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REVIEW ARTICLE

Vasopressin: A Review of Therapeutic Applications

Natalie F. Holt, MD, MPH,*† and Kenneth L. Haspel, MD*†

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ASOPRESSIN (VP) WAS DISCOVERED in 1895 fromthe extract of the posterior pituitary and named for the

arly observation of its vasoconstrictive properties.1 Theeptide is present in various species, both invertebrate andertebrate, with only minor variations in amino acid se-uence. Human VP contains the amino acid arginine, hencehe name arginine vasopressin. It is alternatively referred tos antidiuretic hormone (ADH), reflecting its main physio-ogic function in promoting water retention. (For the remain-er of the text, the term vasopressin and the abbreviation VPill be used in lieu of arginine vasopressin or antidiureticormone.)Since its isolation2 and synthetic preparation,3 VP has

een the subject of much research. Its clinical applicationsange from the management of enuresis to the treatment ofastrointestinal hemorrhage, septic shock, cardiac arrest,nd heart failure. The purpose of this review is to provide anverview of the physiology and pharmacology of this hor-one and its various functions. As with much in medicine,

he discovery of disease states involving VP and/or itseceptors has offered the most insight into VP’s in vivo rolend functional repertoire. As such, an appraisal of theseonditions will be used to review current knowledge andlinical applications of VP and its synthetic agonists andntagonists. Unanswered questions and future research op-ortunities will then be summarized.

VASOPRESSIN PHYSIOLOGY AND PHARMACOLOGY

asopressin Synthesis and Regulation

VP contains 9 amino acids, including 2 cysteines bridgedy a disulphide bond. The gene for VP is on chromosome 2nd neighbors that of oxytocin. The 2 hormones are struc-ural cousins, differing only by 2 amino acids.4,5 VP isynthesized in the magnocellular and parvocellular neuronsf the hypothalamic paraventricular and supraoptic nucleiFig 1). It is transcribed as a larger prohormone with the

From the *Veterans Affairs Connecticut Healthcare System, Westaven Campus, West Haven, CT; and †Department of Anesthesiology,ale University School of Medicine, New Haven, CT.Address reprint requests to Natalie F. Holt, MD, MPH, Veterans

ffairs Connecticut Healthcare System, West Haven Campus, Depart-ent of Anesthesiology, 950 Campbell Avenue, West Haven, CT 06516.-mail: natalie.holt@va.govPublished by Elsevier Inc.1053-0770/10/2402-0022$36.00/0doi:10.1053/j.jvca.2009.09.006Key words: vasopressin, vaptans, arginine vasopressin, antidiuretic

wormone, vasopressors

30 Journal of Cardiothor

arrier protein neurophysin, and it is cleaved into its finalorm while in transit via the supraoptic-hypophyseal tract toecretory granules in the posterior pituitary gland.4 Upontimulation, VP is released from its storage granules andapidly enters the bloodstream via the well-vascularizedosterior pituitary capillary bed, which is devoid of a blood-rain barrier.The most important stimulus for VP release is a change in

lasma osmolality that is sensed via peripheral receptors near theortal vein and central receptors near the third ventricle. Informa-ion from peripheral receptors ascends via the vagus nerve throughhe medulla to the hypothalamic nuclei. The system is preciselyegulated to maintain plasma osmolality between 285 and 295Osm/kg H2O. There is a linear relationship between plasma VP

oncentrations and plasma osmolality, and a change on the orderf only 1 pg/mL in VP concentration produces a measureabledjustment in urine specific gravity.6

VP is also responsive to changes in blood pressure, as sensedy baroreceptors in the left heart, aortic arch, and carotid sinus.nder ordinary physiologic conditions, VP has a limited role inlood pressure regulation. Evidence for this is in the lack ofypertensive effect seen among patients with the syndrome ofnappropriate antidiuretic hormone secretion (SIADH), inhich concentrations of VP are well above normal levels.7

hereas an alteration in plasma osmolality of only 1% effectsmeasurable change in plasma VP concentrations, blood pres-

ure must drop by more than 10% to stimulate VP release.6

owever, with significant drops in blood pressure, plasma VPoncentrations increase exponentially, in contrast to the linearP response seen with changes in osmolality.4

Other conditions have been noted to alter VP release either inivo or in vitro; these include pain, hypoxemia, and hypogly-emia.8 Acetylcholine, histamine, catecholamines, prostaglan-ins, and nitric oxide (NO) appear to stimulate VP release,hereas opioids seem to inhibit VP release.9 Furthermore, a

ole for VP has been postulated in human functions other thansmo- and baroregulation, including social behavior10 and tem-erature regulation.11

Normal plasma VP concentrations vary among individualsut are usually on the order of 1 to 5 pg/mL. Diurnal variations observed, with a nighttime increase to approximately 2 timeshat of daytime levels.12 The half-life of VP is between 5 and 20inutes.13 It is metabolized in the liver and kidneys. VP release

riggers a number of negative feedback loops. The reduction inlasma osmolality inhibits VP synthesis. Adrenocorticotropinormone (ACTH), whose release is stimulated by VP, increaseslucocorticoid concentration, which inhibits VP secretion. Inddition, VP induces a structural change in its own receptors,

hich inhibits their downstream interaction with G-proteins

acic and Vascular Anesthesia, Vol 24, No 2 (April), 2010: pp 330-347

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nd results in cell sequestration of membrane-bound receptors.4

pproximately 10% to 20% of VP stores are available formmediate release in response to stimulation.14 Secretion di-

inishes with persistent stimulation, as suggested by the bi-hasic course of plasma VP concentrations in pathologic con-itions such as septic shock.15 Orally administered VP isapidly hydrolyzed by trypsin, rendering it inactive.16,17 There-ore, exogenous VP must be administered parenterally and by

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ranscribed as a larger prohormone with the carrier protein neur

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edical illustration used with permission of Elsevier. All rights reser

ontinuous infusion because of its short half-life. t

asopressin Receptor Distribution andignaling Pathways

eceptor Subtypes and Distribution

VP receptors are widely distributed in the body, and 3istinct receptor subtypes have been identified (Table 1). V1also referred to as V1a) receptors are found primarily onascular smooth muscle where they contribute to vasoconstric-

Origin of vasopressin

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sin, and it is cleaved into its final form while in transit via the

ry gland. Upon stimulation, VP is released from its storage granules

itary capillary bed, which is devoid of a blood-brain barrier. (Netter

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keletal tissues. They also are present on platelets where theyromote platelet aggregation. In the liver, V1-receptor activa-ion stimulates glycogenolysis and glucose secretion. In thedrenal gland, it promotes aldosterone and cortisol release. V1eceptors also have been found in the myometrium where theyediate uterine contractions. V1 receptors are selectively dis-

ributed in the kidney as well, such that activation constrictsfferent but not afferent arterioles.5 This effect appears to beediated by local release of NO18 and accounts for the obser-

ation that, although VP given to patients in shock statesromotes vasoconstriction, it also tends to increase glomerularltration rate and urinary output. Finally, there are V1 receptors

n the central nervous system, including the hypothalamus,mygdala, and cerebellum. V1 receptors in the brainstem seemo enhance baroreceptor-mediated inhibition of sympatheticervous system (SNS) activity;19,20 they also are postulated toave a role in other complex functions such as social memory,tress adaptation, and mood.21

Although V1 receptors are present in the kidney, V2 recep-ors predominate and are concentrated on cells of the distalonvoluted tubule and collecting duct. V2-receptor activationn the kidney stimulates gene transcription and cell membranentegration of aquaporin channels, which increase water per-eability at the luminal side of renal collecting duct cells.ater is then translocated to the basolateral cell surface and

eturned to the intravascular compartment. V2 receptors arelso expressed on the vascular endothelium, as evidenced byhe increased levels of von Willebrand factor (vWF), factorIII, and plasminogen activator that accompany the adminis-

ration of V2-receptor agonists.5,22

V3 (also called V1b) receptors have been identified in thenterior pituitary and elsewhere in the central nervous system.hrough these receptors, VP is believed to act as a neuromodu-

ator. It appears to stimulate ACTH secretion via the activationf the corticotropin-releasing hormone (CRH). This is sup-orted by the observation that exogenously administered CRH

Table 1. Distribution an

VP Receptor Subtype Location

V1 Vascular smooth muscle Vasoconstriction (Platelets Platelet aggregatiAdrenal gland Aldosterone and cLiver Glycogenolysis anGastrointestinal tract PeristalsisMyometrium Uterine contractioBrain Regulation of bloo

Temperature reguRole in emotional

Kidney Efferent arteriolarV2 Kidney Free water resorp

channels on renVascular smooth muscle VasodilationVascular endothelium Release of von W

V3 Anterior pituitary NeuromodulationBrain Stress adaptationPancreas Insulin synthesisHeart Atrial natriuretic p

ith VP result in substantially higher plasma cortisol levels d

ompared with the administration of CRH alone.13,23 Further-ore, during cardiopulmonary resuscitation (CPR) and early

epsis, short-term rises in serum ACTH and cortisol levels haveeen observed in patients treated with VP compared withatecholamines.24,25 V3-receptor activation also seems to pro-ote the secretion of other hormones, including prolactin,

rowth hormone, insulin, angiotensin, endothelin, and atrialatriuretic peptide (ANP), although the in vivo relevance ofhese properties remains to be established.26–29 Finally, V3eceptors have possible roles in social behavior and regulationf mood.21,30,31

Consistent with the observed molecular similarity betweenP and oxytocin, VP has been found to interact with oxytocin

eceptors, although with an affinity approximately one-tenth asreat as that of oxytocin. Recently, the interaction of VP withardiac oxytocin receptors has been found to promote ANPelease and subsequent natriuresis.32 The role of this system inivo has yet to be fully elucidated.VP also has activity at purinergic receptors, whose intrinsic

igand is the phosphate moiety of adenosine triphosphate.5 Inuinea pigs, VP infused into the coronary circulation has beenound to cause vasoconstriction via interaction at purinorecep-ors in the cardiac endothelium.33 However, these results haveot been reproduced consistently in vitro34 or animal models,35

nd the clinical significance of VP’s affinity for the purinore-eptor in humans remains to be shown.

ownstream Signaling

VP activity is mediated intracellularly through second mes-engers (Fig 2). V1 and V3 receptors act via a phosphatidyl-nositol pathway, producing inositol triphosphate and diacyl-lycerol, which, in turn, activate protein kinase C and increasentracellular calcium entry. In contrast, V2 receptor effects areediated by adenyl cyclase and cyclic adenosine monophos-

hate.12,36 As previously mentioned, other mechanisms for VPction, including locally induced NO release, also have been

ction of VP Receptors

Function

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333VASOPRESSIN

ynthetic Vasopressin Analogs

The development of VP analogs with longer half-lives andeceptor-specificity greatly enhanced the practical applicationf VP therapy. In 1968, octapressin was shown to improveenal blood flow in patients with cirrhosis.37 In 1985, Lenz etl38 found similar effects with another synthetic analog, orni-ressin. At present, the only clinically used VP analogs areerlipressin (TP) and desmopressin (DDAVP) (Fig 3).

P

TP (triglycyl lysine vasopressin) is a 12 amino acid peptidehose active metabolite is lysine vasopressin. Relative to VP,

t exhibits a greater degree of V1-receptor specificity (2.2:1ompared with 1:1 for AVP).39 Because lysine vasopressin iseleased into the systemic circulation gradually, when com-ared with VP, TP has a longer duration of action that allowsor bolus injection. However, because bolus dosing has beeninked to a higher frequency of systemic side effects, includingyocardial ischemia and skin necrosis, continuous infusion

herapy is favored.40,41 Like VP, TP is only available for pa-ental use. Of note, TP, but not VP, has been shown to dilatentrahepatic vessels, thereby enhancing blood flow through theepatic artery in patients with cirrhotic liver disease and portalypertension.42–44 TP has been available in Europe and Asia for

Fig 2. VP activity is mediated intracellularly through second mes-

engers. V1 and V3 receptors act via a phosphatidylinositol pathway,

roducing inositol triphosphate (IP3) and diacylglycerol (DAG), which in

urn activate protein kinase C and increase intracellular calcium entry.

2-receptor effects are mediated by adenyl cyclase and cyclic adenosine

onophosphate (cAMP). Receptor activation leads to synthesis and cell

embrane integration of aquaporin channels onto the luminal side of

enal collecting duct cells, which increases their permeability to water.

ree water is in turn translocated to the basolateral surface of renal

ollecting duct cells and returned to the central circulation. ATP, aden-

sine triphosphate; AVP, arginine vasopressin; cAMP, cyclic adenosine

onophosphate; DAG, diacylglycerol; Gq/Gs �, �, �, G protein sub-

mnits; IP3, inositol (1,4,5) trisphosphate; PIP2, phosphatidylinositol (4,5)-

isphosphate. (Reprinted with permission.13)

ore than 2 decades where it is considered the treatment ofhoice for the emergency management of bleeding esophagealarices. In addition, it is used “off-label” in treating patientsith refractory arterial hypotension. In 2004, the United Statesood and Drug Administration (FDA) granted TP orphan drugtatus as the only therapy being studied for the treatment ofatients with acute and rapidly progressive hepatorenal syn-rome (HRS); the following year, it was placed on the “fastrack” for FDA New Drug Approval where it remains at theime of this publication.45

DAVP

DDAVP (1-deamino-8-D-arginine vasopressin) was the firstnd remains the only clinically available VP agonist with2-receptor specificity (V2:V1 receptor affinity approximately,000-3,000 times that of VP).46 Intravenous, intranasal, sub-utaneous, and oral preparations of DDAVP are now standardreatment for patients with central diabetes insipidus (DI). Inhe 1970s, 2 independent research groups discovered thatDAVP increased the release of vWF and factor VIII.47– 49

his led to the use of prophylactic DDAVP to reduce peri-perative bleeding in patients with some types of von Wil-ebrand disease as well as hemophilia and uremia-inducedlatelet dysfunction (see section on Disorders of Hemosta-is).50 –52

asopressin Antagonists

Hyponatremia is one of the most common diagnoses inospitalized patients, occurring in the context of many condi-ions, including the syndrome of inappropriate antidiuretic hor-

Fig 3. VP contains 9 amino acids, including 2 cysteines bridged by

disulphide bond. The synthetic VP analogs desmopressin (DDAVP)

nd terlipressin (TP) are structurally similar to VP but differ slightly in

mino acid sequences. Relative to VP, the first amino acid of DDAVP

as been deaminated, and the arginine at the eighth position is in the

extro rather than the levo form. TP is a 12 amino acid prodrug

apable of slowly releasing lysine vasopressin, which accounts for its

onger half-life and V1-receptor specificity relative to vasopressin.

one (SIADH) secretion, congestive heart failure, and cirrho-

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is. Although fluid restriction and diuretics are often effective atreating hyponatremia, prolonged treatment may impair renalunction. In the 1990s, several nonpeptide vasopressin antago-ists, also called vaptans, were developed to oppose VP-nduced free water conservation present in these conditions.53

onivaptan is a parenterally formulated vaptan and the onlyaptan with substantial activity at both V1 and V2 receptors.everal other vaptans including tolvaptan, lixivaptan, moza-aptan, and satavaptan are specific V2-receptor antagonists andre available in oral form.54–57 All have shown therapeuticfficacy in terms of increasing urine output and raising serumodium concentrations. They are generally well tolerated, withhirst and dry mouth being among the most common sideffects.58 Vaptans are hepatically metabolized; conivaptan is aotent inhibitor of the CYP34A enzyme, and, as such, its usean alter the serum concentrations of many concomitantlyelivered drugs.58,59

VASOPRESSIN IN PATHOPHYSIOLOGIC CONDITIONS:DISORDERS OF PLASMA OSMOLALITY

I

DI is a condition characterized by the excess production ofnappropriately dilute urine. Loss of free water in excess ofolute leads to plasma hyperosmolality. The following 2 mainauses of DI are recognized: (1) a lack of VP secretion (pitu-tary or central DI) and 2) an impaired renal response to VPnephrogenic DI). Central DI is acquired and may occur frombrain tumor, infection, injury, or status postpituitary surgery.DAVP is now the mainstay of treatment for central DI. In

Table 2. Common Indications and Dosi

Indication

VP and Synthetic VP AnalogsCardiac arrestRefractory hypotension

Bleeding esophageal varices, hepatorenal syndrome

von Willebrand disease, hemophilia A, uremic platelet dysfun

Central diabetes insipidus

Abdominal distentionNocturnal enuresis

Vasopressin antagonistsHyponatremia, congestive heart failure, cirrhosis

Abbreviations: IV, intravenously; IM, intramuscularly; SC, subcutan*Current American Heart Association and European Resuscitation C

o epinephrine therapy in the management of pulseless cardiac arrest.f VP in refractory cases.137,138

ddition, DDAVP is used in the temporary treatment of noc- c

urnal enuresis, which is caused by a maturational delay in theormal nocturnal increase in VP secretion.Nephrogenic DI may be acquired or congenital. Genetic

efects in the V2 receptor, which is encoded on the X chro-osome, are responsible for most cases of congenital nephro-

enic DI. Defects in the aquaporin channel, encoded on chro-osome 12, also can cause congenital nephrogenic DI.21,60–62

ertain drugs, most notably lithium, interfere with the kidney’sbility to respond to VP and are responsible for acquired casesf nephrogenic DI. Relative to congenital cases, acquired neph-ogenic DI is usually of a milder form.21,63 Because patientsith nephrogenic DI do not respond appropriately to VP,DAVP is ineffective. To date, treatment has consisted of a

ow-sodium, low-protein diet; aggressive hydration; and theossible addition of nonsteroidal anti-inflammatory drugsnd/or diuretics, which, paradoxically, reduce urinary output inhese patients. Recent research indicates that V2-receptor an-agonists may help stabilize mutant VP receptors responsibleor some cases of nephrogenic DI and thereby improve theiresponsiveness to endogenous VP.64 However, investigations inhis area are still preliminary, and clinical application remainsnclear.

yponatremia

IADH

SIADH describes a condition in which there is dysregulationf VP secretion. The hallmark of SIADH is euvolemic hypo-atremia and urine osmolality in excess of plasma osmolality.irst described in the late 1950s, SIADH is one of the most

r VP, VP Analogs, and VP Antagonists

Drug Dose

VP 40 U IV � 1-2 dose(s)*VP 0.01-0.04 U/min IVTP 1-2 mg IV every 4-6 hours

0.1-0.4 mg/h IVVP 0.2-1.0 U/min IVTP 1-2 mg IV every 4-6 hoursDDAVP 0.3 �g/kg IV

300 �g intranasallyVP 5-10 U IM or SCDDAVP 5-40 �g intranasally

0.3-0.6 mg orally daily1-4 �g IV daily

VP 5-10 U IMDDAVP 5-20 �g intranasally

0.2-0.6 mg orally at bedtime

Conivaptan 20-80 mg IV dailyTolvaptan 15-90 mg orally dailyLixivaptan 25-250 mg orally twice daily

ly.il guidelines advise a single dose of intravenous VP as an alternativever, there is evidence to support the administration of a second dose

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onjunction with a number of pathologic states, including HIVnfection and tumors that produce ectopic VP (eg, pulmonarymall-cell carcinoma). SIADH is also a common postoperativeondition in which pain may contribute to excess VP secre-ion.67 In addition, medications are known to cause SIADH,ncluding phenothiazines, tricyclic antidepressants, nicotine,arbamazepine, and antineoplastic drugs such as vincristine andyclophosphamide.4,68

Most cases of SIADH are temporary and may be managed byuid restriction and/or diuretic therapy. In more severe orhronic conditions, drug therapy may be required. Demeclocy-line, a tetracycline agent, was traditionally a preferred phar-acotherapeutic option. Demeclocycline interferes with the

ellular response to VP in the kidney by impairing the forma-ion of the second messenger cyclic adenosine monophos-hate.57,69 Lithium also interferes with the renal response to VPecretion, but side effects precluded its routine use as a treat-ent for SIADH.70,71

The development of VP antagonists has introduced a newreatment option for patients with severe cases of SIADH andther chronic illnesses that cause symptomatic hyponatremia oruid retention. Intravenous conivaptan is the only vaptan FDA-pproved for the treatment of euvolemic or hypervolemic hy-onatremia in hospitalized patients (Table 2). Treatment withonivaptan consistently increases urinary output and raiseserum sodium concentrations.57,72,73 At doses used in clinicalractice, there is no effect on systemic blood pressure, althought high doses hypotension may occur because of V1-receptorlockade.

ongestive Heart Failure and Cirrhosis

Hyponatremia has been found to be an independent predictorf major complications, rehospitalization, and mortality in pa-ients with congestive heart failure.74–81 In a post hoc analysisf data from the Evaluation Study of Congestive Heart Failurend Pulmonary Artery Catheterization Effectiveness trial, base-ine and persistent hyponatremia were found to be independentredictors of hospitalization for heart failure and mortality over6-month follow-up period.82 Among these patients, suppres-

ion of VP release that would be expected because of hypona-remia is overridden by baroreceptor activation in the aorticrch and carotid sinus resulting from low cardiac output. En-anced activity of the renin-angiotensin-aldosterone systemRAAS) also may promote VP secretion.72,78,83,84

Gheorghiade et al85 studied the impact of 3 doses ofolvaptan in a double-blind placebo-controlled trial of 254atients with chronic heart failure. Over the 25-day studyeriod, reductions in body weight and edema, as well as nor-alization of serum sodium concentration in hyponatremic

atients, were observed in patients treated with tolvaptan butot placebo. Tolvaptan therapy was well tolerated and pro-uced no appreciable changes in heart rate, systemic bloodressure, or renal function. Interestingly, only 6.3% of thetudy population had abnormal VP levels at baseline, andolvaptan treatment did not produce a statistically significantncrease in VP levels; therefore, tolvaptan’s therapeutic mech-nism of action has yet to be fully established. However, theesults of this trial have since been substantiated by several

ther large-scale, randomized, placebo-controlled studies, in- f

luding the Acute and Chronic Therapeutic Impact of Vaso-ressin Antagonist in Congestive Heart Failure trial86 and thefficacy of Vasopressin Antagonist in Heart Failure Study witholvaptan trial.87,88

Other trials of V2 antagonists have been conducted amongatients with hyponatremia from cirrhosis, SIADH, and con-estive heart failure. All have shown efficacy in terms oformalization of serum sodium concentration.74,75,86,89–93 Manyave reported symptomatic benefits including reduced edemand increased ease of breathing.82,86–88,94,95 One study identifiedmprovements in self-assessed mental health over a 30-dayreatment period.91,96 Whether serum sodium normalizationonfers benefit in terms of morbidity and mortality remainsncertain. In animal models of congestive heart failure, V1/V2ntagonist therapy has been shown to improve fluid regulationnd reduce cardiac hypertrophy.96–102 Studies in humans havexhibited mixed results. A few short-term trials withonivaptan103 and tolvaptan104 have shown reductions in righttrial and pulmonary artery occlusion pressures and modestlymproved left ventricular function. However, in a 12-weeklacebo-controlled trial of oral conivaptan therapy in patientsith class III heart failure, no impact on functional capacity or

xercise tolerance was shown.105

The Multicenter Evaluation of Tolvaptan Effect On Remod-ling trial studied the impact of long-term tolvaptan therapy ingroup of 240 patients with New York Heart Association class

I or III heart failure and ejection fractions �30%. In a 1-yearollow-up, tolvaptan-treated patients exhibited statistically non-ignificant increases in left ventricular ejection fraction; inddition, there was a trend toward lower rates of mortality andeart failure–related hospitalizations.106 However, in the Effi-acy of Vasopressin Antagonist in Heart Failure Study witholvaptan trial, the largest study to date, investigators werenable to identify improvement in heart function, physicalealth, or overall mortality over a median 9.9-month follow-uperiod.88 Patient recruitment is now underway for the BAL-NCE study, a phase III randomized multicenter double-blind,lacebo-controlled, parallel study of oral lixivaptan for theanagement of hyponatremia in patients hospitalized for heart

ailure.72 BALANCE will study the safety and efficacy of oralixivaptan for increasing serum sodium concentration and willssess the impact of therapy on rehospitalization as well asll-cause and cardiovascular mortality.

DISORDERS OF HEMOSTASIS

on Willebrand Disease and Disordersf Coagulation

In the 1970s, 2 research groups independently discoveredhat DDAVP enhanced the release of factor VIII, vWF, andlasminogen activator, thereby promoting platelet aggregationnd coagulation.47–49 This effect is mediated via V2 receptorsresent on the vascular endothelium.107 Mannucci et al48 werehe first to show the effectiveness of DDAVP in reducingleeding during dental extraction in a group of 25 patients withemophilia A or von Willebrand disease.48 Since then, DDAVPas achieved widespread use in the perioperative managementf patients with von Willebrand disease type 1, which results

rom a partial quantitative reduction in vWF. DDAVP is tran-

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iently effective in most patients with von Willebrand diseaseypes 2A, 2M, and 2N, which are caused by qualitative vWFefects, although its prophylactic use in these patients is moreontroversial.51,52,108 Paradoxically, in patients with von Wille-rand disease type 2B, DDAVP may cause thrombocytopeniand thereby increase bleeding risk.52 DDAVP is also used toeduce perioperative bleeding in patients with hemophilia And other conditions associated with coagulation dysfunction,uch as uremia109–111 and cirrhosis.112–115 In addition, it hasroven effective at improving platelet function and reducinglood loss in patients treated with antiplatelet agents such asspirin and ticlopidine.112,116–119 The mechanism of this effectppears to involve more than stimulation of procoagulant re-ease but remains to be fully explained.120

erioperative Bleeding

In the 1980s, speculation was raised that prophylacticDAVP administration might help reduce blood loss in pa-

ients without intrinsic bleeding disorders who were undergo-ng complex surgical procedures at risk for large blood loss.nitial favorable results were reported by several groups in theontext of spinal fusion, major joint arthroplasty, and cardiacurgeries.118,120,121 However, subsequent studies and severaleta-analyses failed to reproduce these benefits.92,122–129 In aeta-analysis of 12 randomized controlled trials of DDAVP in

ardiac surgery, Cattaneo et al50 in fact found more than doublehe incidence of myocardial infarction in DDAVP-treated pa-ients compared with placebo-treated controls (4.4% v 1.6%),lthough the result was not statistically significant. Therefore,lthough DDAVP may help promote surgical hemostasis, itsse seems best reserved for select cases.50,92,127,130–132

ariceal Bleeding

In patients with cirrhotic liver disease, fibrotic tissue impairsntrahepatic blood flow, leading to the formation of dilatedplanchnic collateral vessels and portal venous hypertension.ecause of their high pressure and large shunt volume, rupturef these collaterals is often a lethal complication of advancediver disease. Both VP and TP are first-line therapies in theanagement of variceal hemorrhage because both have pow-

rful vasoconstrictive effects in splanchnic vascular beds. Com-ared with VP, TP appears to have a wider safety profile and islso the only drug that has shown a survival benefit comparedith placebo.133 However, TP remains unavailable in thenited States.

DISORDERS OF HYPOPERFUSION

epatorenal Syndrome

Patients with portal hypertension and cirrhosis develop atate of relative arterial hypotension caused by distention ofplanchnic blood vessels and underfilling of the central arterialree. This results in activation of the RAAS and SNS, whichromotes water and sodium retention and vasoconstriction.AAS activation and relative central hypovolemia impairlood flow to vital organs. Progressive renal failure originatingrom liver cirrhosis is one of the most difficult complications toreat and as such is associated with a high level of morbidity

nd mortality. Two forms of HRS are recognized; type I HRS d

s rapidly progressive and usually results in death within dayso weeks unless liver transplantation is performed. The coursef type II HRS is more variable; however, median survival is onhe order of 6 months.134

In addition to splanchnic vasoconstriction, TP has beenound to reduce portal venous pressure and blood flow throughortosystemic shunts as well as to dilate intrahepatic bloodessels, leading to increased hepatic blood volume. To thextent that the latter effect restores blood volume to the centralirculation, there is attenuation of RAAS and SNS-mediatedasoconstriction, which increases renal blood flow and helpsreserve renal function. TP is now under active investigation inhe management of patients with type I HRS as a bridge therapyo liver transplant. In clinical trials, treatment has been showno improve both renal and cardiovascular function and possiblyonfer survival benefit.133,135–139 Current evidence supportsarly intervention to maximize treatment benefits.

eptic Shock

Septic shock represents a pathologic state in which vasodi-ation results in hypoperfusion and ultimately end-organ dys-unction. Absolute and relative hypovolemia are frequentlyresent as a result of fever-induced evaporative and gastroin-estinal losses and fluid extravasation from the intravascularpace caused by capillary leak. In addition, pathologic vasodi-ation persists despite significant reductions in systemic bloodressure. Multiple mechanisms appear to mediate this response,ncluding increased NO production and activation of potassiumhannels that relax vascular smooth muscle.140–142

In the early phase of sepsis, VP levels are acutely elevatednd then decline rapidly as the condition progresses.143–148 Theepletion of endogenous VP appears to contribute to the vaso-ilation associated with advanced sepsis,149 and an inverseelationship between patient survival and endogenous serumP levels in the late stage of shock has been observed.150 As aotent secretagogue, endotoxin may deplete glandular stores ofP.151–153 High levels of circulating catecholamines and NO

lso have been shown to suppress VP release.154 Impairedaroreceptor-mediated VP secretion seems also to play aole.140,146

Landry et al146 were the first to report that the infusion ofxogenous VP in a series of 5 patients with septic shockroduced a measurable improvement in vascular tone and in-reased urinary output (Table 2).146 This is in contrast to theegligible hypertensive effect of exogenous VP when admin-stered to healthy, euvolemic adults.146 The Vasopressin andeptic Shock Trial was a multicenter, randomized trial aimed atssessing the impact of adding VP to norepinephrine therapy inreating patients with septic shock.155 The study involved 779atients. Adverse events were similar in both groups. Theuthors found no difference between groups in the primaryndpoint measure of 28-day mortality or in the frequency ofajor organ dysfunction. However, patients treated with VP

id exhibit increases in creatinine clearance and urinary output.urthermore, in subgroup analyses, VP exhibited treatmentenefit among patients with less severe sepsis (based on nor-pinephrine infusion �15 �g/min at enrollment) as well as inhose at risk of renal dysfunction (based on Brussels organ

ysfunction criteria, serum creatinine �2.0 mg/dL).155

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Acting on the knowledge that VP enhances corticotropinesponsiveness and that patients in shock states often exhibitelative adrenal insufficiency, Russell et al156 recently evaluatedhe impact of concomitant VP and corticosteroid therapy ineptic patients. In a post hoc analysis of data from the Vaso-ressin and Septic Shock Trial, the authors found a statisticallyignificant reduction in mortality at 28 days among patientsreated with the combination of corticosteroids and VP aspposed to corticosteroids and norepinephrine (35.9% v 44.7%,� 0.03). Equally interesting was the finding that among

atients who did not receive corticosteroid therapy, thosereated with VP had a higher rate of mortality compared withhose who received norepinephrine (33.7% v 21.3%, p � 0.06).he authors found that patients treated with corticosteroids hadsubstantially greater increase in plasma VP levels relative to

hose who did not receive steroid therapy, which they hypoth-sized might account for the difference in therapeutic responseo VP among study groups. Although corticosteroid treatmentas not randomized in this study, the results offer compelling

vidence of an interaction between corticosteroids and VP inatients with shock and imply the need for further studies onhe use of combination therapies in the management of theseatients.In Europe, research has been performed using the synthetic

P analog TP in the treatment of patients in septic shock.’Brien et al157 first reported the successful use of TP in 8

eptic patients with refractory hypotension despite tradi-ional therapies. Subsequent reports, including a random-zed, prospective trial, confirmed these findings.158 –160 Aecent trial has been conducted comparing continuous infu-ion TP with norepinephine or VP as first-line therapy in thereatment of patients with resuscitated septic shock.161 Pre-iminary reports suggest no harm and possibly some benefitrom TP treatment. A prospective, randomized clinical trials currently underway to identify the optimal TP dose for thisndication (TESTT-I).161,162

Data are extremely limited on the impact of VP or TP on theutcome of pediatric patients with septic shock. Based on theew published case reports, VP deficiency appears to play aesser role in the pathophysiology of septic shock in the pedi-tric population compared with adults; however, VP and itsnalogs have in select cases resulted in some benefit. Untilore research is performed, it seems reasonable to cautiously

dvise the use of VP or TP as rescue therapy in pediatricatients with refractory shock. Reported doses have variedidely. For TP, boluses as low as 7 �g/kg every 12 hours andto 20 �g/kg every 4 hours have been used; however, contin-

ous infusions using doses as high as 10 to 20 �g/kg/h alsoave been reported.21,163,164 When VP has been used, bolusoses of 0.01 to 0.3 U/kg or continuous infusions of 0.0002 to.004 �g/kg/min appear to be most common with dose titrationo effect.163,165,166

In summary, the preferred treatment of vasodilatory shockaused by sepsis remains unknown. Whether a single approachs appropriate for all patients is also unclear. Studies to datemphasize the value of early pharmacologic intervention toupport arterial blood pressure and organ perfusion, and theotential benefit of combination therapy is under active inves-

igation. Although more research remains to be done, low-dose m

P (0.01-0.04 U/min) is now commonly used in the manage-ent of septic patients and is endorsed by international sepsis

reatment guidelines.167

ardiac Arrest

Although epinephrine has been the mainstay of pharmaco-ogic therapy for cardiac arrest, longstanding concerns over therug’s adverse profile (eg, increased myocardial oxygen de-and, arrhythmogenic potential, and postresuscitation hyper-

ension) have motivated research into alternative therapies.ecognizing VP as an important vasoactive hormone in theody’s intrinsic neuroendocrine stress response, in the 1990s,nterest in the potential role of VP in the setting of cardiacrrest heightened. Lindner et al168,169 were the first to report thatatients in cardiac arrest exhibited high levels of circulating VPnd, furthermore, that substantially higher levels of the hor-one were present in survivors compared with nonsurvi-

ors.168,169 Subsequent animal studies suggested that thexogenous administration of VP in cardiac arrest improvedital organ perfusion, neurologic outcomes, and short-termurvival.170 –176

Studies in human cardiac arrest patients have not consis-ently shown benefit from VP therapy; however, there also hasot been convincing evidence of demonstrable harm.177 On thisasis, in its updated advanced cardiac life support guidelineseleased in 2000, the American Heart Association (AHA) ac-nowledged the use of 40 U of intravenous VP as an alternativeo either the first or second dose of epinephrine in the contextf pulseless ventricular fibrillation or ventricular tachycar-ia. In 2005, AHA guidelines were revised to support the usef VP in all cases of pulseless cardiac arrest. Guidelines ofhe European Resuscitation Council (ERC) echo this recom-endation (Table 2).178

As with research in the treatment of septic shock, interest inhe potential benefit of combination therapy to treat cardiacrrest soon followed. Initial studies suggested a possible sur-ival benefit with the combined use of epinephrine and VP.179

ubsequently, a large-scale randomized, controlled trial involv-ng nearly 3,000 patients with out-of-hospital cardiac arrestompared injection of 1 mg of epinephrine and 40 U of VP tomg of epinephrine and saline placebo. The study failed to

dentify a benefit from the addition of VP in any of the mea-ured endpoints, which included return of spontaneous circu-ation, neurologic outcome at discharge, and out-of-hospitalnd 1-year survival.180 More recently, a randomized, placebo-ontrolled study involving 100 patients with refractory in-ospital cardiac arrest found that the addition of intravenousorticosteroids to VP and epinephrine conferred a survivalenefit.181

Information regarding the use of VP in pediatric cardiacrrest is extremely limited. Some early reports suggested aenefit.182 However, a recent analysis identified worse outcomeith respect to return of spontaneous circulation but no differ-

nce in the rate of hospital discharge with the use of VP.183

hese results may be biased by the tendency for VP to be useds a “last resort” among patients with prolonged arrest andhose with more significant underlying pathology. Therefore,lthough VP may be part of the armamentarium for the treat-

ent of pediatric cardiac arrest, there is too little research at

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his time to endorse its routine use, and, as such, the use of VPoes not appear in the AHA’s algorithm for the managementf pulseless arrest in pediatric patients.184 However, basedn published reports, when used for this indication, VPoses of 0.4 U/kg and TP doses of 15 to 20 �g/kg have beenuggested.165

Research on treatments for cardiac arrest is fraught withomplications; lack of patient homogeneity and study settingeg, in-hospital v out-of-hospital arrest) complicate the com-arison of study results. Furthermore, it is difficult to judgehat amount of investigational research and/or clinical expe-

ience should constitute grounds for a change in routine patientanagement. In fact, because studies on VP in the setting of

ardiac arrest are mixed, the AHA and ERC’s decisions tonclude VP on advanced cardiac life support algorithms have inact been met with circumspection. For one, critics emphasizehe high cost of VP relative to epinephrine (a single VP dose ispproximately 15 times more expensive than that of epineph-ine) as well as the additional cost and complications associatedith arming emergency medical response personnel and in-ospital “crash carts” with both drugs.177 Revisions to the AHAnd ERC’s guidelines are expected within the next 2 to 3 years,nd it remains to be seen whether VP will keep its place on theesuscitation algorithms endorsed by these organizations.

emorrhagic Shock

Given VP’s known effectiveness in controlling gastrointes-inal hemorrhage, several researchers have applied VP or itsnalogs to the management of patients presenting with trauma-nduced hemorrhagic shock. Voelckel et al185,186 reported en-anced renal perfusion and postresuscitation hemodynamic sta-ility in pigs treated with conventional CPR plus VP comparedith CPR plus epinephrine after experimentally induced hypo-olemia and cardiac arrest. Subsequently, in a similar experi-ental model, the same group reported favorable results with

he use of VP as first-line therapy for uncontrolled hemorrhagichock when compared with either fluid or epinephrine therapylone.186,187 Several case reports have acknowledged a favor-ble impact with VP as a temporizing measure to support bloodressure during triage of trauma victims.147,188–190 However,ome research suggests that although VP may help restorelood pressure and reduce resuscitative fluid requirements, thisenefit may come at the expense of adverse metabolic andemodynamic consequences, including lactic acidemia and aecline in cardiac index.191 Currently, a multicenter, random-zed controlled trial, the Vasopressin in Traumatic Hemor-hagic Shock (VITRIS) trial, is being organized in Europe tonvestigate the impact of VP in the prehospital management ofncontrolled hemorrhagic shock. It is expected that the resultsf this trial will help form more definitive recommendations onhe use of VP in the context of hemorrhagic shock.192–194

nesthesia-Induced Hypotension

Under ordinary circumstances, arterial blood pressure isaintained through the complementary action of the (1) SNS,

2) RAAS, and (3) vasopressinergic response. VP’s role inorrecting hypotension is in essence an emergency mechanism

hat manifests when other systems fail or are overwhelmed. s

onventionally used agents for both general and neuraxialnesthesia alter the SNS response to hypotension. Evidenceuggests that epidural anesthesia also impairs the renin re-ponse to hypotension via the blockade of renal SNS dis-harge.195–197 Much of the hypotension induced by anestheticss catechol responsive, as shown by the effective use of vaso-ressors such as phenylephrine and ephedrine to treat anesthe-ia-induced vasodilation. However, clinical experience sug-ests that at least some of the hypotension induced bynesthesia is refractory to catecholamines. In dogs, sympatheticlockade caused by epidural anesthesia has been shown tonduce a compensatory rise in endogenous VP secretion. Inumans, the exogenous administration of VP has been useduccessfully to treat catechol-resistant hypotension.198 VP ap-ears to be particularly useful in treating hypotension in anes-hetized patients who also are treated with angiotensin-convert-ng enzyme (ACE) inhibitors or angiotensin receptor blockersecause these patients suffer from concomitant SNS and RAASysfunction.198–206

VP also has been used successfully in the management ofardiovascular collapse because of anaphylaxis occurring undereneral anesthesia. Schummer et al207,208 reported the success-ul use of VP for this indication in 7 patients whose hypoten-ion was refractory to conventional catecholamine treatmentncluding epinephrine and norepinephrine. The authors sug-ested that VP in this context may in addition to its vasocon-tricting effect also exert anti-inflammatory action by bluntingO production.

ostcardiotomy/Cardiopulmonary Bypass–Inducedypotension

It has been estimated that approximately 10% of cardiacurgery patients experience vasodilatory hypotension that is notxplained by primary myocardial dysfunction or sepsis.209 Ex-racorporeal circulation or cardiopulmonary bypass inducesemostatic derangements that make patients especially prone toostoperative blood loss. Relative depletion of coagulationactors and fibrinogen as well as platelet dysfunction contributeo this condition. Additionally, cytokine release induced byndothelial injury induces vasodilation that exacerbates theemodynamic impact of postoperative blood loss.210–212

Patients undergoing cardiac surgery also experience signifi-ant fluctuations in serum VP concentrations. The initiation ofardiopulmonary bypass (CPB) is associated with a dramaticise in serum VP levels; this is followed by a gradual return toaseline in the postoperative period.213–216 In some patients, VPevels are inappropriately low relative to the degree of postop-rative hypotension and contribute to refractory vasodilatoryhock. Risk factors for the development of post-CPB vasodi-atory hypotension include low presurgical ejection fractionnd the use of ACE inhibitors.209 In these patients, exogenousP infusion has been found to effectively increase mean arte-

ial pressure (MAP) and reduce catecholamine require-ents.209,217,218 Furthermore, in a double-blind, randomized

rial, prophylactic VP infusion begun before the initiation ofPB was shown to improve hemodynamic stability in patientsndergoing coronary artery bypass graft surgery or valvular

urgery who also were treated with ACE inhibitors.206 De-

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reases in time to extubation and length of intensive care unittay also were observed.

Dunser et al219 investigated the impact of VP infusion among1 patients with catechol-resistant postcardiotomy shock. Theyound that VP infusion was associated with significant in-reases in MAP, left ventricular stroke work index, and sys-emic vascular resistance along with a decrease in heart rate ando change in cardiac index or stroke volume index.219 Theseesults have been substantiated by other studies.218,220

The unique benefits and risks of VP therapy to treat vasodila-ory hypotension remain to be fully established. Some groups havedentified a reduction in markers of myocardial ischemia associ-ted with VP infusion.205,221 In a swine model, at low flow ratesuch as those used during CPB, Mayr et al222 found that VPmproved coronary artery blood flow and did not increase coro-ary vascular resistance.223 However, high-dose VP therapy suchs that used to control bleeding has been known to cause coronaryasoconstriction and produce a substantial negative inotropic ef-ect.224,225 The use of VP in patients with cardiogenic as opposedo vasodilatory hypotension is likely to pose the most risk ofxacerbating myocardial dysfunction.

There is also evidence to suggest that VP therapy may conferrenal-protective effect. VP infusion initiated in patients with

efractory post-CPB hypotension has been shown to increaserine output,218 and the use of VP to treat hypotension after leftentricular assist device insertion has resulted in improvedecovery of renal function.226 On the other hand, VP is a potentplanchnic vasoconstrictor and may promote gastrointestinalschemia in at-risk patients. VP also increases platelet aggre-ation, which could promote thrombogenesis and impair mi-rocirculation. However, no data suggest that these complica-ions are common.

Several vasopressors in addition to VP, including norepi-ephrine, phenylephrine, and methylene blue, have been showno increase MAP in postcardiotomy hypotension. To date, theres insufficient evidence to suggest the use of one exclusivegent.227 However, existing data clearly place VP among theherapeutic options.

ther Shock States

Evidence from case reports has offered the use of VP or itsnalogs as rescue therapy in other conditions associated withefractory hypotension including overdoses of calcium channellockers228 and tricyclic antidepressants229 as well as traumaticrain injury.230 By virtue of their sporadic occurrence, evidencef the efficacy of VP and VP analogs for these unusual cir-umstances will remain anecdotal.

The explanation for why VP successfully reverses cate-holamine-refractory vasodilation is not firmly established, buteveral hypotheses have been offered. Both catecholamines andP exert some of their vasoconstrictive effects by increasing

ntracellular calcium in vascular smooth muscle cells. In addi-ion, however, VP blocks cyclic guanosine monophosphate-ediated vasodilation produced by inflammatory mediators

uch as interleukin 1, ANP, and NO.209,231–233 VP also inhibitsdenosine triphosphate–mediated potassium channel activationn vascular smooth muscle cells, which improves vascularesponsiveness to catecholamine therapy.234–238 Vascular tone

lso may be restored by virtue of VP-mediated release of p

ortisol.239 The existence of these multimodal mechanismsikely explains the effectiveness of VP therapy in shock statesf various etiologies.

ther Applications

Several nonpeptide VP antagonists are in various stages oflinical trials for a wide assortment of clinical indications.1-receptor antagonists including relcovaptan are under inves-

igation for the management of Raynaud’s disease,240 prema-ure labor,241,242 dysmenorrhea,243,244 and Meniere’s disease.245

1-receptor antagonists also are offering new potential ineducing cortisol levels in patients with ACTH-independentorms of Cushing syndrome caused by aberrant adrenocor-ical receptors.246

The finding that cyclic adenosine monophosphate promotesenal epithelial cell growth has prompted investigations on thetility of V2-receptor antagonist therapy for slowing the pro-ression of renal dysfunction in patients with polycystic kidneyisease.247–255 Studies of V2-receptor antagonists for other in-ications including the reduction of intraocular pressure inatients with glaucoma256,257 and the minimization of cerebraldema and infarct size after ischemic brain injury256,258–261 arelso underway.

In the neuropsychiatric arena, V3 antagonist therapy hashown promise in reducing stress-induced cortisol secretionnd exerting anxiolytic and mood-elevating effects in rodentodels.262–277 SSR-149415, the only orally active V3-receptor

ntagonist, is currently in phase II clinical trials to evaluate itsfficacy in humans (Table 2).59,272

ADVERSE EFFECTS OF DRUG THERAPY

P and VP Analogs

planchnic Perfusion

Despite its beneficial role, significant adverse effects haveeen reported with both VP and its analogs. Although VPedistributes blood flow to vital organs, it does so in part at thexpense of splanchnic and peripheral tissue perfusion. As such,P has been observed to induce skin necrosis and severe limb

schemia, particularly when administered through peripheraleins.162,278–282 A decrease in bile flow and increases in biliru-in and transaminase levels also have been reported.158,220,223,283

xperimental models have produced conflicting results on theffect of VP or V1 agonists on gut microcirculation; someroups have measured an increase in the mucosal-arterial pCO2

radient, implying the potential for impaired mesenteric circu-ation.24,278,283–286 However, this result has not been consistentlyuplicated.285,287 The potentially deleterious effect of VP onplanchnic perfusion seems keenly influenced by the overalluid status of the patient when therapy is initiated; VP admin-

stered in the context of hypovolemia appears particularly det-imental, whereas VP in fluid-resuscitated states may result inet improvement in splanchnic hemodynamics.288 There areimilar conflicting reports on the effects of VP on coronaryessels; but acute myocardial ischemia has been observed

articularly with bolus dosing of TP.224,289

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ardiac Index

Concern also has been raised that VP may worsen post-esuscitation acidemia and increase the risk of reperfusionnjury-induced multiorgan system dysfunction, despite im-roving arterial blood pressure and limiting resuscitative fluidolume requirements.191,192 Although VP therapy may restorelood pressure, depression of cardiac index has been ob-erved.24,146,158–160,203,223,286,290 However, this impact seems toary based on initial cardiac index. Specifically, Luckner etl223 showed that although VP decreased the cardiac index inatients with initially elevated cardiac indices, it had littleffect in patients whose cardiac index was normal at the start ofherapy and actually improved cardiac indices in patients withow starting values. This has led investigators to speculate thathe change in cardiac index observed with VP therapy mayepresent an appropriate adaptive response to blood pressureormalization rather than a pathologic effect on myocardialunction.40

emostasis

The activation of V1 receptors increases intracellular cal-ium and promotes platelet aggregation. V2-receptor stimula-ion promotes coagulation via release of vWF and plasminogenctivator. Theoretically, these hemostatic effects may compro-ise microcirculation, promote thromboembolism, and/or

ause bleeding complications related to thrombocytopenia. Al-hough some groups have observed a drop in platelet count withontinuous VP infusion and TP bolus therapy, thromboelastog-aphy, when performed, has failed to uncover functional coag-lation impairment.158,280,223,283,291,292

luid and Electrolyte Balance

Although VP is known to possess antidiuretic properties via V2eceptor activation in the kidneys, in the setting of septic shock,P and VP analog therapy consistently have been shown to

ncrease urinary output.140,155 Hyponatremia is a rare event andnly seems to be of concern when high-dose therapy is used.289

In summary, the pathophysiology of shock and the tradi-

ional catecholamine therapy used to treat it often entail organ- r

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pecific compromise; as such, patient prognosis is grim a priori.lthough conflicting reports have been published, there is no

onvincing evidence from human studies to suggest that ad-erse consequences occur in excess among patients treated withP or its analogs. Therefore, although definitive guidelines

emain forthcoming, VP and VP analog therapy have earnedeserved roles in the treatment armamentarium of catechol-mine-refractory shock.

P Antagonists

Relatively few adverse effects have been identified with VPntagonist treatment. In animal models, conivaptan has beenssociated with fetal malformations at subtherapeutic levelsnd has delayed labor onset in pregnant rats. It is therefore toe avoided in pregnancy. Conivaptan also substantially altershe concentrations of many concomitantly administered drugsecause of its powerful inhibition of the CYP3A4 enzyme. Forhis reason, it is only available in parenteral form, and theecommended duration of therapy is limited to 4 consecutiveays.56,59,73,97

Thirst, dry mouth, polyuria, and overrapid correction ofyponatremia are among the more common side effects ob-erved with the vaptans. They are usually only clinically rele-ant when high-dose therapy is used in conjunction with fluidestriction.53,57,59

CONCLUSION

Vasopressin is a homeostatic neuroendocrine hormonehose chief role is to maintain plasma osmolality. Although

mportant in health, in the study of disease states, the breadth ofP’s functional repertoire, now known to include regulation ofascular tone, alteration of blood coagulability, modulation ofood, and stress activation, has become apparent. Relative VP

epletion or abundance has been shown in multiple pathologictates, making VP agonist and antagonist therapies excitingargets of study in fields as disparate as psychiatry and criticalare medicine. The extent to which these therapies may im-rove patient outcomes and alter the natural history of disease

emain questions for ongoing research.

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