This chapter is relevant to Section G8(i) of the 2017 CICM Primary Syllabus, which asks the exam candidate to "understand the detailed pharmacology of inotropes and vasopressors". It is a summary of the pharmacological properties of vasopressin, with a focus on its use as a vasoactive infusion.
Now, when one normally calls something a "summary", one implies that the information is sensibly condensed into several small easily digestible snack-like pieces. This definition cannot apply to the following, which more closely resembles a multiple-course degustation banquet, a structured feast the excesses of which end in a messy pile of bloated drunks. Some of the information is repeated from previous discussions of the physiology of vasopressin as it relates to the control of extracellular osmolality; the rest is material more relevant to people who deploy vasopressin in the treatment of shock.
Chemical Structure of 8-Arginine Vasopressin
8-arginine vasopressin is a synthetic analogue of an endogenous nonapeptide hormone.
It is indistinguishable from the endogenous hormone.
It is a cyclical peptide: The two cysteines are joined by a disulfide bridge, and this curls the molecule into something of a pretzel.
Since its discovery in 1895, pituitary extract has been just that- extract of pituitary glands, fresh or dried. Whose glands, you ask? Those of oxen, it seems. Interest in its clinical use (and, I suppose, the practical inconvenience of having to extract, dry and process industrial quantities of bovine pituitary glands) has ultimately led to the de novo synthesis of it by du Vigneaud in 1955 (he had already synthesized oxytocin by the same method, and received the Nobel Prize in Chemistry for it).
Combined with 0.5% chlorobutanol as a preservative, it comes in a 1ml ampoule of 20 "pressor units" per ml.
What the hell is a "pressor unit", you ask?
Standards of vasopressin dose measurement: the Pressor Unit
The "pressor unit" is defined as a quantity of pressor agent which is equivalent in pressor activity to the activity of 0.5 milligram of the USP Standard Powdered Pituitary U.S.P., a USP posterior pituitary reference standard. Yes, there is a standard of pressor activity, analogous to the platinum rod used as the international standard of the metre, or to the unit standard of heparin (keeping the liquid state of refrigerated cat blood, etc.)
Like the metre, it is ancient, and has a weird history. Dale and Laidlaw first described the standard in 1912, before the actions of the different posterior pituitary hormones were known. The "infundibular extracts" were tested on the uterus of the virgin guinea pig, which was found to contract with nicely predictable linear responsiveness to successively increased doses of the extract. However, subsequent modifications of the method resorted to using rat uterus, the authors complaining about the expense of obtaining guinea pigs in post-war Britain. As the difference between the two posterior pituitary hormones became apparent in coming years, and as synthetic analogues became available, the USP units became separated into the "oxytocic unit" (used to compare uterine activity) and the "vasopressor unit" (used to compare the effect on the blood pressure of the rat).
The USP standard was a homogenised extract of the posterior pituitary, weighing about 20mg, which was distributed to laboratories in the 1950s to standardise the purification of posterior pituitary hormones. The definition is used to this day, even though now there are better ways to measure vasopressin dose. Synthetic vasopressin is very pure and potent; 1 mg of pure vasopressin corresponds to about 600 pressor units.
Oxytocin, terlipressin and desmopressin are chemically related to vasopressin.
Lets look at oxytocin.
The leucine at the 8th position here makes this molecule an 8-leucine oxytocin, identical to the synthetic oxytocin.
Yes, there is crossreactivity. Oxytocin has a mild antidiuretic effect, and large quantities of vasopressin can stimulate uterine contractions. However, in contrast to vasopressin, a bolus of oxytocin causes hypotension. There is little agreement as to why: some have blamed the chlorobutanol preservative, others point to the release of atrial natriuretic peptide. Oxytocin receptors are also present in blood vessels, suggesting a direct role.
Terlipressin is a longer molecule:
The lysine at the 8th position here makes this molecule an triglycine-lysine vasopressin. The glycines are enzymatically cleaved by endothelial peptidases, and the result of the breakdown is lysine-vasopressin, identical to pig vasopressin. The elimination half-life of terlipressin is thus about 50 minutes, but the effect lasts for 6 hours.
Desmopressin is a cysteine-deaminated version.
Whatever the deamination of cysteine contributes to the function of desmopressin, is an exercise left up to the reader to discover. It is thought that the substitution of a D-stereoisomer for arginine is a feature which protects the desmopressin from rapid metabolism by the various endothelial peptidases. This grants it a duration of action lasting 6 to 14 hours.
Administration and absorption
- Usually given as an intravenous infusion
- Vasopressin has almost 0% oral bioavailability; it is destroyed by trypsin in the gut.
- It is 30% protein bound
- It has a small volume of distribution, about 2/3rds of the extracellular fluid volume.
Volume of Distribution = 0.14 to 0.2 L per Kg, depending on who you read
Vasopressin really should be given via a central line. Like noradrenaline, is was once routinely administered via peripheral veins; and like noradrenaline gangrenous complications plagued its use.
Unlike noradrenaline, it did not seem to extravasate spontaneously, so its effect on the vasa venorum may not be as pronounced (given that the gangrenous complications were typically the effect of IVC dislodgement).
Metabolism and Clearance
Half life = 17 – 35 minutes
65% of Vasopressin is excreted unchanged in the kidneys
35% of Vasopressin is metabolized by endothelial peptidases in the kidney and liver.
The key feature which renders vasopressin vulnerable to this form of elimination is the 8th amino acid, arginine. A substitution for dextro-arginine results in greatly increased half life (eg. desmopressin).
Physiology of vasopressin receptors
There are two main classes of vasopressin receptor. Vasopressin is ancient, pre-dating the divergence of vertebrates and invertebrates, and virtually all animals have some sort of vasopressin-like peptides.
V1 receptors: the vasopressor receptors
These are Gq-protein coupled receptors, just like the Alpha-1 adrenoceptors.
They are heptaspanning membrane proteins. Their activation causes smooth muscle contraction, by stimulating the release of calcium from the sarcoplasmic reticulum.
This is essentially the same thing the alpha-1 receptors do. The chief distinction is that the vasopressin receptors are more widely distributed.
Their effect is not modified by changes in pH (no matter how acidotic you are, the amount of vasopressin you need does not change very much; in contrast to catecholamine receptors which lose their sensitivity at a low pH)
Plus, both vasopressin and catecholamine receptors can be activated at the same time, which is why the vasopressin infusion can be used as a noradrenaline-sparing drug in the ICU.
The effects of V1 vasopressin receptor activation
- Vasoconstriction (everywhere), which is not reversed by sympathetic blockade
- That's right, all vessels: including splanchnic circulation, coronaries, and the brain.
- Platelet aggregation – Vasopressin is also stored in their granules
- Increased intestinal motility
- Increased glycogenolysis in the hepatocytes
- Increased ACTH release
- Increased smooth muscle cell growth
- Increased prostaglandin synthesis
V2 receptors: the antidiuretic receptors
These are Gs-protein coupled receptors.
At the principle cells of the collecting tubule, the activated protein Kinase A causes the migration of aquaporin-containing vesicles to the apical membrane of the cell. This greatly increases the water permeability of this cell. Water flows into the cell along a concentration gradient.
In order to maintain this concentration gradient, vasopressin receptors also activate an active urea transporter (VRUT).
The effects of V2 vasopressin receptor activation
- Insertion of aquaporins into the apical membrane of principle cells, thus antidiuresis which results from reabsorption of water into the renal medulla
- Also increase urea transport into the medulla, to maintain the gradient
- Also increase sodium transport in the thick ascending limb
- Increased circulating Factor VIII and von Willebrand factor
The distribution of vasopressin receptors
V1 vasopressin receptors are ubiquitous; the most dense distribution is seen in the vascular smooth muscle. The distribution among vascular beds is also ubiquitous – with notable exceptions. For instance, vasopressin receptors are expressed in the efferent, but not the afferent arterioles of the kidney; the result is a tendency of vasopressin to increase the rate of glomerular filtration. This explains why shocked critically ill patients experience an increase (rather than a decrease) of urine output when the vasopressin infusion is commenced.
Additionally, vasopressin receptors are found in the brain (where we don't really know what they do), and the platelets (where it increases intracellular calcium and creates conditions favourable for platelet activation)
The relationship of vasopressin dose and physiological effect
At low doses, vasopressin acts as an antidiuretic hormone. The normal levels of vasopressin secretion in response to hyperosmolar states range up to a certain maximal effect.
Even though vasopressin concentration continues to rise, at a serum concentration of 5pM (picomoles) the maximal urinary concentration is achieved, and no greater water retention is possible. After this point, defence of osmolality must be accomplished by increasing water intake, rather than preventing water loss.
However, vasopressin levels will continue to increase in response to decreased blood pressure.
V1 receptor effects dominate this dose range. Via V1 receptors, vasopressin is a pure vasopressor, causing vasoconstriction without any chronotropic or inotropic effect. The levels increase in an exponential fashion; in animal models of haemorrhagic and septic shock the levels can increase 200-fold. The resulting systemic vasoconstriction preserves the perfusion of vital organs while sacrificing the more expendable tissues.
However, in sustained severe shock, this effect loses its oomph.
Relative vasopressin deficiency in shock states
In both haemorrhagic and septic shock, the circulating levels of vasopressin seem to decrease, which probably contributes to the severity of shock. This is thought to be the consequence of pituitary vasopressin depletion. Obviously, this can be addressed with supplemental vasopressin. And yes, studies of septic pigs and haemorrhaging dogs have suggested that the vasopressin deficiency in shock states is readily answered by exogenous vasopressin infusion.
Hemodynamic effects of vasopressin infusion
Differences between the hemodynamic effects of vasopressin and the catecholamines
Vasopressin is not anything like the catecholamines. In contrast to them, vasopressin has variable effects depending on the expression of different receptors in different vascular beds. Not only that, but the effect can vary depending on dose.
And to top it off, in low (non-pressor) doses vasopressin has been show to actually act as a vasodilator in pulmonary arteries (of the rat), renal arteries (also of the rat), cerebral arteries (of the dog) and coronary arteries (of the monkeys), which seems to be related to L-arginine being synthesized into nitric oxide under the influence of V1 receptors.
Unlike noradrenaline, which causes a predictable vasopressor response in healthy people, vasopressin in the healthy human is a relatively weak pressor agent. The reason behind this is the increased sensitivity of the baroreceptor reflex mediated by V1 receptors in the brain. The administration of vasopressin causes more bradycardia than an equivalently vasoactive dose of noradrenaline – the heart rate decrease is greater.
The above graph is an extrapolation of the famous article by Allwood et al (1963), which investigated the effects of catecholamines on healthy humans. Vasopressin was not tested - the graph is my own confabulation. However, it is supported by the cardiovascular data presented by the VASST investigators, who found that the most significant hemodynamic difference between their noradrenaline and vasopressin group was the slower heart rate among the vasopressin-treated patients.
In the denervated heart, vasopressin has a positive inotropic effect, presumably by affecting V1 receptors in the myocardium, making more calcium ions available to support contraction. The
Vasopressin causes a vasoconstriction of vessels in the skeletal muscle, fat, the pancreas, and the thyroid gland.
The vasoconstricting effect on the mesentery, coronary and cerebral circulation is not as pronounced with vasopressin as it is with the catecholamines. However, the higher the dose, the more coronary vasoconstriction there will be.
Dose-response relationship of vasopressin infusion in animal studies
Unlike the linear, predictable dose-response curve of noradrenaline, vasopressin has a more traditional S-shaped dose-response curve, which demonstrates the diminishing effect it has at high doses. It has a considerably (order of magnitude) greater potency than noradrenaline, and escalating doses yield a disproportionately greater response at the middle dose range.
So, Pang and Tabrizchi specified that their dose range for noradrenaline was from 3.0 x 10-10 to 8.0 x 10-9 mol/kg/min, and the dose range for vasopressin was 4.5 x 10-11 to 1.4x10-9 mol/kg/min. One can recognise that the molar mass of vasopressin (C46H65N13O12S2) is 1056.22g. Thus, the tested dose range is 0.0475 to 1.48 mcg/kg/min. If we believe that 1mg of vasopressin equates to about 600 units, we can say that 1 unit weighs 1.667mcg. Thus, the dose range in the rat was from 0.03 to 0.89 units per kg per min.
That to me seems like a completely insane dose rate, unless my maths are horribly wrong. Compare with the recommended human dose:the infusion rate for vasopressin in the treatment of shock in adults is 0.6-2.4 units per hr, i.e. 0.01– 0.04 units/min, or 0.00014 to 0.0066 units/min/kg for a 70kg human.
However, we must recall that in healthy mammals with a preserved autonomic nervous system, vasopressin is a relatively weak vasoconstrictor. Perhaps the rats were less responsive for this reason. In contrast, septic humans seem to have a greatly increased sensitivity to vasopressin, and the doses they require are substantially lower.
Dose-response relationship of vasopressin infusion in humans
It seems the consenting participation of healthy humans was more difficult to secure for vasopressin research than for noradrenaline; we must make do with data collected from patients in severe septic shock. True, this does not reflect the "real" physiological dose-response relationship - given their known hypersensitivity to vasopressin - but it is more applicable to bedside use in the ICU.
Don't pay attention to the extrapolated graph. The abovementioned study did not find a dose-response curve for vasopressin. The degree of improvement in MAP was not related to dose. They did, however, establish that at doses over 0.03 units per minute (1.8 units/hr) the cardiac index decreased significantly.
Furthermore, they mentioned that beyond 0.04 units/min there was no further improvement in hemodynamic parameters, suggesting that this is the point where the dose-response curve begins to plateau. This may have given rise to the manufacturer's dosing recommendation.
Potentiation of adrenergic vasoconstriction by vasopressin
In addition to its own direct effects, vasopressin seems to enhance the catecholamine sensitivity of mammalian blood vessels (in one specific instance, the mesenteric artery of the rat).
This means that the commencement of a vasopressin infusion together with noradrenaline will lead to a greater improvement in blood pressure than would be expected from a simple additive effect.
Effect of vasopressin on coronary arterial pressure and blood flow
As previously mentioned, vasopressin can act as a vasodilator in some select groups of vessels, and certainly some monkey coronaries had dilated for some investigators at some point. However in a series of anaesthetised dogs vasopressin consistently decreased coronary blood flow and increased coronary vascular resistance.
What are we to make of this? The pragmatic intensivist would have two questions. In the patient with untreated ischaemic heart disease, will vasopressin decrease myocardial perfusion? And, in a normal patient with normal coronary arteries, will vasopressin precipitate a myocardial infarction?
The answer seems to be dose-dependent. It is known that at low doses, vasopressin actually dilates coronary arteries (at the same time constricting peripheral non-essential vascular beds, thereby distributing blood flow to vital organs).
At moderate doses there is no significant effect on coronary vascular resistance. This is supported by human data: the VASST investigators reported on the cardiac safety of vasopressin in septic shock, and concluded that there was no significant increase in adverse cardiac effects at their studied dose range (0.01 - 0.03 units/min, or 0.6-1.8 units per hr).
However, at high doses myocardial perfusion seems to suffer, and with it the cardiac output. So one would be advised to avoid high-dose vasopressin in patients with untreated coronary artery stenosis, as it could be counterproductive. With a high enough dose, even healthy coronaries will vasoconstrict enough to produce ischaemia. This correlates with human studies which report an increase in the frequency of cardiac arrest among septic patients receiving more than 0.05 units/min (3 units/hr).
Effect of vasopressin on cardiac output
Again, there is a strange relationship of dose and response here. At levels resembling normal circulating levels, activation of V1 vasopressin receptors in the heart increases cardiac output. So, it acts as an inotrope, but the doses required for this effect are very small, and one may never see these effects in clinical practice.
As the dose is increased, coronary perfusion decreases because of coronary vasoconstriction. Combine this decrease in myocardial perfusion with the savage increase in afterload, and you can see why the cardiac output is observed to decrease with high dose vasopressin infusion.
Effect of vasopressin on cerebral arterial pressure and blood flow
Yes, perhaps in low (non-pressor) doses vasopressin has some vasodilatory effects on cerebral arteries. However, we also know that at higher doses, in the anaesthetised rat cerebral blood vessels are constricted by vasopressin. One might be forgiven for thinking that this has negative implications for the human brain, particularly in the setting of cerebral vasospasm (i.e. following a subarachnoid haemorrhage). Though some authors have reported its (relatively safe) use as a supplemental vasopressor in SAH, they caution their readers to carefully watch for vasospasm.
Effect of vasopressin on pulmonary vascular resistance
Vasopressin infusion decreases pulmonary arterial pressure in the rat. The authors hypothesise that this is a nitric oxide related effect. Among the work performed on humans, we may view studies in septic shock patients and those recovering from cardiopulmonary bypass. Each group has failed to demonstrate much of an increase in pulmonary arterial pressure at therapeutic doses. This is a contrast with catecholamines, which (owing to the alpha-1 receptors in the pulmonary circulation) can cause significant pulmonary vasoconstriction.
Effect of acidosis on vasopressin receptor sensitivity
Investigators who marinaded some rat tail arteries in acidic brine had concluded that in conditions of metabolic acidosis, alpha-1 receptor responses are blunted. However, no such blunting occurred for vasopressin receptors; the arteries constricted as briskly as ever. This suggests that in severe metabolic acidosis vasopressin receptor sensitivity is well preserved.
Indications for use
Vasopressin alone or together with noradrenaline in septic shock
This is perhaps the most popular application for vasopressin.
There was a period in the history of vasopressin use, during which it was thought to be somehow superior to noradrenaline as a single agent for severe septic shock. Subsequent studies have demonstrated that together, the vasopressors are more effective than when they are used alone, and that there is no real difference between them in terms of survival.
- Vasopressin together with noradrenaline seems to be better than noradrenaline alone in small studies which looked at hemodynamic parameters rather than survival. On its own high dose vasopressin was no better than noradrenaline alone.
- The VASST trial from 2008, on a substrate of 778 recruited patients, demonstrated that vasopressin didn’t change 28th day mortality when compared to noradrenaline (except maybe in "mild" septic shock, where it seemed to be slightly better).
- In 2013, the VASST investigators also took a look at the cardiac safety of vasopressin in septic shock, and concluded that it does not have a detrimental effect on the hearts of septic shock patients.
- Weirdly, in spite of what we know about the cardiovascular effects of high-dose vasopressin, a small open-label trial of two different vasopressin doses has demonstrated that there is not much difference in adverse events and mortality between 2 units/hr compared to 4 units/hr. In spite of these findings, the Surviving Sepsis people recommend you keep your dose at 2 units/hr, and go no higher.
So, even though it is an apparently safe way to augment haemodynamic support for septic shock patients, the use of vasopressin does not seem to confer a survival benefit, which is sad news for the vasopressin enthusiast.
Vasopressin in cardiogenic shock
Given the relatively benign effect of moderate-dose vasopressin on cardiac output, pulmonary vessels and coronary vascular resistance, it is surprising how little literature there is on the subject of its use in cardiogenic shock. One retrospective analysis of 36 patients who developed cardiogenic shock after MI has confirmed that it increases MAP without any additional fatal cardiac embarrassment. Similarly, the Germans have published a small case series.
Vasopressin may also be an attractive alternative to traditional catecholamines in the treatment of certain catecholamine-intolerant cardiogenic shock states as HOCM and Takotsubo cardiomyopathy (where you cannot afford to stimulate the beta-1 receptors).
Vasopressin in post-bypass vasoplegia
The profoundly vasodilated state of the recently cardiotomised post-bypass patient calls for harsh vasopressors, and arginine vasopressin seems a logical choice. Indeed, this has been experimented with.
In a randomised controlled trial (where vasopressin was compared to placebo and standard care) a peri-operative infusion of 2 units/hr seemed to decrease post-CABG vasoplegia. A review article of vasopressor selection in vasoplegic shock has recommended the use of vasopressin for this purpose.
Additionally, vasopressin seems to have an advantage over noradrenaline when it comes to managing the hypotension which resulted from the use of milrinone. The authors of a 52-patient study of these drugs concluded that the beneficial effect of this vasopressin-on-milrinone interaction lies in the ability to increase systemic vascular resistance while decreasing right ventricular afterload.
Vasopressin in haemorrhagic shock
There has been some interesting data arising from some dog models of irreversible haemorrhagic shock, resistant to volume replacement and catecholamines. In these dogs, MAP was effectively restored with vasopressin, when all else had failed. Paramilitary-sounding articles call attention to the fact that its use in the field may prevent progression to cardiac arrest in severe trauma. This contrasts with the empirical finding that vasopressin use is associated with increased 72-hour mortality in trauma patients (from 41% to 55%). A recent review article summarised the available animal studies and case series, and was unable to recommend anything except more studies. One such study is the VITRIS trial, carried out in the European prehospital setting. According to their website, it is still going.
Vasopressin in the maintenance of cerebral perfusion following subarachnoid haemorrhage
As previously discussed, there is really only one study of vasopressin as a supplementary vasopressor in subarachnoid haemorrhage, and it was far from conclusive- though i this small series (22 patients) vasopressin had no adverse effects on cerebral perfusion, the authors were less than enthusiastic about its broad applicability, recommending that people make their own decisions.
Vasopressin use as something other than a vasopressor
- As a treatment for bleeding oesophageal varices;
Taking advantage of the fact that vasopressin is particularly good at decreasing splanchnic circulation. In this application vasopressin has largely been surpassed by Terlipressin (which has a longer half life)
- As an antidiuretic hormone in treating diabetes insipidus,
vasopressin has largely been surpassed by Desmopressin (which has a longer half life, and is administered nasally)
- As a treatment for uremic platelet dysfunction,
vasopressin has also been surpassed by Desmopressin
- As a treatment for von Willebrands disease,
vasopressin has been surpassed by Desmopressin
- Water intoxication: if you are hyponatremic, vasopressin will cause you to retain more free water
- Coronary artery disease: vasopressin may exacerbate your angina
- Cerebral vessel vasospasm eg. in subarachnoid haemorrhage - laying aside arguments about its safety in SAH, once you have vasospasm established vasopressin is probably not your drug of choice.
- Late pregnancy: large doses of vasopressin may have an oxytocin-like effect (owing to its great structural similarity to oxytocin) and this can cause uterine contractions to start prematurely
Drugs which increase the effect of vasopressin
- High dose opiates
Drugs which inhibit the effect of vasopressin
- Low dose opiates
- Small amounts over the long term may cause hyponatremia
- Chronic administration of large amounts of vasopressin will eventually cause necrosis of the extremities, like any other vasopressor.
- Desmopressin is free from these effects because its used in smaller doses.
Acute toxicity and overdose
- A large bolus of vasopressin may transiently cause massive hypertension and cutaneous pallor, with a sudden urge to defecate.
Management of acute toxicity
There is no convenient antagonist to this drug. A vasodilator infusion of some variety may be useful.
Vasopressin receptor antagonists (such as the "vaptan" group of drugs) may play some role...