not known whether plasma vasopressin levels should be checked to determine relative deficiency of vasopressin before this is administered. It is not possible to determine whether an individual patient has relatively low vasopressin levels based on clinical information only [107]. At this time, routine testing of vasopressin levels does not appear to be feasible due to time requirement for processing the test (about 1 week). Clinical response to a trial of vasopressin is likely to be the best option in determining who would respond to this treatment.

Concerns about vasopressin use

The strong vasoconstrictive properties of vasopressin raise concerns about hypoperfusion in several vascular beds. Among these, the splanchnic circulation is perhaps the one of most concern since gut hypoperfusion may be a contributor to the development of multiorgan dysfunction syndrome. As reviewed above, the data regarding vasopressin’s effects on splanchnic perfusion are conflicting. Although vasopressin does not appear to worsen gastrointestinal perfusion in humans when volume status is optimized [49], the possibility of splanchnic hypoperfusion cannot be excluded. Similarly, there remain concerns regarding myocardial ischemia, which was reported at high doses (10–25 times the dose currently used for septic shock) or delivered via central venous catheter [163, 164].

Available data suggest that the risk of myocardial ischemia from low-dose vasopressin (<0.04 U/min) is small, even when it is administered via a central venous catheter [144, 145]. However, in a retrospective study by Holmes et al., there was increased mortality in patients with septic shock treated with vasopressin when compared to historical controls [134]. Although the majority of patients died due to refractory shock and multiorgan system failure, there was an increased incidence of cardiac arrests, which could potentially be attributed to vasopressin use. One patient developed pulseless electrical activity following a drop in cardiac output with vasopressin at 0.03 U/min. However, it is important to note that the dose of vasopressin was more than 0.05 U/min in four out of six patients who had cardiac arrest. Given the lack of large, randomized, controlled studies addressing the potential adverse effects of vasopressin on the heart, clinicians must remain cautious when using vasopressin, particularly in patients with underlying cardiovascular disease. While nitroglycerin was recommended with high-dose vasopressin in the management of variceal bleeding, there are no data suggesting a need for nitroglycerin with low-dose vasopressin.

Vasopressin is a potent vasoconstrictor of skin vessels at high doses [165, 166]. Extravasation of even small amounts of vasopressin can cause local skin necrosis [167]. Thus, administration via peripheral vessels should be avoided if possible. Bilirubin levels may increase during vasopressin infusion [49]. Although a direct cause and effect relationship has not been demonstrated and no clear mechanisms are known, liver function tests should be followed closely during vasopressin infusion.

Complications related to “low”-dose vasopressin appear to be infrequent and minor and can generally be prevented by avoiding bolus administration and infusion rates greater than 0.04 U/min.

Terlipressin

Terlipressin is a non-selective, synthetic analog of vasopressin that has a slightly greater affinity for vascular V1 receptors than vasopressin (V1/V2 receptor ratio of 2.2 versus 1 for vasopressin) [168]. It has been utilized in Europe in the management of variceal hemorrhage with improved outcome and has been suggested to become first-line therapy due to its improved tolerance compared to endoscopic intervention [2, 4]. It has also been successfully used in the management of hepatorenal syndrome with even greater treatment success when used in conjunction with albumin [3, 5, 169].

Terlipressin may have some advantages over vasopressin. It is less expensive than vasopressin and its long half-life (about 6 h) makes single dose boluses possible, whereas vasopressin is given as an infusion for several days. A single dose of terlipressin (1–2 mg) increases systemic blood pressure within 10–20 min in patients with septic shock. This improvement in blood pressure is sustained for at least 5 h [147]. This is an important attribute of terlipressin as rebound hypotension following discontinuation of vasopressin infusion is a common phenomenon in septic shock [144]. However, bolus infusion may be limited due to potential adverse effects such as increased pulmonary vascular resistance and uncontrolled rise in blood pressure and, therefore, continuous infusion may be preferable [170, 171].

In an experimental model of sepsis, terlipressin increased mean arterial blood pressure in control and endotoxic animals, albeit with a greater increase in the latter [172]. Pulmonary vascular resistance did not change in the control group but increased in the septic animals. It is not clear whether this was due to the reduction in cardiac output or direct vasoconstrictive effects of vasopressin. Interestingly, terlipressin decreased oxygen delivery and consumption in both groups, possibly due to decreased oxygen demand (rather than a decrease in cardiac output). This might be due to antipyretic effects via central V1 receptor and anti-inflammatory effects via release of catecholamines and subsequent activation of β2-adrenergic receptors [173].

Conclusion

The available data regarding the use of vasopressin to sustain blood pressure and organ perfusion in septic shock are, in general, encouraging. Its catecholamine receptor-independent mechanism of action positions vasopressin as a highly useful vasoconstrictor that should be considered early in the course of septic shock when catecholamine infusion rates are being escalated following volume resuscitation. We believe that this approach offers the possibility of forestalling the development of catecholamine unresponsive shock.