Last updated: 02/13/2015
Vasopressin (also, anti-diuretic hormone (ADH) or arginine vasopressin (AVP)) has been shown to be a very effective vasopressor, especially in circumstances where patients are vasopressin depleted and have become reliant on catecholamines for blood pressure regulation. Concerns for the use vasopressin tend to center on how it compares to other vasopressors, especially norepinephrine, and risks of digital and mesenteric ischemia.
Vasopressin is a nonapeptide, synthesized as a pro-hormone in neuronal cell bodies of the posterior hypothalamus. Physiologically, vasopressin release is stimulated through the renin-angiotensin-aldosterone-system and through osmoreceptors in the posterior pituitary. Vasopressin acts on V1, V2, V3 (V1b) receptors, which broadly speaking, mediate peripheral vasoconstriction, water resorption in the kidneys, and corticotropin secretion, respectively. It also acts on oxytocin receptors. However, these receptor mediated effects can have paradoxical outcomes depending on the organ in question, etiology of hypotension, and presence of other catecholamines. Vasopressin is thought to act independently of conventional vasopressors and inotropes that act via alpha- and beta-adrenergic receptors, although the effects of vasopressin in the presence or absence of catecholamines has not been fully elucidated.
While vasopressin acts upon vasopressin receptors, other commonly used vasopressors such as norepinephrine and phenylephrine act upon adrenergic receptors. Norepinephrine acts primarily on alpha and to a lesser extent beta-1 adrenergic receptors and phenylephrine acts selectively on alpha-1 adrenergic receptors. Clinically, this is important because vasopressin and the catecholaminergic drugs act differently while having similar effects on blood pressure.
Vasopressin increases vascular smooth muscle tone through a variety of mechanisms that include activation of V1vascular receptors, modulation of ATP-sensitive K+channels, modulation of nitric oxide (NO) and the potentiation of adrenergic and other vasoconstrictor agents . This causes an increase in arterial blood pressure.
Most of the cardiac effects of vasopressin act via the V1 receptor. Puzzlingly, vasopressin can cause coronary vasoconstriction or vasodilation and exert positive or negative inotropic effects depending on dose administered or the specifics of the experimental model. In hypotensive cardiac surgery patients, the use of vasopressin may be superior to norepinephrine.
Vasopressin’s effect on renal physiology is complicated. Vasopressin largely mediates water resorption in the nephron tubules via V2 receptors located in the collecting duct, and to a lesser extent in the ascending limb, which stimulates aquaporin-2-laden vesicles to the luminal surface. However, V1 receptors are also located on the endothelium whereby they stimulate nitric oxide formation and stimulate vasodilation of medullary interstitial cells among the vasa recta, thus opposing the water retention effects of V2 receptor agonism (but likely also maintaining perfusion). V1 receptor stimulation causes decreased blood flow to the inner medula without affecting the outer medulla. V1 receptors are additionally located along the efferent arteriole, but not along the afferent arteriole. This has the net effect of increasing GFR and increasing urine output.
Vasopressin has a very short half-life. In cases of prolonged shock, vasopressin is rapidly released and then depleted, thereby suggesting that, especially in early shock states, vasopressin is a useful adjunct to norepinephrine. Furthermore, vasopressin maintains its potency in the setting of acidosis and hypoxia, while catecholamines may not. Vasopressin may be particularly beneficial in acidotic states as it may inhibit KATP channels more effectively than catecholamines . However, these effects have been observed only in animal models. These rationales have formed the basis for large randomized controlled studies in patients with shock. In general, vasopressin has been shown to be a safe and appropriate alternative to norepinephrine in septic, cardioplegic, and hemorrhagic shock states.
Vasopressin can be a safe substitute for norepinephrine in the setting of septic shock. VASST was a multicenter, randomized double blinded trial in 778 patients with septic shock. Patients were randomized to either receive Vasopressin (0.01- 0.03 units/min) or norepinephrine (5-15 ug/min), plus open-label vasopressors to maintain MAPs 65-75mmHg. The primary endpoint was death within 28 days after beginning infusions. In patients with “less severe” shock, vasopressin was superior to norepinephrine (mortality 26.5% vs 35.7%, NNT=10.7). This benefit was not demonstrated in those with more severe septic shock. There were no statistically significant differences in serious adverse events including cardiac complications, life threatening arrhythmias, mesenteric ischemia, hyponatremia, digital ischemia, and CVA.
The VASST results mirror those of the VANCS trial, a randomized double blinded control study of 300 cardiac surgery patients . Subjects resistant to fluid challenge were randomized to either norepinephrine (10-60 ug/min) or vasopressin (0.01-0.06 units/min) to maintain MAP > 65mmHg. The primary endpoint was composite mortality or severe complications (stroke, mechanical ventilation > 48h, sternal wound infection, reoperation, acute renal failure) within 30 days. Mortality occurred in 32% of vasopressin group and 49% norepinephrine group (NNT=5.9). Atrial fibrillation was found in 63.8% of vasopressin group and 82.1% norepinephrine group (NNT=5.5). No statistically significant difference between groups of digital ischemia, mesenteric ischemia, hyponatremia, and myocardial infarction. However, concerns regarding the statistical methods and potential for bias of this study have been raised <access-date>3/18/2019</access-date>.
Hemorrhagic & Hypovolemic shock:
The argument for early use of vasopressin in the setting of hemorrhagic shock is to decrease the size of the vascular compartment while adding volume . Blood loss requiring massive fluid resuscitation can be complicated by intravascular extravasation. Blood products are often not able to keep pace with blood counts and coagulopathy. Vasopressin has the advantage of maintaining potency in acidic and hypoxic conditions, whereas catecholamines lose their potency. Given a concern for neuroprotection following trauma, a systematic review found that vasopressin and hypertonic-hyperoncotic solution strategy was better able to increase cerebral perfusion pressure and cerebral oxygenation compared to norepinephrine and hypertonic-hyperoncotic solution in the first 10 minutes . A vasopressin analogue (Terlipressin) had a similar effect over Lactated Ringers. Unfortunately, most studies in hemorrhagic and hypovolemic shock are based on animal models of hemorrhage. There is a need for future trials as to the effects of vasopressin in us humans.
Concerns for the use of vasopressin is usually due to its association with digital and mesenteric ischemia. These studies are often limited by lack of randomization and use of concurrent norepinephrine, among other inotropes and vasopressors. In Van Haren et al., 13 patients with septic shock were prospectively given vasopressin after fluid bolus, dobutamine, and norepinephrine to maintain MAPs > 50mmHg. These patients were not randomized. Gastric tonometry was used to determine gut perfusion which was found to be decreased in the study population, but again this study was not randomized and there was no control group . Dunser et al. retrospectively analyzed the incidence and risk factors for skin lesions in 63 critically ill patients receiving arginine vasopressin with catecholamine-resistant vasodilatory shock. Catecholamine resistance was defined failing effect of increasing norepinephrine 0.2ug/kg/min over 2 hours for maintenance of MAPs >60mmHg. Vasopressin doses were given 4-6 units/hour. 30% of patients developed skin lesions. But again, this was a retrospective study without randomization, and there was no control or matched group making generalization of the effects of vasopressin very difficult.
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