Vasopressin

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. It has come up in past papers, most notably in Question 20 from the first paper of 2017 and Question 22 from the first paper of 2013.

Now, when one normally calls something a "summary", one implies that the information is sensibly condensed into several small easily digestible snack-like pieces. Carrying on with the food metaphor, what follows is more like eating out of the garbage. Occasional interesting morsels are buried under layers of irrelevant or duplicated material. To save the readers from his worst excesses, the author has attempted to combine all the exam-essential elements into the grey box which follows.

Chemical structure and chemical relatives of vasopressin are a fascinating topic, and 

a characteristically unhinged discussion of the vasopressin receptor agonist class is carried on in the chapter on the pharmacology of vasopressin an its analogues, exiled into the lower hells of the endocrinology section because that is where the relevant CICM syllabus item was. On the other hand, it was felt that this vasopressor-focused entry was necessary and should belong in the cardiovascular section, as that is more logical for the intensivist who will be using this substance mainly to manipulate the cardiovascular system. That same intensivist will, more than likely, also have little interest in the details of disulfide bridges and cyclical peptide molecule structures. For that reason, here the reader will be spared those details, and instead redirected to works like Glavaš et al (2022).

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

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

Vasopressin receptors are G-protein-coupled receptors and produce their effect very rapidly through IP3-mediated intracellular calcium release (in the vase of the Gq-coupled V1 receptors) and cAMP-mediated exocytosis of aquaporin-lined vesicles (in the case of the Gs-coupled V2 receptors). The "vasopressin and friends" chapter has a more content-rich explanation of their function, and what follows is a brief point-form reminder:

• V1 receptors are the vasopressor receptors. These are Gq-protein coupled receptors, just like the alpha-1 adrenoceptors. Their activation causes smooth muscle contraction, by stimulating the release of calcium from the sarcoplasmic reticulum, which is essentially the same thing the alpha-1 receptors do. The chief distinction is that the vasopressin receptors are more widely distributed, and that the affinity of V1 receptors for vasopressin does not break down in the presence of acidosis. V1 receptor activation produces vasoconstriction in basically all vascular beds, including splanchnic circulation, coronaries, and the brain, but not in the pulmonary circulation.
• V2 receptors are the antidiuretic receptors. These are Gs-protein coupled receptors, which means they mediate their effects by increasing cAMP levels and activating protein kinase A, which then stimulates the migration of aquaporin-containing vesicles to the apical membrane of the principal cells of the collecting duct.  This greatly increases the water permeability of the cell, which produces the reabsorption of water in this part of the nephron (because that is where the concentration gradient is greatest). In order to maintain this concentration gradient, vasopressin receptors also activate an active urea transporter (VRUT).

V1 vasopressin receptors are ubiquitous; the densest 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 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

Contraindications

• 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

Interactions

Drugs which increase the effect of vasopressin

• Tricyclics
• High dose opiates
• NSAIDs
• Barbiturates
• Nicotine
• Catecholamines

Drugs which inhibit the effect of vasopressin

• Ethanol
• Phenytoin
• Corticosteroids
• Haloperidol
• Phenergan
• Low dose opiates

Chronic toxicity

• 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...