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Emerging Role of Vasopressin
MK Daga*, KJ Singh**, N Kumar***
Abstract
Ionotropic agents are frequently used in vasodilatory shock like conditions of septic or nonseptic origin.
Conventional catecholamines such as norepinephrine are used at a very high dose with possibility of adverse
effects in many patients. One often encounters refractoriness to these drugs. Infusion of vasopressin (VP)
which is detectable at inappropriately low level in advanced phase of septic shock might allow withdrawal
of catecholamines, as it maintains adequate mean arterial pressure (MAP), improves urine output and
leaves perfusion of vital organs unhindered. Vasopressin has been found to be superior to epinephrine in
animal models and some human trials, especially in patients with resistant ventricular fibrillation (VF) while
doing cardiopulmonary resuscitation (CPR). Analogues of VP have also been used for diuresis in patients
of hepatorenal syndrome. ©
INTRODUCTION
asopressin (VP) better known as antidiuretic
hormone is a nonapeptide synthesized in
hypothalamus and released from posterior pituitary
gland.1 It is an important hormone from the point of
view of maintaining cardiovascular homeostasis in the
body. It has been used for long time in patients of central
diabetes insipidus and also in patients with variceal
bleed but its vasopressor properties are now under
review to be exploited in certain critical illness.
Septic shock is one such condition characterized
by diminished arteriolar tone in the body. VP which
has unique action of constricting peripheral arterioles
while leaving blood flow to vital organs unhindered,
may be better than other vasopressor agents or at least
can augment their action in a favorable way.2-4 Studies
have shown the effectiveness of VP in decreasing
catecholamine requirement in septic schock.2,5,6 Other
condition with nonseptic vasodilatory shock such as
those occurring post cardiopulmonary bypass (CPB) or
after placement of left ventricular assist devices (LVAD)
may similarly benefit from this drug.7,8
This molecule has also been studied by many authors
for possible use during cardiopulmonary resuscitation
(CPR) either alone or in combination with epinephrine
and results have been encouraging.9 Analogues of this
drug have also been found to be useful in eliciting a
paradoxical diuretic effect in patients with hepatorenal
syndrome and refractory ascitis.10
V
*Professor; **Ex Senior Resident; ***Senior Resident, Department
of Medicine, Maulana Azad Medical College and Associated Lok
Nayak Hospital, New Delhi.
Received : 18.10.2004; Revised : 29.9.2005; Accepted : 3.4.2006
376
PHYSIOLOGY OF VASOPRESSIN ACTION
Supraoptic and paraventricular nuclei of hypothalamus
synthesize VP, which then migrates to axonal terminals
of these neurons at posterior pituitary gland and is stored
here in granular from1. Its release is regulated by osmotic
and nonosmotic stimuli. Apart from hyperosmolality,
profound hypovolemia and shock are one of the most
potent non osmotic stimuli for release of VP1,11. This
effect is mediated via afferent impulses from stretch
receptors in aortic arch and carotid sinus and to a lesser
degree from left arterial stretch receptors.1 Discharges
from these afferent inputs inhibit VP release and vice
versa. Despite its potent vasoconstrictor action, this
hormone dose not have any significant effect on blood
pressure in normal individuals.2,5 this is probably the
result of baroreceptor mediated decrease in heart rate.2
But its role in maintaining cardiovascular homeostasis
is significant in conditions of shock and animals with
diabetes insipidus tolerate shock poorly.12 The normal
fasting blood level of VP is 4 pg/ml, a concentration
enough for its action on renal collecting ducts.1,12 But
its vasopressor effects require a much higher serum
concentration (about 10-200 pg/ml).12 In early phase of
shock its plasma level may reach > 100 pg/ml but levels
come down later and may be inappropriately low in
prolonged septic shock.1,13,14
Actions of VP are mediated via its three receptor
subtypes designated as V1 (V1R/V1a), V2 (V2R) and V3
(V1b).1,11 V1 vascular receptors mediate vasoconstrictor
effect of VP through activation of phospholipase C and
increasing cytosolic Ca++, V2 renal receptors mediate its
antidiuretic effect and V3 pituitary receptors are central
receptors that cause adrenocorticotropin hormone
(ACTH) release. VP also acts on oxytocin receptor
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© JAPI • VOL. 54 • MAY 2006
(OTR) which is important from the point of view of its
vasodilator action on certain vital organs through nitric
oxide (NO) mediated pathway.1 Fig. 1 summarizes the
physiological effects of VP.
EMERGING CLINICAL USES OF VP
1. Septic shock : This is a type of vasodilatory shock,
found in patients having serious infections. Shock like
state is the result of profound vasodilation in most
of the peripheral arteriolar bed in various tissues,
resulting in reduced perfusion of vital organs. It has 50%
mortality despite treatment with fluids, antibiotic and
vasopressor agents.15 Probable mechanisms responsible
for this vasodilatory state are enumerated in Table
1. Many patients of septic shock show poor response
to conventional catecholamine, probably related to
receptor downregulation, increased NO level and
activation of K+ ATP channels in blood vessel smooth
muscle cells.5,12,13,15
Most form of shock like states cause high levels of VP
levels in the body. But haemorrhage and septic shock
cause biphasic changes in vasopressin concentrations,
high concentrations in early shock which decreases
as the shock state progresses. It has been observed
by Landry et al and also corroborated in other studies
as well.13-15 Probable reason for this VP deficiency is
depletion of neurohypophyseal stores after prolonged
Fig. 1 :
Table 1 : Actions of exogenous vasopressin infusion
C-GMP
Inhibition K+ATP channels
Counters vasopressin deficiency
Improves catecholamine responsiveness
© JAPI • VOL. 54 • MAY 2006
stimulation.12 Apart from this, autonomic insufficiency
which leads to impaired release of VP and elevated
endogenous norepinephrine levels that have a central
inhibitory effect on vasopressin release have also been
implicated for its low level in this condition. Autonomic
dysfunction was observed by some workers, when they
found that reflex bradycardia was not seen in these
patients when they were given pharmacological doses
of VP.5,13,14
In addition to adequate volume replacement,
catecholamine vasopressors (especially norepinephrine) are the mainstay of treatment in these
patients, to maintain adequate mean arterial pressure.
The response to catecholamine is poor and high doses
are associated with potentially fatal adverse effects.
These include decreased renal and mesenteric blood
flow, increased pulmonary vascular resistance and
arrhythmias resulting from β adrenergic effect. Poor
response to catecholamine is in part due to receptor
downregulation. 15 In contrast to catecholamine
treatment, patients of septic shock have increased
responsiveness to VP even in low doses.2,5,6,11,13,15,16
In many studies VP infusion in the dose of 0.01-0.04
U/min resulted in improved mean arterial pressure
and permitted withdrawal of catacholarmines.2,5,6,13,15
Apart from this it has also been found to improve urine
output.2,6,13 This reversal of oliguria is not only related
to improvement of mean arterial pressure, because
norepinephrine dosage to maintain similar arterial
pressure does not result in same urine output. In a
prospective randomised controlled study of 48 patients
with catecholamine resistant shock it was shown that a
combined infusion of vasopressin and norepinephrine
was superior to norepinephrine alone.17
Vasodilatory effect of VP in cerebral, coronary
and pulmonary vasculature is likely to make it more
beneficial in this condition.1,2 VP also inactivates K+ATP
channel and also blunts c-GMP response of nitric oxide
(NO), the two important mechanisms of vasodilation in
septic shock.12 Early data from different studies point
to a favorable outcome in patients managed with low
dose vasopressin infusion in septic shock, but whether
it translates into mortality benefit remains to be seen.
Large scale studies are needed to collect significant
clinical data before recommendation can be made.
2. Nonseptic vasodilatory shock : Nonseptic causes of
vasodilatory shock are prolonged cardiopulmonary
bypass(CPB), after placement of mechanical assist
devices, cyanide poisoning, carbon monoxide
intoxication, and late irreversible phase of haemorrhagic
shock. 12 Generalization regarding these nonseptic
causes of vasodilatory shock cannot be made because
different pathogenic mechanisms may be in the core of
initiation of the event, though final common pathway
of vasodilatory process may be the same.12 Hence even
though VP is effective in septic shock, clinical studies
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377
are required before this treatment strategy could be
employed in these settings. Studies so far have been
done in post CPB patients and after left ventricular assist
device (LVAD) placements and results have favored
its use in these situations presenting as vasodilatory
shock.
In a study by Argenziano et al, 10 patients with
vasodilatory shock after placement of LVAD on
weaning from CPB, were given at 0.10/min or placebo.7
Baseline plasma VP was inappropriately low in 7 of
the 10 patients. Infusion of VP significantly improved
mean arterial pressure and norepinephrine requirement
was decreased. In another study by Argenziano et al,
145 patients undergoing CPB for elective surgery were
enrolled for a prospective study.8 Vasodilatory shock
was found to be associated with VP deficiency especially
in patients with low ejection fraction and those receiving
ACE inhibitors. VP significantly improved mean arterial
pressure reducing the requirement for catecholamines.
Similar studies conducted by Rosenzwig et al and
Morales et al have shown significant benefit from using
VP as a pressor agent in this situation.
3. Cardiopulmonary resuscitation (CPR) : Epinephrine
which has been used for many decades during CPR
has recently come under criticism. 16,19 Use of this
drug is associated with many β receptor mediated
adverse effects. 16 It increases myocardial oxygen
consumption, predisposes to ventricular arrhythmia,
causes ventilation perfusion defect due to pulmonary
vasoconstriction and may lead to post resuscitation
myocardial dysfunction.16 There is lack of clinical data
about its efficacy in CPR.16,18 Moreover epinephrine
reduces myocardial action potential, increasing the
possibility of reentry action potentials hitting excitable
tissue which in turn may provoke or stabilize VF.16 In a
recent study its effect was found to be no better than a
saline placebo.19 Certain other studies point out that its
use has not enhanced hospital discharge rate. Despite
lack of clinical data supporting its use, it is still being
recommended by European and American guidelines
for adult advanced life support, because of lack of an
alternative vasopressor agent which can be employed
in this setting.
One of the important determinant for responsiveness
of ventricular fibrillation (VF) to defibrillation is
maintenance of coronary perfusion pressure (CPP)
above 20-30 mmHg.18 So an alternative drug should
have sufficient vasoconstrictor activity to improve
CPP during CPR and should also leave the cerebral
perfusion intact for better neurological outcome. Recent
research works have focused on VP to be employed
either as an alternative to epinephrine or to be used
in conjunction with it during CPR, however current
international guidelines for CPR considers vasopressin
only as a secondary alternative to epinephrine because
of limited clinical data on efficacy of vasopressin.
378
Lindner and colleagues measured levels of endothelin,
catecholamines, VP and ACTH before and during
CPR in 60 patients.20 Results showed that patients who
could be resuscitated had significant higher plasma
VP concentration and ACTH concentration than those
who could not be revived. In contrast, catecholamine
concentration was more in failed resuscitation group.
In many porcine models of CPR, VP treated group
was found to have better outcome when chances of
resuscitation and neurological recovery was assessed.18
It has also been found to increase adrenal medullar
blood flow during CPR.21
In the first prospective trial in humans Linder and
colleagues compared 40 U iv VP to 1 mg iv epinephrine in
patients with resistant VF (those not reverting after 3 DC
shock) in an out-of-hospital setting.9 Out of 40 patients
enrolled in the study significantly higher number could
be resuscitated with VP and 24 hr survival was better
in VP treated group. However when this protocol was
conducted for in-hospital patient population in another
study no significant survival advantage was observed,
probably because of other comorbid conditions in
this patient population.22 Synergistic effect of VP and
epinephrine was studied by Mulligan et al on CPP
during CPR in animal model.23 Increase in CPP was
more rapid in the group receiving both drugs than with
VP alone, whereas CPP was maintained for significantly
longer duration either with VP or VP + epinephrine
than epinephrine alone. This animal study showed us
that due to rapid response of epinephrine and longer
duration of action of VP it may be advantageous to use
both the drugs together. It has been suggested to first
administer 1mg of epinephrine, followed alternately
by 40 IU of vasopressin and 1mg epinephrine every 3
mins in adult cardiac arrest victims regardless of initial
electrocardiographic rhythm.24
Other factors which can be advantageous when iv
access is not easy is, rapid absorption of VP though
endotracheal and intraosseous route.16 Epinephrine
requires considerably higher doses for endotracheal
absorption.
Present guidelines by American Heart Association
and European Resuscitation Council for adult advanced
cardiac life support recommend use of 40 U VP as an
alternative to 1 mg epinephrine in adult patients with
resistant VF (level II b evidence).25,26 But as of now it
has not been recommended for want of adequate clinical
data in patients having pulseless electrical activity,
asystole and in pediatric population. Further trials on
a larger scale may confirm our faith in this drug while
performing CPR.
4. Hepatorenal syndrome (HRS) : Despite being an
antidiuretic hormone, it has diuretic effect in certain
clinical situation. VP analogues have been utilized
in patients of hepatorenal syndrome, in whom even
diuretics and dopamine (low dosage) are not effective.
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© JAPI • VOL. 54 • MAY 2006
Terlipressin and ornithine vasopressin have been used
in cirrhotic patients with renal dysfunction and reversal
of oliguria along with improvement in renal parameters
have been observed.27 In patients of refractory ascites,
terlipressin restored sensitivity to exogenous arterial
natriuretic peptide. It has been postulated that VP
analogues, by reverting peripheral vasodilation in HRS
restore blood flow to renal cortical tissue, improving
oliguria. Vasopressin analogues used in conjunction
with albumin improve renal function in hepatorenal
syndrome.28,29
In the study by Eisenman and co workers low dose
VP was found to cause diuresis not only in patients of
HRS but also is patients of end-stage heart failure10.
First of these two conditions is characterized by
peripheral vasodilation, the other one by peripheral
vasoconstriction. So they proposed that the diuretic
action of VP analogues is not due to its action on
peripheral vasculature, but probably its effect on V1
receptors in kidney, or because of synergistic effect with
ANP and oxytocin, in volume overloaded patients.
NOTE OF CAUTION
2.
3.
4.
5.
6.
7.
8.
9.
Use of VP may be associated with some adverse
effects. Although most of the reports have not cited
any adverse consequences of low dose VP, some of
the reports have found rise in liver enzymes, bilirubin
and decrease in platelet counts after VP use.6 This is
particularly true if doses of more than 0.04 U/min are
used. These effects are probably due to gastrointestinal
ischemia and coagulation system derangement. Some
of the other reports have associated the drug with
arrhythmia, myocardial infarction, hyponatraemia,
anaphylaxis, bronchospasm and urticaria besides
severe skin necrosis after its extravasation.11,29 Cost
is the other factor which dampens the enthusiasm of
using it on a wider scale. It is very costly in comparison
to epinephrine.
10.
11.
12.
13.
14.
15.
CONCLUSION
VP can be used in catecholamine resistant vasodilatory
shock of either septic or non septic origin decreasing the
requirement of catecholamine to maintain adequate
mean arterial pressure. But whether it changes the
mortality statistics remains to be seen. Currently VP is
recommended for use in adult patients with resistant
VF as an alterative to epinephrine but not recommended
for asystole, pulseless electrical activity and in pediatric
population. Good diuretic response of VP analogues
when used in low doses in volume loaded patient of
HRS and refractory ascites has been seen. Long term
outcome of the use of vasopressin for these newer uses
is still unknown. Scope of use may widen after further
controlled clinical studies.
16.
17.
18.
19.
20.
REFERENCES
1.
Holmes CL, Patel BM, Russell JA, Wally KR. Physiology of
© JAPI • VOL. 54 • MAY 2006
21.
www.japi.org
vasopressin relevant to management of septic shock. Chest
2001;120:989-1002.
Patel BM, Chittock DR, Russel JA, Wally KR. Beneficial effects
of short term vasopressin infusion during severe septic shock.
Anesthesiology 2002;96:576-82.
Vanhoute PM, Shephered JT. Vasopressin induces
endothelium depended relaxation of cerebral and coronary
but not of systemic arteries. J Hypertens 1984;2(suppl):
S421-2.
Evora PR, Pearson PJ, Schaff HV. Arginine vasopressin induces
endothelium dependent vasodilation of pulmonary artery: V1
receptor mediated production of nitric oxide. Chest 1993;103:12415.
Landry DW, Levin HR, Gallans EM, Seo S, Alessandro DD,
Oz MC, Oliver JA. Vasopressin presser hypersensitivity in
vasodilatory septic shock. Crit Care Med 1997;25:1279-82.
Holnes CL, Walley KR, Chittock DR, Lehman T, Russell JA. The
effects of vasopressin on hemodynamics and renal function in
severe septic shock: a case series. Intensive Care Med 2001;27:141621.
Argenziano M, Choudhri AF, Oz MC, Rose EA, Smith Cr, Landry
DW. Circulation 1997;96(suppl II):286-II290.
Argenziano M, Chen JM, Choudhri AF. Management of
vasodilatory shock after cardiac surgery: Identification of
predisposing factors and use of a novel pressor agent. Thorac
Cardiovasc Surg 1998;116:973-30.
Linder KH, Dirks B, Strohmenger HU, Prengel AW, Linder
IM, Lurie KG. Randomised comparison of epinephrine and
vasopressin in patients with out of hospital ventricular
fibrillation. Lancet 1997;349(Feb 22):535-7.
Eisenman A, Armali Z, Eart R, Bankir L, Baruch Y. Low dose
vasopressin restores diuresis both in patients with hepatorenal
syndrome and in anuric patients with end stage heart failure.
Journal of Internal Medicine 1999;246:183-90.
Ranger GS. The physiology and emerging role of antidiuretic
hormone. IJCP 2002;56:777-82.
Landry DW, Oliver JA. The pathogenesis of vasodilatory shock.
N Eng J Med 2001;345:588-95.
Tsuneyoshi I, Yamada H, Kakihana Y, Nakamura M, Nakano
Y, Boyle WA. Hemodynamic and metabolic effects of low dose
vasopressin infusion in vasodilatory Septic shock. Crit Care Med
2001;29:487-93.
Landry DW, Levin HR, Gallant EM, Ashton RC, Seo S, Alessandro
DD, O2 MC, Oliver JA. Vasopressin deficiency contributes to the
vasodilation of septic shock. Circulation 1997;95:1122-25.
Malay MB, Ashton RC, Landry DW, Townsend RN. Low dose
vasopressin in the treatment of vasodilatory septic shock and
(discussion). J Trauma 1999;47:699-705.
Wenzd V, Lindner KH. Employing vasopressin during
cardiopulmonary resuscitation and vasodilatory shock as
a lifesparing vasopressor. Cardiovascular Research 2001;51:
529-41.
Dunser MW, Matr AJ, Ulmer H, et al. Arginine vasopressin
in advanced vasodilatory shock. A prospective randomized
controlled study. Circulation 2003;107:2313-9.
Wenzel V, Lindner KH, Krismer AC, Miller EA, Voleckel WG,
Lingnau W. Repeated administration of vasopressin but not
epinephrine maintains coronary perfusion pressure after early
and late administration during prolonged cardiopulmonary
resuscitation in pigs. Circulation 1999;99:1379-84.
Woodhouse SP, Cox S, Boyd P, Case G, Weber M. High dose
and standard dose adrenalin don’t alter survival compared with
placebo, in cardiac arrest. Resuscitation 1995;30:243-9.
Lindner KH, Heak T, Keller A, Bothner U, Lurie KG. Release
of endogenous vasopressin during and after cardiopulmonary
resuscitation. Heart 1996;75:145-50.
Krisme Dc, Wengel V, Voelckel WG, Stadlbauer KH, Berger
379
22.
23.
24.
25.
HW, Schaefer A, Lindner KH. Effect of vasopressin on adrenal
gland regional perfusion during experimental cardiopulmonary
resuscitation. Resuscitation 2003;56:223-8.
Still IG, Hebert PC, Wells GA, Vandemheen KL, Tang ASL,
Higginson LAJ, Dreyer JF, Clement C, Battram V, Watpool
I, Mason S, Klassen T, Weitzman BN. Vasopressin versus
epinephrine for inhospital cardiac arrest: a randomized
controlled trial. Lancet 2001;358:105-9.
Mulligan KA, Mcknite SH, Lindner KH, Lindstrom PJ, Detloft
B, Lurie KG: Synegish
Anette C. Krismer, Volker Wenzel, Karl H Standlbauer
et al. Vasopressin during cardiopulmonary resuscitation:
A progress report. Crit Care Med 2004;32(No.9 suppl):
S432-S435.
Anon. International consensus on science, American Heart
Association: guidelines 2000 for cardiopulmonary resuscitation
26.
27.
28.
29.
and emergency cardiovascular care. Circulation 2000;102(suppl
ii):1384.
Hadengue A, Gadens A, Criostra E, Negro F, Morean R, Valle D.
Terlipressin in the treatment of hepatorenal syndrome a double
blind crossover study. Hepatol 1995;22:165A (abstract).
Dunser MW, Mayr AJ, Ulmer H, Ritsch N, Knotzer H, Pajk W,
Luckaner G, Mutz NJ, Hasibeder WR. The effects of vasopression
on systemic hemodynamics in catecholamine resistant septic an
postcardiotomy shock: a retrospective analysis. Anesth Analg
2001;93:7-13.
Rodriguez-Perez F,Groszmann RJ. Pharmacological treatment
of portal hypertension. Gastroenterology Clinics of North America
1992;21:15-40.
Kam PCA, Williams S, Yoong Vasopressin FFY and terlipressin
pharmacology and its clinical relevance. Anaesthesia 2004;59:9931001.
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