Vasopressin (AVP) was one of
the first synthesized peptide hormones, used to treat diabetes insipidus
(DI) and gastrointestinal (GI) hemorrhage for the last five decades [1].
It was discovered by Oliver and Schafer in 1895 by demonstrating the
vasopressor effects of posterior pituitary extracts, while Farini and
Velden described its antidiuretic effects by successfully treating DI
with neurohypophyseal extracts, providing the name antidiuretic hormone
[2]. Later, Vigneaud and Turner isolated vasopressin and proved that the
same neurohypophyseal hormone possessed both antidiuretic and
vasopressor activity [1,3].
Currently, vasopressin and terlipressin (AVP/TP) have
emerged as promising agents for the management of refractory shock in
critically ill children. However, their effects on various vascular beds
and tissues are complex and sometimes apparently paradoxical.
Physiology AND Pharmacology
Synthesis and metabolism of vasopressin
Vasopressin, a nonapeptide with a disulphide bridge
between two cysteines, is synthesized in the magnocellular neurons of
the hypothalamic paraventricular and supraoptic nuclei as a prohormone "preprovasopressin".
It is degraded to provasopressin before reaching posterior pituitary
along the neuronal axons, and is finally converted to the active
vasopressin releasing neurophysin-II and co-peptin [4].
Only 10-20% of the intracellular stores are available
for immediate release in response to appropriate stimuli; however,
secretion diminishes on sustained stimulus. Vasopressin synthesis,
transport and storage takes about 1-2 hours [4]. It is metabolised by
renal and hepatic vasopressinase enzymes with 5-15% urinary excretion.
Vasopressin has a short half life (5-15 minutes) and pressor effect
lasts for 30-60 minutes.
Mean serum levels usually remain below 4 pg/ml under
normal conditions, which can go upto 10-20 pg/mL as an antidiuretic
response [4-5]. In vasodilatory shock, a biphasic response is observed
and initial high levels (upto 30-300 pg/mL) gradually fall as the shock
progresses so as to reach as low as 4-30 pg/mL after 36 hours of
established shock [4-5].
Regulation of vasopressin secretion
In healthy subjects, AVP secretion is primarily
regulated by changes in the plasma osmolarity sensed by peripheral
osmoreceptors near hepatic portal veins and central osmoreceptors in the
subfornical organ nuclei of the brain. Low plasma volume and arterial
blood pressure (BP) increase AVP levels without disrupting normal
osmoregulation. Atrial and ventricular baroreceptors sense change in
plasma volume while aortic arch and carotid sinus receptors signal BP
changes. More than 10% reduction in BP is needed to induce a response,
as against 1% change in plasma osmolarity [4-6].
Other important stimuli include pain, hypoxia,
nausea, pharyngeal stimuli, and hormones (e.g. norepinephrine,
acetylcholine, histamine, dopamine and angiotensin-II), endotoxins and
pro-inflammatory cytokines. Vasopressin release is inhibited by opioids,
γ-aminobutyric
acid (GABA), atrial natriuretic peptide (ANP) and nitric oxide (NO)
[4-5].
Vasopressin Receptors
Vasopressin acts via G-protein coupled receptors,
which are classified according to the location and second messenger
pathways into V1 (Vascular),
V2 (Renal), and V3
(Pituitary). Additionally, AVP also exerts some action via OTR
(Oxytocin) and P2
(Purinergic) receptors [4,7]. (Table I)
TABLE I Vasopressin Receptors Physiology
Receptor s |
Organs/Tissues |
Effects |
Intracellular Signaling/
transmitters |
V1 R (V1
receptors, |
Vascular smooth muscle |
Vasoconstriction? |
Increased intracellular
Ca++ |
previously |
|
|
via Phosphoinositide
pathway |
V1a
receptors) |
Myocardium |
Inotropy |
Increased intracellular
Ca++ |
|
Platelets |
Platelet Aggregation |
Selective renal
efferent arteriolar |
|
Kidney |
Diuresis |
constriction via local
NO release |
|
Myometrium |
Uterine contraction |
|
|
Liver |
Glycogenolysis |
|
|
Bladder, spleen,
adipocytes, |
Vasodilation |
|
|
testis |
|
|
|
Brain |
Role in social memory,
|
|
|
|
circadian
rhythm, |
|
|
|
emotional learning,
|
|
|
|
stress adaptation |
|
V2 R (V2
receptors) |
Renal collecting duct |
Increased permeability
|
Increased cAMP via
adenylate |
|
Vascular smooth muscles |
to water |
cyclase |
|
Vascular endothelium |
Vasodilation |
NO mediated |
|
|
Release of von-willebrand
|
|
|
|
factor/VIII |
|
V3 R
(Previously |
Pituitary |
Neurotransmitter ACTH
release |
Phosphokinase C
pathway, Increased |
V1b
receptors) |
|
|
cAMP via G protein |
Oxytocin (OTR) |
Uterus, mammary gland
|
Smooth muscle
contraction |
Phospholipase C
mediated increased |
receptors |
|
|
intracellular Ca++ |
|
Vascular endothelium |
Vasodilation |
Increase in
intracellular Ca++ |
|
Heart |
ANP release |
mediated NO release |
Purinergic (P2
R) |
Myocardium |
Increased cardiac
contractility |
Increase in
intracellular Ca++ |
receptors |
Cardiac endothelium |
Selective coronary
vasodilation |
NO mediated |
ACTH –
Adrenocorticotrophic Hormone, ANP – atrial natriuretic peptide,
NO – nitric oxide, cAMP – cyclic adenosine mono phosphate, cGMP
– cyclic guanosine monophosphate |
Systemic Effects
The major functions of vasopressin include
osmoregulation and vasoconstriction. Under normal conditions, its main
role is in regulation of water balance with minimal effect on BP.
Vasopressin also plays a role in other physiological functions e.g.
hemostasis, temperature regulation, memory, sleep cycle, and insulin and
corticotrophin release [8-9].
Vasoconstrictor effects
Vasopressin binds to vasopressin specific membrane
bound V1 receptors (AVPR1A)
in vascular smooth muscles and leads to vasoconstriction by increasing
intracellular calcium levels via phosphoinositide pathway. In septic
shock, AVP also restores vascular tone, by blocking K+-sensitive
ATP channels in dose dependent manner, and via amelioration in increased
c-GMP levels by decreasing inducible NO-synthase enzymes [4-5,7].
Vasodilator effects
Unlike catecholamines, vasopressin induces
vasodilatation in pulmonary, renal and cerebral circulation through V2R
or OTR mediated NO release [10-11]. Vasodilator effect is exhibited
particularly at low doses unlike its dose dependent vasoconstrictor
effect.
Pulmonary vascular effects
Vasopressin induces pulmonary vasodilatation via V1R
mediated release of endothelium derived NO [11]. This is particularly
relevant in septic shock, where increased pulmonary vascular tone and
resistance is usually seen. Vasopressin also decreases pulmonary
arterial pressure in normal or hypoxic conditions mediated via ANP [12].
Renal effects
The complex renal effects are determined by interplay
between osmoregulatory and renovascular effects. Antidiuretic effect is
mediated via V2R, located on
the basolateral membrane of tubular epithelium of the collecting ducts,
increasing intracellular c-AMP levels through adenylate cyclase pathway.
It leads to fusion of aquaporin vesicles with luminal membrane
increasing intracellular water content, which further equilibrates
osmotically with interstitial fluid resulting in concentrated urine
[4,7]. Paradoxically, low dose vasopressin in septic shock exhibit
diuretic effect, possibly through V1R
mediated selective renal efferent arteriolar constriction, NO mediated
afferent arteriolar vasodilatation, and down regulation of V2R
[7,13].
Endocrine effects
In pharmacologic doses, AVP increases plasma cortisol
level through V3R mediated
ACTH release, effect most likely mediated via NO and c-GMP [9]. This is
particularly important in critically ill children, given the prevalence
of adrenocortical dysfunction. Vasopressin is reported to mediate ANP
and angiotensin-II secretion as well as stimulate prolactin and
endothelin-I release [9].
Effects on coagulation system
Vasopressin causes aggregation of human platelets.
Selective V2-agonist
desmopressin stimulates factor VIIIc, von Willebrand factor, and
plasminogen activator release from vascular endothelial cells, promoting
effective platelet adhesion. Based on this effect vasopressin has been
used to treat bleeding due to functional platelet disorders [14].
Vasopressin Analogues
Terlipressin
Terlipressin (triglycyl lysine-vasopressin) is a
longer-acting analogue containing 12 amino acids, and is slowly cleaved
to lysine-vasopressin by endo-and exopeptidases in liver and kidney over
4-6 hrs, making intermittent bolus use feasible rather than continuous
infusion.
Relative to AVP, its affinity for V1R
is higher than V2R (2.2:1
compared to 1:1). Additionally, terlipressin does not appear to increase
fibrinolytic activity, unlike vasopressin [15]. Terlipressin has been
extensively studied and used in adults with acute variceal bleeding and
hepatorenal syndrome, before emerging as potential therapeutic option in
a variety of shock states [16].
Desmopressin
Desmopressin or DDAVP (1-deamino-8-D-arginine
vasopressin) is selective V2-agonist
with an antidiuretic-to-vasopressor ratio 4000 times than that of AVP
[17,18].
Therapeutic Applications
Approved uses for vasopressin and analogs include DI,
nocturnal enuresis, gastrointestinal bleeding, hemophilia-A,
von-Willebrand disease, and bleeding due to platelet dysfunction.
Currently, vasopressin is emerging as a potent vasopressor to treat
vasodilatory shock states and cardiac arrest; however, it is still not
recognized as a standard of care and is being evaluated in trials.
Indications and doses of vasopressin/analogs are given in Table
II and various studies evaluating its therapeutic uses in
children are summarized in Web Table I.
TABLE II Indications and Doses of Vasopressin and Analogs [63-64]
Indication |
Drug |
Dose |
Nocturnal enuresis |
DDAVP |
Intranasally: 5-20 µg (in children > 6 years)Orally: 0.2-0.4
mg/d at bedtime |
Central diabetes insipidus |
DDAVP |
Intranasally: 5-30 µg/d Q 8-12 hr Orally: 0.05-0.2 mg/d Q 8-12
hr IV/SC: 2-4 µg/d Q 8-12 hr |
|
AVP |
IM/SC: 2.5-10U/dose 2-4 times/day IV infusion: 0.0005 U/kg/hr
initially, double every 30 min upto 0.01 U/kg/hr |
Hemophilia-A, von Willebrand |
DDAVP |
Intranasally: <50 kg - 150 µg; |
disease, platelet dysfunctions |
|
>50 kg - 300 µg IV: 0.3 µg/kg (>3 months), repeat if needed,
give 30 min before procedure |
|
|
|
Bleeding esophageal varices |
AVP |
Initial IV bolus 0.3 U/kg (maximum: 20 U) followed by infusion:
0.002-0.01 U/kg/min |
|
TP |
IV: 10 – 20 µg/kg every 4 – 6 hrs or 1 – 2 mg Q 4 – 6 hr (in
adolescents & adults) |
Refractory vasodilatory shock |
AVP |
IV infusion: 0.0005-0.002 U/kg/min (variable, from as low as
0.00005 U/kg/min upto 0.008 U/kg/min) |
|
TP |
IV bolus: 10 – 20 µg/kg every 4 – 6 hrs |
|
|
IV infusion: 10 µg/kg/hr |
Cardiac arrest |
AVP |
IV bolus: 0.4 U/kg |
|
TP |
IV bolus: 10 – 20 µg/kg |
DDAVP – Desmopressin, AVP – Arginine Vasopressin, TP –
Terlipressin, IV – intravenous, IM – intramuscular, SC –
subcutaneous |
Nocturnal enuresis
DDAVP is used to treat nocturnal enuresis, caused by
maturational delay in normal nocturnal increase in AVP secretion [18].
Diabetes insipidus
In DI, renal tubular collecting ducts are unable to
concentrate urine which can be Central or Nephrogenic. Central DI is due
to congenital or acquired deficiency of AVP secretion. Nephrogenic DI
arises from defective or absent vasopressin receptor sites or aquaporins
with resultant inappropriate response to vasopressin.
In Central DI, vasopressin increases cellular
permeability of collecting ducts, resulting in renal reabsorption of
water and forms the mainstay of treatment [19]. Vasopressin may also be
used safely to diagnose type of DI due to shorter half life with lesser
risk of volume overload. Doses are variable and titrated according to
serum/urinary sodium and osmolality, and urine output [20].
Bleeding esophageal varices
Upper GI bleeding is reported in 6-25% of PICU
admissions [21-22]; however, incidence of serious lower GI bleeding has
not been well established [23]. Use of vasopressin is intended to
decrease portal venous pressure and optimize clotting and hemostasis.
Although it may provide effective control of bleeding, vasopressin is
still a secondary treatment option, as evidence supporting improved
survival is scarce [24].
Presently, endoscopic sclerotherapy or band ligation
is considered to be the first-line therapy for bleeding esophageal
varices followed by vasoactive drugs i.e. octreotide (somatostatin
analogue), vasopressin and terlipressin [25].
Vasodilatory shock states
Vasodilatory shock can be the final common pathway in
a variety of shock states including sepsis, post-perfusion syndrome
following CPB, prolonged hemorrhage, hypovolemia, anaphylaxis,
cardiogenic shock and carbon monoxide poisoning. They share common
pathogenic mechanisms responsible for vascular smooth muscle dysfunction
and hyporesponsiveness to catecholamines e.g. activation of ATP
sensitive K+-channels,
NO-synthase stimulation and vasopressin deficiency [26-27]. This
relative deficiency is attributable to (i) depleted
neurohypophyseal AVP stores, (ii) autonomic dysfunction leading
to impaired baro-reflex mediated release, (iii) increased
neurohypophyseal NO production, and (iv) central inhibitory
effects of increased norepinephrine on AVP production [5,7,27].
Vasopressin has emerged as a useful therapeutic
option in vasodilatory shock to reverse the mechanisms responsible for
vasoplegia and catecholamine resistance.
Dose in pediatric shock is not very well documented
and is extrapolated from adult data. In various studies, vasopressin was
used in a dose of 0.00005 to as high as 0.008 U/kg/min [28,29]; however,
in a RCT evaluating vasopressin in pediatric shock, vasopressin was used
in dose range of 0.0005-0.002 U/kg/min [30]. TP dose used in the RCT was
20 µg/kg/6h for maximum 96 hours [31].
Septic shock
In septic shock, catecholamines often have a
diminished vasopressor action and more than half of the patients
succumbing to sepsis die from advanced cardiovascular failure, which is
refractory to conventional therapy. In these patients, vasopressin
hypersensitivity is observed with significant increase in BP, mediated
via: (i) direct V1R
mediated vasoconstriction;(ii) unlike catecholamine receptors,
absolute or relative AVP deficiency allow V1R
to remain available and block mechanisms inducing their downregulation;
(iii) absent bradycardia reflex in critically ill patients with
autonomic failure; (iv) potentiating vasopressor efficacy of
catecholamines through blockage of ATP sensitive K+-channels
and resulting membrane hyperpolarization and vasodilation; and (v)
finally, increased ACTH and cortisol release [4-5,7,9,27]. Vasopressin
induced selective pulmonary, coronary, cerebral vasodilatation, and
improved urine output and creatinine clearance, make it more beneficial
in preserving vital organ functions in sepsis as compared to
catecholamines [10-13].
However, judicious use of AVP/TP is warranted, as
characteristic vasodilation seen in adult septic shock is a late feature
of pediatric septic shock, where myocardial dysfunction is more common
and the majority of septic shock cases have low cardiac index with only
about 20% presenting in the typical warm shock [32]. Additionally,
children in septic shock often change hemodynamic profile and as the
disease progresses, transformation from vasodilatory shock to a
hypodynamic shock with high systemic vascular resistance (SVR) is not
uncommon. Therefore, AVP/TP should be used with cardiac output (CO) and
central venous oxygen saturation (ScvO2)
monitoring, as they can reduce CO due to potent vasoconstriction [33].
Post-cardiopulmonary bypass vasodilatory shock
Post CPB vasodilatory hypotension, not associated
with primary cardiogenic or septic shock, has been reported in nearly
10% of cardiac surgeries [34]. This is attributed mainly to systemic
inflammatory response activated by CPB via endothelial injury, release
of cytokines and other inflammatory mediators, as well as to nonspecific
activators e.g. surgical trauma, blood loss or transfusion, and
hypothermia. Other contributory factors include prolonged CPB, long term
ACE inhibitor or beta blocker therapy, or post-bypass amiodarone and
phosphodiestrase-III inhibitors.
Apart from these mechanisms, inappropriately low AVP
secretion may be another important factor in producing low SVR
hypotension. Low dose vasopressin therapy in this condition has been
shown to improve BP as well as restore catecholamines sensitivity by a
mechanism similar to that seen in septic shock [34].
Anaphylactic shock
Acute cardiovascular collapse in anaphylaxis results
from immune mediated release of inflammatory mediators producing
systemic vasodilation and increased capillary permeability, resulting in
mixed distributive-hypovolemic shock [35]. Optimal vasoactive action of
vasopressin i.e. vasoconstriction in skin, skeletal muscle,
intestine and fat, with relatively less coronary and renal
vasoconstriction, and cerebral vasodilatation, has supported the use of
AVP in adrenaline refractory anaphylactic shock.
Currently, no controlled trials or guidelines on AVP
use in anaphylactic shock are available, and its use is recommended on
the basis of case reports and laboratory experiences, In different cases
reports, 2-15 U (0.03-0.15U/kg) vasopressin have been used [36-38].
Hemorrhagic shock
Patients with advanced hemorrhagic shock usually
respond poorly to both volume and catecholamine therapy due to resistant
vasodilation secondary to accumulated vasodilatory metabolites produced
by ischemic-reperfusion injury and coexisting severe acidosis
inactivating catecholamine receptors. These patients with complete
cardiovascular collapse have an extremely poor prognosis and AVP has
been used as a rescue therapy in such cases considering its inherent
vasopressor effect. Vasopressin also decreases bleeding by shifting the
blood away from the subdiaphragmatic site of injury to the vital organs.
This specific effect may be life-saving in patients with uncontrolled
hemorrhage resulting from subdiaphragmatic injury [39].
As RCTs evaluating the role of vasopressin in
hemorrhagic shock are currently unavailable, even limited clinical and
laboratory data available may support its use in selected patients, who
would otherwise rapidly collapse [40-42].
Pediatric cardiopulmonary resuscitation
Cardiac arrest in children is often the terminal
result of progressive respiratory failure or shock rather than sudden
primary cardiac event as commonly seen in adults. Prolonged CPR often
has dismal prognosis, along with severe neurological impairment among
survivors. For more than four decades, epinephrine has
been the drug of choice in cardiac arrest for restoring spontaneous
circulation based on its ability to maintain diastolic BP and subsequent
blood flow to heart. However, adult and pediatric studies have shown no
clear survival benefit of epinephrine and rather elucidated adverse
effects [43-44].
Vasopressin causes profound vasoconstriction with
shunting of blood to heart and brain, and unlike epinephrine, this
vasoconstriction continues even in presence of
severe acidosis that accompanies cardiopulmonary arrest. Additionally,
vasopressin has shown to improve cerebral perfusion during
CPR with better neurologic outcome in animal studies. It also enhances myocardial
oxygen delivery without marked increase in consumption observed with
catecholamine mediated β1-adrenergic
receptor activation.
In RCTs of in-hospital and out-of-hospital arrests in
adults, vasopressin had comparable efficacy to epinephrine [45,46].
Although improved return of spontaneous circulation (ROSC) with
vasopressin therapy was demonstrated in a few pediatric reports [47-49],
two other reports failed to demonstrate any survival benefit [50,51].
Therefore, further research is necessary to evaluate the long term
outcome and safety of vasopressin in pediatric CPR. During CPR,
vasopressin can also be given endotracheally in the same IV dose, if
IV/IO route can not be accessed rapidly [52].
Vasopressin during organ recovery
Low dose AVP infusion has been evaluated as a
vasopressor in critically ill children treated for DI during brain death
and organ recovery in a retrospective matched-controlled study. AVP has
shown good pressure effects and they were more likely to wean from alpha
agonists than controls, without adverse affect on transplant organ
function [53].
Pulmonary hypertension
Vasopressin has been successfully used in infants
with pulmonary hypertension secondary to congenital diaphragmatic hernia
[54-56] and after correction of total anomalous pulmonary venous return
[57] refractory to other conventional therapies, to improve BP and to
decrease pulmonary artery pressure.
Sedation related hypotension
One RCT evaluated the role of low-dose vasopressin
infusion to prevent sedation/analgesia related hypotension in
non-septic, hemodynamically stable but critically ill children,
considering the fact that vasopressin leads to redistribution of
mesenteric blood. However, AVP therapy was associated with decreased
urine output, hyponatremia, and rebound hypotension, thus limiting the
prophylactic vasopressin use for sedation-related hypotension [58].
Current recommendations on vasopressin use
American College of Critical Care Medicine Clinical
Guidelines 2007 for hemodynamic support of pediatric and neonatal septic
shock recommended that AVP/TP can be used in catecholamine-resistant
shock with high cardiac index and low SVR. However, as these agents can
reduce CO, they should be used with CO/ScvO2
monitoring [33]. Pediatric Sepsis Guidelines for resource-limited
countries developed by Intensive Care Chapter of Indian Academy of
Pediatrics recommended AVP therapy as a last resort in patients with
catecholamine-resistant warm shock [59].
Although, latest American Heart Association
guidelines have recommended the use of one dose of vasopressin to
replace either the first or second dose of epinephrine in treatment of
adult cardiac arrest, no recommendations were made on its routine use in
pediatric patients [60,61]. European Resuscitation Council guidelines
2010 also did not support or refute the use of AVP/TP as an alternative
to or in combination with adrenaline in any cardiac arrest rhythm;
however, these drugs could be used in cardiac arrest refractory to
several adrenaline doses [62].
Cost-effectiveness
Cost of the vasopressin may be an inhibiting factor
at current market values, as it costs around 25-30 times than that of
adrenaline. Still, AVP therapy is not as expensive as extended ICU stay
of even one day with costlier antibiotics, and it would help in lowering
the overall long-term cost in patient care [63-64]. As no RCT is
currently available to determine the cost-effectiveness of vasopressin,
significant clinical benefits would need to be demonstrated to
cost-justify the routine substitution of adrenaline with vasopressin in
cardiac arrest.
Adverse Effects
Due to potent vasoconstrictor action, there is always
a concern that vasopressin therapy may impair capillary blood flow and
tissue oxygenation. Safety data of vasopressin in pediatric patients are
limited and a number of adverse effects were reported depending upon
dose and duration, underlying disease process, co-morbidities, and
concurrent use of other vasopressors. Complications are more common when
vasopressin is co-administered with moderate to high dose of
norepinephrine [5].
Cardiac complications include coronary ischemia,
myocardial infarction, ventricular arrhythmias (ventricular tachycardia
and asystole), and severe hypertension [64]. Other reported adverse
effects include severe GI ischemia leading to bowel necrosis,
hyponatremia, anaphylaxis, bronchospasm, urticaria, angioedema, rashes,
venous thrombosis, local irritation at injection site, and peripheral
vasoconstriction leading to cutaneous gangrene [65].
Conclusion
While vasopressin continues to be a useful agent to
treat DI and GI hemorrhage, it is emerging as a potentially life saving
therapy in critically ill children with a variety of vasodilatory shock.
Both adult and pediatric studies have demonstrated the efficacy of
rescue AVP therapy in reversing shock due to sepsis or following
cardiotomy/CPB, when other vasopressors are escalated to high infusion
rates with potential adverse effects. Limited laboratory and adult data
along with a few pediatric reports support the use of vasopressin as an
adjunctive therapy for prolonged cardiac arrest and irreversible
hypovolemic and anaphylactic shock. However, large controlled trials are
necessary to define the efficacy, dosage, ideal initiation time, and
safety profile in children, as evidence is limited due to the
retrospective nature of existing studies and small numbers of patients.
Thus, vasopressin is not a standard of care as of now
and it should be considered as a rescue therapy in situations like
catecholamine-refractory shock and cardiac arrest in children, with
close monitoring for adverse effects.
Competing interests: None stated; Funding:
None.
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