Few clinical trials have directly

CLNCAL CONSULTATON CLNCAL CONSULTATON for vasopressor-dependent septic shock PAUL M. SZUMTA, CHRSTOPHER M. ENFANTO, BONNE GREENWOO, AN MCHAEL E. WECHSLER The Clinical Consultation column provides brief recommendations on handling specific pharmacotherapeutic problems in clinical practice. The problems addressed may be general or specialized but of wide interest. The column provides readers with relevant insights into optimum drug-therapy management by pharmacists. Recommendations are made on the basis of scientific literature and the author s clinical judgment and personal experience. Pharmacists in various settings, including drug information centers, are encouraged to submit manuscripts, ideas, and comments to AJHP (ajhp@ashp.org). Few clinical trials have directly compared vasoactive treatments of septic shock for their impact on morbidity and mortality. Traditional treatment for refractory hypotension has remained relatively unchanged for several decades; catecholamines including norepinephrine, epinephrine, phenylephrine, dopamine, and dobutamine are the standard treatments used to maintain perfusion pressure. 1,2 Recently, because of the resistance to catecholamines during septic shock, attention has turned toward the use of the noncatecholamine agent vasopressin. 3 is emerging as a viable first-line treatment option for improving hemodynamics and decreasing catecholamine requirements in refractory septic shock. Our article discusses the dosage, efficacy, and safety of vasopressin therapy for vasopressor-dependent septic shock. Background. The most common and most frequently studied cause of vasodilatory shock is sepsis. Septic shock requires prompt attention and appropriate treatment. n November Am J Health-Syst Pharm. 2005; 62:1931-6 2004, guidelines for the management of severe sepsis and septic shock were published by the Surviving Sepsis Campaign, an international group of experts on critical care and infectious diseases. 2 The purpose of the guidelines was to improve outcomes in patients with septic shock by providing a standardized management approach. According to the guidelines, initial treatment should include broad-spectrum antibiotic therapy and fluid resuscitation. Appropriate minimum hemodynamic goals consist of a central venous pressure of 8 12 mm Hg, a mean arterial pressure (MAP) of 65 mm Hg, urine output of 0.5 ml/kg/hr, and central venous oxygen saturation of 70%. n many cases, fluid resuscitation alone will not PAUL M. SZUMTA, PHARM.., BCPS, is Clinical Pharmacy Practice Manager; CHRSTOPHER M. ENFANTO, PHARM.., is Clinical Pharmacist; and BONNE GREENWOO, PHARM.., is Pharmacy Resident, epartment of Pharmacy; and MCHAEL E. WECHSLER, M.., M.M.SC., is MCU Attending Physician, epartment of Medicine, Brigham and Women s Hospital, Boston, MA. Address correspondence to r. Szumita at maintain MAPs above 65 mm Hg; therefore, the addition of a catecholamine or noncatecholamine vasoactive agent must be considered. The choice of vasopressor agent depends on the type of shock, the clinical situation, and the drug s possible adverse effects. espite a lack of trials directly comparing vasopressors effects on morbidity and mortality, the Surviving Sepsis Campaign guidelines recommend dopamine or norepinephrine, rather than phenylephrine or epinephrine, as a firstline vasopressor to correct hypotension. 2 opamine increases MAP and cardiac output, primarily by increasing stroke volume and heart rate. opamine may be particularly useful in patients with compromised systolic function, but it has cardiac risks, such as tachycardia and other arrhythmias. Norepinephrine increases MAP through vasoconstriction but elicits little change in heart rate and less increase in stroke volume than dopamine. Phenylephrine and epinephrine should be considered second-line agents, because phenylephrine may decrease stroke volume and epinephrine may induce tachycardia and have negative effects on splanchnic circulation. 2 Additional vasopressor agents are often necessary to maintain perfusion of vital organs. n addition to the epartment of Pharmacy, Brigham and Women s Hospital, Tower L2, 75 Francis Street, Boston, MA 02115 (pszumita@ partners.org). Copyright 2005, American Society of Health-System Pharmacists, nc. All rights reserved. 1079-2082/05/0902-1931$06.00. O 10.2146/ajhp040614 Am J Health-Syst Pharm Vol 62 Sep 15, 2005 1931

CLNCAL CONSULTATON osage Conversions the aforementioned catecholamines, the noncatecholamine agent vasopressin should be considered for patients with septic shock. The guidelines recommend adding vasopressin 0.01 0.04 unit/min to therapy for refractory septic shock. 2 Because of vasopressin deficiency in sepsis, vasopressin may emerge as an appropriate first-line agent. 4 Using MELNE, we reviewed the literature for the past 10 years regarding the use of continuous-infusion vasopressin in patients with septic shock. All reviewed data were current through October 1, 2004. Only relevant clinical trials and journal articles were reviewed and evaluated for clinical applicability and currency. We included trials in which vasopressin was administered as either first-line or second-line treatment in patients with refractory septic shock.. is a hormone synthesized in the hypothalamus and released from the posterior pituitary gland in response to an increase in plasma osmolality or a reduction in effective blood volume or arterial blood pressure. 5 t exerts its primary actions through interaction with the vasopressin 1 (V1) and vasopressin 2 (V2) receptors. The two major roles of the V2-receptor are maintenance of plasma osmolality and regulation of hypovolemia. Through its action on V2-receptors in the renal collecting-duct system, vasopressin exerts antidiuretic effects by altering the permeability of the collecting ducts to water. 6 Binding of vasopressin to V1-receptors in vascular smooth muscle causes increased intracellular release of calcium and increased extracellular calcium influx, resulting in muscle contraction and peripheral vasoconstriction. Additionally, V1-receptor binding can lead to glycogenolysis, platelet aggregation, adrenocorticotropic hormone release, and growth of vascular smooth muscle cells. n contrast, catecholamines raise blood pressure through activation of α- and β-adrenergic receptors. The osmotic effects of vasopressin occur at serum concentrations of 1 7 pg/ml, whereas smooth muscle regulation occurs at concentrations of 10 200 pg/ml. 1 Only 10 20% of total pituitary stores of vasopressin can be readily released at one time, with continued stimulation reducing the secretion rate. 5 Hypotension is a potent stimulus for the release of endogenous vasopressin. n septic shock, plasma vasopressin levels are initially elevated to maintain adequate blood pressure and organ perfusion. However, vasoactive levels of vasopressin can become rapidly depleted by continued stimulation. This is different from traditional catecholamine levels, which are actually increased in sepsis. Landry and colleagues 4 demonstrated this phenomenon in a prospective study of 19 septic shock patients who were found to have significantly lower mean ± S.. plasma vasopressin levels than 12 cardiogenic shock patients (3.1 ± 1.0 pg/ml versus 22.7 ± 2.2 pg/ml [p < 0.001]). Ten of the 19 patients received i.v. vasopressin at a dosage of 0.04 unit/ min. n these patients, mean systolic arterial pressure increased from 92 to 146 mm Hg. Additionally, mean systemic vascular resistance increased 79%, and cardiac output decreased by 12%. 4 Although involving only a small number of patients, this study supports replacement of endogenous levels of vasopressin to assist the body in mounting an appropriate physiological response to widespread vasodilation. Reports on vasopressin for septic shock. Blood pressure and hemodynamics. Landry et al. 7 reported a case series of five patients in vasodilatory shock who received vasopressin 0.01 0.05 unit/min. Arterial blood pressure increased within minutes (from a mean ± S.. systolic blood pressure of 94 ± 4 mm Hg and a mean ± S.. diastolic blood pressure of 50 ± 2 mm Hg to a mean ± S.. systolic blood pressure of 142 ± 5 mm Hg and a mean ± S.. diastolic blood pressure of 63 ± 4 mm Hg [p < 0.01]). This occurred as a result of increased mean ± S.. systemic vascular resistance (from 739 ± 52 to 1308 ± 108 dyne sec/cm 5 [p < 0.05]). n four of the patients, concomitant catecholamine vasopressors were discontinued, and arterial pressure was maintained by vasopressin alone. Another case series demonstrated improvements in MAP and decreases in cardiac output among 50 medical surgical intensive care unit (CU) patients who were treated with a 48-hour infusion of vasopressin at an average dosage of 0.05 unit/min (range, 0.01 0.06 unit/ min). 8 There were also significant decreases in the dosages of concurrent pressors. ünser et al. 9 reported a prospective, randomized, controlled trial to evaluate hemodynamic responses and organ function in 48 patients treated with both vasopressin and norepinephrine or with norepinephrine alone. Twenty-four patients with catecholamine-resistant vasodilatory shock received a combined infusion of vasopressin 4 units/hr (0.07 unit/min) and norepinephrine, and 24 patients received norepinephrine alone. The norepinephrine infusion rate exceeded 0.5 μg (as the bitartrate salt) per kilogram per minute to maintain all study participants at a minimum MAP of 70 mm Hg. At 48 hours, the patients treated with vasopressin plus norepinephrine had significantly lower mean ± S.. heart rates (93 ± 15 beats/min versus 98 ± 19 beats/ min [p = 0.003]) and significantly higher MAPs (81 ± 8 mm Hg versus 75 ± 12 mm Hg [p < 0.001]) than the patients receiving norepinephrine alone. Mean ± S.. norepinephrine requirements were significantly lower in the group receiving vasopressin (0.34 ± 0.25 μg/kg/min versus 0.54 ± 0.42 μg/kg/min [p < 0.001]). Cardiac index, stroke volume index, and left ventricular stroke work index were 1932 Am J Health-Syst Pharm Vol 62 Sep 15, 2005

CLNCAL CONSULTATON also significantly higher in the vasopressin group. When used for 48 hours in addition to norepinephrine, vasopressin improved hemodynamic measures and reduced norepinephrine requirements. Reducing catecholamine dosages may be beneficial in reducing the adverse reactions related to high dosages of catecholamines observed in septic shock. Another study evaluated the effects of vasopressin on blood pressure and hemodynamics. Klinzig and colleagues 10 conducted a small prospective study in 12 CU patients with septic shock who required norepinephrine to maintain MAPs above 70 mm Hg. At a mean dosage of 0.47 units/min (range, 0.06 1.8 units/min), vasopressin was able to maintain MAPs above goal for several hours without additional norepinephrine. The authors noted significant decreases in mean ± S.. heart rate (from 96 ± 14 beats/min to 80 ± 16 beats/min) and cardiac index (from 3.8 ± 1.3 L/min/m 2 to 3.0 ± 1.1 L/min/m 2 ) in patients maintained on vasopressin. The purpose of this study was to determine the utility of vasopressin as a replacement for norepinephrine. The dosages used to achieve and maintain desired MAPs were substantially higher than the low fixed dosage of 0.01 0.04 unit/min currently recommended for refractory hypotension. 2 Safety data were not reported. n a retrospective single-center cohort study, Hall et al. 11 investigated the early blood pressure effects of vasopressin as initial drug therapy compared with dosage-adjusted catecholamines in patients with septic shock. These authors reviewed the use of vasopressin, norepinephrine, and dopamine in 150 medical surgical CU patients. Fifty patients received low, fixed-dose vasopressin 0.04 unit/min. Forty-nine patients received norepinephrine and 51 dopamine, and both agents were adjusted to achieve a MAP of >70 mm Hg or a systolic blood pressure of >90 mm Hg. Patients were excluded from the study if the dopamine dosage was 5 μg/kg/min without adjustment. One hour after infusion, the MAP and mean systolic blood pressure were not significantly different among the three groups. There was an absolute increase in heart rate in the dopamine group compared with the vasopressin group. The need for rescue therapy (defined as additional vasopressor therapy to maintain blood pressure at any point after one hour of treatment with the initial agent) was significantly greater in the dopamine group (48%) than in the norepinephrine group (27%) and the vasopressin group (25%). There were no differences among the groups in 28-day mortality, CU length of stay, or hospital length of stay. The authors concluded that, like dosage-adjusted norepinephrine or dopamine, the addition of a low fixed dosage of vasopressin (0.04 unit/min) can increase blood pressure in septic shock patients. Although it was a retrospective cohort analysis, this study suggested that vasopressin is effective as a first-line pressor agent. A retrospective chart audit sought to determine the effects of continuous vasopressin infusion in patients with septic shock. 12 The records of 102 surgical, medical, burn, and neurology CU patients who received vasopressin for septic shock were reviewed. Selected patients had a documented or suspected infection, met two of four criteria for systemic inflammatory response syndrome, had at least one failing organ, and received vasopressin. Fifty-eight patients received dopamine hydrochloride at a mean ± S.. rate of 10.9 ± 6.2 μg/kg/min, 25 patients received norepinephrine 0.2 ± 0.2 μg/kg/min, 5 patients received phenylephrine hydrochloride 1.3 ± 0.4 μg/kg/min, 4 patients received dobutamine 5.6 ± 3.2 μg (as the hydrochloride salt) per kilogram per minute, and 3 patients received epinephrine 0.2 ± 0.2 μg (as the hydrochloride salt) per kilogram per minute. The mean ± S.. vasopressin dosage regimen was 0.11 ± 0.17 unit/min for 53.8 ± 71.5 hours. Compared with baseline, vasopressin infusion significantly improved MAP within one hour, significantly reduced heart rate within four hours, and significantly reduced the hourly dopamine dose by 25% within eight hours. These effects persisted through 96 hours. Other decreases in catecholamine dosages were not significantly different among the groups, most likely because of the small number of patients receiving other catecholamines. Urine output did not significantly change from baseline. The authors concluded that vasopressin infusion was effective in increasing MAP and reducing heart rate while decreasing the dopamine dosage in patients with septic shock. ünser and colleagues 13 conducted a retrospective analysis in 60 critically ill general and surgical CU patients, of whom 35 had septic shock and 25 had postcardiotomy shock. Patients received vasopressin 4 6 units/hr (0.07 0.1 unit/min), followed by a norepinephrine infusion to maintain MAP above 70 mm Hg. administration was subsequently reduced when norepinephrine requirements decreased to less than 0.4 μg/kg/min. caused a significant decrease in heart rate (24%) and cardiac index (21%), while significantly increasing MAP (29%) and systemic vascular resistance (56%). At 72 hours, norepinephrine requirements had decreased by 76%. as a first-line agent demonstrated significant, favorable effects on hemodynamics; however, the study cohort included postcardiotomy shock patients in addition to septic shock patients. Also, the authors gave a range for the vasopressin dosage but did not specify how this dosage was targeted in each patient. Patel et al. 14 conducted a prospective, double-blind, randomized, con- Am J Health-Syst Pharm Vol 62 Sep 15, 2005 1933

CLNCAL CONSULTATON osage Conversions trolled trial to assess the effects of short-term vasopressin infusion. Twenty-four patients with severe septic shock (defined as sepsis with end-organ dysfunction) who were adequately volume resuscitated and taking high-dose vasopressors received an infusion of vasopressin 0.01 unit/min for four hours. Adjustment to achieve a maximum infusion rate of 0.08 unit/min was allowed. At four hours, vasopressin decreased heart rate and cardiac index in the patients; however, the reductions were not statistically significant. MAP did not change, but there was a nonsignificant increase in systemic vascular resistance. significantly reduced the requirement for norepinephrine. The median infusion rate was 0.06 unit/min. Although the effects on hemodynamics were not significant, improvement was apparent during the four-hour study period. n a double-blind, placebocontrolled clinical trial, Malay et al. 15 assessed the role of a low fixed dosage of vasopressin for septic shock. Five patients with septic shock and vasodilatory hypotension were included in each treatment group and received either placebo or vasopressin 0.04 unit/min. At 24 hours, systolic blood pressure, MAP, and systemic vascular resistance had increased significantly in the vasopressin group. Cardiac index and heart rate both decreased, but the differences from baseline were not significant. Urine output. Klinzig et al. 10 and Obritsch et al. 12 observed no changes in hourly urine production during or after administration of vasopressin. n the Klinzig et al. trial, administration of relatively high doses of vasopressin occurred over only a few hours, so extrapolation from the data is difficult. Conversely, both a case series by Holmes et al. 16 and the randomized controlled trial by Patel et al. 14 found improvements in urine output after just four hours of administration. n the Holmes et al. study, urine output increased by 79% in 50 medical surgical CU patients at 4 hours; further increases were observed at 24 and 48 hours but were not significant. n the trial by Patel et al., urine output doubled from baseline during the four-hour infusion period. n the case series by Landry et al., 7 three of the five patients who were administered vasopressin for several days had increased urine output. n a prospective case-control study, 16 critically ill patients with sepsis were reported to have significant increases in urine output during a 16-hour infusion of vasopressin 0.04 unit/min. 17 The improvement in urine output in some trials but not in others may have been due to the timing of vasopressin administration in relation to the onset of septic shock. has been shown to cause a paradoxical diuretic effect in patients with early septic shock, but at high dosages (>0.04 unit/min), it can, much like catecholamines, cause a dose-dependent fall in renal blood flow, glomerular filtration rate, and sodium excretion. 3 t is interesting, however, that in the cases in which urine output increased, the duration of vasopressin infusion ranged from hours to days. Table 1 summarizes selected reports of vasopressin s effects on hemodynamics and urine output. Mucosal blood flow. n the randomized, controlled trial by ünser et al. 9 comparing vasopressin plus norepinephrine with norepinephrine alone, the authors used the partial pressure of carbon dioxide (PCO 2 ) in gut mucosa (PrCO 2 ) and the gradient of PrCO 2 to arterial PCO 2 (Pr-aCO 2 ) to assess gastrointestinal perfusion. Both PrCO 2 and Pr-aCO were significantly lower in vasopressin-treated 2 patients. The authors suggested that this indicated improvement in gastrointestinal perfusion. Patel and colleagues 14 also measured the gastric arterial PCO 2 gradient and found that it did not change significantly in the vasopressin or norepinephrine groups from baseline to four hours. The authors suggested that the lack of change in this measure indicated a lack of deleterious effects of vasopressin on gastric perfusion or function. n general, it is difficult to associate these specific laboratory findings with clinical outcomes. Adverse drug reactions. ünser and colleagues 9 found that patients treated with norepinephrine alone Table 1. Effect of nfusion on Selected Variables in Patients with Septic Shock a Ref. 4 7 9 b 10 11 12 13 c 14 15 16 17 Type of Evidence Case series Case series Prospective study Prospective study Prospective study Prospective study d Prospective study e n 10 5 48 12 150 102 60 24 10 50 16 Effect HR CO SVR UO CR a n all reports, blood pressure or mean arterial pressure increased. HR = heart rate, CO = cardiac output or cardiac index, SVR = systemic vascular resistance, UO = urine output, CR = catecholamine requirement, = not reported, = decreased, = increased. b Left ventricular stroke-work index increased. c Pulmonary artery pressure decreased. d Placebo-controlled trial. e Case control trial. 1934 Am J Health-Syst Pharm Vol 62 Sep 15, 2005

CLNCAL CONSULTATON had a significantly higher frequency of new-onset tachyarrhythmia (54.3%) than recipients of vasopressin plus norepinephrine (8.3%). There were no differences between the groups in the occurrence of myocardial ischemia or myocardial infarction. n a retrospective analysis, ünser et al. 18 reported on the frequency of ischemic skin lesions in 63 general and surgical CU patients who received a continuous i.v. infusion of vasopressin. All patients had catecholamine-resistant vasodilatory shock. Over a mean of 53 hours, 19 of the 63 patients developed ischemic skin lesions while receiving vasopressin. However, the infusion rate ranged from 0.07 to 0.1 unit/min, which is higher than the 0.01 0.04 unit/min generally recommended for refractory hypotension. Septic shock and preexistent peripheral arterial occlusive disease were identified as significant independent risk factors for development of the skin lesions. n the study by Hall et al., 11 31% of patients in the norepinephrine group had atrial arrhythmia, versus only 12% of patients in both the vasopressin and dopamine groups (p = 0.028). Venous thromboembolism was more common in the vasopressin group (14%) than in the norepinephrine group (2%) or the dopamine group (8%). There were no differences in peripheral vascular necrosis. Obritsch et al. 12 reported that, during the vasopressin infusion, nine patients experienced cardiac arrest, eight had ischemic digits and extremities, one had a myocardial infarction, and one had hyponatremia. n all but one of these patients, the vasopressin dosage was 0.04 unit/min. n another retrospective analysis by ünser et al., 13 platelet counts, creatine kinase MB, and troponin decreased and aspartate transaminase, alanine transaminase, and total bilirubin increased. Although these changes were significant, the authors did not observe clinically overt adverse events they believed to be due to the administration of vasopressin. n the case series of 50 critically ill medical surgical CU patients with septic shock, 6 patients who received vasopressin had cardiac arrest. 16 Five of the patients were receiving more than 0.03 unit/min, with dosages exceeding 0.05 unit/min for four of these patients. iscussion. A complete analysis of the efficacy of vasopressin in patients with septic shock presents difficulties. The studies are relatively few and have differing methodologies, interventions, and endpoints. A wide range of vasopressin dosages have been used in septic shock patients, and the timing and length of intervention have varied considerably. nformation on adverse events derives from trials that used both high and low dosages for different periods. Although some data support the use of continuously infused vasopressin for distributive shock, questions remain as to when and how much vasopressin should be given in the clinical setting of septic shock. A low fixed dosage of 0.01 0.04 unit/min has been shown to be beneficial in increasing blood pressure and systemic vascular resistance; it also decreases other catecholamine requirements while minimizing adverse reactions in patients with vasodilatory septic shock. n early shock, vasopressin levels are elevated, but physiological levels become rapidly depleted, with deficiency noted within six hours. This can be due to both impaired secretion and depletion. Concentrations can fall below 10 pg/ml by 36 hours (normal concentrations range from 10 to 200 pg/ml in hypotensive states). 1 epleted physiological levels of vasopressin make vascular V1-receptors available for activation. At a dosage of 0.04 unit/hr, plasma vasopressin concentrations reach 290 pg/ml. 17 Activation of V1-receptors by vasopressin can help restore perfusion via constriction of vascular smooth muscle. Unlike vasopressin levels, plasma levels of catecholamines are markedly increased during septic shock. 1 Therefore, fewer α-adrenergic receptors are available for activation. With escalating dosages of catecholamines, α-adrenergic receptors can become supersaturated, leading to increased adverse effects and very little, if any, additional hemodynamic benefit. This scenario outlines one of the primary causes of catecholamine-resistant shock in this patient population. Early administration of vasopressin can help restore the physiological levels needed to maintain blood pressure in septic shock. has also been shown to reduce the need for higher dosages of other catecholamines, specifically norepinephrine, phenylephrine, and dopamine. This can be of benefit, since the patient may have fewer adverse effects associated with highdose catecholamines and since the total amount of time patients are receiving vasopressors may decrease. The mechanism of action of vasopressin is independent of adrenergic stimulation, suggesting that the drug has an additive effect. The ability of vasopressin to cause vasoconstriction nonadrenergically, enabling the clinician to lower other vasopressor dosages, can be one of the keys to successfully treating hypotension and poor tissue perfusion and to minimizing adverse drug reactions. Cardiac output during septic shock initially increases and systemic vascular resistance decreases (with various degrees of myocardial dysfunction), leading to a high-output, low-resistance state. does not directly activate β-receptors and does not have a direct effect on cardiac output. Some researchers have found a decrease in cardiac output with vasopressin use, which can be of benefit in early septic shock. n late septic shock, a percentage of pa- Am J Health-Syst Pharm Vol 62 Sep 15, 2005 1935

CLNCAL CONSULTATON osage Conversions tients will have low cardiac output, so the addition of norepinephrine may be important. Several studies have found a significant improvement in urine output as early as 4 hours after the initiation of low-dose vasopressin ( 0.04 unit/min); other studies found increases 6 24 hours after initiation. 7,14,16,17,19,20 When higher dosages of vasopressin are used (>0.04 unit/min), there is a trend toward a dose-dependent decrease in renal perfusion pressure and glomerular filtration rate. The above-mentioned benefits have been seen when initiating vasopressin infusion early (in the first 24 hours) and maintaining the infusion for as long as 96 hours. Although adverse events can occur, including ischemic skin lesions in the distal limbs, elevated hepatic transaminase concentrations, elevated total serum bilirubin concentrations, and myocardial ischemia, these reactions appear to be rare at the recommended dosage of 0.01 0.04 unit/min. Clinical events indicating an increased risk of coagulation and gastrointestinal hypoperfusion are also rare when a vasopressin infusion is initiated and maintained at a low fixed rate. 9,17,21-23 n the past, vasopressin has been avoided because of its adverse-effect profile, but it clearly has significant benefits in septic shock patients when used at a low fixed dosage if fluid resuscitation and initial vasopressor therapy fail to improve hypotension and tissue perfusion. has been shown to be effective and safe. For patients with vasopressor-dependent septic shock, vasopressin (in addition to supportive care with i.v. fluids, antibiotics, ventilator support, and stress-dose corticosteroids) can be recommended as one of the first vasopressors added and one of the last discontinued for restoring hemodynamics and minimizing adverse effects and the need for exogenous catecholamines. Further trials are needed to determine the impact of vasopressin on morbidity and mortality. Conclusion. The early initiation of vasopressin for septic shock at a low fixed dosage (0.01 0.04 unit/min) helps restore and maintain normal physiological levels of vasopressin, therefore helping the body mount an appropriate response to widespread vasodilation. The use of vasopressin as a first-line pressor agent is crucial, because physiological levels can become depleted as early as six hours after the onset of severe hypotension. may make it possible to reduce the dosage of other catecholamines and thus lower the potential for adverse effects. References 1. Landry W, Oliver JA. The pathogenesis of vasodilatory shock. N Engl J Med. 2001; 345:588-95. 2. ellinger RP, Carlet JM, Masur H et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004; 32:858-71. 3. Mutlu GM, Factor P. Role of vasopressin in the management of septic shock. ntensive Care Med. 2004; 30:1276-91. 4. Landry W, Levin HR, Gallant EM et al. deficiency contributes to the vasodilation of septic shock. Circulation. 1997; 95:1122-5. 5. Holmes CL, Patel BM, Russell JA et al. Physiology of vasopressin relevant to management of septic shock. Chest. 2001; 120:989-1002. 6. Jackson EK. and other agents affecting the renal conservation of water. n: Hardman JG, Limbird LE, Gilman AG, eds. Goodman and Gilman s the pharmacological basis of therapeutics. 10th ed. New York: McGraw-Hill; 2001. 7. Landry W, Levin HR, Gallant EM et al. pressor hypersensitivity in vasodilatory septic shock. Crit Care Med. 1997; 25:1279-82. 8. Holmes CL, Walley KR, Chittock R et al. The effects of vasopressin on hemodynamics and renal function in severe septic shock: a case series. ntensive Care Med. 2001; 27:1416-21. 9. unser MW, Mayr AJ, Ulmer H et al. Arginine vasopressin in advanced vasodilatory shock: a prospective, randomized, controlled study. Circulation. 2003; 107:2313-9. 10. Klinzig S, Simon M, Reinhart K et al. High-dose vasopressin is not superior to norepinephrine in septic shock. Crit Care Med. 2003; 31:2646-50. 11. Hall LG, Oyen LJ, Taner CB et al. Fixeddose vasopressin compared with titrated dopamine and norepinephrine as initial vasopressor therapy for septic shock. Pharmacotherapy. 2004; 24:1002-12. 12. Obritsch M, Jung R, Fish et al. Effects of continuous vasopressin infusion in patients with septic shock. Ann Pharmacother. 2004; 38:1117-22. 13. unser MW, Mayr AJ, Ulmer H et al. The effects of vasopressin on systemic hemodynamics in catecholamine-resistant septic and postcardiotomy shock: a retrospective analysis. Anesth Analg. 2001; 93:7-13. 14. Patel BM, Chittock R, Russell JA et al. Beneficial effects of short-term vasopressin infusion during severe septic shock. Anesthesiology. 2002; 96:576-82. 15. Malay MB, Ashton RC Jr, Landry W et al. Low-dose vasopressin in the treatment of vasodilatory septic shock. J Trauma. 1999; 47:699-705. 16. Holmes CL, Walley KR, Chittock R et al. The effects of vasopressin on hemodynamics and renal function in severe septic shock: a case series. ntensive Care Med. 2001; 27:1416-21. 17. Tsuneyoshi, Yamada H, Kakihana Y et al. Hemodynamic and metabolic effects of low-dose vasopressin infusions in vasodilatory septic shock. Crit Care Med. 2001; 29:487-93. 18. unser MW, Mayr AJ, Tur A et al. schemic skin lesions as a complication of continuous vasopressin infusion in catecholamine-resistant vasodilatory shock: incidence and risk factors. Crit Care Med. 2003; 31:1394-8. 19. Rudichenko VM, Beierwaltes WH. Arginine vasopressin-induced renal vasodilation mediated by nitric oxide. J Vasc Res. 1995; 32:100-5. 20. Gutkowska J, Jankowski M, Lambert C et al. Oxytocin releases atrial natriuretic peptide by combining with oxytocin receptors in the heart. Proc Natl Acad Sci U S A. 1997; 94:11704-9. 21. Van Haren F, Rozendaal F, Van der Hoeven J. The effect of vasopressin on gastric perfusion in catecholamine-dependent patients in septic shock. Chest. 2003; 124:2256-60. 22. Sirinek KR, Levine BA. High dose vasopressin for acute variceal hemorrhage. Clinical advantages without adverse effects. Arch Surg. 1988; 123:876-80. 23. Greenwald RA, Rheingold OJ, Chiprut RO et al. Local gangrene: a complication of peripheral Pitressin therapy for bleeding esophageal varices. Gastroenterology. 1978; 74:744-6. 1936 Am J Health-Syst Pharm Vol 62 Sep 15, 2005