Vasopressin and its role in critical

care
Andrew Sharman BSc (Hons) MRCP FRCA
James Low DCH FRCA DICM

Key points

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Vasopressin or antidiuretic hormone is a potent insert into the apical membrane of the distal
Vasopressin is an
endogenous hormone which is responsible for tubules and collecting duct cells. V2 receptors
endogenous hormone
responsible primarily for regulating plasma osmolality and volume. It are essential for plasma volume and osmolality
osmoregulation and blood acts as a neurotransmitter in the brain to control. Their presence on endothelial cells
volume control. control circadian rhythm, thermoregulation, and induces the release of Von Willebrand Factor
adrenocorticotrophic hormone release (ACTH). (VWF) and Factor VIII:coagulant (FVIII:c).
Vasopressin use in cranial
diabetes insipidus and The therapeutic use of vasopressin has become VWF protects FVIII from breakdown in plasma
variceal bleeding is well increasingly important in the critical care and is important in binding platelets to the site
established. environment in the management of cranial dia- of bleeding.
betes insipidus, bleeding abnormalities, oeso- V3 receptors are found mainly in the
In asystolic cardiac arrest,
there is increasing evidence phageal variceal haemorrhage, asystolic cardiac pituitary. They are Gq-coupled G-protein recep-
that vasopressin may be arrest, and septic shock. tors which increase intracellular calcium when
more effective than activated. They are thought to be involved in
epinephrine in restoring Physiology ACTH release and may act as a neurotrans-
cardiac output. mitter or mediator involved with memory con-
Vasopressin is a nonapeptide, synthesized as solidation or retrieval and body temperature
Vasopressin depletion in
septic shock may contribute a pro-hormone in magnocellular neurone cell regulation.1, 2
to catecholamine-resistant bodies of the paraventricular and supraoptic Vasopressin has equal affinity for OTR as
hypotension. nuclei of the posterior hypothalamus. It is oxytocin. Activation of these receptors raises
bound to a carrier protein, neurohypophysin, intracellular calcium via the phospholipase C
Vasopressin replacement in
septic shock may correct and transported along the supraoptic hypophy- and phosphoinositide pathway. They are found
some of the haemodynamic seal tract to the axonal terminals of magnocel- predominantly on myometrium and vascular
disturbance but has yet to lular neurones located in the posterior pituitary. smooth muscle. In addition, they are located on
be shown to reduce Synthesis, transport, and storage takes 1–2 h. vascular endothelial cells where they increase
mortality. Normal plasma concentrations are ,4 pg ml21. constitutive endothelial nitric oxide synthase
It has a half-life of 10 –35 min, being metab- activity, increasing nitric oxide, which is a
olized by vasopressinases which are found in potent vasodilator. It is postulated that OTR
Andrew Sharman BSc (Hons) MRCP the liver and kidney. Vasopressin acts on V1, placement on vascular endothelium and their
FRCA
V2, V3, and oxytocin-type receptors (OTR). subsequent activation may account for vaso-
Specialist Registrar in Critical Care and
Anaesthesia
V1 receptors are found on vascular smooth pressin’s selective response on different vascu-
Derbyshire Royal Infirmary muscle of the systemic, splanchnic, renal, and lar beds. V1 and V2 receptors located on the
Southern Derbyshire Acute Hospitals coronary circulations. They are also located on vascular endothelium may also have a role by
NHS Foundation Trust
London Road
myometrium and platelets. These G-protein- increasing NO production.3
Derbyshire DE1 2QY coupled receptors activate phospholipase C
UK via Gq G-protein, which ultimately leads to an
Control of release
James Low DCH FRCA DICM increase in intracellular calcium. The major
Consultant in Critical Care and effect is to induce vasoconstriction, the magni- Table 1 illustrates the factors which affect the
Anaesthesia tude of which is dependent on the vascular release of vasopressin. Most factors ( physical
Department of Critical Care bed. In the pulmonary circulation, vasodilation or chemical) cause direct stimulation of vaso-
Derbyshire Royal Infirmary
Southern Derbyshire Acute Hospitals is produced via nitric oxide release. pressin release. Hypoxaemia and acidosis
NHS Foundation Trust V2 receptors are predominantly located in stimulate the carotid body chemoreceptors
London Road the distal tubule and collecting ducts of the causing vasopressin release. Catecholamine
Derbyshire DE1 2QY
UK kidney. These G-protein-coupled receptors stimulation of central adrenergic receptors has
Fax: þ44 1332 254967 stimulate Gs G-protein to activate adenylate a variety of effects on vasopressin release. At
E-mail: [email protected] cyclase, increasing CAMP, causing the mobil- low concentration, catecholamines activate
(for correspondence)
ization of aquaporin channels. These channels a1 receptors inducing vasopressin release. At
doi:10.1093/bjaceaccp/mkn021
134 Continuing Education in Anaesthesia, Critical Care & Pain | Volume 8 Number 4 2008
& The Board of Management and Trustees of the British Journal of Anaesthesia [2008]. All rights reserved. For
Permissions, please email: [email protected]
 Vasopressin and its role in critical care

Table 1 The major factors involved in the release of vasopressin from the posterior
pituitary. *Norepinephrine can stimulate release by a1 receptors and inhibit release
by stimulation of a2 and b receptors

Stimulate release Inhibit release

Increasing plasma osmolality Decreasing plasma osmolality

Reduced plasma volume Increased plasma volume
Chemical mediators Chemical mediators
Norepinephrine*, dopamine, Opioids, GABA, ANP, norepinephrine*
acetylcholine, histamine,

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prostaglandins, angiotensin II,
endotoxin, cytokines
Nausea, vomiting
Pain, Stress
Hypoxia, "PaCO2, acidosis
Exercise, IPPV

higher concentration, their actions on a2 and b receptors inhibit

vasopressin release.3 Fig. 1 The structure of vasopressin (8-arginine-vasopressin) which is the
exact synthetic protein of human endogenous vasopressin is shown.
The most potent stimulus for vasopressin release is an increased Terlipressin (triglycyl-lysine-vasopressin) is a prodrug requiring the enzymic
plasma osmolality. Central osmoreceptors in the subfornical organ cleavage of the three glycyl residues to form the active lysine vasopressin
nuclei, located outside the blood –brain barrier, monitor systemic found naturally in pigs. Desmopressin, DDAVP, is an arginine vasopressin
plasma osmolality. Peripheral osmoreceptors are found in the analogue.
portal veins and give early warning of ingested food and fluid
osmolality. Signals are transmitted via the vagus to the nucleus Pharmacology
tractus solitarius, area postrema, and ventrolateral medulla, and
finally to the paraventricular nuclei and supraoptic nuclei, where In most mammals, 8-arginine vasopressin is the native antidiuretic
vasopressin is manufactured in the magnocellular neurone cell hormone. Original preparations were extracted from posterior pitu-
bodies. Osmolality is finely controlled in the range of 275–290 itary cells (Fig. 1). It is now made as a synthetic peptide, argipres-
mOsm kg21. A 2% decrease in total body water results in a sin. It is metabolized in a way similar to endogenous vasopressin
doubling of the vasopressin plasma concentration. This acts on V2 and has a half-life of 24 min.
receptors increasing the collecting duct permeability to water. Tri-glycyl-lysine-vasopressin is terlipressin or glypressin.
Conversely, a 2% increase in total body water will result in Arginine is replaced with lysine at position 8 and has three glycine
maximal suppression of vasopressin release and maximally dilute residues at the beginning of the peptide. The lysine substitution
urine of 100 mOsm kg21. makes it identical to pig vasopressin. The three glycine residues
Plasma volume and the resultant change in arterial pressure are make terlipressin a prodrug. In the body, these are enzymatically
less sensitive controllers of vasopressin release, but the potential cleaved by endothelial peptidases to produce lysine vasopressin. It
response far exceeds that induced by changes in plasma osmolality. has an elimination half-life of 50 min, but an effect half-life of 6 h.
A 20–30% reduction in mean arterial pressure (MAP) is needed to Desmopressin (1-deamino-8-O-arginine-vasopressin, DDAVP)
induce a response. This results in a reduced arterial baroreceptor is a synthetic analogue of arginine vasopressin. It has 10 times the
output causing an exponential increase in vasopressin release. The antidiuretic action of vasopressin, but 1500 times less vasoconstric-
response to a reduction in plasma volume and its effect on vaso- tor action. These modifications make metabolism slower (half-life
pressin release is not well defined but is probably qualitatively and of 158 min).
quantitatively similar. An 8–10% reduction in plasma volume,
detected by atrial stretch receptors, is required to induce an expo- Therapeutic uses
nential increase in vasopressin release. A reduction in plasma
Cranial diabetes insipidus
volume increases the sensitivity of the osmoreceptors and vice
versa. However, as the plasma volume decreases, it becomes The causes of diabetes insipidus are listed in Table 2. In cranial
increasingly difficult to maintain a normal plasma osmolality. The diabetes insipidus, there is a lack of vasopressin due to destruction
defence of plasma volume always takes precedence over plasma of part or all of the hypothalamus or pituitary gland. This is in
osmolality. Less is known about acute elevations in arterial contrast to nephrogenic diabetes insipidus where there is a resist-
pressure and volume, but both appear to suppress vasopressin ance of the kidney to vasopressin’s action. Clinically, the patient
release.4 produces vast quantities of dilute urine. The key feature is that

Continuing Education in Anaesthesia, Critical Care & Pain j Volume 8 Number 4 2008 135
Vasopressin and its role in critical care

Table 2 The causes of diabetes insipidus circulation opens up to allow the return of blood to the systemic
Cranial Nephrogenic circulation through shunts. One of these is the intrinsic and
extrinsic gastro-oesophageal veins. These veins become increasing
Familial Familial dilated, forming varices. Vasopressin, acting via V1 receptors,
Idiopathic Idiopathic
Neurosurgery
reduces portal blood flow, portal systemic collateral blood flow,
Tumours and variceal pressure. Its side-effects include increased peripheral
Craniopharyngioma; hypothalamic gliomas; Renal tubular acidosis; vascular resistance, reduced cardiac output, and decreased coronary
metastases, e.g. breast; lymphoma/leukaemia hypokalaemia; hypercalcaemia
Infections Drugs
blood flow. The combined use of glyceryl trinitrate with vasopres-

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Tuberculosis; meningitis; cerebral abscess Lithuim; glibenclamide; sin has been shown to reduce these side-effects. Terlipressin, a
demeclocycline prodrug of vasopressin, is more commonly used. A Cochrane
Infiltrations
Sarcoidosis
review6 found that terlipressin produced a relative risk reduction in
Vascular mortality from variceal haemorrhage of 34% compared with
Haemorrhage; aneurysms; thrombosis placebo. The i.v. dose is typically 2 mg 4 hourly.
Trauma
Head injury
Asystolic cardiac arrest
Epinephrine has been considered the main drug for resuscitation
urine osmolality is inappropriately low compared with the plasma
for over 100 years. Recently, some doubt has been cast over its
osmolality. Desmopressin (DDAVP) can reduce the polyuria,
use. Patients who were sucessfully resuscitated with epinephrine
nocturia, and polydypsia. It is given nasally, sublingually, i.m., or
showed increased myocardial oxygen consumption and ventricular
if in critical care setting, i.v..
arrhythmias, ventilation– perfusion mismatch, and myocardial dys-
function post-resuscitation. In survivors of cardiac arrest, vasopres-
Syndrome of inappropriate antidiuretic hormone
sin levels have been shown to be higher than in those who died.
The syndrome of inappropriate antidiuretic hormone is a form of Wenzel and colleagues7 performed a multicentre randomized
hyponatraemia where the level of antidiuretic hormone is inappropri- double-blinded trial in 1186 patients who had an out-of-hospital
ate to the osmotic or volume stimuli, almost a reverse of cranial dia- cardiac arrest. They were randomly assigned to receive either 40
betes insipidus. The causes can be grouped into ectopic secretion by IU of vasopressin or 1 mg of epinephrine during resuscitation. In
tumours, particularly small cell carcinoma of the lung, central the asystolic group, significantly more patients reached hospital
nervous system disorders, including tumours, infection, and trauma, who received vasopressin, compared with those who received epi-
and pulmonary lesions, mainly infections and drugs, for example, nephrine (29% vs 20%, P¼0.02). In the vasopressin group, 4.7%
carbamazepine. There are strict diagnostic criteria which include the were discharged from hospital compared with 1.5% in the epineph-
need for normovolaemia, normal endocrine, cardiac, and liver func- rine group. Of the 732 patients where spontaneous circulation was
tion, in the presence of urinary osmolality greater than plasma not achieved initially, in those who received vasopressin then
osmolality. Treatment is the correction of hyponatraemia appropriate epinephrine, 25.6% reached hospital and 6.7% were discharged
to the speed of onset and eradication of the underlying cause. compared with 16.4% and 1.7% of those who received epinephrine
alone. There was no difference between the groups in those
Bleeding abnormalities patients who suffered pulseless electrical activity or ventricular
fibrillation cardiac arrests. There is a suggestion that vasopressin
Vasopressin acts via extra-renal V2 receptors to increase predomi-
may work better than epinephrine in hypoxaemic, acidotic con-
nantly FVIII:c and VWF. These actions are very useful in certain ditions. Other trials have shown a varying response to vasopressin
types of Von Willebrand disease and in mild forms of haemophilia
in all forms of cardiac arrest. These differences may be related to
A, where there is a relative deficiency of FVIII:c. Likewise, in
poor initial cardiopulmonary resuscitation and prolonged time to
patients with impaired platelet function due to drugs such as advanced life support. The trend suggests a better outcome in the
aspirin or renal failure, DDAVP (0.3 mg kg21 i.v. over 15– 30 min)
vasopressin groups, if there was delayed or prolonged resuscitation.
may be useful before minor surgical procedures. The exact mech-
The use of epinephrine in resuscitation is universal, yet there is a
anism of its effect in these situations is not fully understood, but paucity of evidence to show it improves survival in humans. The
the increase in FVIII levels which allows activation of FX and the
European resuscitation guidelines state there is insufficient evi-
more efficient activation of platelets are all important.5
dence for the use of vasopressin with or instead of epinephrine in
any type of cardiac arrest and that further evidence is required.
Oesophageal variceal haemorrhage
Septic shock
In chronic liver disease, fibrosis of the liver results in an increase
in portal venous pressure as the mesenteric blood requires increas- The cause of hypotension in septic shock is multifactorial.
ing pressure to flow through the scarred liver. Eventually, collateral Inappropriate vasodilation compromises organ perfusion. Fluid,

136 Continuing Education in Anaesthesia, Critical Care & Pain j Volume 8 Number 4 2008
 Vasopressin and its role in critical care

vasoconstrictors, and inotropes are usually used to maintain Vasopressin blocks these potassium-sensitive ATP channels, restor-
arterial pressure. Norepinephrine is the most commonly used ing vascular tone. The additional action on other hormone systems
vasoconstrictor. Unfortunately, cardiac and vascular smooth like cortisol and endothelin1 may also play a role in the mainten-
muscle can become resistant, requiring increasing doses of norepi- ance of arterial pressure.
nephrine. This produces adverse effects which include increasing The use of vasopressin is not without side-effects. Myocardial
tissue oxygen demand, reducing renal and mesenteric blood flow, ischaemia may occur, but this effect is limited by avoiding high
pulmonary hypertension, and arrhythmias. Vasopressin’s role in doses. A varied effect on splanchnic blood flow has been found.
maintaining arterial pressure has been investigated in septic shock. At lower doses, a minimal response occurs provided the patients

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Landry and colleagues8 were the first to show vasopressin was are adequately intravascularly filled. Both the dosage and timing of
inappropriately low in vasodilatory septic shock. In 19 patients the use of vasopressin in sepsis are currently under investigation.
with vasodilatory septic shock, vasopressin levels were 3.1 pg However, in the literature, a dose range of 0.01 –0.04 IU min21 is
ml21 with systolic arterial pressure (SAP) of 92 mm Hg and commonly used to replace falling vasopressin levels. It is usually
cardiac output of 8 litre min21 (all data are given as mean values). started when increasing norepinephrine doses are being used to
In patients who had cardiogenic shock, vasopressin levels were maintain arterial pressure. It is best administered through central
22.7 pg ml21. If an infusion of 0.04 IU min21 of vasopressin was access as extravasations can cause skin necrosis.
started, SAP increased from 92 to 146 mm Hg and then decreased The vasopressin and septic shock trial (VASST)10 was the first
when vasopressin was withdrawn. An infusion of 0.01 IU min21 multicentre, blinded randomized trial comparing low dose vaso-
was shown to increase vasopressin levels into the normal range in pressin with norepinephrine in 778 patients with septic shock. The
these patients suggesting that reduced secretion, not increased use of vasopressin did not reduce mortality but was shown to be as
metabolism, was the cause of vasopressin deficiency. safe as norepinephrine. Vasopressin is acknowledged as an adjunct
Why vasopressin is low in septic shock is open to conjecture. vasopressor in the Surviving Sepsis Guidelines and certainly its use
There appears to be a biphasic response. Initially, vasopressin is increasing, but further investigations are needed to define its
levels are elevated but 6 h after the onset of hypotension levels exact role in sepsis related hypotension.
may be inappropriately low for the degree of hypotension. Possible
explanations include exhaustion of stores and autonomic nervous
system dysfunction. Large doses of norepinephrine are inhibitory
to vasopressin release. Nitric oxide, an inflammatory mediator, References
may also act on the pituitary to prevent release.4 1. Holmes CL, Patel BM, Russell JA, Walley KR. The physiology of
Numerous case studies and small trials show vasopressin vasopresin relevant to the management of septic shock. Chest 2001;
120: 989– 1002
increases arterial pressure in septic shock. The largest randomized
2. Kam PCA, Williams S, Yoong FFY. Vasopressin and terlipressin: pharma-
prospective controlled study was published in 2003 by Dunser and cology and its clinical relevance. Anaesthesia 2004; 59: 993–1001
colleagues.9 In this study, 48 patients with catecholamine-resistant
3. Barrett LK, Singer M, Clapp LH. Vasopressin: mechanism of action on
vasodilatory shock were prospectively randomized to receive a com- vasculature in health and in septic shock. Crit Care Med 2007; 35:
bined infusion of vasopressin, 4 IU h21 (0.066 IU min21) and nor- 33–40
epinephrine or norepinephrine alone to maintain a MAP above 4. Mutlu GM, Factor P. Role of vasopressin in the management of septic
70 mm Hg. The vasopressin group showed a significant increase in shock. Intensive Care Med 2004; 30: 1276–91
MAP, cardiac index, systemic vascular resistance index, and left- 5. Ozgonenel B, Rajpurkar M, Lusher JM. How do you treat bleeding
ventricular stroke work index as well as reduced norepinephrine disorders with desmopressin. Postgrad Med J 2007; 83: 159–63
requirements and heart rates. Compared with the norepinephrine 6. Ioannou G, Doust J, Rockey DC. Terlipressin in acute oesophageal
variceal haemorrhage. Cochrane Database Syst Rev 2003: CD002147.
group, there was better preservation of gut mucosal blood flow and doi:10.1002/14651858.CD002147
a significantly lower incidence of tachyarrhythmias. 7. Wenzel V, Krismer AC, Arntz R, Sitter H, Stadlbauer KH, Linner KH. A
In sepsis, there is an increased sensitivity to vasopressin. The comparison of vasopressin and epinephrine for out of hospital cardio-
theories suggested include increased receptor density as endogen- pulmonary resuscitation. N Engl J Med 2004; 350: 105– 13
ous vasopressin levels are reduced and alteration in receptor 8. Landry DW, Levin HR, Gallant EM, et al. Vasopressin deficiency contrib-
expression on different vascular beds with possible changes in utes to the vasodilation of septic shock. Circulation 1997; 95: 1122–5
signal transduction. Vasopressin and norepinephrine are believed 9. Dunser MW, Mayr AJ, Ulmer H, et al. Arginine vasopressin in advanced
vasodilatory shock: a prospective randomised control study. Circulation
to have a synergistic action when used together. Vasopressin
2003; 107: 2313– 9
increases intracellular calcium, maintaining vascular tone when
10. Russell JA, Walley KR, Singer J, Gordon AC, Hebert PC, Cooper J.
norepinephrine receptor sensitivity is reduced. In endotoxic shock, Vasopressin versus norepinephrine infusion in patients with septic
excessive activation of potassium-sensitive ATP channels causes shock. N Engl J Med 2008; 358: 877 –87
increased potassium conductance leading to the closure of voltage-
gated calcium channels and the reduction in vascular tone. Please see multiple choice questions 16 –18

Continuing Education in Anaesthesia, Critical Care & Pain j Volume 8 Number 4 2008 137