Vasopresina en SS Review

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Arginine vasopressin in the treatment of

vasodilatory septic shock *

Cheryl L. Holmesa MD, FRCPC

Clinical Instructor

University of British Columbia, Division of Critical Care, Department of Medicine,

Kelowna General Hospital, BC, Canada

Keith R. Walley* MD, FRCPC

Professor of Medicine

University of British Columbia, Division of Critical Care, Department of Medicine,

St. Paul’s Hospital, Vancouver, BC, Canada

Vasodilatory septic shock is characterized by profound vasodilation of the peripheral circulation,

relative refractoriness to catecholamines and a relative deficiency of the posterior pituitary hor-mone, vasopressin. Arginine vasopressin is effective in restoring vascular tone in vasodilatoryseptic shock and may be associated with decreased mortality in less severe septic shock aswell as improved mortality and decreased renal failure in septic shock patients at risk for renalfailure.

Key words: acute renal failure; adrenergic agents; antidiuretic hormone; arginine Vasopressin;hypotension; muscle, smooth, vascular/physiology; norepinephrine; nitric oxide; potassium chan-nels; shock, septic; vasoconstriction; vasodilation; vasopressin.

VASODILATORY SEPTIC SHOCK

Vasodilatory septic shock refers to a state of hypotension and organ dysfunction dueto 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.

Paul’s Hospital Foundation Scientist.

* Corresponding author. Keith R. Walley, MD, UBC McDonald Research Laboratories, St. Paul’s Hospital,

1081 Burrard Street, Vancouver, BC, Canada V6Z 1Y6. Tel.: þ604 806 8136; Fax: þ604 806 8351.E-mail addresses: [email protected] (C.L. Holmes), [email protected] (K.R. Walley).a Tel.: þ1 250 212 9450; Fax: þ1 250 764 9083.

1521-6896/$ - see front matter ª 2008 Published by Elsevier Ltd.

Best Practice & Research Clinical AnaesthesiologyVol. 22, No. 2, pp. 275–286, 2008

doi:10.1016/j.bpa.2008.03.002

available online at http://www.sciencedirect.com

mailto:[email protected]


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characterized by decreased cardiac output, hypotension and profound vasoconstric-tion in the peripheral circulation. In vasodilatory shock there is a complex interactionbetween pathologic vasodilation, relative and absolute hypovolaemia, myocardial de-pression, and altered blood flow distribution, which occur as a consequence of the in-flammatory responsive to injury.1 Sepsis is the most frequent cause of vasodilatoryshock, however, vasodilatory shock is also the final common pathway for prolonged

and severe shock of any cause.2

Endogenous vasopressin release is essential for both osmotic and cardiovascularhomeostasis. A deficiency of vasopressin exists in septic shock and replacement of physiologic levels of vasopressin can restore vascular tone and may improve organfunction in vasodilatory septic shock.

Pathogenesis of vasodilatory septic shock

Vasodilation in septic shock is due to inappropriate activation of vasodilator mech-anisms and failure of vasoconstrictor mechanisms in vascular smooth muscle

despite high plasma catecholamine levels and activation of the renin-angiotensinsystem. Three mechanisms have been implicated: activation of ATP-sensitive andcalcium-regulated potassium channels (KATP and KCaþþ channels) in the plasmamembrane of vascular smooth muscle, activation of the inducible form of nitricoxide synthase (NOS) and depletion of the pituitary stores of vasopressin(Figure 1).2

Vasopressin deficiency in septic shock

Vasopressin is synthesized in the hypothalamus and then transported down the pitu-

itary stalk and stored in the posterior pituitary gland. Plasma vasopressin levels arenormally less than 4 pg/mL in overnight fasted, hydrated humans.3 Both septic andhaemorrhagic shock are associated with a biphasic response in vasopressin levels.Hypotension is a profound stimulus to increase plasma vasopressin levels. In earlyshock, increased secretion of vasopressin leads to appropriately high plasma levelsof vasopressin to defend organ perfusion.4–6 As the shock state progresses, plasmavasopressin levels fall6,7, for reasons that are not entirely clear. Several investigatorshave observed inappropriately low vasopressin levels in established septic shock andvasodilatory shock.6,8–18

Landry and coworkers were the first to demonstrate that patients in advanced vas-

odilatory septic shock had inappropriately low plasma levels of vasopressin and fur-thermore, exogenous infusion of low-dose arginine vasopressin increasedvasopressin levels, indicating that the low vasopressin levels in septic shock weredue to impaired vasopressin secretion, not increased vasopressin metabolism orclearance.8

Many studies report vasopressin levels in the late phases of septic shock. Lin andcoworkers studied vasopressin and norepinephrine levels in 182 patients presentingto the emergency department in the first six hours who had sepsis, severe sepsisand septic shock.17 Interestingly, vasopressin levels were highest in severe sepsisand lowest in patients with septic shock, consistent with enhanced pituitary secre-

tion of vasopressin in severe sepsis and then depletion of stores in established septicshock. Also interesting was that norepinephrine levels were highest in septic shock (Table 1).17 Russell calculated the vasopressin to norepinephrine (VP/NE) ratios inthese patients and found that in sepsis and severe sepsis the ratio was similar

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



(1/165) but that in the septic shock patients is much lower (1/1000).19 Thus it ap-pears that even in early septic shock there is a deficiency of vasopressin relativeto norepinephrine.

The reason for the relative deficiency of vasopressin in vasodilatory septic shock isuncertain: and at least four mechanisms have been proposed. First, early enhancedsecretion of vasopressin leads to depletion of neurohypophysial stores in advanced

shock.

20

Second, others have postulated autonomic insufficiency in sepsis

21

citinglack of baroreflex-mediated bradycardia after vasopressin infusion as evidence of autonomic insufficiency.8 Third, low concentrations of norepinephrine excite central

Figure 1. Mechanisms of Vasodilatory Shock .2 Septic shock and states of prolonged shock causing tis-

sue 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 vaso-

pressin. The abbreviation cGMP denotes cyclic guanosine monophosphate.

Table 1. Vasopressin and norepinephrine levels in patients in emergency with sepsis, severe sepsis and

septic shock.17,19

Sepsis

(N¼ 54)

Severe sepsis

(N¼ 56)

Septic shock

(N¼ 72)

Vasopressin (pg/ml) 10.6 6.5 21.8 4.1 3.6 2.5Norepinephrine 1720 320 3600 1000 3650 980

VP/NE Ratio 1/165 1/165 1/1000

Treatment of vasodilatory septic shock 277



vasopressinergic neurons whereas elevated norepinephrine levels have a central inhib-itory effect on vasopressin release.22 Finally, increased nitric oxide production by vas-cular endothelium within the posterior pituitary during sepsis may inhibit vasopressinproduction.23

Vasopressin administration can restore vascular tone in vasodilatory shock

Continuous infusion of vasopressin restores vascular tone in vasoplegic (catechol-amine-resistant) shock states by several mechanisms2 including activation of vasopres-sin 1 receptors (V1R’s), modulation of KATP channels, modulation of nitric oxide, andpotentiation of adrenergic and other vasoconstrictor agents.24,25

Vasopressin binds to V1 receptors, which are found in high density on vascularsmooth muscle. V1 receptor binding stimulates phospholipase C and produces the in-tracellular 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 smoothmuscle.

An important mechanism by which vasopressin restores vascular tone in vasoplegic(catecholamine-resistant) shock states may be its ability to close KATP channels.26 Ac-tivation of KATP channels is a critical mechanism in the hypotension and vasodilationcharacteristic of vasodilatory shock. Agents which close KATP channels (such as sulfo-nylureas) increase arterial pressure and systemic vascular resistance in vasodilatoryshock due to hypoxia, septic shock, and in the late, vasodilatory phase of haemorrhagicshock.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 vaso-pressor drugs that occurs in vasodilatory shock. The vasodilating effect of NO is me-diated mainly by the activation of myosin light-chain phosphatase. However, NO alsoactivates Kþ channels in the vascular smooth muscle.29,30 Agents which block NO syn-thesis during septic shock increase arterial pressure and decrease the doses of vaso-constrictor catecholamines needed to maintain arterial pressure.31 Vasopressin mayrestore vascular tone in vasodilatory shock states by blunting the increase in cGMPthat is induced by NO and by decreasing synthesis of inducible NO synthase that isstimulated 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 un-known but possibilities include coupling between G protein-coupled receptors(GPCRs)37, interaction between G-proteins and interference with GPCR down-regulation through arrestin trafficking.25

CLINICAL TRIALS OF ARGININE VASOPRESSIN IN SEPTIC SHOCK

Clinical trials show that infusion of low-dose vasopressin in patients who have vasodi-latory shock decreases norepinephrine dose requirements, maintains blood pressure

and cardiac output, decreases pulmonary vascular resistance and increases urine out-put.8,10–14,38–47 These observations suggest that low-dose vasopressin could improverenal and other organ function in septic shock. We now examine the key trials of vasopressin in septic shock in detail.




Preliminary studies of arginine vasopressin for septic shock

Landry and coworkers were the first to report that very low doses of the argininevasopressin (from 0.01 to 0.05 U/min) were effective in restoring vascular tone ina case series of five patients with vasodilatory shock due to sepsis.38 They also re-ported increased urine output in three of five patients on infusion of vasopressin.Landry and co-workers went on to investigate the possibility that vasopressin defi-ciency contributes to the vasodilation in septic shock by prospectively studying 19patients with vasodilatory septic shock.8 They observed that compared with patientsin cardiogenic shock, patients in advanced vasodilatory septic shock had inappropri-ately low plasma levels of vasopressin (22.7 2.2 pg/mL in cardiogenic shock patientsvs. 3.1 0.4 pg/mL in the septic shock patients).8 They went on to confirm their initialfindings that although arginine vasopressin is a weak pressor in normal subjects, itsadministration at 0.04 U/min to patients with septic shock who were receiving catechol-amines increased arterial pressure due to increased systemic vascular resistance. Further-more, in patients with septic shock who were receiving vasopressin as the sole pressor, itswithdrawal resulted in hypotension and vasopressin administration at 0.01 U/minresulted in plasma concentrations of 30 pg/mL and increased arterial blood pressure.

Patel and coworkers were the first to study the effects in septic shock in a double-blind randomized controlled trial of vasopressin vs. norepinephrine.14 Patients wererandomized to a double-blinded four hour infusion of either norepinephrine at2 mcg/min to 16 mcg/min (n¼ 11) or vasopressin at 0.01 U/min to 0.08 U/min(n¼ 13) and open-label vasopressors were titrated to maintain blood pressure ata pre-specified level. Patients who received vasopressin had a significant (80%) reduc-tion in vasopressor dose requirement to maintain blood pressure. Interestingly, urineoutput doubled and creatinine clearance increased by 75% in the patients who re-

ceived vasopressin. On the basis of this study, the authors concluded that a short-term infusion of vasopressin spared norepinephrine use and improved some measuresof renal function in patients with septic shock. They also demonstrated that vasopres-sin could be successfully studied in a double blind fashion when norepinephrine wasused as control in equipotent vasopressor doses to vasopressin.

Vasopressin and Septic Shock Trial (VASST)

Using Patel’s study design, our group conducted a randomized controlled trial of vaso-pressin 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 mini-mum of 5 mcg/min of norepinephrine infusion were allocated to either low-dose vaso-pressin (0.01–0.03 U/min) or norepinephrine infusion (5–15 mcg/min) in addition toopen-label vasopressors. All vasopressors were titrated and weaned according to proto-cols to maintain a target blood pressure. The primary end point was 28-day mortality. Pa-tients were analyzed according to the a priori strata of more severe and less severe septicshock, based on the level of vasopressor use at baseline. In VASST, 779 patients were ran-domized and infused with the study drug (vasopressin n¼ 397, norepinephrine n¼ 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 pre-

dicted in the vasopressin and norepinephrine groups, compared to previous reports per-haps 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 vasopres-sin (35.4%) and norepinephrine (39.3%, P ¼ 0.26): and there was no difference between




groups in mortality at 90 days (43.9% and 49.6% respectively, P ¼ 0.11). There were nodifferences in the overall rates of serious adverse events (vasopressin, 10.3% and norepi-nephrine, 10.5%, P¼ 1.0). Thus, clinicians using an evidence-based approach now maychoose norepinephrine alone or norepinephrine plus low dose vasopressin as vasopres-sors to manage patients with severe septic shock. The data exclude with 95% confidencea harm of vasopressin of greater than 2.9% or a benefit of greater than 10.7%. Thus, a non-

inferiority analysis of these data demonstratesthat vasopressin plus low dose norepineph-rine is not inferior to norepinephrine alone even when rigorous non-inferiority criteriaare applied – largely because the trend is towards benefit with vasopressin.

Since the trend is towards benefit of vasopressin, what additional evidence is avail-able to the clinician to help guide the choice between low-dose vasopressin plus nor-epinephrine versus norepinephrine alone? In the prospectively defined stratum of lesssevere septic shock in VASST mortality was significantly lower in the vasopressin-treated group at 28 days (26.5% vs. 35.7%, P ¼ 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 kidneyfunction and End-stage kidney disease, Figure 4).50 In the patients who were ‘‘at-risk’’ for renal failure (increase in serum creatinine 1.5 baseline, decrease in GFRby 25% or urine output< 0.5 mL/kg/hr for 6 hrs) the vasopressin treated patients(n¼ 53) compared to the norepinephrine patients (n ¼ 53) had significantly reduced28-day (30.8% vs. 54.7%, P¼ 0.01) and 90-day (37.3% vs. 62.3%, P ¼ 0.01) mortality.This remained significant after adjustment for potential confounders. The at-risk patients treated with vasopressin were also less likely to develop renal failure overthe 28 day study period compared to the at-risk patients treated with norepinephrine(21.2% vs. 41.2%, P¼ 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, inter-

quartile range 1.7–4.9 pmol/L) and did not change in the norepinephrine group. Lowdose vasopressin infusion increased vasopressin levels to medians of 73.6 pmol/L (in-terquartile range 58.6 to 94.7 pmol/L) at six hours and 98.0 pmol/L (interquartile range67.1 to 127.8 pmol/L) at 24 hours (Figure 3), confirming the restoration of plasmalevels of vasopressin appropriate for shock.

In summary, the Vasopressin And Septic Shock Trial did not find a difference be-tween low-dose vasopressin plus norepinephrine and norepinephrine alone suggestingthat either approach is reasonable. However, vasopressin may be beneficial in the less-

severe septic shock subgroup (those patients on <15 mcg/min norepinephrine at base-line) and possibly for patients at risk for renal failure. VASST confirmed the relativedeficiency of vasopressin in septic shock and administration of 0.01 to 0.03 U/min re-stored plasma vasopressin to an appropriate level in septic shock. Additional studiesare needed to confirm or refute these subgroup findings, and to understand whetherearlier use of vasopressin, or different doses of vasopressin could further improve theoutcomes 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), threeevidence-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 ¼ 0.77 at day 28 and P ¼ 0.92 at day 90), (B) Patients in less severe stratum

(P¼ 0.05 at day 28 and P ¼ 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.



0

20

40

60

80

100

120

140

7 days72 hours24 hours6 hoursBaseline

Timepoint

P l a s m a v a s o p r e s s i n l e v e l

( p m o l / L , m e d i a n

+ I Q R )

VASOPRESSIN

NOREPINEPHRINE

Figure 3. VASST: Plasma vasopressin levels over time in patients receiving a vasopressin infu-

sion18 (on-line supplement), n¼ 54, (black squares), patients in the vasopressin group once vasopressin

infusions had stopped (open squares) and patients in the norepinephrine group, n ¼ 53, (grey circles). Values

are medianþ interquartile range. (Note: 1 pmol/L¼ 1.08 pg/mL). Used with permission

Figure 4. RIFLE Criteria50 Proposed classification scheme for acute renal failure (ARF). The classification

system includes separate criteria for creatinine and urine output (UO). A patient can fulfill the criteria

through changes in serum creatinine (SCreat) or changes in UO, or both. The criteria that lead to the worst

possible classification 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). *GFR¼Glomerular Filtra-

tion Rate; ARF Acute Renal Failure




vasopressin pending further studies. In a systematic review of the literature of vaso-pressor and inotropic support in septic shock published in 2004, the role of vasopres-sin remained uncertain.1 The recommendation stated, ‘‘Vasopressin use may beconsidered in patients with refractory shock despite adequate fluid resuscitationand high-dose conventional vasopressors. Pending the outcome of ongoing trials, itis not recommended as a replacement for norepinephrine or dopamine as a first-line agent. If used in adults, it should be administered at infusions rates of 0.01–

0.04 units/min’’.1

REFERENCES

*1. Beale RJ, Hollenberg SM, Vincent JL & Parrillo JE. Vasopressor and inotropic support in septic shock: an

evidence-based review. Critical Care Medicine 2004; 32(11 Suppl): S455–S465.

Table 2. Dosing guidelines: add 30 U vasopressin to 250 mL normal saline: concentration 0.12 U/mL.

Dose units/min Dose units/hr Rate mL/hour

0.01 0.6 5

0.02 1.2 10

0.03 1.8 15

Practice Points based on VASST

Arginine vasopressin should be considered as adjunctive hemodynamic therapyin septic shock patients, particularly in:

B Patients requiring between 5 and 15 mcg/min norepinephrine infusionafter adequate fluid resuscitation.

B Patients at risk for renal failure according to RIFLE criteria (increase inserum creatinine 1.5 baseline, decrease in GFR by 25% or urine out-put< 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 confirm or refute the subgroup findings of VASST and to understand whether earlier use of vasopressin or different dosesof vasopressin could further improve the outcomes of critically ill patients.




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