REVIEW ARTICLE

Vasopressin: A Review of Therapeutic Applications

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

ASOPRESSIN (VP) WAS DISCOVERED in 1895 from carrier protein neurophysin, and it is cleaved into its final Vthe extract of the posterior pituitary and named for the form while in transit via the supraoptic-hypophyseal tract to early observation of its vasoconstrictive properties.1 The secretory granules in the posterior pituitary gland.4 Upon peptide is present in various species, both invertebrate and stimulation, VP is released from its storage granules and vertebrate, with only minor variations in amino acid se- rapidly enters the bloodstream via the well-vascularized quence. Human VP contains the amino acid arginine, hence posterior pituitary capillary bed, which is devoid of a blood- the name arginine vasopressin. It is alternatively referred to brain barrier. as antidiuretic hormone (ADH), reflecting its main physio- The most important stimulus for VP release is a change in logic function in promoting water retention. (For the remain- plasma osmolality that is sensed via peripheral receptors near the der of the text, the term vasopressin and the abbreviation VP portal vein and central receptors near the third ventricle. Informa- will be used in lieu of arginine vasopressin or antidiuretic tion from peripheral receptors ascends via the vagus nerve through hormone.) the medulla to the hypothalamic nuclei. The system is precisely Since its isolation2 and synthetic preparation,3 VP has regulated to maintain plasma osmolality between 285 and 295 been the subject of much research. Its clinical applications mOsm/kg H2O. There is a linear relationship between plasma VP range from the management of enuresis to the treatment of concentrations and plasma osmolality, and a change on the order gastrointestinal hemorrhage, septic shock, cardiac arrest, of only 1 pg/mL in VP concentration produces a measureable and heart failure. The purpose of this review is to provide an adjustment in urine specific gravity.6 overview of the physiology and pharmacology of this hor- VP is also responsive to changes in blood pressure, as sensed mone and its various functions. As with much in medicine, by baroreceptors in the left heart, aortic arch, and carotid sinus. the discovery of disease states involving VP and/or its Under ordinary physiologic conditions, VP has a limited role in receptors has offered the most insight into VP’s in vivo role blood pressure regulation. Evidence for this is in the lack of and functional repertoire. As such, an appraisal of these hypertensive effect seen among patients with the syndrome of conditions will be used to review current knowledge and inappropriate antidiuretic hormone secretion (SIADH), in clinical applications of VP and its synthetic agonists and which concentrations of VP are well above normal levels.7 antagonists. Unanswered questions and future research op- Whereas an alteration in plasma osmolality of only 1% effects portunities will then be summarized. a measurable change in plasma VP concentrations, blood pres- sure must drop by more than 10% to stimulate VP release.6 VASOPRESSIN PHYSIOLOGY AND PHARMACOLOGY However, with significant drops in blood pressure, plasma VP Vasopressin Synthesis and Regulation concentrations increase exponentially, in contrast to the linear 4 VP contains 9 amino acids, including 2 cysteines bridged VP response seen with changes in osmolality. by a disulphide bond. The gene for VP is on chromosome 2 Other conditions have been noted to alter VP release either in and neighbors that of oxytocin. The 2 hormones are struc- vivo or in vitro; these include pain, hypoxemia, and hypogly- 8 tural cousins, differing only by 2 amino acids.4,5 VP is cemia. Acetylcholine, histamine, catecholamines, prostaglan- synthesized in the magnocellular and parvocellular neurons dins, and nitric oxide (NO) appear to stimulate VP release, 9 of the hypothalamic paraventricular and supraoptic nuclei whereas opioids seem to inhibit VP release. Furthermore, a (Fig 1). It is transcribed as a larger prohormone with the role for VP has been postulated in human functions other than osmo- and baroregulation, including social behavior10 and tem- perature regulation.11 From the *Veterans Affairs Connecticut Healthcare System, West Normal plasma VP concentrations vary among individuals Haven Campus, West Haven, CT; and †Department of Anesthesiology, but are usually on the order of 1 to 5 pg/mL. Diurnal variation Yale University School of Medicine, New Haven, CT. is observed, with a nighttime increase to approximately 2 times Address reprint requests to Natalie F. Holt, MD, MPH, Veterans that of daytime levels.12 The half-life of VP is between 5 and 20 Affairs Connecticut Healthcare System, West Haven Campus, Depart- minutes.13 It is metabolized in the liver and kidneys. VP release ment of Anesthesiology, 950 Campbell Avenue, West Haven, CT 06516. triggers a number of negative feedback loops. The reduction in E-mail: [email protected] plasma osmolality inhibits VP synthesis. Adrenocorticotropin Published by Elsevier Inc. 1053-0770/10/2402-0022$36.00/0 hormone (ACTH), whose release is stimulated by VP, increases doi:10.1053/j.jvca.2009.09.006 glucocorticoid concentration, which inhibits VP secretion. In Key words: vasopressin, vaptans, arginine vasopressin, antidiuretic addition, VP induces a structural change in its own receptors, hormone, vasopressors which inhibits their downstream interaction with G-proteins

330 Journal of Cardiothoracic and Vascular Anesthesia, Vol 24, No 2 (April), 2010: pp 330-347 VASOPRESSIN 331

Neurosecretory Ending (posterior pituitary) Forebrain Pituicyte processes pathways noxA noxA

Brain stem pathways

Fibroblast Capillary Neurosecretory Endothelium vesicles Mast cell Collagen space Basement membrane Paraventricular Arterial supply nucleus Blood borne Origin of vasopressin to hypothalamus signals reaching Supraoptic nucleus Cell of SON and PVN Neurohypophyseal supraoptic tract nucleus Axonal Herring bodies transport Fenestrated Posterior lobe of secretory capillary Anterior lobe (neurohypophysis) product

Site of vasopressin Posterior absorption lobe

Venous drainage of posterior lobe

Inferior hypophyseal artery

Fig 1. VP is synthesized in the magnocellular and parvocellular neurons of the hypothalamic paraventricular and supraoptic nuclei. It is transcribed as a larger prohormone with the carrier protein neurophysin, and it is cleaved into its final form while in transit via the supraoptic-hypophyseal tract to secretory granules in the posterior pituitary gland. Upon stimulation, VP is released from its storage granules and rapidly enters the bloodstream via the well-vascularized posterior pituitary capillary bed, which is devoid of a blood-brain barrier. (Netter medical illustration used with permission of Elsevier. All rights reserved.) (Color version of figure is available online.)

and results in cell sequestration of membrane-bound receptors.4 Vasopressin Receptor Distribution and Approximately 10% to 20% of VP stores are available for Signaling Pathways immediate release in response to stimulation.14 Secretion di- Receptor Subtypes and Distribution minishes with persistent stimulation, as suggested by the bi- phasic course of plasma VP concentrations in pathologic con- VP receptors are widely distributed in the body, and 3 ditions such as septic shock.15 Orally administered VP is distinct receptor subtypes have been identified (Table 1). V1 rapidly hydrolyzed by trypsin, rendering it inactive.16,17 There- (also referred to as V1a) receptors are found primarily on fore, exogenous VP must be administered parenterally and by vascular smooth muscle where they contribute to vasoconstric- continuous infusion because of its short half-life. tion, especially in vascular beds of the mesentery, skin, and 332 HOLT AND HASPEL

Table 1. Distribution and Function of VP Receptors

VP Receptor Subtype Location Function

V1 Vascular smooth muscle Vasoconstriction (mesentery, skin, skeletal tissue) Platelets Platelet aggregation Adrenal gland Aldosterone and cortisol release Liver Glycogenolysis and glucose release Gastrointestinal tract Peristalsis Myometrium Uterine contraction Brain Regulation of blood pressure and heart rate Temperature regulation Role in emotional learning, social memory, circadian rhythm, stress adaptation Kidney Efferent arteriolar constriction V2 Kidney Free water resorption via gene transcription and cell membrane integration of aquaporin channels on renal collecting duct cells Vascular smooth muscle Vasodilation Vascular endothelium Release of von Willebrand factor, factor VIII V3 Anterior pituitary Neuromodulation ¡ corticotrophin, growth hormone, prolactin secretion Brain Stress adaptation Pancreas Insulin synthesis and release Heart Atrial natriuretic peptide synthesis and release

skeletal tissues. They also are present on platelets where they compared with the administration of CRH alone.13,23 Further- promote platelet aggregation. In the liver, V1-receptor activa- more, during cardiopulmonary resuscitation (CPR) and early tion stimulates glycogenolysis and glucose secretion. In the sepsis, short-term rises in serum ACTH and cortisol levels have adrenal gland, it promotes aldosterone and cortisol release. V1 been observed in patients treated with VP compared with receptors also have been found in the myometrium where they catecholamines.24,25 V3-receptor activation also seems to pro- mediate uterine contractions. V1 receptors are selectively dis- mote the secretion of other hormones, including prolactin, tributed in the kidney as well, such that activation constricts growth hormone, insulin, angiotensin, endothelin, and atrial efferent but not afferent arterioles.5 This effect appears to be natriuretic peptide (ANP), although the in vivo relevance of mediated by local release of NO18 and accounts for the obser- these properties remains to be established.26–29 Finally, V3 vation that, although VP given to patients in shock states receptors have possible roles in social behavior and regulation promotes vasoconstriction, it also tends to increase glomerular of mood.21,30,31 filtration rate and urinary output. Finally, there are V1 receptors Consistent with the observed molecular similarity between in the central nervous system, including the hypothalamus, VP and oxytocin, VP has been found to interact with oxytocin amygdala, and cerebellum. V1 receptors in the brainstem seem receptors, although with an affinity approximately one-tenth as to enhance baroreceptor-mediated inhibition of sympathetic great as that of oxytocin. Recently, the interaction of VP with nervous system (SNS) activity;19,20 they also are postulated to cardiac oxytocin receptors has been found to promote ANP have a role in other complex functions such as social memory, release and subsequent natriuresis.32 The role of this system in stress adaptation, and mood.21 vivo has yet to be fully elucidated. Although V1 receptors are present in the kidney, V2 recep- VP also has activity at purinergic receptors, whose intrinsic tors predominate and are concentrated on cells of the distal ligand is the phosphate moiety of adenosine triphosphate.5 In convoluted tubule and collecting duct. V2-receptor activation guinea pigs, VP infused into the coronary circulation has been in the kidney stimulates gene transcription and cell membrane found to cause vasoconstriction via interaction at purinorecep- integration of aquaporin channels, which increase water per- tors in the cardiac endothelium.33 However, these results have meability at the luminal side of renal collecting duct cells. not been reproduced consistently in vitro34 or animal models,35 Water is then translocated to the basolateral cell surface and and the clinical significance of VP’s affinity for the purinore- returned to the intravascular compartment. V2 receptors are ceptor in humans remains to be shown. also expressed on the vascular endothelium, as evidenced by the increased levels of von Willebrand factor (vWF), factor Downstream Signaling VIII, and plasminogen activator that accompany the adminis- VP activity is mediated intracellularly through second mes- tration of V2-receptor agonists.5,22 sengers (Fig 2). V1 and V3 receptors act via a phosphatidyl- V3 (also called V1b) receptors have been identified in the inositol pathway, producing inositol triphosphate and diacyl- anterior pituitary and elsewhere in the central nervous system. glycerol, which, in turn, activate protein kinase C and increase Through these receptors, VP is believed to act as a neuromodu- intracellular calcium entry. In contrast, V2 receptor effects are lator. It appears to stimulate ACTH secretion via the activation mediated by adenyl cyclase and cyclic adenosine monophos- of the corticotropin-releasing hormone (CRH). This is sup- phate.12,36 As previously mentioned, other mechanisms for VP ported by the observation that exogenously administered CRH action, including locally induced NO release, also have been with VP result in substantially higher plasma cortisol levels described.18 VASOPRESSIN 333

Synthetic Vasopressin Analogs The development of VP analogs with longer half-lives and receptor-specificity greatly enhanced the practical application of VP therapy. In 1968, octapressin was shown to improve renal blood flow in patients with cirrhosis.37 In 1985, Lenz et al38 found similar effects with another synthetic analog, orni- pressin. At present, the only clinically used VP analogs are terlipressin (TP) and desmopressin (DDAVP) (Fig 3).

TP TP (triglycyl lysine vasopressin) is a 12 amino acid peptide whose active metabolite is lysine vasopressin. Relative to VP, it exhibits a greater degree of V1-receptor specificity (2.2:1 compared with 1:1 for AVP).39 Because lysine vasopressin is released into the systemic circulation gradually, when com- pared with VP, TP has a longer duration of action that allows for bolus injection. However, because bolus dosing has been linked to a higher frequency of systemic side effects, including myocardial ischemia and skin necrosis, continuous infusion 40,41 Fig 3. VP contains 9 amino acids, including 2 cysteines bridged by therapy is favored. Like VP, TP is only available for pa- a disulphide bond. The synthetic VP analogs desmopressin (DDAVP) rental use. Of note, TP, but not VP, has been shown to dilate and terlipressin (TP) are structurally similar to VP but differ slightly in intrahepatic vessels, thereby enhancing blood flow through the amino acid sequences. Relative to VP, the first amino acid of DDAVP hepatic artery in patients with cirrhotic liver disease and portal has been deaminated, and the arginine at the eighth position is in the hypertension.42–44 TP has been available in Europe and Asia for dextro rather than the levo form. TP is a 12 amino acid prodrug capable of slowly releasing lysine vasopressin, which accounts for its longer half-life and V1-receptor specificity relative to vasopressin.

more than 2 decades where it is considered the treatment of choice for the emergency management of bleeding esophageal varices. In addition, it is used “off-label” in treating patients with refractory arterial hypotension. In 2004, the United States Food and Drug Administration (FDA) granted TP orphan drug status as the only therapy being studied for the treatment of patients with acute and rapidly progressive hepatorenal syn- drome (HRS); the following year, it was placed on the “fast track” for FDA New Drug Approval where it remains at the time of this publication.45

DDAVP DDAVP (1-deamino-8-D-arginine vasopressin) was the first and remains the only clinically available VP agonist with V2-receptor specificity (V2:V1 receptor affinity approximately 2,000-3,000 times that of VP).46 Intravenous, intranasal, sub- cutaneous, and oral preparations of DDAVP are now standard treatment for patients with central diabetes insipidus (DI). In the 1970s, 2 independent research groups discovered that DDAVP increased the release of vWF and factor VIII.47–49 Fig 2. VP activity is mediated intracellularly through second mes- sengers. V1 and V3 receptors act via a phosphatidylinositol pathway, This led to the use of prophylactic DDAVP to reduce peri- producing inositol triphosphate (IP3) and diacylglycerol (DAG), which in operative bleeding in patients with some types of von Wil- turn activate protein kinase C and increase intracellular calcium entry. lebrand disease as well as hemophilia and uremia-induced V2-receptor effects are mediated by adenyl cyclase and cyclic adenosine platelet dysfunction (see section on Disorders of Hemosta- monophosphate (cAMP). Receptor activation leads to synthesis and cell sis).50–52 membrane integration of aquaporin channels onto the luminal side of renal collecting duct cells, which increases their permeability to water. Free water is in turn translocated to the basolateral surface of renal Vasopressin Antagonists collecting duct cells and returned to the central circulation. ATP, aden- Hyponatremia is one of the most common diagnoses in osine triphosphate; AVP, arginine vasopressin; cAMP, cyclic adenosine monophosphate; DAG, diacylglycerol; Gq/Gs ␣, ␤, ␥, G protein sub- hospitalized patients, occurring in the context of many condi- units; IP3, inositol (1,4,5) trisphosphate; PIP2, phosphatidylinositol (4,5)- tions, including the syndrome of inappropriate antidiuretic hor- bisphosphate. (Reprinted with permission.13) mone (SIADH) secretion, congestive heart failure, and cirrho- 334 HOLT AND HASPEL

Table 2. Common Indications and Dosing for VP, VP Analogs, and VP Antagonists

Indication Drug Dose

VP and Synthetic VP Analogs Cardiac arrest VP 40 U IV ϫ 1-2 dose(s)* Refractory hypotension VP 0.01-0.04 U/min IV TP 1-2 mg IV every 4-6 hours 0.1-0.4 mg/h IV Bleeding esophageal varices, hepatorenal syndrome VP 0.2-1.0 U/min IV TP 1-2 mg IV every 4-6 hours von Willebrand disease, hemophilia A, uremic platelet dysfunction DDAVP 0.3 ␮g/kg IV 300 ␮g intranasally Central diabetes insipidus VP 5-10 U IM or SC DDAVP 5-40 ␮g intranasally 0.3-0.6 mg orally daily 1-4 ␮g IV daily Abdominal distention VP 5-10 U IM Nocturnal enuresis DDAVP 5-20 ␮g intranasally 0.2-0.6 mg orally at bedtime Vasopressin antagonists Hyponatremia, congestive heart failure, cirrhosis Conivaptan 20-80 mg IV daily Tolvaptan 15-90 mg orally daily Lixivaptan 25-250 mg orally twice daily

Abbreviations: IV, intravenously; IM, intramuscularly; SC, subcutaneously. *Current American Heart Association and European Resuscitation Council guidelines advise a single dose of intravenous VP as an alternative to epinephrine therapy in the management of pulseless cardiac arrest. However, there is evidence to support the administration of a second dose of VP in refractory cases.137,138

sis. Although fluid restriction and diuretics are often effective at turnal enuresis, which is caused by a maturational delay in the treating hyponatremia, prolonged treatment may impair renal normal nocturnal increase in VP secretion. function. In the 1990s, several nonpeptide vasopressin antago- Nephrogenic DI may be acquired or congenital. Genetic nists, also called vaptans, were developed to oppose VP- defects in the V2 receptor, which is encoded on the X chro- induced free water conservation present in these conditions.53 mosome, are responsible for most cases of congenital nephro- Conivaptan is a parenterally formulated vaptan and the only genic DI. Defects in the aquaporin channel, encoded on chro- vaptan with substantial activity at both V1 and V2 receptors. mosome 12, also can cause congenital nephrogenic DI.21,60–62 Several other vaptans including tolvaptan, lixivaptan, moza- Certain drugs, most notably lithium, interfere with the kidney’s vaptan, and satavaptan are specific V2-receptor antagonists and ability to respond to VP and are responsible for acquired cases are available in oral form.54–57 All have shown therapeutic of nephrogenic DI. Relative to congenital cases, acquired neph- efficacy in terms of increasing urine output and raising serum rogenic DI is usually of a milder form.21,63 Because patients sodium concentrations. They are generally well tolerated, with with nephrogenic DI do not respond appropriately to VP, thirst and dry mouth being among the most common side DDAVP is ineffective. To date, treatment has consisted of a effects.58 Vaptans are hepatically metabolized; conivaptan is a low-sodium, low-protein diet; aggressive hydration; and the potent inhibitor of the CYP34A enzyme, and, as such, its use possible addition of nonsteroidal anti-inflammatory drugs can alter the serum concentrations of many concomitantly and/or diuretics, which, paradoxically, reduce urinary output in delivered drugs.58,59 these patients. Recent research indicates that V2-receptor an- tagonists may help stabilize mutant VP receptors responsible VASOPRESSIN IN PATHOPHYSIOLOGIC CONDITIONS: for some cases of nephrogenic DI and thereby improve their 64 DISORDERS OF PLASMA OSMOLALITY responsiveness to endogenous VP. However, investigations in this area are still preliminary, and clinical application remains DI unclear. DI is a condition characterized by the excess production of inappropriately dilute urine. Loss of free water in excess of Hyponatremia solute leads to plasma hyperosmolality. The following 2 main SIADH causes of DI are recognized: (1) a lack of VP secretion (pitu- itary or central DI) and 2) an impaired renal response to VP SIADH describes a condition in which there is dysregulation (nephrogenic DI). Central DI is acquired and may occur from of VP secretion. The hallmark of SIADH is euvolemic hypo- a brain tumor, infection, injury, or status postpituitary surgery. natremia and urine osmolality in excess of plasma osmolality. DDAVP is now the mainstay of treatment for central DI. In First described in the late 1950s, SIADH is one of the most addition, DDAVP is used in the temporary treatment of noc- common diagnoses in hospitalized patients.65,66 It is observed in VASOPRESSIN 335 conjunction with a number of pathologic states, including HIV cluding the Acute and Chronic Therapeutic Impact of Vaso- infection and tumors that produce ectopic VP (eg, pulmonary pressin Antagonist in Congestive Heart Failure trial86 and the small-cell carcinoma). SIADH is also a common postoperative Efficacy of Vasopressin Antagonist in Heart Failure Study with condition in which pain may contribute to excess VP secre- Tolvaptan trial.87,88 tion.67 In addition, medications are known to cause SIADH, Other trials of V2 antagonists have been conducted among including phenothiazines, tricyclic antidepressants, nicotine, patients with hyponatremia from cirrhosis, SIADH, and con- carbamazepine, and antineoplastic drugs such as vincristine and gestive heart failure. All have shown efficacy in terms of cyclophosphamide.4,68 normalization of serum sodium concentration.74,75,86,89–93 Many Most cases of SIADH are temporary and may be managed by have reported symptomatic benefits including reduced edema fluid restriction and/or diuretic therapy. In more severe or and increased ease of breathing.82,86–88,94,95 One study identified chronic conditions, drug therapy may be required. Demeclocy- improvements in self-assessed mental health over a 30-day cline, a tetracycline agent, was traditionally a preferred phar- treatment period.91,96 Whether serum sodium normalization macotherapeutic option. Demeclocycline interferes with the confers benefit in terms of morbidity and mortality remains cellular response to VP in the kidney by impairing the forma- uncertain. In animal models of congestive heart failure, V1/V2 tion of the second messenger cyclic adenosine monophos- antagonist therapy has been shown to improve fluid regulation phate.57,69 Lithium also interferes with the renal response to VP and reduce cardiac hypertrophy.96–102 Studies in humans have secretion, but side effects precluded its routine use as a treat- exhibited mixed results. A few short-term trials with ment for SIADH.70,71 conivaptan103 and tolvaptan104 have shown reductions in right The development of VP antagonists has introduced a new atrial and pulmonary artery occlusion pressures and modestly treatment option for patients with severe cases of SIADH and improved left ventricular function. However, in a 12-week other chronic illnesses that cause symptomatic hyponatremia or placebo-controlled trial of oral conivaptan therapy in patients fluid retention. Intravenous conivaptan is the only vaptan FDA- with class III heart failure, no impact on functional capacity or approved for the treatment of euvolemic or hypervolemic hy- exercise tolerance was shown.105 ponatremia in hospitalized patients (Table 2). Treatment with The Multicenter Evaluation of Tolvaptan Effect On Remod- conivaptan consistently increases urinary output and raises eling trial studied the impact of long-term tolvaptan therapy in serum sodium concentrations.57,72,73 At doses used in clinical a group of 240 patients with New York Heart Association class practice, there is no effect on systemic blood pressure, although II or III heart failure and ejection fractions Ͻ30%. In a 1-year at high doses hypotension may occur because of V1-receptor follow-up, tolvaptan-treated patients exhibited statistically non- blockade. significant increases in left ventricular ejection fraction; in addition, there was a trend toward lower rates of mortality and Congestive Heart Failure and Cirrhosis heart failure–related hospitalizations.106 However, in the Effi- Hyponatremia has been found to be an independent predictor cacy of Vasopressin Antagonist in Heart Failure Study with of major complications, rehospitalization, and mortality in pa- Tolvaptan trial, the largest study to date, investigators were tients with congestive heart failure.74–81 In a post hoc analysis unable to identify improvement in heart function, physical of data from the Evaluation Study of Congestive Heart Failure health, or overall mortality over a median 9.9-month follow-up and Pulmonary Artery Catheterization Effectiveness trial, base- period.88 Patient recruitment is now underway for the BAL- line and persistent hyponatremia were found to be independent ANCE study, a phase III randomized multicenter double-blind, predictors of hospitalization for heart failure and mortality over placebo-controlled, parallel study of oral lixivaptan for the a 6-month follow-up period.82 Among these patients, suppres- management of hyponatremia in patients hospitalized for heart sion of VP release that would be expected because of hypona- failure.72 BALANCE will study the safety and efficacy of oral tremia is overridden by baroreceptor activation in the aortic lixivaptan for increasing serum sodium concentration and will arch and carotid sinus resulting from low cardiac output. En- assess the impact of therapy on rehospitalization as well as hanced activity of the renin-angiotensin-aldosterone system all-cause and cardiovascular mortality. (RAAS) also may promote VP secretion.72,78,83,84 Gheorghiade et al85 studied the impact of 3 doses of DISORDERS OF HEMOSTASIS tolvaptan in a double-blind placebo-controlled trial of 254 von Willebrand Disease and Disorders patients with chronic heart failure. Over the 25-day study of Coagulation period, reductions in body weight and edema, as well as nor- malization of serum sodium concentration in hyponatremic In the 1970s, 2 research groups independently discovered patients, were observed in patients treated with tolvaptan but that DDAVP enhanced the release of factor VIII, vWF, and not placebo. Tolvaptan therapy was well tolerated and pro- plasminogen activator, thereby promoting platelet aggregation duced no appreciable changes in heart rate, systemic blood and coagulation.47–49 This effect is mediated via V2 receptors pressure, or renal function. Interestingly, only 6.3% of the present on the vascular endothelium.107 Mannucci et al48 were study population had abnormal VP levels at baseline, and the first to show the effectiveness of DDAVP in reducing tolvaptan treatment did not produce a statistically significant bleeding during dental extraction in a group of 25 patients with increase in VP levels; therefore, tolvaptan’s therapeutic mech- hemophilia A or von Willebrand disease.48 Since then, DDAVP anism of action has yet to be fully established. However, the has achieved widespread use in the perioperative management results of this trial have since been substantiated by several of patients with von Willebrand disease type 1, which results other large-scale, randomized, placebo-controlled studies, in- from a partial quantitative reduction in vWF. DDAVP is tran- 336 HOLT AND HASPEL siently effective in most patients with von Willebrand disease is rapidly progressive and usually results in death within days types 2A, 2M, and 2N, which are caused by qualitative vWF to weeks unless liver transplantation is performed. The course defects, although its prophylactic use in these patients is more of type II HRS is more variable; however, median survival is on controversial.51,52,108 Paradoxically, in patients with von Wille- the order of 6 months.134 brand disease type 2B, DDAVP may cause thrombocytopenia In addition to splanchnic vasoconstriction, TP has been and thereby increase bleeding risk.52 DDAVP is also used to found to reduce portal venous pressure and blood flow through reduce perioperative bleeding in patients with hemophilia A portosystemic shunts as well as to dilate intrahepatic blood and other conditions associated with coagulation dysfunction, vessels, leading to increased hepatic blood volume. To the such as uremia109–111 and cirrhosis.112–115 In addition, it has extent that the latter effect restores blood volume to the central proven effective at improving platelet function and reducing circulation, there is attenuation of RAAS and SNS-mediated blood loss in patients treated with antiplatelet agents such as vasoconstriction, which increases renal blood flow and helps aspirin and ticlopidine.112,116–119 The mechanism of this effect preserve renal function. TP is now under active investigation in appears to involve more than stimulation of procoagulant re- the management of patients with type I HRS as a bridge therapy lease but remains to be fully explained.120 to liver transplant. In clinical trials, treatment has been shown to improve both renal and cardiovascular function and possibly Perioperative Bleeding confer survival benefit.133,135–139 Current evidence supports In the 1980s, speculation was raised that prophylactic early intervention to maximize treatment benefits. DDAVP administration might help reduce blood loss in pa- Septic Shock tients without intrinsic bleeding disorders who were undergo- ing complex surgical procedures at risk for large blood loss. Septic shock represents a pathologic state in which vasodi- Initial favorable results were reported by several groups in the lation results in hypoperfusion and ultimately end-organ dys- context of spinal fusion, major joint arthroplasty, and cardiac function. Absolute and relative hypovolemia are frequently surgeries.118,120,121 However, subsequent studies and several present as a result of fever-induced evaporative and gastroin- meta-analyses failed to reproduce these benefits.92,122–129 In a testinal losses and fluid extravasation from the intravascular meta-analysis of 12 randomized controlled trials of DDAVP in space caused by capillary leak. In addition, pathologic vasodi- cardiac surgery, Cattaneo et al50 in fact found more than double lation persists despite significant reductions in systemic blood the incidence of myocardial infarction in DDAVP-treated pa- pressure. Multiple mechanisms appear to mediate this response, tients compared with placebo-treated controls (4.4% v 1.6%), including increased NO production and activation of potassium although the result was not statistically significant. Therefore, channels that relax vascular smooth muscle.140–142 although DDAVP may help promote surgical hemostasis, its In the early phase of sepsis, VP levels are acutely elevated use seems best reserved for select cases.50,92,127,130–132 and then decline rapidly as the condition progresses.143–148 The depletion of endogenous VP appears to contribute to the vaso- Variceal Bleeding dilation associated with advanced sepsis,149 and an inverse relationship between patient survival and endogenous serum In patients with cirrhotic liver disease, fibrotic tissue impairs VP levels in the late stage of shock has been observed.150 As a intrahepatic blood flow, leading to the formation of dilated potent secretagogue, endotoxin may deplete glandular stores of splanchnic collateral vessels and portal venous hypertension. VP.151–153 High levels of circulating catecholamines and NO Because of their high pressure and large shunt volume, rupture also have been shown to suppress VP release.154 Impaired of these collaterals is often a lethal complication of advanced baroreceptor-mediated VP secretion seems also to play a liver disease. Both VP and TP are first-line therapies in the role.140,146 management of variceal hemorrhage because both have pow- Landry et al146 were the first to report that the infusion of erful vasoconstrictive effects in splanchnic vascular beds. Com- exogenous VP in a series of 5 patients with septic shock pared with VP, TP appears to have a wider safety profile and is produced a measurable improvement in vascular tone and in- also the only drug that has shown a survival benefit compared creased urinary output (Table 2).146 This is in contrast to the with placebo.133 However, TP remains unavailable in the negligible hypertensive effect of exogenous VP when admin- United States. istered to healthy, euvolemic adults.146 The Vasopressin and DISORDERS OF HYPOPERFUSION Septic Shock Trial was a multicenter, randomized trial aimed at assessing the impact of adding VP to norepinephrine therapy in Hepatorenal Syndrome treating patients with septic shock.155 The study involved 779 Patients with portal hypertension and cirrhosis develop a patients. Adverse events were similar in both groups. The state of relative arterial hypotension caused by distention of authors found no difference between groups in the primary splanchnic blood vessels and underfilling of the central arterial endpoint measure of 28-day mortality or in the frequency of tree. This results in activation of the RAAS and SNS, which major organ dysfunction. However, patients treated with VP promotes water and sodium retention and vasoconstriction. did exhibit increases in creatinine clearance and urinary output. RAAS activation and relative central hypovolemia impair Furthermore, in subgroup analyses, VP exhibited treatment blood flow to vital organs. Progressive renal failure originating benefit among patients with less severe sepsis (based on nor- from liver cirrhosis is one of the most difficult complications to epinephrine infusion Ͻ15 ␮g/min at enrollment) as well as in treat and as such is associated with a high level of morbidity those at risk of renal dysfunction (based on Brussels organ and mortality. Two forms of HRS are recognized; type I HRS dysfunction criteria, serum creatinine Ն2.0 mg/dL).155 VASOPRESSIN 337

Acting on the knowledge that VP enhances corticotropin VP (0.01-0.04 U/min) is now commonly used in the manage- responsiveness and that patients in shock states often exhibit ment of septic patients and is endorsed by international sepsis relative adrenal insufficiency, Russell et al156 recently evaluated treatment guidelines.167 the impact of concomitant VP and corticosteroid therapy in septic patients. In a post hoc analysis of data from the Vaso- Cardiac Arrest pressin and Septic Shock Trial, the authors found a statistically Although epinephrine has been the mainstay of pharmaco- significant reduction in mortality at 28 days among patients logic therapy for cardiac arrest, longstanding concerns over the treated with the combination of corticosteroids and VP as drug’s adverse profile (eg, increased myocardial oxygen de- opposed to corticosteroids and norepinephrine (35.9% v 44.7%, mand, arrhythmogenic potential, and postresuscitation hyper- p ϭ 0.03). Equally interesting was the finding that among tension) have motivated research into alternative therapies. patients who did not receive corticosteroid therapy, those Recognizing VP as an important vasoactive hormone in the treated with VP had a higher rate of mortality compared with body’s intrinsic neuroendocrine stress response, in the 1990s, those who received norepinephrine (33.7% v 21.3%, p ϭ 0.06). interest in the potential role of VP in the setting of cardiac The authors found that patients treated with corticosteroids had arrest heightened. Lindner et al168,169 were the first to report that a substantially greater increase in plasma VP levels relative to patients in cardiac arrest exhibited high levels of circulating VP those who did not receive steroid therapy, which they hypoth- and, furthermore, that substantially higher levels of the hor- esized might account for the difference in therapeutic response mone were present in survivors compared with nonsurvi- to VP among study groups. Although corticosteroid treatment vors.168,169 Subsequent animal studies suggested that the was not randomized in this study, the results offer compelling exogenous administration of VP in cardiac arrest improved evidence of an interaction between corticosteroids and VP in vital organ perfusion, neurologic outcomes, and short-term patients with shock and imply the need for further studies on survival.170–176 the use of combination therapies in the management of these Studies in human cardiac arrest patients have not consis- patients. tently shown benefit from VP therapy; however, there also has In Europe, research has been performed using the synthetic not been convincing evidence of demonstrable harm.177 On this VP analog TP in the treatment of patients in septic shock. basis, in its updated advanced cardiac life support guidelines O’Brien et al157 first reported the successful use of TP in 8 released in 2000, the American Heart Association (AHA) ac- septic patients with refractory hypotension despite tradi- knowledged the use of 40 U of intravenous VP as an alternative tional therapies. Subsequent reports, including a random- to either the first or second dose of epinephrine in the context ized, prospective trial, confirmed these findings.158–160 A of pulseless ventricular fibrillation or ventricular tachycar- recent trial has been conducted comparing continuous infu- dia. In 2005, AHA guidelines were revised to support the use sion TP with norepinephine or VP as first-line therapy in the of VP in all cases of pulseless cardiac arrest. Guidelines of treatment of patients with resuscitated septic shock.161 Pre- the European Resuscitation Council (ERC) echo this recom- liminary reports suggest no harm and possibly some benefit mendation (Table 2).178 from TP treatment. A prospective, randomized clinical trial As with research in the treatment of septic shock, interest in is currently underway to identify the optimal TP dose for this the potential benefit of combination therapy to treat cardiac indication (TESTT-I).161,162 arrest soon followed. Initial studies suggested a possible sur- Data are extremely limited on the impact of VP or TP on the vival benefit with the combined use of epinephrine and VP.179 outcome of pediatric patients with septic shock. Based on the Subsequently, a large-scale randomized, controlled trial involv- few published case reports, VP deficiency appears to play a ing nearly 3,000 patients with out-of-hospital cardiac arrest lesser role in the pathophysiology of septic shock in the pedi- compared injection of 1 mg of epinephrine and 40 U of VP to atric population compared with adults; however, VP and its 1 mg of epinephrine and saline placebo. The study failed to analogs have in select cases resulted in some benefit. Until identify a benefit from the addition of VP in any of the mea- more research is performed, it seems reasonable to cautiously sured endpoints, which included return of spontaneous circu- advise the use of VP or TP as rescue therapy in pediatric lation, neurologic outcome at discharge, and out-of-hospital patients with refractory shock. Reported doses have varied and 1-year survival.180 More recently, a randomized, placebo- widely. For TP, boluses as low as 7 ␮g/kg every 12 hours and controlled study involving 100 patients with refractory in- 2to20␮g/kg every 4 hours have been used; however, contin- hospital cardiac arrest found that the addition of intravenous uous infusions using doses as high as 10 to 20 ␮g/kg/h also corticosteroids to VP and epinephrine conferred a survival have been reported.21,163,164 When VP has been used, bolus benefit.181 doses of 0.01 to 0.3 U/kg or continuous infusions of 0.0002 to Information regarding the use of VP in pediatric cardiac 0.004 ␮g/kg/min appear to be most common with dose titration arrest is extremely limited. Some early reports suggested a to effect.163,165,166 benefit.182 However, a recent analysis identified worse outcome In summary, the preferred treatment of vasodilatory shock with respect to return of spontaneous circulation but no differ- caused by sepsis remains unknown. Whether a single approach ence in the rate of hospital discharge with the use of VP.183 is appropriate for all patients is also unclear. Studies to date These results may be biased by the tendency for VP to be used emphasize the value of early pharmacologic intervention to as a “last resort” among patients with prolonged arrest and support arterial blood pressure and organ perfusion, and the those with more significant underlying pathology. Therefore, potential benefit of combination therapy is under active inves- although VP may be part of the armamentarium for the treat- tigation. Although more research remains to be done, low-dose ment of pediatric cardiac arrest, there is too little research at 338 HOLT AND HASPEL this time to endorse its routine use, and, as such, the use of VP Conventionally used agents for both general and neuraxial does not appear in the AHA’s algorithm for the management anesthesia alter the SNS response to hypotension. Evidence of pulseless arrest in pediatric patients.184 However, based suggests that epidural anesthesia also impairs the renin re- on published reports, when used for this indication, VP sponse to hypotension via the blockade of renal SNS dis- doses of 0.4 U/kg and TP doses of 15 to 20 ␮g/kg have been charge.195–197 Much of the hypotension induced by anesthetics suggested.165 is catechol responsive, as shown by the effective use of vaso- Research on treatments for cardiac arrest is fraught with pressors such as phenylephrine and ephedrine to treat anesthe- complications; lack of patient homogeneity and study setting sia-induced vasodilation. However, clinical experience sug- (eg, in-hospital v out-of-hospital arrest) complicate the com- gests that at least some of the hypotension induced by parison of study results. Furthermore, it is difficult to judge anesthesia is refractory to catecholamines. In dogs, sympathetic what amount of investigational research and/or clinical expe- blockade caused by epidural anesthesia has been shown to rience should constitute grounds for a change in routine patient induce a compensatory rise in endogenous VP secretion. In management. In fact, because studies on VP in the setting of humans, the exogenous administration of VP has been used cardiac arrest are mixed, the AHA and ERC’s decisions to successfully to treat catechol-resistant hypotension.198 VP ap- include VP on advanced cardiac life support algorithms have in pears to be particularly useful in treating hypotension in anes- fact been met with circumspection. For one, critics emphasize thetized patients who also are treated with angiotensin-convert- the high cost of VP relative to epinephrine (a single VP dose is ing enzyme (ACE) inhibitors or angiotensin receptor blockers approximately 15 times more expensive than that of epineph- because these patients suffer from concomitant SNS and RAAS rine) as well as the additional cost and complications associated dysfunction.198–206 with arming emergency medical response personnel and in- VP also has been used successfully in the management of hospital “crash carts” with both drugs.177 Revisions to the AHA cardiovascular collapse because of anaphylaxis occurring under and ERC’s guidelines are expected within the next 2 to 3 years, general anesthesia. Schummer et al207,208 reported the success- and it remains to be seen whether VP will keep its place on the ful use of VP for this indication in 7 patients whose hypoten- resuscitation algorithms endorsed by these organizations. sion was refractory to conventional catecholamine treatment including epinephrine and norepinephrine. The authors sug- Hemorrhagic Shock gested that VP in this context may in addition to its vasocon- Given VP’s known effectiveness in controlling gastrointes- stricting effect also exert anti-inflammatory action by blunting tinal hemorrhage, several researchers have applied VP or its NO production. analogs to the management of patients presenting with trauma- induced hemorrhagic shock. Voelckel et al185,186 reported en- Postcardiotomy/Cardiopulmonary Bypass–Induced hanced renal perfusion and postresuscitation hemodynamic sta- Hypotension bility in pigs treated with conventional CPR plus VP compared It has been estimated that approximately 10% of cardiac with CPR plus epinephrine after experimentally induced hypo- surgery patients experience vasodilatory hypotension that is not volemia and cardiac arrest. Subsequently, in a similar experi- explained by primary myocardial dysfunction or sepsis.209 Ex- mental model, the same group reported favorable results with tracorporeal circulation or cardiopulmonary bypass induces the use of VP as first-line therapy for uncontrolled hemorrhagic hemostatic derangements that make patients especially prone to shock when compared with either fluid or epinephrine therapy postoperative blood loss. Relative depletion of coagulation alone.186,187 Several case reports have acknowledged a favor- factors and fibrinogen as well as platelet dysfunction contribute able impact with VP as a temporizing measure to support blood to this condition. Additionally, cytokine release induced by pressure during triage of trauma victims.147,188–190 However, endothelial injury induces vasodilation that exacerbates the some research suggests that although VP may help restore hemodynamic impact of postoperative blood loss.210–212 blood pressure and reduce resuscitative fluid requirements, this Patients undergoing cardiac surgery also experience signifi- benefit may come at the expense of adverse metabolic and cant fluctuations in serum VP concentrations. The initiation of hemodynamic consequences, including lactic acidemia and a cardiopulmonary bypass (CPB) is associated with a dramatic decline in cardiac index.191 Currently, a multicenter, random- rise in serum VP levels; this is followed by a gradual return to ized controlled trial, the Vasopressin in Traumatic Hemor- baseline in the postoperative period.213–216 In some patients, VP rhagic Shock (VITRIS) trial, is being organized in Europe to levels are inappropriately low relative to the degree of postop- investigate the impact of VP in the prehospital management of erative hypotension and contribute to refractory vasodilatory uncontrolled hemorrhagic shock. It is expected that the results shock. Risk factors for the development of post-CPB vasodi- of this trial will help form more definitive recommendations on latory hypotension include low presurgical ejection fraction the use of VP in the context of hemorrhagic shock.192–194 and the use of ACE inhibitors.209 In these patients, exogenous VP infusion has been found to effectively increase mean arte- Anesthesia-Induced Hypotension rial pressure (MAP) and reduce catecholamine require- Under ordinary circumstances, arterial blood pressure is ments.209,217,218 Furthermore, in a double-blind, randomized maintained through the complementary action of the (1) SNS, trial, prophylactic VP infusion begun before the initiation of (2) RAAS, and (3) vasopressinergic response. VP’s role in CPB was shown to improve hemodynamic stability in patients correcting hypotension is in essence an emergency mechanism undergoing coronary artery bypass graft surgery or valvular that manifests when other systems fail or are overwhelmed. surgery who also were treated with ACE inhibitors.206 De- VASOPRESSIN 339 creases in time to extubation and length of intensive care unit cortisol.239 The existence of these multimodal mechanisms stay also were observed. likely explains the effectiveness of VP therapy in shock states Dunser et al219 investigated the impact of VP infusion among of various etiologies. 41 patients with catechol-resistant postcardiotomy shock. They found that VP infusion was associated with significant in- creases in MAP, left ventricular stroke work index, and sys- Other Applications temic vascular resistance along with a decrease in heart rate and Several nonpeptide VP antagonists are in various stages of no change in cardiac index or stroke volume index.219 These clinical trials for a wide assortment of clinical indications. 218,220 results have been substantiated by other studies. V1-receptor antagonists including relcovaptan are under inves- The unique benefits and risks of VP therapy to treat vasodila- tigation for the management of Raynaud’s disease,240 prema- tory hypotension remain to be fully established. Some groups have ture labor,241,242 dysmenorrhea,243,244 and Meniere’s disease.245 identified a reduction in markers of myocardial ischemia associ- V1-receptor antagonists also are offering new potential in 205,221 ated with VP infusion. In a swine model, at low flow rates reducing cortisol levels in patients with ACTH-independent 222 such as those used during CPB, Mayr et al found that VP forms of Cushing syndrome caused by aberrant adrenocor- improved coronary artery blood flow and did not increase coro- tical receptors.246 223 nary vascular resistance. However, high-dose VP therapy such The finding that cyclic adenosine monophosphate promotes as that used to control bleeding has been known to cause coronary renal epithelial cell growth has prompted investigations on the vasoconstriction and produce a substantial negative inotropic ef- utility of V2-receptor antagonist therapy for slowing the pro- fect.224,225 The use of VP in patients with cardiogenic as opposed gression of renal dysfunction in patients with polycystic kidney to vasodilatory hypotension is likely to pose the most risk of disease.247–255 Studies of V2-receptor antagonists for other in- exacerbating myocardial dysfunction. dications including the reduction of intraocular pressure in There is also evidence to suggest that VP therapy may confer patients with glaucoma256,257 and the minimization of cerebral a renal-protective effect. VP infusion initiated in patients with edema and infarct size after ischemic brain injury256,258–261 are refractory post-CPB hypotension has been shown to increase also underway. urine output,218 and the use of VP to treat hypotension after left In the neuropsychiatric arena, V3 antagonist therapy has ventricular assist device insertion has resulted in improved shown promise in reducing stress-induced cortisol secretion recovery of renal function.226 On the other hand, VP is a potent and exerting anxiolytic and mood-elevating effects in rodent splanchnic vasoconstrictor and may promote gastrointestinal models.262–277 SSR-149415, the only orally active V3-receptor ischemia in at-risk patients. VP also increases platelet aggre- gation, which could promote thrombogenesis and impair mi- antagonist, is currently in phase II clinical trials to evaluate its 59,272 crocirculation. However, no data suggest that these complica- efficacy in humans (Table 2). tions are common. Several vasopressors in addition to VP, including norepi- ADVERSE EFFECTS OF DRUG THERAPY nephrine, phenylephrine, and methylene blue, have been shown VP and VP Analogs to increase MAP in postcardiotomy hypotension. To date, there is insufficient evidence to suggest the use of one exclusive Splanchnic Perfusion agent.227 However, existing data clearly place VP among the therapeutic options. Despite its beneficial role, significant adverse effects have been reported with both VP and its analogs. Although VP Other Shock States redistributes blood flow to vital organs, it does so in part at the Evidence from case reports has offered the use of VP or its expense of splanchnic and peripheral tissue perfusion. As such, analogs as rescue therapy in other conditions associated with VP has been observed to induce skin necrosis and severe limb refractory hypotension including overdoses of calcium channel ischemia, particularly when administered through peripheral 162,278–282 blockers228 and tricyclic antidepressants229 as well as traumatic veins. A decrease in bile flow and increases in biliru- 158,220,223,283 brain injury.230 By virtue of their sporadic occurrence, evidence bin and transaminase levels also have been reported. of the efficacy of VP and VP analogs for these unusual cir- Experimental models have produced conflicting results on the cumstances will remain anecdotal. effect of VP or V1 agonists on gut microcirculation; some The explanation for why VP successfully reverses cate- groups have measured an increase in the mucosal-arterial pCO2 cholamine-refractory vasodilation is not firmly established, but gradient, implying the potential for impaired mesenteric circu- several hypotheses have been offered. Both catecholamines and lation.24,278,283–286 However, this result has not been consistently VP exert some of their vasoconstrictive effects by increasing duplicated.285,287 The potentially deleterious effect of VP on intracellular calcium in vascular smooth muscle cells. In addi- splanchnic perfusion seems keenly influenced by the overall tion, however, VP blocks cyclic guanosine monophosphate- fluid status of the patient when therapy is initiated; VP admin- mediated vasodilation produced by inflammatory mediators istered in the context of hypovolemia appears particularly det- such as interleukin 1, ANP, and NO.209,231–233 VP also inhibits rimental, whereas VP in fluid-resuscitated states may result in adenosine triphosphate–mediated potassium channel activation net improvement in splanchnic hemodynamics.288 There are on vascular smooth muscle cells, which improves vascular similar conflicting reports on the effects of VP on coronary responsiveness to catecholamine therapy.234–238 Vascular tone vessels; but acute myocardial ischemia has been observed also may be restored by virtue of VP-mediated release of particularly with bolus dosing of TP.224,289 340 HOLT AND HASPEL

Cardiac Index specific compromise; as such, patient prognosis is grim a priori. Concern also has been raised that VP may worsen post- Although conflicting reports have been published, there is no resuscitation acidemia and increase the risk of reperfusion convincing evidence from human studies to suggest that ad- injury-induced multiorgan system dysfunction, despite im- verse consequences occur in excess among patients treated with proving arterial blood pressure and limiting resuscitative fluid VP or its analogs. Therefore, although definitive guidelines volume requirements.191,192 Although VP therapy may restore remain forthcoming, VP and VP analog therapy have earned blood pressure, depression of cardiac index has been ob- deserved roles in the treatment armamentarium of catechol- served.24,146,158–160,203,223,286,290 However, this impact seems to amine-refractory shock. vary based on initial cardiac index. Specifically, Luckner et al223 showed that although VP decreased the cardiac index in VP Antagonists patients with initially elevated cardiac indices, it had little Relatively few adverse effects have been identified with VP effect in patients whose cardiac index was normal at the start of antagonist treatment. In animal models, conivaptan has been therapy and actually improved cardiac indices in patients with associated with fetal malformations at subtherapeutic levels low starting values. This has led investigators to speculate that and has delayed labor onset in pregnant rats. It is therefore to the change in cardiac index observed with VP therapy may be avoided in pregnancy. Conivaptan also substantially alters represent an appropriate adaptive response to blood pressure the concentrations of many concomitantly administered drugs normalization rather than a pathologic effect on myocardial because of its powerful inhibition of the CYP3A4 enzyme. For function.40 this reason, it is only available in parenteral form, and the recommended duration of therapy is limited to 4 consecutive Hemostasis days.56,59,73,97 The activation of V1 receptors increases intracellular cal- Thirst, dry mouth, polyuria, and overrapid correction of cium and promotes platelet aggregation. V2-receptor stimula- hyponatremia are among the more common side effects ob- tion promotes coagulation via release of vWF and plasminogen served with the vaptans. They are usually only clinically rele- activator. Theoretically, these hemostatic effects may compro- vant when high-dose therapy is used in conjunction with fluid mise microcirculation, promote thromboembolism, and/or restriction.53,57,59 cause bleeding complications related to thrombocytopenia. Al- though some groups have observed a drop in platelet count with CONCLUSION continuous VP infusion and TP bolus therapy, thromboelastog- Vasopressin is a homeostatic neuroendocrine hormone raphy, when performed, has failed to uncover functional coag- whose chief role is to maintain plasma osmolality. Although ulation impairment.158,280,223,283,291,292 important in health, in the study of disease states, the breadth of VP’s functional repertoire, now known to include regulation of Fluid and Electrolyte Balance vascular tone, alteration of blood coagulability, modulation of Although VP is known to possess antidiuretic properties via V2 mood, and stress activation, has become apparent. Relative VP receptor activation in the kidneys, in the setting of septic shock, depletion or abundance has been shown in multiple pathologic VP and VP analog therapy consistently have been shown to states, making VP agonist and antagonist therapies exciting increase urinary output.140,155 Hyponatremia is a rare event and targets of study in fields as disparate as psychiatry and critical only seems to be of concern when high-dose therapy is used.289 care medicine. The extent to which these therapies may im- In summary, the pathophysiology of shock and the tradi- prove patient outcomes and alter the natural history of disease tional catecholamine therapy used to treat it often entail organ- remain questions for ongoing research.

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