Intensive Care Med (2004) 30:12761291DOI 10.1007/s00134-004-2283-8 R EV I EW

Gkhan M. MutluPhillip Factor

Role of vasopressin in the managementof septic shock

Published online: 21 April 2004 Springer-Verlag 2004

This work was supported by the AmericanHeart Association, HL-66211, and theEvanston Northwestern HealthcareResearch Institute.

G. M. Mutlu ())Pulmonary and Critical Care Medicine,Northwestern University Feinberg Schoolof Medicine,303 E. Chicago Avenue, Tarry 14707,Chicago, IL 60611, USAe-mail: g-mutlu@northwestern.eduTel.: +1-312-9088163Fax: +1-312-9084650

P. FactorPulmonary,Allergy and Critical Care Medicine,Columbia University Collegeof Physicians and Surgeons,Room P&S 10-502, 630 W. 168th Street,New York, NY 10032, USA

Abstract Vasopressin is a potentvasopressor for improving organperfusion during septic shock. Therationale for the use of vasopressin isits relative deficiency of plasma lev-els and hypersensitivity to its vaso-pressor effects during septic shock.Growing evidence suggests that low-dose (

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[7, 8]. Pro-vasopressin is generated by the removal ofthe signal peptide from prepro-vasopressin and glycosy-lation in magnocellular neurons in the hypothalamus.Vasopressin precursors migrate along neuronal axons thatterminate in the posterior hypophysis. (Fig. 2) Additionalpost-translational processing of pro-vasopressin occurswithin neurosecretory vesicles yielding vasopressin andneurophysin, which are secreted from axon terminals inthe posterior pituitary.

Most newly synthesized vasopressin is stored intra-cellularly, only 1020% of the total hormonal pool withinthe posterior pituitary can be readily released. The timefrom synthesis to release of the hormone into the systemiccirculation is about 1.5 h [9]. Once secreted into the cir-culation, vasopressin is accompanied, but not bound, byits carrier protein, neurophysin II, which does not appear

to have any independent biological activity. The plasmahalf-life of vasopressin is short, about 515 m. Thus,plasma concentrations [normal: 1 pg/ml (1012 m)] reflectrecent release of active hormone. Clearance occursthrough vasopressinases in the liver and kidneys and isconcentration independent. Vasopressin is also found inlarge quantities in platelets. Accordingly, vasopressinconcentration in platelet-rich plasma is approximatelyfive- to six-fold higher than in platelet-depleted plasma.

Mechanisms of action

Vasopressin has several important physiological functionsincluding water retention by the kidneys and constrictionof vascular smooth muscle (Table 1). Vasopressin exertsits effects via interaction with a family of membrane-bound G protein-coupled vasopressin-specific receptors,V1 and V2. The V1 receptors are located on vascularsmooth muscle cells whereas V2 receptors are on thebasolateral surface of cells of the distal convoluted tu-bules and medullary collecting ducts. There are also V3receptors that are located on the anterior hypophysis andpancreatic islet cells, in the latter they play a role in in-sulin secretion [10].

While both receptors function via activation of gua-nosine triphosphate-binding proteins, their second mes-sengers are different [11]. V1 receptor-ligand interactionslead to activation of phospholipase C, which promoteshydrolysis of phosphatidylinositol-(4,5)-biphosphate andthe formation of inositol (1,4,5)-triphosphate and diacyl-glycerol (Fig. 3). Inositol (1,4,5)-triphosphate (IP3) actsas a second messenger that interacts with its own receptoron the endoplasmic reticulum promoting mobilization ofcalcium from intracellular stores and, thereby, leading tovascular smooth muscle contraction [11]. The V2 receptoris coupled to adenyl cyclase, which produces cAMP(cyclic adenosine monophosphate). Subsequent activationof cAMP-dependent protein kinases (PK) such as PKAcauses recruitment of water channel proteins (aquaporin-2[AQP2], a member of AQP family proteins) from cyto-plasmic vesicles into the luminal membrane of the renaltubule, thereby increasing permeability of the luminal cellmembrane to water [12]. Vasopressin may also increase

Fig. 2 Central neural pathways important in vasopressin synthesisand release. Vasopressin is synthesized in the cell bodies of mag-nocellular neurons located in the paraventricular nuclei within thehypothalamus and released into the bloodstream after migration viathe supraoptic-posterior hypophyseal tract

Table 1 Antidiuretic versusvasoconstrictive effects of va-sopressin

Antidiuretic effect Vasocontrictive effect

Function Maintenance of blood osmolality andvolume

Maintenance of blood pressure

Stimulus Increased blood osmolality Decreased blood volume (>10%)Sensor type Osmoreceptors (hypothalamus), volume

receptors (atria of heart)Baroreceptors (carotid sinus and aorticarch)

Receptortype

V2 (distal tubules and collecting ducts) V1 (vascular smooth muscle cells)

Response Increased H2O uptake in kidney VasoconstrictionEffect Restoration of serum osmolality Restoration of blood volume and

pressure

Fig. 1 The amino acid sequence of the nonapeptide vasopressin

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translocation of AQP2 to the membrane and opening ofindividual water channels [13]. Once APQ2s are recruit-ed, the bulk of water flow across the collecting tubuleproceeds through epithelial cells rather than via intracel-lular junctional complexes [14, 15].

Vascular bed dependent functions

In addition to its antidiuretic action, vasopressin hasfunctions that depend on the sensitivity of a vascular bedto vasopressin; most notable of these are its effects on thesystemic and pulmonary circulation.

Systemic circulation

On a molar basis, vasopressin is a more potent vasocon-strictor than angiotensin II or norepinephrine [16]. Va-sopressin constricts systemic arteries via V1 receptors in adose-dependent fashion. However, exogenous vasopressinhas negligible vasopressor activity in healthy individuals,nor are patients with the syndrome of inappropriate an-tidiuretic hormone predisposed to hypertension [17, 18,19]. The overall effect of vasopressin on systemic bloodpressure is minimal at normal plasma concentrations, asvasoconstriction is generally counteracted by barorecep-tor-mediated reduction in cardiac output [20]. Although,similar baroreflex-mediated effects offset the rise in blood

pressure with other vasopressors, it is more pronouncedwith vasopressin [21].

The difference in pressor response between vasopres-sin and other vasopressors may reflect a centrally medi-ated effect via activation of brain V1 receptors causing aleftward shift of the heart rate-arterial pressure baroreflexresponse [21, 22, 23, 24, 25, 26]. The site involved in themodulation of the baroreflex control of heart rate by va-sopressin appears to be area postrema, where there is highexpression of V1 receptors [21, 26, 27, 28]. In contrast tovasopressin, catecholamines do not have an effect on areapostrema and therefore do not cause a similar degree ofbaroreflex response [21, 27]. Accordingly, a supra-phys-iologic dose of vasopressin (approximately 50 times thenormal) is usually required to cause significant increasesin mean arterial blood pressure in normal animals andhumans [29, 30].

While in vitro and animal studies show an increase inintracellular calcium concentration and inotropic effectafter stimulation of myocardial V1 receptors [31, 32],vasopressin may have net negative inotropic and chro-notropic effects due to increased vagal and decreasedsympathetic tone as well as decreased coronary bloodflow (a consequence of coronary vasoconstriction) whencirculating levels of vasopressin are high [33].

The degree of vasoconstriction by vasopressin differsamong vascular beds [34, 35]. Vasopressin is more potentin skin, skeletal muscle, adipose tissue and pancreas thanin mesenteric, coronary and cerebral circulations [33, 36].

Fig. 3 Mechanisms of action of vasopressin at the cellular level.Both V1 and V2 vasopressin receptors are G protein-coupled re-ceptors. A Stimulation of V1 receptor by vasopressin leads todissociation of Gq. The a-subunit of Gq then stimulates PLCb,which promotes hydrolysis of PIP2, leading to increase in the levelsof DAG and IP3 intracellularly. The IP3 acts on its specific receptor(IP3R) on the endoplasmic reticulum membrane promoting releaseof calcium from intracellular stores. B Interaction of vasopressinwith its V2 receptor causes dissociation of Gs into its subunits,

among which the a-subunit stimulates adenyl cyclase. Activation ofadenyl cyclase leads to an increase in cAMP, which then activatesPKA and the insertion of the pre-synthesized water channel (AQP2)into membrane. AQP-2 aquaporin-2, DAG diacylglycerol, GTPguanosine triphosphate, GDP guanosine diphosphate, IP3 inositol(1,4,5)-triphosphate, IP3R inositol (1,4,5)-triphosphate receptor,PIP2 phosphatidylinositol (4,5)-biphosphate, PKA protein kinaseA, PLCb phospholipase Cb, V1 V1 vasopressin receptor, V2 V2vasopressin receptor

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Diminished vasoconstrictor effect in coronary and cere-bral circulations may be due to the paradoxical release ofnitric oxide (NO) by vasopressin in these vascular beds[37]. Recently, a small study of intrabrachial adminis-tration of vasopressin reported a dose-dependent biphasicchange (vasoconstriction followed by vasodilation) offorearm blood vessels in humans [38]. Sustained infusionwas associated with preservation of the vasodilatory ef-fect, which was presumed to be mediated by NO, how-ever, tachyphylaxis to the constrictive effects of vaso-pressin was noted. The receptor subtype responsible forvasodilation is uncertain, however the V2 receptor ago-nist, 1-desamino[8-D-arginine]vasopressin (DDAVP) de-creases peripheral vascular resistance and causes facialflushing in humans and peripheral vasodilation in dogs.Similarly, inhibition of V2 receptors hinders the va-sodilatory response of the renal afferent arteriole to va-sopressin [39, 40]. Alternately, it has been suggested thatendothelial oxytocin receptors may mediate vasopressin-induced NO production and vasodilation [41].

The effect of vasopressin on splanchnic perfusion iscontroversial. While earlier studies reported reducedmesenteric perfusion even at physiologic concentrations(as low as 10 pg/ml) [42, 43, 44, 45, 46, 47], more recentdata using a vasopressin analog in endotoxemic animalssuggest otherwise [48]. This discrepancy may be at-tributed to differences in volume status between studies.Asfar and colleagues challenged endotoxic animals withfluids prior to administration of the V1 specific analog,terlipressin [48]. Vasopressin increased systemic bloodpressure without affecting gastrointestinal hemodynamicsin fluid-challenged animals. These results suggest thatmaintenance of normal intravascular volume preventsvasopressin-induced reductions in splanchnic perfusion.

A similar discrepancy about the effects of vasopressinon gastrointestinal perfusion has been observed in humanstudies. Paralleling the results of the most recent animalstudy [48], Dnser and colleagues reported an improve-ment in gastrointestinal mucosal perfusion (assessed bygastric tonometry) in patients with septic shock duringcombined vasopressin and norepinephrine infusion com-pared to norepinephrine alone [49]. The differences be-tween this study and earlier studies may be due to the useof higher concentrations and bolus application of vaso-pressin in earlier investigations [50].

Pulmonary circulation

Vasopressin vasodilates the pulmonary circulation de-creasing pulmonary vascular resistance and pressure un-der both normal and hypoxic conditions as a consequenceof V1 receptor-mediated release of NO from endothelialcells [41, 51, 52, 53]. Pulmonary artery vasodilation oc-curs with low concentrations of vasopressin [54]. Pul-monary vascular resistance does increase when extremely

high levels of plasma vasopressin are achieved (>300 pg/ml) [55]. Unlike other vasoactive agents, such as epi-nephrine [56], vasopressin does not appear to alter ven-tilation perfusion relationships [57] in patients who un-dergo cardiopulmonary resuscitation, thus, this findingmay not be relevant in the setting of vasodilatory shock.

Other functions

Vasopressin acts within the central nervous system tolower body temperature and facilitate memory consoli-dation and retrieval [58, 59]. It also heightens hypo-thalamic sensitivity to corticotropin-releasing hormone,thereby increasing adrenocorticotropic hormone (ACTH)release and cortisol production [60, 61]. This effect islikely carried out through NO and cGMP (cyclic guano-sine monophosphate) via central V3 receptors, which werepreviously thought to be V1 receptor subtypes [62]. Va-sopressin does not appear to affect oxytocin release [63].

Activation of V1 receptors by high levels of vasopressinleads to platelet aggregation [39, 64]. Extra-renal V2 re-ceptors appear to mediate the release of several coagula-tion factors (Factor VIIIc, and von Willebrand factor) inresponse to the administration of DDAVP, which is aselective V2-agonist (antidiuretic/vasoconstrictive ratio4000:1) [65, 66]. It has been suggested, but not proven, thatDDAVP decreases peripheral vascular resistance and,consequently, systemic blood pressure and increases plas-ma renin activity via vascular V2 receptors [67], althoughsuch receptors remain to be identified on endothelial cells.

Regulation of secretion

Vasopressin secretion is regulated by both serum osmo-lality (osmoregulation) and blood pressure (baroregula-tion) and is released in response to a variety of stimuli(hemorrhage, hypoxia, hypertonic saline) in normal hu-mans and animals. (Table 2) Both in normal humans and

Table 2 Factors important in vasopressin release

Osmotic regulationPlasma osmolality

Baroregulation (volume status/hemodynamics)Blood volume (change in total or effective vascular volume)Blood pressure

Others factorsNausea/emesisGlycopeniaStressTemperatureEndotoxinCytokinesAngiotensinHypoxemiaDrugs

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experimental animals, vasopressin release is attenuatedor eliminated by pretreatment with glucocorticoids [68].This downregulation of vasopressin release is mediatedby a direct effect of glucocorticoids on the hypothalamusand/or neurohypophysis [69]. Vasopressin and cortico-tropin-releasing hormone co-localize in neurohypophy-seal parvocellular neurons projecting to the median emi-nence and the neurohypophyseal portal blood supply ofthe anterior pituitary. Levels of both vasopressin andcorticotropin-releasing hormone in these neurons are in-versely related to plasma glucocorticoid levels. However,vasopressin appears to be considerably less sensitive tonegative feedback than the corticotropin-releasing factor-ACTH system. Since neurohypophyseal vasopressin isinvolved in the control of ACTH secretion, it is likely thatthe modulation of neurohypophyseal vasopressin by glu-cocorticoids is part of the overall regulation of ACTHsecretion.

Under normal conditions, vasopressin secretion is reg-ulated primarily by changes in plasma osmolality [70, 71](Fig. 4). In healthy adults, the osmotic threshold for va-sopressin secretion ranges from 275 to 290 mosmol/kg(average about 280 mosmol/kg). When plasma osmolalityis less than 280 mosmol/kg, plasma vasopressin levelsrange from 0.5 to 2 pg/ml (less than 4 pg/ml) [72]. Ingeneral, a 1 mosmol/kg rise in plasma osmolality shouldincrease plasma vasopressin levels by 0.38 pg/ml andurinary osmolality by 100 mosmol/kg [13, 73, 74]. Maxi-mally to suppress plasma vasopressin (

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regulation. In the elderly, osmoreceptor sensitivity is en-hanced whereas baroregulation is blunted.

Vasopressin during septic shock

Pathophysiology of septic shock

Septic shock is characterized by physiologically inap-propriate vasodilation leading to organ hypoperfusiondespite adequate fluid resuscitation [84]. The mechanismsof hypotension during septic shock are multifactorial andinclude relative hypovolemia, ineffective intravascularvolume and myocardial dysfunction. Blood return to theright ventricle is typically diminished because of relativehypovolemia due to a combination of loss of intravascularvolume from capillary leak and increased venous capac-itance. Blood return to the left ventricle is also compro-mised due to increased pulmonary vascular resistance.

Excessive vasodilation during septic shock occurs de-spite increased catecholamine levels and activation of therenin-angiotensin-aldosterone system [85, 86, 87, 88].Hyposensitivity of a-adrenergic receptors to catechola-mines due to tissue hypoxia and acidosis also contributesto vasodilation.

The membrane potential of arterial smooth musclecells is regulated by adenosine triphosphate (ATP) sen-sitive K+-channels, which are important regulators of ar-terial tone [89, 90]. The opening of K+-channels closesvoltage-dependent Ca2+-channels, decreasing intracellularcalcium levels leading to smooth muscle relaxation andvasodilation [91]. Septic shock is associated with activa-tion of these K+-ATP channels [89, 90]. Activation of theinducible form of NO synthase and deficiency of vaso-pressin also contribute to the vasodilation of septic shock.

Current management

In addition to identification of the nidus infection, judi-cious fluid administration to compensate for effectivehypovolemia due to vasodilation is an important earlystep in the resuscitation of patients with septic shock [92].This is an especially salient concern because absolutehypovolemia may develop as intravascular volume lossdue to third spacing from capillary leak and increasedinsensible losses are common during sepsis. However, theassessment of volume status and adequacy of the fluidresuscitation is challenging and often based on clinicalgrounds. Therefore, it is not unusual to under-resusci-tate these patients. In fact, Rivers et al. reported that therequirement for adequate fluid resuscitation in septicshock is frequently more than 5 L of crystalloids wheninvasive monitoring techniques are utilized [92].

Persistent hypotension with evidence of organ hypo-perfusion despite volume resuscitation necessitates vaso-

pressor agents. Vasopressors such as dopamine, norepi-nephrine, phenylephrine and epinephrine, alone or incombination, are typically used to treat septic shock. Insome patients, these agents prove ineffective in main-taining adequate organ perfusion due to attenuated vaso-pressor response [93, 94, 95]. Similarly, there is a de-creased response to the potent endogenous vasopressors,endothelin-1 and angiotensin II [96]. Differences in re-sponsiveness to catecholamines among individuals arecommonly observed and may represent differences ofvolume status, duration of septic shock (late versus early),phenotypic variations in responsiveness to endotoxin andother inflammatory mediators, and possibly downregula-tion and/or impairment of catecholamine receptors [94,97, 98]. While numerous studies report the attributes ofvasopressor regimens for the treatment of hypotension, itis important to bear in mind that there are no data thatconvincingly demonstrate a survival benefit with the useof any particular catecholamine or combination of cate-cholamines in septic shock.

Vasopressin physiology during septic shock

Two unique attributes of vasopressin make it well suitedfor the management of septic shock: (1) there often existsa relative deficiency of vasopressin and (2) the sensitivityof the systemic circulation to vasopressin during septicshock is increased (Table 3).

Vasopressin is important in maintaining arterial bloodpressure during hypotension. Indeed, most forms of shockare associated with appropriately high levels of vaso-pressin (Fig. 5). Vasoconstrictive properties of vasopres-sin are important, especially when intravascular volumeor arterial blood pressure is threatened as inhibition of V1receptors causes marked hypotension in subjects witharterial underfilling [16, 17, 29]. The primary stimulus forvasopressin release in hypotensive states is baroreceptor-

Table 3 Rationale for low dose vasopressin in the management ofseptic shock

1. Relative vasopressin deficiencyObserved during late shockLevels begin to decline as early as 6 hRelative deficiency (levels

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mediated [99]. It is noteworthy that exogenous vaso-pressin does not result in a marked pressor response whenadministered to volume-depleted, hypotensive patients,perhaps because the V1 receptors on vascular smoothmuscle are already occupied by endogenous hormone [23,100, 101].

Endotoxin stimulates vasopressin release directly, in-dependent of baroreceptor activity [102]. Experimentalendotoxemia is associated with a prompt rise in vaso-pressin levels as early as 15 min after its administration[45, 103]. In addition, acute phase cytokines [i.e. inter-leukin-1b (IL-1b), IL-6, tumor necrosis-a] enhance va-sopressin production [104, 105, 106].

Plasma vasopressin levels demonstrate a biphasicpattern during septic shock, in both animals and humans,that is characterized by a significant rise in early septicshock. Conversely, vasopressin levels in late septic shockare inappropriately low for the degree of hypotension.This decline begins as early as 6 h after the diagnosis ofseptic shock and results in relative deficiency within 36 h[107] In a recent study by Sharshar et al., all patients werenoted to have levels below 10 pg/ml within 24 h of thediagnosis of septic shock [107]. It is noteworthy that thisrelative deficiency contributes to diminished vasocon-striction (10100 pg/ml) but does not affect antidiureticaction (07 pg/ml).

Low vasopressin levels are most likely due to impairedvasopressin secretion, rather than increased metabolism asvasopressinase levels remain undetectable during estab-lished septic shock [90, 108]. A single study of three pa-tients reported undetectable plasma vasopressinase levels,which were attributed to renal and hepatic dysfunction

commonly seen in septic patients [108]. Proposed mech-anisms for reduced serum vasopressin during sepsis in-clude the exhaustion of pituitary stores caused in responseto baroreceptor-mediated release, autonomic dysfunction,inhibitory effects of increased norepinephrine and in-creased release of NO in the posterior pituitary, (whichmay downregulate vasopressin production) [90, 109,110]. In fact, sepsis may lead to hypothalamic dysfunc-tion/failure and NO mediated reductions of vasopressin[111].

The other unique attribute of vasopressin is increasedsensitivity to its vasoconstrictive effects during septicshock [110]. Although the precise mechanism of thismarked sensitivity to vasopressin during septic shock isnot known at this time, it is probably multifactorial. Lowplasma concentrations of vasopressin during septic shockmake its V1 receptors available for binding by exoge-nously administered hormone. In contrast, exogenouscatecholamines must compete for receptor-binding siteswith endogenous catecholamines, which already occupythese receptors and lead to receptor desensitization/downregulation. Alternately, increased sensitivity mayresult from altered baroreflexes during septic shock. Lossof autonomic nervous regulation has been reported inhyperdynamic states such as septic shock and portal hy-pertension [112, 113]. There is a dissociated cardiovas-cular response to vasopressin in states of dysautonomiapreventing the negative inotropic effect that normallyoffsets its vasopressor effect [23, 114]. Conceivably,sepsis may alter V1 receptor response in area postremaand alter the normal baroreflex response.

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

Other factors contributing to increased sensitivity tovasopressin include potentiation of the vasoconstrictiveeffects of catecholamines [117] and vasopressin-mediateddirect inactivation of K+-ATP channels in a dose-depen-dent manner [118]. Vasopressin enhances the sensitivityof the vasculature to the effects of catecholamines, po-tentiating the contractile effect of catecholamines, elec-trical stimulation and KCl in the arteries [119, 120, 121].This effect is most likely mediated by prostaglandins as itcan be inhibited by cortisol and lithium. Vasopressin alsostimulates synthesis of the most potent vasopressorknown, endothelin-I [122, 123]. Vasopressins effect onK+-ATP channels is particularly interesting as these

Fig. 5 Plasma vasopressin level in normal, healthy individuals andpatients with septic shock (early versus late shock) and other typesof vasodilatory shock. Vasopressin levels during late phase ofseptic shock are lower compared to early septic shock

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channels are important regulators of arterial tone and playa key role in the pathogenesis of septic shock and prob-ably in decreased responsiveness to catecholamines [89,90, 124]. Vasopressin also attenuates endotoxin and IL-1b-stimulated generation of NO [120, 125] and directlydecreases intracellular concentrations of cGMP, the sec-ond messenger of NO [126, 127]. In the setting of per-sistent lactic acidosis, cGMP levels are high and likelycontribute to the peripheral vasodilation and subsequentpersistent hypotension during septic shock. Whatever thecause, heightened sensitivity probably compensates fordecreased serum levels and reduced receptor densityduring septic shock.

The presence and contribution of adrenal insufficiencyand the need for steroid therapy in septic shock are un-resolved controversies. Vasopressin may provide anotherfavorable effect by increasing cortisol levels. Pharmaco-logic doses of vasopressin in animals and humans inducea prompt rise in plasma cortisol levels. Theoretically,depressed levels of vasopressin may be a contributor tothe relative adrenal insufficiency found in some patientswith septic shock.

Differences between vasopressin and other vasopressors

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

Another important difference between vasopressin andcatecholamines is extrarenal V2 receptor-mediated vaso-dilation in selected vascular beds [40, 131]. Vasodilationoccurs at low concentrations and appears to be NO-me-diated [51, 54]. Interestingly, arteries of the circle ofWillis are more sensitive to the vasodilatory effects ofvasopressin than other intracranial and extracranial arte-ries [132].

Vasopressin also differs from catecholamines in termsof its effects on the kidneys. Besides its antidiuretic ef-

fects and osmoregulatory properties, vasopressin causes aparadoxical diuretic effect in patients with hepatorenalsyndrome, congestive heart failure [133] and early septicshock (0.04 U/min) cause a dose-dependent fall in renal bloodflow, glomerular filtration rate and sodium excretion[140, 141]. Afferent arteriole and medullary vessels ap-pear to be the most sensitive parts of the renal vascula-ture. A V1 receptor antagonist can block the vasocon-strictor action of vasopressin on the afferent arteriole.Interestingly, even norepinephrine-induced vasoconstric-tion of the afferent arteriole can be abolished by treat-ment with vasopressin if the V1 receptor is blocked.

Clinical evidence for the use of vasopressinin septic shock

Despite available experimental data and increased en-thusiasm for vasopressin in the management of septicshock, there are no clinical data to suggest any superiority(i.e., outcome benefits) over conventional pressors for thetreatment of septic shock. Available studies about vaso-pressin in the management of septic shock consist of caseseries [110, 142], retrospective analyses [134, 143] andseveral small, randomized, controlled trials [49, 144, 145,146]. Similar to vasopressin, terlipressin, a vasopressinanalog, has also been shown to improve hemodynamicsduring septic shock in a case series [147] (Table 5). Va-sopressin is effective in restoring blood pressure, de-creasing the need for catecholamines in septic shockand also other forms of vasodilatory shock, such as latephase hemorrhagic shock [148], post-cardiotomy [143,

Table 4 Differences betweenlow-dose vasopressin and cate-cholamines as a vasopressor

Vasopressin Catecholamines

Receptor pathway V1 a-adrenergic receptorsPlasma levels during septic shock Increased (early shock) Increased

Decreased (late shock)Vasopressor effect during hypoxia and acidosis Preserved DiminishedEffects on renal vessels (afferent arteriole) Vasodilation Vasoconstriction

Diuresis and natriuresis

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149, 150, 151, 152, 153], post left-ventricular assist de-vice placement [154], solid organ transplantation [155,156, 157] and milrinone-induced hypotension [158] (Ta-ble 6).

In all case series and randomized clinical trials, vaso-pressin has been shown to improve systemic blood pres-sure without significant adverse effects on cardiac func-tion or pulmonary hemodynamics [49, 110, 134, 142, 143,

144, 145]. In some studies there was improvement incardiac output [143, 153, 159, 160], probably due to thedecreased use of norepinephrine, attenuation of endotoxinand IL-1b stimulated generation of NO [120], and in-creased intracellular calcium in myocardial cells [31, 32].In some patients with septic shock, after hemodynamicstability had been achieved with vasopressin, attempts todiscontinue it were unsuccessful [145]. A combination of

Table 5 Studies about vaso-pressin use in septic shock

Investigator Type Numberof patients

Findings

Landry et al. [110] Case series 10 " BP, " SVR, # COLandry et al. [142] Case series 5 " BP, " SVR, " urine outputMalay et al. [145] Prospective placebo

controlled10 " BP, " SVR, # CI

Dnser et al. [143] Retrospective 60 " BP, " SVR, # CI, # PAP# catecholamine requirement

Tsuneyoshi et al.[144]

Prospective casecontrolled

16 " BP, " SVR, " urine output

Holmes et al. [134] Retrospective 50 " BP, " urine output, # CI# catecholamine requirement

Dnser et al. [49] Prospective 48 " BP, " SVR, " CI, " LVSWIPatel et al. [146] Prospective 24 " BP, " urine output

# catecholamine requirementOBrien et al. [147] Case series 8 " BP, # CO(Terlipressin) # catecholamine requirement

BP blood pressure, SVR systemic vascular resistance, CO cardiac output, CI cardiac index, LVSWI leftventricular stroke work index

Table 6 Studies about vaso-pressin use in other forms ofvasodilatory shock

Investigator Type Numberof patients

Findings

Postcardiotomy shockArgenziano et al. [154] Prospective 10 " BP, " SVR

placebo-controlledArgenziano et al. [149] Retrospective 40 " BP, " SVR

# catecholamine requirementArgenziano et al. [150] Retrospective 20 " BP, # CI

# catecholamine requirementRosenzweig et al. [151] Retrospective 11 " BP

# catecholamine requirementMorales et al. [152] Retrospective 50 " BP, " SVR

# catecholamine requirementDnser et al. [143] Retrospective 60 " BP, " SVR, # CI, # PAP

# catecholamine requirementDnser et al. [153] Retrospective 41 " BP, " SVR," LVSWI

# catecholamine requirementMilrinone-induced hypotensionGold et al. [158] Case series 3 " BP

# catecholamine requirementLate phase of hemorrhagic shockMorales et al. [148] Case series 2 " BP

# catecholamine requirementOrgan donorsYoshioka et al. [157] Prospective 16 " BP, " SVR, " survival time

# catecholamine requirementIwai et al. [156] Prospective 25 " BP, " SVR, " CIChen et al. [155] Prospective 10 " BP

# catecholamine requirement

BP blood pressure, SVR systemic vascular resistance, CO cardiac output, CI cardiac index, PAPpulmonary artery pressure, LVSWI left ventricular stroke work index

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vasopressin and norepinephrine appears to be more ef-fective than norepinephrine alone in treating hemody-namic instability during vasodilatory shock [49].

Despite a growing body of evidence for the use ofvasopressin in patients who remain hypotensive despiteescalating doses of catecholamines, no data is availableabout its role as a first-line vasopressor. Given that earlierachievement of a normal hemodynamic status may im-prove outcome in septic shock [92], it would make senseto administer vasopressin early in the disease beforerefractory hypotension develops, to prevent end-organdamage. Doing so may allow diminution of the amountsof other vasopressors, which could potentially forestalldevelopment of insensitivity to catecholamines. However,lack of clinical evidence on its use early in the course ofdisease along with no proof of outcome benefit render ittoo premature to make such recommendations at thispoint.

Vasopressin dose during septic shock

Exogenous vasopressin can generate plasma concentra-tions similar to that expected for a particular degree ofhypotension and causes a marked pressor response pro-vided intravascular volume is adequate [110]. Infusionof vasopressin at 0.01 U/min raises plasma vasopressinlevels to approximately 30 pg/ml, which are slightlyhigher than the levels reported in patients with cardio-genic shock (about 23 pg/ml) [29, 110]. Raising the in-fusion rate to 0.04 U/min increases plasma levels to100 pg/ml [29, 110], which is substantially higher than thelevels found during cardiogenic shock [110] and the de-gree of hypotension [161, 162]. Similarly, studies of low-dose vasopressin (0.010.04 U/min) in septic shock canalso produce plasma levels that are appropriate for thedegree of hypotension.

Volume-resuscitated, septic patients usually respond tovasopressin with a rise in blood pressure. However, thereremain several unanswered questions, such as which cri-teria should be used for titration of the vasopressin dose inorder to get optimal benefits from the treatment, whatshould be the target blood pressure and its role (or perhapsrelative contraindication) in low output septic shock. It isalso not clear whether vasopressin infusion should bestarted at a specific dose (i.e., 0.01 U/min) and titratedaccording to the hemodynamic response, as in the case ofconventional vasopressors. It is also not known whetherplasma vasopressin levels should be checked to determinerelative deficiency of vasopressin before this is adminis-tered. It is not possible to determine whether an individualpatient has relatively low vasopressin levels based onclinical information only [107]. At this time, routinetesting of vasopressin levels does not appear to be feasibledue to time requirement for processing the test (about1 week). Clinical response to a trial of vasopressin is

likely to be the best option in determining who wouldrespond to this treatment.

Concerns about vasopressin use

The strong vasoconstrictive properties of vasopressinraise concerns about hypoperfusion in several vascularbeds. Among these, the splanchnic circulation is perhapsthe one of most concern since gut hypoperfusion may be acontributor to the development of multiorgan dysfunctionsyndrome. As reviewed above, the data regarding vaso-pressins effects on splanchnic perfusion are conflicting.Although vasopressin does not appear to worsen gastro-intestinal perfusion in humans when volume status isoptimized [49], the possibility of splanchnic hypoperfu-sion cannot be excluded. Similarly, there remain concernsregarding myocardial ischemia, which was reported athigh doses (1025 times the dose currently used for septicshock) or delivered via central venous catheter [163,164].

Available data suggest that the risk of myocardialischemia from low-dose vasopressin (

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References

1. Oliver G, Schaefer EA (1895) On thephysiological action of extract of pi-tuitary body and certain other glandu-lar organs. J Physiol 18:277279

2. Escorsell A, Ruiz del Arbol L, PlanasR, Albillos A, Banares R, Cales P,Pateron D, Bernard B, Vinel JP, BoschJ (2000) Multicenter randomized con-trolled trial of terlipressin versussclerotherapy in the treatment of acutevariceal bleeding: the TEST study.Hepatology 32:471476

3. Ortega R, Gines P, Uriz J, Cardenas A,Calahorra B, De Las Heras D, GuevaraM, Bataller R, Jimenez W, Arroyo V,Rodes J (2002) Terlipressin therapywith and without albumin for patientswith hepatorenal syndrome: results ofa prospective, nonrandomized study.Hepatology 36:941948

4. Combier E, Levacher S, Letoumelin P,Joseph A, Pourriat JL, de PouvourvilleG (1999) Cost-effectiveness analysisof the terlipressin-glycerin trinitratecombination in the pre-hospital man-agement of acute gastro-intestinalhaemorrhage in cirrhotic patients.Intensive Care Med 25:364370

5. Antoniades C, Auzinger G (2003)Terlipressin and albumin for the he-patorenal syndrome. Hepatology37:946, Authors reply 946

6. Anonymous (2000) Guidelines 2000for cardiopulmonary resuscitation andemergency cardiovascular care. Part 6:Advanced cardiovascular life support:Section 6: Pharmacology II: agents tooptimize cardiac output and bloodpressure. The American Heart Asso-ciation in collaboration with the In-ternational Liaison Committee on Re-suscitation. Circulation 102:I-129135

7. Rao VV, Loffler C, Battey J, Hans-mann I (1992) The human gene foroxytocin-neurophysin I (OXT) isphysically mapped to chromosome20p13 by in situ hybridization.Cytogenet Cell Genet 61:271273

8. Riddell DC, Mallonee R, Phillips JA,Parks JS, Sexton LA, Hamerton JL(1985) Chromosomal assignment ofhuman sequences encoding argininevasopressin-neurophysin II and growthhormone releasing factor. Somat CellMol Genet 11:189195

9. Sklar AH, Schrier RW (1983) Centralnervous system mediators of vaso-pressin release. Physiol Rev 63:12431280

10. Lee B, Yang C, Chen TH, al-Azawi N,Hsu WH (1995) Effect of AVP andoxytocin on insulin release: involve-ment of V1b receptors. Am J Physiol269:E10951100

11. Birnbaumer M (2000) Vasopressinreceptors. Trends Endocrinol Metab11:406110

prevented by avoiding bolus administration and infusionrates greater than 0.04 U/min.

Terlipressin

Terlipressin is a non-selective, synthetic analog of vaso-pressin that has a slightly greater affinity for vascular V1receptors than vasopressin (V1/V2 receptor ratio of 2.2versus 1 for vasopressin) [168]. It has been utilized inEurope in the management of variceal hemorrhage withimproved outcome and has been suggested to becomefirst-line therapy due to its improved tolerance comparedto endoscopic intervention [2, 4]. It has also been suc-cessfully used in the management of hepatorenal syn-drome with even greater treatment success when used inconjunction with albumin [3, 5, 169].

Terlipressin may have some advantages over vaso-pressin. It is less expensive than vasopressin and its longhalf-life (about 6 h) makes single dose boluses possible,whereas vasopressin is given as an infusion for severaldays. A single dose of terlipressin (12 mg) increasessystemic blood pressure within 1020 min in patients withseptic shock. This improvement in blood pressure issustained for at least 5 h [147]. This is an important at-tribute of terlipressin as rebound hypotension followingdiscontinuation of vasopressin infusion is a commonphenomenon in septic shock [144]. However, bolus in-fusion may be limited due to potential adverse effectssuch as increased pulmonary vascular resistance and un-

controlled rise in blood pressure and, therefore, continu-ous infusion may be preferable [170, 171].

In an experimental model of sepsis, terlipressin in-creased mean arterial blood pressure in control and en-dotoxic animals, albeit with a greater increase in the latter[172]. Pulmonary vascular resistance did not change inthe control group but increased in the septic animals. It isnot clear whether this was due to the reduction in cardiacoutput or direct vasoconstrictive effects of vasopressin.Interestingly, terlipressin decreased oxygen delivery andconsumption in both groups, possibly due to decreasedoxygen demand (rather than a decrease in cardiac output).This might be due to antipyretic effects via central V1receptor and anti-inflammatory effects via release ofcatecholamines and subsequent activation of b2-adrener-gic receptors [173].

Conclusion

The available data regarding the use of vasopressin tosustain blood pressure and organ perfusion in septic shockare, in general, encouraging. Its catecholamine receptor-independent mechanism of action positions vasopressin asa highly useful vasoconstrictor that should be consideredearly in the course of septic shock when catecholamineinfusion rates are being escalated following volume re-suscitation. We believe that this approach offers thepossibility of forestalling the development of catechol-amine unresponsive shock.

1287

12. Deen PM, Verdijk MA, Knoers NV,Wieringa B, Monnens LA, van Os CH,van Oost BA (1994) Requirement ofhuman renal water channel aquaporin-2 for vasopressin-dependent concen-tration of urine. Science 264:9295

13. Berl T, Robertson GL (2000) Patho-physiology of water metabolism. In:Brenner BM (ed) Brenner & RectorsThe Kidney. Saunders, Philadelphia,pp 866924

14. Fushimi K, Uchida S, Hara Y, HirataY, Marumo F, Sasaki S (1993) Clon-ing and expression of apical mem-brane water channel of rat kidneycollecting tubule. Nature 361:549552

15. Nielsen S, DiGiovanni SR, Chris-tensen EI, Knepper MA, Harris HW(1993) Cellular and subcellular im-munolocalization of vasopressin-regu-lated water channel in rat kidney. ProcNatl Acad Sci U S A 90:1166311667

16. Reid IA, Schwartz J (1984) Role ofvasopressin in the control of bloodpressure. In: Martini L, Ganong WF(eds) Frontiers in neuroendocrinology.Raven Press, New York, pp 177197

17. Wagner HWJ, Braunwald E (1956)The pressor effect of the antidiureticprinciple of the posterior pituitary inorthostatic hypotension. J Clin Invest35:14121418

18. Ohnishi K, Saito M, Nakayama T,Hatano H, Okuda K (1987) Effects ofvasopressin on portal hemodynamicsin patients with portal hypertension.Am J Gastroenterol 82:135138

19. Morton JJ, Padfield PL (1986) Vaso-pressin and hypertension in man.J Cardiovasc Pharmacol 8(Suppl 7):S101106

20. Abboud FM, Floras JS, Aylward PE,Guo GB, Gupta BN, Schmid PG(1990) Role of vasopressin in cardio-vascular and blood pressure regula-tion. Blood Vessels 27:106115

21. Undesser KP, Hasser EM, HaywoodJR, Johnson AK, Bishop VS (1985)Interactions of vasopressin with thearea postrema in arterial baroreflexfunction in conscious rabbits. Circ Res56:410417

22. Luk J, Ajaelo I, Wong V, Wong J,Chang D, Chou L, Reid IA (1993)Role of V1 receptors in the action ofvasopressin on the baroreflex controlof heart rate. Am J Physiol 265:R524529

23. Cowley AW Jr, Monos E, Guyton AC(1974) Interaction of vasopressin andthe baroreceptor reflex system in theregulation of arterial blood pressure inthe dog. Circ Res 34:505514

24. Cox BF, Hay M, Bishop VS (1990)Neurons in area postrema mediatevasopressin-induced enhancementof the baroreflex. Am J Physiol258:H19431946

25. Webb RL, Osborn JW Jr, CowleyAW Jr (1986) Cardiovascular actionsof vasopressin: baroreflex modulationin the conscious rat. Am J Physiol251:H1244251

26. Tribollet E, Ueta Y, Heitz F,Marguerat A, Koizumi K, YamashitaH (2002) Up-regulation of vasopressinand angiotensin II receptors in thethalamus and brainstem of inbredpolydipsic mice. Neuroendocrinology75:113123

27. Peuler JD, Edwards GL, Schmid PG,Johnson AK (1990) Area postrema anddifferential reflex effects of vasopres-sin and phenylephrine in rats. Am JPhysiol 258:H12551259

28. Xue B, Gole H, Pamidimukkala J, HayM (2003) Role of the area postrema inangiotensin II modulation of barore-flex control of heart rate in consciousmice. Am J Physiol Heart Circ Physiol284:H10031007

29. Mohring J, Glanzer K, Maciel JA Jr,Dusing R, Kramer HJ, Arbogast R,Koch-Weser J (1980) Greatly en-hanced pressor response to antidiuretichormone in patients with impairedcardiovascular reflexes due to idio-pathic orthostatic hypotension.J Cardiovasc Pharmacol 2:367376

30. Cowley AW Jr, Switzer SJ, GuinnMM (1980) Evidence and quantifica-tion of the vasopressin arterial pressurecontrol system in the dog. Circ Res46:5867

31. Xu YJ, Gopalakrishnan V (1991)Vasopressin increases cytosolic free[Ca2+] in the neonatal rat cardiomy-ocyte. Evidence for V1 subtype re-ceptors. Circ Res 69:239245

32. Fujisawa S, Iijima T (1999) On theinotropic actions of arginine vaso-pressin in ventricular muscle of theguinea pig heart. Jpn J Pharmacol81:309312

33. Laszlo FA, Laszlo F Jr, De Wied D(1991) Pharmacology and clinicalperspectives of vasopressin antago-nists. Pharmacol Rev 43:73108

34. Garcia-Villalon AL, Garcia JL,Fernandez N, Monge L, Gomez B,Dieguez G (1996) Regional differ-ences in the arterial response to vaso-pressin: role of endothelial nitric ox-ide. Br J Pharmacol 118:18481854

35. Moursi MM, van Wylen DG, DAlecyLG (1985) Regional blood flowchanges in response to mildly pressordoses of triglycyl desamino lysine andarginine vasopressin in the consciousdog. J Pharmacol Exp Ther 232:360368

36. Liard JF, Deriaz O, Schelling P,Thibonnier M (1982) Cardiac outputdistribution during vasopressin infu-sion or dehydration in conscious dogs.Am J Physiol 243:H663669

37. Vanhoutte PM, Katusic ZS, ShepherdJT (1984) Vasopressin induces endo-thelium-dependent relaxation of cere-bral and coronary, but not of systemic,arteries. J Hypertens Suppl 2:S421422

38. Affolter JT, McKee SP, Helmy A,Jones CR, Newby DE, Webb DJ(2003) Intra-arterial vasopressin inthe human forearm: pharmacodynam-ics and the role of nitric oxide.Clin Pharmacol Ther 74:916

39. Bichet DG, Razi M, Lonergan M,Arthus MF, Papukna V, Kortas C,Barjon JN (1988) Hemodynamic andcoagulation responses to 1-de-samino[8-D-arginine] vasopressin inpatients with congenital nephrogenicdiabetes insipidus. N Engl J Med318:881887

40. Liard JF (1992) cAMP and extrarenalvasopressin V2 receptors in dogs.Am J Physiol 263:H18881891

41. Thibonnier M, Conarty DM, PrestonJA, Plesnicher CL, Dweik RA,Erzurum SC (1999) Human vascularendothelial cells express oxytocin re-ceptors. Endocrinology 140:13011309

42. Cronenwett JL, Baver-Neff BS,Grekin RJ, Sheagren JN (1986) Therole of endorphins and vasopressin incanine endotoxin shock. J Surg Res41:609619

43. Avontuur JA, Bruining HA, Ince C(1995) Inhibition of nitric oxide syn-thesis causes myocardial ischemia inendotoxemic rats. Circ Res 76:418425

44. Wilson MF, Brackett DJ, Archer LT,Hinshaw LB (1980) Mechanisms ofimpaired cardiac function by vaso-pressin. Ann Surg 191:494500

45. Brackett DJ, Schaefer CF, TompkinsP, Fagraeus L, Peters LJ, Wilson MF(1985) Evaluation of cardiac output,total peripheral vascular resistance andplasma concentrations of vasopressinin the conscious, unrestrained rat dur-ing endotoxemia. Circ Shock 17:273284

46. Heyndrickx GR, Boettcher DH,Vatner SF (1976) Effects of angioten-sin, vasopressin and methoxamine oncardiac function and blood flow dis-tribution in conscious dogs. Am JPhysiol 231:15791587

47. Schmid PG, Abboud FM, WendlingMG, Ramberg ES, Mark AL, HeistadDD, Eckstein JW (1974) Regionalvascular effects of vasopressin: plasmalevels and circulatory responses.Am J Physiol 227:9981004

1288

48. Asfar P, Pierrot M, Veal N, Moal F,Oberti F, Croquet V, Douay O, GalloisY, Saumet JL, Alquier P, Cales P(2003) Low-dose terlipressin improvessystemic and splanchnic hemodynam-ics in fluid-challenged endotoxic rats.Crit Care Med 31:215220

49. Dunser MW, Mayr AJ, Ulmer H,Knotzer H, Sumann G, Pajk W,Friesenecker B, Hasibeder WR (2003)Arginine vasopressin in advanced va-sodilatory shock: a prospective, ran-domized, controlled study. Circulation107:23132319

50. Shelly MP, Greatorex R, Calne RY,Park GR (1988) The physiological ef-fects of vasopressin when used tocontrol intra- abdominal bleeding.Intensive Care Med 14:526531

51. Okamura T, Ayajiki K, Fujioka H,Toda N (1999) Mechanisms underly-ing arginine vasopressin-induced re-laxation in monkey isolated coronaryarteries. J Hypertens 17:673678

52. Russ RD, Walker BR (1992) Role ofnitric oxide in vasopressinergic pul-monary vasodilatation. Am J Physiol262:H743747

53. Evora PR, Pearson PJ, Schaff HV(1993) Arginine vasopressin inducesendothelium-dependent vasodilatationof the pulmonary artery. V1-receptor-mediated production of nitric oxide.Chest 103:12411245

54. Okamura T, Toda M, Ayajiki K, TodaN (1997) Receptor subtypes involvedin relaxation and contraction by argi-nine vasopressin in canine isolatedshort posterior ciliary arteries.J Vasc Res 34:464472

55. Wallace AW, Tunin CM, Shoukas AA(1989) Effects of vasopressin on pul-monary and systemic vascular me-chanics. Am J Physiol 257:H12281234

56. Tang W, Weil MH, Gazmuri RJ, SunS, Duggal C, Bisera J (1991) Pulmo-nary ventilation/perfusion defects in-duced by epinephrine during cardio-pulmonary resuscitation. Circulation84:21012107

57. Loeckinger A, Kleinsasser A, WenzelV, Mair V, Keller C, Kolbitsch C,Recheis W, Schuster A, Lindner KH(2002) Pulmonary gas exchange aftercardiopulmonary resuscitation witheither vasopressin or epinephrine.Crit Care Med 30:20592062

58. Pittman QJ, Wilkinson MF (1992)Central arginine vasopressin and en-dogenous antipyresis. Can J PhysiolPharmacol 70:786790

59. Perras B, Pannenborg H, Marshall L,Pietrowsky R, Born J, Lorenz Fehm H(1999) Beneficial treatment of age-related sleep disturbances with pro-longed intranasal vasopressin. J ClinPsychopharmacol 19:2836

60. Antoni FA (1993) Vasopressinergiccontrol of pituitary adrenocorticotro-pin secretion comes of age. FrontNeuroendocrinol 14:76122

61. Tucci JR, Espiner EA, Jagger PI,Lauler DP, Thorn GW (1968) Vaso-pressin in the evaluation of pituitary-adrenal function. Ann Intern Med69:191202

62. Bugajski J, Gadek-Michalska A,Olowska A, Borycz J, Glod R (1997)Role of nitric oxide in the vasopressin-induced corticosterone secretion inrats. J Physiol Pharmacol 48:805812

63. Moos F, Freund-Mercier MJ, GuerneY, Guerne JM, Stoeckel ME, RichardP (1984) Release of oxytocin andvasopressin by magnocellular nucleiin vitro: specific facilitatory effectof oxytocin on its own release.J Endocrinol 102:6372

64. Haslam RJ, Rosson GM (1972) Ag-gregation of human blood platelets byvasopressin. Am J Physiol 223:958967

65. Mannucci PM, Aberg M, Nilsson IM,Robertson B (1975) Mechanism ofplasminogen activator and factor VIIIincrease after vasoactive drugs. Br JHaematol 30:8193

66. Richardson DW, Robinson AG (1985)Desmopressin. Ann Intern Med103:228239

67. Hirsch AT, Dzau VJ, Majzoub JA,Creager MA (1989) Vasopressin-me-diated forearm vasodilation in normalhumans. Evidence for a vascular va-sopressin V2 receptor. J Clin Invest84:418426

68. Raff H (1987) Glucocorticoid inhibi-tion of neurohypophysial vasopressinsecretion. Am J Physiol 252:R635644

69. Papanek PE, Sladek CD, Raff H(1997) Corticosterone inhibition ofosmotically stimulated vasopressinfrom hypothalamic-neurohypophysialexplants. Am J Physiol 272:R158162

70. Dunn FL, Brennan TJ, Nelson AE,Robertson GL (1973) The role ofblood osmolality and volume in regu-lating vasopressin secretion in the rat.J Clin Invest 52:32123219

71. Wade CE, Keil LC, Ramsay DJ (1983)Role of volume and osmolality in thecontrol of plasma vasopressin in de-hydrated dogs. Neuroendocrinology37:349353

72. Cowley AW Jr, Cushman WC, QuillenEW Jr, Skelton MM, Langford HG(1981) Vasopressin elevation in es-sential hypertension and increasedresponsiveness to sodium intake.Hypertension 3:I-93100

73. Robinson AG, Verbalis JG (2003)Posterior pituitary gland. In: LarsenPR, Kronenberg HM, Melmed S,Polonsky KS (eds) Williams Textbookof Endocrinology. Saunders, Philadel-phia, pp 281330

74. Robertson GL, Shelton RL, Athar S(1976) The osmoregulation of vaso-pressin. Kidney Int 10:2537

75. Lee ME, Thrasher TN, Keil LC,Ramsay DJ (1986) Cardiac receptors,vasopressin and corticosteroid releaseduring arterial hypotension in dogs.Am J Physiol 251:R614620

76. Goetz KL, Wang BC, Sundet WD(1984) Comparative effects of cardiacreceptors and sinoaortic baroreceptorson elevations of plasma vasopressinand renin activity elicited by haemor-rhage. J Physiol (Paris) 79:440445

77. Hammer M, Olgaard K, Schapira A,Bredgaard Sorensen M, Jensen K,Bonde-Petersen F (1988) Hypovolem-ic stimuli and vasopressin secretion inman. Acta Endocrinol (Copenh)118:465473

78. Leimbach WN Jr, Schmid PG, MarkAL (1984) Baroreflex control of plas-ma arginine vasopressin in humans.Am J Physiol 247:H638644

79. De Lima J, Caillens H, Beaufils M,Ardaillou R (1981) Effects of furose-mide-induced plasma volume reduc-tion on plasma antidiuretic hormonein normal and hypertensive subjects.Clin Nephrol 15:246251

80. Callahan MF, Ludwig M, Tsai KP,Sim LJ, Morris M (1997) Barorecep-tor input regulates osmotic controlof central vasopressin secretion.Neuroendocrinology 65:238245

81. Goldsmith SR, Cowley AW Jr, FrancisGS, Cohn JN (1984) Effect of in-creased intracardiac and arterial pres-sure on plasma vasopressin in humans.Am J Physiol 246:H647651

82. Robertson GL, Athar S (1976) Theinteraction of blood osmolality andblood volume in regulating plasmavasopressin in man. J Clin EndocrinolMetab 42:613620

83. Schrier RW, Berl T, Anderson RJ(1979) Osmotic and nonosmotic con-trol of vasopressin release. Am JPhysiol 236:F321332

84. American College of Chest Physi-cians/Society of Critical Care Medi-cine Consensus Conference (1992)Definitions for sepsis and organ failureand guidelines for the use of innova-tive therapies in sepsis. Crit Care Med20:864874

85. Sylvester JT, Scharf SM, Gilbert RD,Fitzgerald RS, Traystman RJ (1979)Hypoxic and CO hypoxia in dogs:hemodynamics, carotid reflexes andcatecholamines. Am J Physiol236:H2228

1289

86. Benedict CR, Rose JA (1992) Arterialnorepinephrine changes in patientswith septic shock. Circ Shock 38:165172

87. Cumming AD, Driedger AA,McDonald JW, Lindsay RM, Solez K,Linton AL (1988) Vasoactive hor-mones in the renal response to sys-temic sepsis. Am J Kidney Dis 11:2332

88. Chernow B, Roth BL (1986) Pharma-cologic manipulation of the peripheralvasculature in shock: clinical and ex-perimental approaches. Circ Shock18:141155

89. Landry DW, Oliver JA (1992) TheATP-sensitive K+ channel mediateshypotension in endotoxemia and hyp-oxic lactic acidosis in dog. J ClinInvest 1992:20712074

90. Landry DW, Oliver JA (2001) Thepathogenesis of vasodilatory shock.N Engl J Med 345:588595

91. Nelson MT, Quayle JM (1995) Physi-ological roles and properties of potas-sium channels in arterial smoothmuscle. Am J Physiol 268:C799822

92. Rivers E, Nguyen B, Havstad S,Ressler J, Muzzin A, Knoblich B,Peterson E, Tomlanovich M (2001)Early goal-directed therapy in thetreatment of severe sepsis and septicshock. N Engl J Med 345:13681377

93. Chernow B, Rainey TG, Lake CR(1982) Endogenous and exogenouscatecholamines in critical care medi-cine. Crit Care Med 10:409416

94. Tsuneyoshi I, Kanmura Y, YoshimuraN (1996) Nitric oxide as a mediatorof reduced arterial responsiveness inseptic patients. Crit Care Med24:10831086

95. Fink MP, Homer LD, Fletcher JR(1985) Diminished pressor response toexogenous norepinephrine and angio-tensin II in septic, unanesthetized rats:evidence for a prostaglandin-mediatedeffect. J Surg Res 38:335342

96. Hollenberg SM, Tangora JJ,Piotrowski MJ, Easington C, ParrilloJE (1997) Impaired microvascular va-soconstrictive responses to vasopressinin septic rats. Crit Care Med 25:869873

97. Arbour NC, Lorenz E, Schutte BC,Zabner J, Kline JN, Jones M, Frees K,Watt JL, Schwartz DA (2000) TLR4mutations are associated with endo-toxin hyporesponsiveness in humans.Nat Genet 25:187191

98. Paya D, Stoclet JC (1995) Involve-ment of bradykinin and nitric oxidein the early hemodynamic effects oflipopolysaccharide in rats. Shock3:376379

99. Thrasher TN, Keil LC (2000) Systolicpressure predicts plasma vasopressinresponses to hemorrhage and venacaval constriction in dogs. Am J Phy-siol Regul Integr Comp Physiol279:R10351042

100. Wolfer RS, Lovell NH, Brunner MJ(1994) Exogenous arginine vasopres-sin does not enhance carotid barore-flex control in the conscious dog.Am J Physiol 266:R15101516

101. Robinson JL (1986) Effect of vaso-pressin and phenylephrine on arterialpressure and heart rate in consciousdogs. Am J Physiol 251:H253260

102. Kasting NW, Mazurek MF, Martin JB(1985) Endotoxin increases vasopres-sin release independently of knownphysiological stimuli. Am J Physiol248:E420424

103. Wilson MF, Brackett DJ, Tompkins P,Benjamin B, Archer LT, Hinshaw LB(1981) Elevated plasma vasopressinconcentrations during endotoxin andE. coli shock. Adv Shock Res 6:1526

104. Mastorakos G, Weber JS, MagiakouMA, Gunn H, Chrousos GP (1994)Hypothalamic-pituitary-adrenal axisactivation and stimulation of systemicvasopressin secretion by recombinantinterleukin-6 in humans: potential im-plications for the syndrome of inap-propriate vasopressin secretion. J ClinEndocrinol Metab 79:934939

105. Chikanza IC, Petrou P, Chrousos G(2000) Perturbations of arginine vaso-pressin secretion during inflammatorystress. Pathophysiologic implications.Ann N Y Acad Sci 917:825834

106. Zelazowski P, Patchev VK, Zela-zowska EB, Chrousos GP, Gold PW,Sternberg EM (1993) Release of hy-pothalamic corticotropin-releasinghormone and arginine-vasopressin byinterleukin 1 beta and alpha MSH:studies in rats with different suscepti-bility to inflammatory disease. BrainRes 631:2226

107. Sharshar T, Blanchard A, Paillard M,Raphael JC, Gajdos P, Annane D(2003) Circulating vasopressin levelsin septic shock. Crit Care Med31:17521758

108. Sharshar T, Carlier R, Blanchard A,Feydy A, Gray F, Paillard M, RaphaelJC, Gajdos P, Annane D (2002) De-pletion of neurohypophyseal contentof vasopressin in septic shock.Crit Care Med 30:497500

109. Goldsmith SR (1998) Vasopressin de-ficiency and vasodilation of septicshock. Circulation 97:292293

110. Landry DW, Levin HR, Gallant EM,Ashton RC, Seo S, DAlessandro D,Oz MC, Oliver JA (1997) Vasopressindeficiency contributes to the vasodi-lation of septic shock. Circulation95:11221125

111. Rivier C (2003) Role of nitric oxide inregulating the rat hypothalamic-pitui-tary-adrenal axis response to endo-toxemia. Ann N Y Acad Sci 992:7285

112. Godin PJ, Fleisher LA, Eidsath A,Vandivier RW, Preas HL, Banks SM,Buchman TG, Suffredini AF (1996)Experimental human endotoxemia in-creases cardiac regularity: results froma prospective, randomized, crossovertrial. Crit Care Med 24:11171124

113. Moreau R, Hadengue A, Soupison T,Mechin G, Assous M, Roche-Sicot J,Sicot C (1990) Abnormal pressor re-sponse to vasopressin in patients withcirrhosis: evidence for impaired buff-ering mechanisms. Hepatology 12:712

114. Montani JP, Liard JF, Schoun J,Mohring J (1980) Hemodynamic ef-fects of exogenous and endogenousvasopressin at low plasma concentra-tions in conscious dogs. Circ Res47:346355

115. Patel S, Gaspers LD, Boucherie S,Memin E, Stellato KA, Guillon G,Combettes L, Thomas AP (2002) In-ducible nitric-oxide synthase attenu-ates vasopressin-dependent Ca2+ sig-naling in rat hepatocytes. J Biol Chem277:3377633782

116. Bucher M, Hobbhahn J, Taeger K,Kurtz A (2002) Cytokine-mediateddownregulation of vasopressin V(1A)receptors during acute endotoxemia inrats. Am J Physiol Regul Integr CompPhysiol 282:R979984

117. Bartelstone HJ, Nasmyth PA (1965)Vasopressin potentiation of catechol-amine actions in dog, rat, cat and rataortic strip. Am J Physiol 208:754762

118. Wakatsuki T, Nakaya Y, Inoue I(1992) Vasopressin modulates K(+)-channel activities of cultured smoothmuscle cells from porcine coronaryartery. Am J Physiol 263:H491496

119. Hamu Y, Kanmura Y, Tsuneyoshi I,Yoshimura N (1999) The effects ofvasopressin on endotoxin-induced at-tenuation of contractile responses inhuman gastroepiploic arteries in vitro.Anesth Analg 88:542548

120. Kusano E, Tian S, Umino T, TetsukaT, Ando Y, Asano Y (1997) Argininevasopressin inhibits interleukin-1 beta-stimulated nitric oxide and cyclicguanosine monophosphate productionvia the V1 receptor in cultured ratvascular smooth muscle cells.J Hypertens 15:627632

121. Salzman AL, Vromen A, DenenbergA, Szabo C (1997) K(ATP)-channelinhibition improves hemodynamicsand cellular energetics in hemorrhagicshock. Am J Physiol 272:H688694

1290

122. Balakrishnan SM, Gopalakrishnan V,McNeill JR (1997) Endothelin con-tributes to the hemodynamic effects ofvasopressin in spontaneous hyperten-sion. Eur J Pharmacol 334:5560

123. Levin ER (1996) Endothelins as car-diovascular peptides. Am J Nephrol16:246251

124. Takakura K, Taniguchi T, MuramatsuI, Takeuchi K, Fukuda S (2002)Modification of alpha1 -adrenoceptorsby peroxynitrite as a possible mecha-nism of systemic hypotension in sep-sis. Crit Care Med 30:894899

125. Umino T, Kusano E, Muto S, AkimotoT, Yanagiba S, Ono S, Amemiya M,Ando Y, Homma S, Ikeda U, ShimadaK, Asano Y (1999) AVP inhibits LPS-and IL-1beta-stimulated NO andcGMP via V1 receptor in cultured ratmesangial cells. Am J Physiol276:F433441

126. Nambi P, Whitman M, Gessner G,Aiyar N, Crooke ST (1986) Vaso-pressin-mediated inhibition of atrialnatriuretic factor-stimulated cGMPaccumulation in an established smoothmuscle cell line. Proc Natl Acad SciU S A 83:84928495

127. Nambi P, Whitman M, Aiyar N,Crooke ST (1988) Inhibition of for-mation of cyclic AMP and cyclicGMP by vasopressin in smooth-mus-cle cells is insensitive to pertussistoxin. Biochem J 254:449453

128. Taguchi H, Heistad DD, Chu Y, RiosCD, Ooboshi H, Faraci FM (1996)Vascular expression of inducible nitricoxide synthase is associated with ac-tivation of Ca(++)-dependent K+channels. J Pharmacol Exp Ther279:15141519

129. Roth BL, Spitzer JA (1987) Alteredhepatic vasopressin and alpha1-adrenergic receptors after chronicendotoxin infusion. Am J Physiol252:E699702

130. Fox AW, May RE, Mitch WE (1992)Comparison of peptide and nonpeptidereceptor-mediated responses in rat tailartery. J Cardiovasc Pharmacol20:282289

131. Walker BR (1986) Role of vasopressinin the cardiovascular response to hyp-oxia in the conscious rat. Am J Physiol251:H1316323

132. Suzuki Y, Satoh S, Oyama H,Takayasu M, Shibuya M (1993) Re-gional differences in the vasodilatorresponse to vasopressin in canine ce-rebral arteries in vivo. Stroke24:10491053, discussion 10531054

133. Eisenman A, Armali Z, Enat R, BankirL, Baruch Y (1999) Low-dose vaso-pressin restores diuresis both in pa-tients with hepatorenal syndrome andin anuric patients with end-stage heartfailure. J Intern Med 246:183190

134. Holmes CL, Walley KR, Chittock DR,Lehman T, Russell JA (2001) The ef-fects of vasopressin on hemodynamicsand renal function in severe septicshock: a case series. Intensive CareMed 27:14161421

135. Cross RB, Trace JW, Vattuone JR(1974) The effect of vasopressin uponthe vasculature of the isolated perfusedrat kidney. J Physiol 239:435442

136. Aiyar N, Nambi P, Crooke ST (1990)Desensitization of vasopressin sensi-tive adenylate cyclase by vasopressinand phorbol esters. Cell Signal 2:153160

137. Rudichenko VM, Beierwaltes WH(1995) Arginine vasopressin-inducedrenal vasodilation mediated by nitricoxide. J Vasc Res 32:100105

138. Edwards RM, Trizna W, Kinter LB(1989) Renal microvascular effects ofvasopressin and vasopressin antago-nists. Am J Physiol 256:F274278

139. Gutkowska J, Jankowski M, LambertC, Mukaddam-Daher S, Zingg HH,McCann SM (1997) Oxytocin releasesatrial natriuretic peptide by combiningwith oxytocin receptors in the heart.Proc Natl Acad Sci U S A 94:1170411709

140. McVicar AJ (1988) Dose-responseeffects of pressor doses of argininevasopressin on renal haemodynamicsin the rat. J Physiol 404:535546

141. Harrison-Bernard LM, Carmines PK(1994) Juxtamedullary microvascularresponses to arginine vasopressin in ratkidney. Am J Physiol 267:F249256

142. Landry DW, Levin HR, Gallant EM,Seo S, DAlessandro D, Oz MC,Oliver JA (1997) Vasopressin pressorhypersensitivity in vasodilatory septicshock. Crit Care Med 25:12791282

143. Dunser MW, Mayr AJ, Ulmer H,Ritsch N, Knotzer H, Pajk W, LucknerG, Mutz NJ, Hasibeder WR (2001)The effects of vasopressin on systemichemodynamics in catecholamine-re-sistant septic and postcardiotomyshock: a retrospective analysis. AnesthAnalg 93:713

144. Tsuneyoshi I, Yamada H, Kakihana Y,Nakamura M, Nakano Y, Boyle WA3rd (2001) Hemodynamic and meta-bolic effects of low-dose vasopressininfusions in vasodilatory septic shock.Crit Care Med 29:487493

145. Malay MB, Ashton RC Jr, LandryDW, Townsend RN (1999) Low-dosevasopressin in the treatment of va-sodilatory septic shock. J Trauma47:699703, discussion 703705

146. Patel BM, Chittock DR, Russell JA,Walley KR (2002) Beneficial effectsof short-term vasopressin infusionduring severe septic shock.Anesthesiology 96:576582

147. OBrien A, Clapp L, Singer M (2002)Terlipressin for norepinephrine-resis-tant septic shock. Lancet 359:12091210

148. Morales D, Madigan J, Cullinane S,Chen J, Heath M, Oz M, Oliver JA,Landry DW (1999) Reversal by vaso-pressin of intractable hypotension inthe late phase of hemorrhagic shock.Circulation 100:226229

149. Argenziano M, Chen JM, ChoudhriAF, Cullinane S, Garfein E, WeinbergAD, Smith CR Jr, Rose EA, LandryDW, Oz MC (1998) Management ofvasodilatory shock after cardiac sur-gery: identification of predisposingfactors and use of a novel pressoragent. J Thorac Cardiovasc Surg116:973980

150. Argenziano M, Chen JM, Cullinane S,Choudhri AF, Rose EA, Smith CR,Edwards NM, Landry DW, Oz MC(1999) Arginine vasopressin in themanagement of vasodilatory hypoten-sion after cardiac transplantation. JHeart Lung Transplant 18:814817

151. Rosenzweig EB, Starc TJ, Chen JM,Cullinane S, Timchak DM, GersonyWM, Landry DW, Galantowicz ME(1999) Intravenous arginine-vasopres-sin in children with vasodilatory shockafter cardiac surgery. Circulation100:II-182106

152. Morales DL, Gregg D, Helman DN,Williams MR, Naka Y, Landry DW,Oz MC (2000) Arginine vasopressin inthe treatment of 50 patients withpostcardiotomy vasodilatory shock.Ann Thorac Surg 69:102106

153. Dunser MW, Mayr AJ, Stallinger A,Ulmer H, Ritsch N, Knotzer H, PajkW, Mutz NJ, Hasibeder WR (2002)Cardiac performance during vasopres-sin infusion in postcardiotomy shock.Intensive Care Med 28:746751

154. Argenziano M, Choudhri AF, Oz MC,Rose EA, Smith CR, Landry DW(1997) A prospective randomized trialof arginine vasopressin in the treat-ment of vasodilatory shock after leftventricular assist device placement.Circulation 96:II-286290

155. Chen JM, Cullinane S, Spanier TB,Artrip JH, John R, Edwards NM, OzMC, Landry DW (1999) Vasopressindeficiency and pressor hypersensitivityin hemodynamically unstable organdonors. Circulation 100:II-244246

156. Iwai A, Sakano T, Uenishi M, Sugi-moto H, Yoshioka T, Sugimoto T(1989) Effects of vasopressin and cat-echolamines on the maintenance ofcirculatory stability in brain-dead pa-tients. Transplantation 48:613617

1291

157. Yoshioka T, Sugimoto H, Uenishi M,Sakamoto T, Sadamitsu D, Sakano T,Sugimoto T (1986) Prolonged hemo-dynamic maintenance by the com-bined administration of vasopressinand epinephrine in brain death: aclinical study. Neurosurgery 18:565567

158. Gold JA, Cullinane S, Chen J, Oz MC,Oliver JA, Landry DW (2000) Vaso-pressin as an alternative to norepi-nephrine in the treatment of milrinone-induced hypotension. Crit Care Med28:249252

159. Overand PT, Teply JF (1998) Vaso-pressin for the treatment of refractoryhypotension after cardiopulmonarybypass. Anesth Analg 86:12071209

160. Eyraud D, Brabant S, Nathalie D,Fleron MH, Gilles G, Bertrand M,Coriat P (1999) Treatment of intraop-erative refractory hypotension withterlipressin in patients chronicallytreated with an antagonist of the renin-angiotensin system. Anesth Analg88:980984

161. Minaker KL, Meneilly GS, Youn GJ,Landsberg L, Stoff JS, Robertson GL,Rowe JW (1991) Blood pressure, pulseand neurohumoral responses to nitro-prusside-induced hypotension in nor-motensive aging men. J Gerontol46:M151154

162. Robertson GL (1976) The regulationof vasopressin function in health anddisease. Recent Prog Horm Res33:333385

163. Sirinek KR, Levine BA (1988) High-dose vasopressin for acute varicealhemorrhage. Clinical advantageswithout adverse effects. Arch Surg123:876880

164. Gimson AE, Westaby D, Hegarty J,Watson A, Williams R (1986) A ran-domized trial of vasopressin and va-sopressin plus nitroglycerin in thecontrol of acute variceal hemorrhage.Hepatology 6:410413

165. Greenwald RA, Rheingold OJ, ChiprutRO, Rogers AI (1978) Local gangrene:a complication of peripheral Pitressintherapy for bleeding esophageal va-rices. Gastroenterology 74:744746

166. Mogan GR, Wormser GP, GottfriedEB (1980) Infected gangrene. A seri-ous complication of peripheral vaso-pressin administration. Am J Gastro-enterol 73:426429

167. Kahn JM, Kress JP, Hall JB (2002)Skin necrosis after extravasation oflow-dose vasopressin administered forseptic shock. Crit Care Med 30:18991901

168. Bernadich C, Bandi JC, Melin P,Bosch J (1998) Effects of F-180, a newselective vasoconstrictor peptide,compared with terlipressin and vaso-pressin on systemic and splanchnichemodynamics in a rat model of portalhypertension. Hepatology 27:351356

169. Moreau R, Durand F, Poynard T,Duhamel C, Cervoni JP, Ichai P,Abergel A, Halimi C, Pauwels M,Bronowicki JP, Giostra E, Fleurot C,Gurnot D, Nouel O, Renard P, RivoalM, Blanc P, Coumaros D, Ducloux S,Levy S, Pariente A, Perarnau JM,Roche J, Scribe-Outtas M, Valla D,Bernard B, Samuel D, Butel J,Hadengue A, Platek A, Lebrec D,Cadranel JF (2002) Terlipressin inpatients with cirrhosis and type 1 he-patorenal syndrome: a retrospectivemulticenter study. Gastroenterology122:923930

170. Scharte M, Meyer J, Van Aken H,Bone HG (2001) Hemodynamic ef-fects of terlipressin (a synthetic analogof vasopressin) in healthy and endo-toxemic sheep. Crit Care Med29:17561760

171. Medel J, Boccara G, Van de Steen E,Bertrand M, Godet G, Coriat P (2001)Terlipressin for treating intraoperativehypotension: can it unmask myocar-dial ischemia? Anesth Analg 93:5355

172. Westphal M, Stubbe H, SielenkamperAW, Borgulya R, Van Aken H, Ball C,Bone HG (2003) Terlipressin dose re-sponse in healthy and endotoxemicsheep: impact on cardiopulmonaryperformance and global oxygen trans-port. Intensive Care Med 29:301308

173. Guirao X, Kumar A, Katz J, Smith M,Lin E, Keogh C, Calvano SE, LowrySF (1997) Catecholamines increasemonocyte TNF receptors and inhibitTNF through beta 2-adrenoreceptoractivation. Am J Physiol 273:E12031208