Best Practice & Research Clinical Anaesthesiology Vol. 22, No. 2, pp.

275286, 2008
doi:10.1016/j.bpa.2008.03.002 available online at http://www.sciencedirect.com

4 Arginine vasopressin in the treatment of vasodilatory septic shock*

Cheryl L. Holmesa
Clinical Instructor University of British Columbia, Division of Critical Care, Department of Medicine, Kelowna General Hospital, BC, Canada
MD, FRCPC

Keith R. Walley *
Professor of Medicine

MD, FRCPC

University of British Columbia, Division of Critical Care, Department of Medicine, St. Pauls Hospital, Vancouver, BC, Canada

Vasodilatory septic shock is characterized by profound vasodilation of the peripheral circulation, relative refractoriness to catecholamines and a relative deciency of the posterior pituitary hormone, vasopressin. Arginine vasopressin is effective in restoring vascular tone in vasodilatory septic shock and may be associated with decreased mortality in less severe septic shock as well as improved mortality and decreased renal failure in septic shock patients at risk for renal failure. Key words: acute renal failure; adrenergic agents; antidiuretic hormone; arginine Vasopressin; hypotension; muscle, smooth, vascular/physiology; norepinephrine; nitric oxide; potassium channels; shock, septic; vasoconstriction; vasodilation; vasopressin.

VASODILATORY SEPTIC SHOCK Vasodilatory septic shock refers to a state of hypotension and organ dysfunction due to infection. Hypovolaemic, cardiogenic and obstructive forms of shock are
Support: Heart & Stroke Foundation of B.C. and Yukon. Keith R. Walley is a B.C. Lung Association/St. Pauls Hospital Foundation Scientist. * Corresponding author. Keith R. Walley, MD, UBC McDonald Research Laboratories, St. Pauls Hospital, 1081 Burrard Street, Vancouver, BC, Canada V6Z 1Y6. Tel.: 604 806 8136; Fax: 604 806 8351. E-mail addresses: clholmes@telus.net (C.L. Holmes), kwalley@mrl.ubc.ca (K.R. Walley). a Tel.: 1 250 212 9450; Fax: 1 250 764 9083. 1521-6896/$ - see front matter 2008 Published by Elsevier Ltd.
*

276 C. L. Holmes and K. R. Walley

characterized by decreased cardiac output, hypotension and profound vasoconstriction in the peripheral circulation. In vasodilatory shock there is a complex interaction between pathologic vasodilation, relative and absolute hypovolaemia, myocardial depression, and altered blood ow distribution, which occur as a consequence of the inammatory responsive to injury.1 Sepsis is the most frequent cause of vasodilatory shock, however, vasodilatory shock is also the nal common pathway for prolonged and severe shock of any cause.2 Endogenous vasopressin release is essential for both osmotic and cardiovascular homeostasis. A deciency of vasopressin exists in septic shock and replacement of physiologic levels of vasopressin can restore vascular tone and may improve organ function in vasodilatory septic shock. Pathogenesis of vasodilatory septic shock Vasodilation in septic shock is due to inappropriate activation of vasodilator mechanisms and failure of vasoconstrictor mechanisms in vascular smooth muscle despite high plasma catecholamine levels and activation of the renin-angiotensin system. Three mechanisms have been implicated: activation of ATP-sensitive and calcium-regulated potassium channels (KATP and KCa channels) in the plasma membrane of vascular smooth muscle, activation of the inducible form of nitric oxide synthase (NOS) and depletion of the pituitary stores of vasopressin (Figure 1).2 Vasopressin deciency in septic shock Vasopressin is synthesized in the hypothalamus and then transported down the pituitary stalk and stored in the posterior pituitary gland. Plasma vasopressin levels are normally less than 4 pg/mL in overnight fasted, hydrated humans.3 Both septic and haemorrhagic shock are associated with a biphasic response in vasopressin levels. Hypotension is a profound stimulus to increase plasma vasopressin levels. In early shock, increased secretion of vasopressin leads to appropriately high plasma levels of vasopressin to defend organ perfusion.46 As the shock state progresses, plasma vasopressin levels fall6,7, for reasons that are not entirely clear. Several investigators have observed inappropriately low vasopressin levels in established septic shock and vasodilatory shock.6,818 Landry and coworkers were the rst to demonstrate that patients in advanced vasodilatory septic shock had inappropriately low plasma levels of vasopressin and furthermore, exogenous infusion of low-dose arginine vasopressin increased vasopressin levels, indicating that the low vasopressin levels in septic shock were due to impaired vasopressin secretion, not increased vasopressin metabolism or clearance.8 Many studies report vasopressin levels in the late phases of septic shock. Lin and coworkers studied vasopressin and norepinephrine levels in 182 patients presenting to the emergency department in the rst six hours who had sepsis, severe sepsis and septic shock.17 Interestingly, vasopressin levels were highest in severe sepsis and lowest in patients with septic shock, consistent with enhanced pituitary secretion of vasopressin in severe sepsis and then depletion of stores in established septic shock. Also interesting was that norepinephrine levels were highest in septic shock (Table 1).17 Russell calculated the vasopressin to norepinephrine (VP/NE) ratios in these patients and found that in sepsis and severe sepsis the ratio was similar

Treatment of vasodilatory septic shock 277

Figure 1. Mechanisms of Vasodilatory Shock.2 Septic shock and states of prolonged shock causing tissue hypoxia with lactic acidosis increase nitric oxide synthesis, activate ATP-sensitive and calcium-regulated potassium channels (KATP and KCa, respectively) in vascular smooth muscle, and lead to depletion of vasopressin. The abbreviation cGMP denotes cyclic guanosine monophosphate.

(1/165) but that in the septic shock patients is much lower (1/1000).19 Thus it appears that even in early septic shock there is a deciency of vasopressin relative to norepinephrine. The reason for the relative deciency of vasopressin in vasodilatory septic shock is uncertain: and at least four mechanisms have been proposed. First, early enhanced secretion of vasopressin leads to depletion of neurohypophysial stores in advanced shock.20 Second, others have postulated autonomic insufciency in sepsis21 citing lack of baroreex-mediated bradycardia after vasopressin infusion as evidence of autonomic insufciency.8 Third, low concentrations of norepinephrine excite central

Table 1. Vasopressin and norepinephrine levels in patients in emergency with sepsis, severe sepsis and septic shock.17,19 Sepsis (N 54) Vasopressin (pg/ml) Norepinephrine VP/NE Ratio 10.6 6.5 1720 320 1/165 Severe sepsis (N 56) 21.8 4.1 3600 1000 1/165 Septic shock (N 72) 3.6 2.5 3650 980 1/1000

278 C. L. Holmes and K. R. Walley

vasopressinergic neurons whereas elevated norepinephrine levels have a central inhibitory effect on vasopressin release.22 Finally, increased nitric oxide production by vascular endothelium within the posterior pituitary during sepsis may inhibit vasopressin production.23 Vasopressin administration can restore vascular tone in vasodilatory shock Continuous infusion of vasopressin restores vascular tone in vasoplegic (catecholamine-resistant) shock states by several mechanisms2 including activation of vasopressin 1 receptors (V1Rs), modulation of KATP channels, modulation of nitric oxide, and potentiation of adrenergic and other vasoconstrictor agents.24,25 Vasopressin binds to V1 receptors, which are found in high density on vascular smooth muscle. V1 receptor binding stimulates phospholipase C and produces the intracellular second messengers inositol trisphosphate (IP3) and diacylglycerol (DAG) through the Gq/11 pathway. These second messengers then activate protein kinase C and elevate intracellular free calcium to initiate contraction of vascular smooth muscle. An important mechanism by which vasopressin restores vascular tone in vasoplegic (catecholamine-resistant) shock states may be its ability to close KATP channels.26 Activation of KATP channels is a critical mechanism in the hypotension and vasodilation characteristic of vasodilatory shock. Agents which close KATP channels (such as sulfonylureas) increase arterial pressure and systemic vascular resistance in vasodilatory shock due to hypoxia, septic shock, and in the late, vasodilatory phase of haemorrhagic shock.27,28 Modulation of nitric oxide (NO) is another mechanism by which vasopressin exerts vascular control. Nitric oxide contributes to the hypotension and resistance to vasopressor drugs that occurs in vasodilatory shock. The vasodilating effect of NO is mediated mainly by the activation of myosin light-chain phosphatase. However, NO also activates K channels in the vascular smooth muscle.29,30 Agents which block NO synthesis during septic shock increase arterial pressure and decrease the doses of vasoconstrictor catecholamines needed to maintain arterial pressure.31 Vasopressin may restore vascular tone in vasodilatory shock states by blunting the increase in cGMP that is induced by NO and by decreasing synthesis of inducible NO synthase that is stimulated by lipopolysaccharide.32 Vasopressin also potentiates the vasoconstrictor effects of many agents, including norepinephrine33,34 and angiotensin II.35,36 The underlying mechanism of this is unknown but possibilities include coupling between G protein-coupled receptors (GPCRs)37, interaction between G-proteins and interference with GPCR downregulation through arrestin trafcking.25 CLINICAL TRIALS OF ARGININE VASOPRESSIN IN SEPTIC SHOCK Clinical trials show that infusion of low-dose vasopressin in patients who have vasodilatory shock decreases norepinephrine dose requirements, maintains blood pressure and cardiac output, decreases pulmonary vascular resistance and increases urine output.8,1014,3847 These observations suggest that low-dose vasopressin could improve renal and other organ function in septic shock. We now examine the key trials of vasopressin in septic shock in detail.

Treatment of vasodilatory septic shock 279

Preliminary studies of arginine vasopressin for septic shock Landry and coworkers were the rst to report that very low doses of the arginine vasopressin (from 0.01 to 0.05 U/min) were effective in restoring vascular tone in a case series of ve patients with vasodilatory shock due to sepsis.38 They also reported increased urine output in three of ve patients on infusion of vasopressin. Landry and co-workers went on to investigate the possibility that vasopressin deciency contributes to the vasodilation in septic shock by prospectively studying 19 patients with vasodilatory septic shock.8 They observed that compared with patients in cardiogenic shock, patients in advanced vasodilatory septic shock had inappropriately low plasma levels of vasopressin (22.7 2.2 pg/mL in cardiogenic shock patients vs. 3.1 0.4 pg/mL in the septic shock patients).8 They went on to conrm their initial ndings that although arginine vasopressin is a weak pressor in normal subjects, its administration at 0.04 U/min to patients with septic shock who were receiving catecholamines increased arterial pressure due to increased systemic vascular resistance. Furthermore, in patients with septic shock who were receiving vasopressin as the sole pressor, its withdrawal resulted in hypotension and vasopressin administration at 0.01 U/min resulted in plasma concentrations of 30 pg/mL and increased arterial blood pressure. Patel and coworkers were the rst to study the effects in septic shock in a doubleblind randomized controlled trial of vasopressin vs. norepinephrine.14 Patients were randomized to a double-blinded four hour infusion of either norepinephrine at 2 mcg/min to 16 mcg/min (n 11) or vasopressin at 0.01 U/min to 0.08 U/min (n 13) and open-label vasopressors were titrated to maintain blood pressure at a pre-specied level. Patients who received vasopressin had a signicant (80%) reduction in vasopressor dose requirement to maintain blood pressure. Interestingly, urine output doubled and creatinine clearance increased by 75% in the patients who received vasopressin. On the basis of this study, the authors concluded that a shortterm infusion of vasopressin spared norepinephrine use and improved some measures of renal function in patients with septic shock. They also demonstrated that vasopressin could be successfully studied in a double blind fashion when norepinephrine was used as control in equipotent vasopressor doses to vasopressin. Vasopressin and Septic Shock Trial (VASST) Using Patels study design, our group conducted a randomized controlled trial of vasopressin vs. norepinephrine in the Vasopressin And Septic Shock Trial (VASST).18 In this multi-centre, randomized, blinded trial, patients who had septic shock receiving a minimum of 5 mcg/min of norepinephrine infusion were allocated to either low-dose vasopressin (0.010.03 U/min) or norepinephrine infusion (515 mcg/min) in addition to open-label vasopressors. All vasopressors were titrated and weaned according to protocols to maintain a target blood pressure. The primary end point was 28-day mortality. Patients were analyzed according to the a priori strata of more severe and less severe septic shock, based on the level of vasopressor use at baseline. In VASST, 779 patients were randomized and infused with the study drug (vasopressin n 397, norepinephrine n 382). The study was prospectively powered to detect an absolute difference in mortality of 10% from an expected 60%. The observed mortality rates were considerably lower than predicted in the vasopressin and norepinephrine groups, compared to previous reports perhaps because of overall improvements in the care of patients who have septic shock.48 There was no difference in the primary outcome, 28-day mortality, between vasopressin (35.4%) and norepinephrine (39.3%, P 0.26): and there was no difference between

280 C. L. Holmes and K. R. Walley

groups in mortality at 90 days (43.9% and 49.6% respectively, P 0.11). There were no differences in the overall rates of serious adverse events (vasopressin, 10.3% and norepinephrine, 10.5%, P 1.0). Thus, clinicians using an evidence-based approach now may choose norepinephrine alone or norepinephrine plus low dose vasopressin as vasopressors to manage patients with severe septic shock. The data exclude with 95% condence a harm of vasopressin of greater than 2.9% or a benet of greater than 10.7%. Thus, a noninferiority analysis of these data demonstrates that vasopressin plus low dose norepinephrine is not inferior to norepinephrine alone even when rigorous non-inferiority criteria are applied largely because the trend is towards benet with vasopressin. Since the trend is towards benet of vasopressin, what additional evidence is available to the clinician to help guide the choice between low-dose vasopressin plus norepinephrine versus norepinephrine alone? In the prospectively dened stratum of less severe septic shock in VASST mortality was signicantly lower in the vasopressintreated group at 28 days (26.5% vs. 35.7%, P 0.05) (Figure 2B). Similarly, vasopressin may be particularly effective in patients who are at risk of renal dysfunction49, evaluated according to RIFLE criteria (acronym indicating Risk of renal dysfunction; Injury to the kidney; Failure of kidney function, Loss of kidney function and End-stage kidney disease, Figure 4).50 In the patients who were atrisk for renal failure (increase in serum creatinine 1.5 baseline, decrease in GFR by 25% or urine output < 0.5 mL/kg/hr for 6 hrs) the vasopressin treated patients (n 53) compared to the norepinephrine patients (n 53) had signicantly reduced 28-day (30.8% vs. 54.7%, P 0.01) and 90-day (37.3% vs. 62.3%, P 0.01) mortality. This remained signicant after adjustment for potential confounders. The at-risk patients treated with vasopressin were also less likely to develop renal failure over the 28 day study period compared to the at-risk patients treated with norepinephrine (21.2% vs. 41.2%, P 0.02). There was no difference in outcome between vasopressin and norepinephrine groups in the other categories of renal function. Plasma vasopressin levels were extremely low at baseline (median 3.2 pmol/L, interquartile range 1.74.9 pmol/L) and did not change in the norepinephrine group. Low dose vasopressin infusion increased vasopressin levels to medians of 73.6 pmol/L (interquartile range 58.6 to 94.7 pmol/L) at six hours and 98.0 pmol/L (interquartile range 67.1 to 127.8 pmol/L) at 24 hours (Figure 3), conrming the restoration of plasma levels of vasopressin appropriate for shock. In summary, the Vasopressin And Septic Shock Trial did not nd a difference between low-dose vasopressin plus norepinephrine and norepinephrine alone suggesting that either approach is reasonable. However, vasopressin may be benecial in the lesssevere septic shock subgroup (those patients on <15 mcg/min norepinephrine at baseline) and possibly for patients at risk for renal failure. VASST conrmed the relative deciency of vasopressin in septic shock and administration of 0.01 to 0.03 U/min restored plasma vasopressin to an appropriate level in septic shock. Additional studies are needed to conrm or refute these subgroup ndings, and to understand whether earlier use of vasopressin, or different doses of vasopressin could further improve the outcomes of critically ill patients having septic shock. EXPERT RECOMMENDATIONS ON VASOPRESSIN FOR THE TREATMENT OF SEPTIC SHOCK Prior to publication of the Vasopressin And Septic Shock Trial (VASST), three evidence-based guidelines were reported.1,51,52 All recommended cautious use of

Figure 2. VASST: 90-day Kaplan Meier Survival Curves18 (on-line supplement) (A) Patients in more severe stratum (P 0.77 at day 28 and P 0.92 at day 90), (B) Patients in less severe stratum (P 0.05 at day 28 and P 0.03 at day 90). Solid black line is the vasopressin treated group, the dotted line is the norepinephrine treated group, and the vertical line marks day 28. P values were calculated using the log rank statistic.

282 C. L. Holmes and K. R. Walley

140 120

Plasma vasopressin level (pmol/L, median + IQR)

100 80 60 40 20 0

VASOPRESSIN

NOREPINEPHRINE

Baseline

6 hours

24 hours

72 hours

7 days

Timepoint
Figure 3. VASST: Plasma vasopressin levels over time in patients receiving a vasopressin infusion18 (on-line supplement), n 54, (black squares), patients in the vasopressin group once vasopressin infusions had stopped (open squares) and patients in the norepinephrine group, n 53, (grey circles). Values are median interquartile range. (Note: 1 pmol/L 1.08 pg/mL). Used with permission

Figure 4. RIFLE Criteria50 Proposed classication scheme for acute renal failure (ARF). The classication system includes separate criteria for creatinine and urine output (UO). A patient can fulll the criteria through changes in serum creatinine (SCreat) or changes in UO, or both. The criteria that lead to the worst possible classication should be used. Note that the F component of RIFLE (Risk of renal dysfunction, Injury to the kidney, Failure of kidney function, Loss of kidney function and End-stage kidney disease) is present even if the increase in SCreat is under threefold as long as the new SCreat is greater than 4.0 mg/dl (350 mmol/l) in the setting of an acute increase of at least 0.5 mg/dl (44 mmol/l). *GFR Glomerular Filtration Rate; ARF Acute Renal Failure

Treatment of vasodilatory septic shock 283

Table 2. Dosing guidelines: add 30 U vasopressin to 250 mL normal saline: concentration 0.12 U/mL. Dose units/min 0.01 0.02 0.03 Dose units/hr 0.6 1.2 1.8 Rate mL/hour 5 10 15

vasopressin pending further studies. In a systematic review of the literature of vasopressor and inotropic support in septic shock published in 2004, the role of vasopressin remained uncertain.1 The recommendation stated, Vasopressin use may be considered in patients with refractory shock despite adequate uid resuscitation and high-dose conventional vasopressors. Pending the outcome of ongoing trials, it is not recommended as a replacement for norepinephrine or dopamine as a rstline agent. If used in adults, it should be administered at infusions rates of 0.01 0.04 units/min.1

Practice Points based on VASST  Arginine vasopressin should be considered as adjunctive hemodynamic therapy in septic shock patients, particularly in: B Patients requiring between 5 and 15 mcg/min norepinephrine infusion after adequate uid resuscitation. B Patients at risk for renal failure according to RIFLE criteria (increase in serum creatinine 1.5 baseline, decrease in GFR by 25% or urine output < 0.5 mL/kg/hr for 6 hrs).  The dose of arginine vasopressin should be between 0.01 and 0.03 U/min.  Table 2: Dosing Guidelines: Add 30 U vasopressin to 250 mL normal saline: concentration 0.12 U/mL.

Research agenda  Additional studies are needed to conrm or refute the subgroup ndings of VASST and to understand whether earlier use of vasopressin or different doses of vasopressin could further improve the outcomes of critically ill patients.

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286 C. L. Holmes and K. R. Walley 50. Bellomo R, Ronco C, Kellum JA et al. Acute renal failure denition, outcome measures, animal models, uid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Critical Care 2004; 8(4): R204R212. *51. Dellinger RP, Carlet JM, Masur H et al. Surviving sepsis campaign guidelines for management of severe sepsis and septic shock. Critical Care Medicine 2004; 32(3): 858873. *52. Rhodes A & Bennett ED. Early goal-directed therapy: an evidence-based review. Critical Care Medicine 2004; 32(11 Suppl): S448S450.