Pharmacotherapeutic group: Vasopressin and analogues, ATC code: H01BA01
Mechanism of action
Argipressin (arginine vasopressin) is an endogenous hormone with osmoregulatory, vasopressor, haemostatic and central nervous system effects. The peripheral effects of arginine vasopressin are mediated by various vasopressin receptors, specifically the V1a, V1b and V2 vasopressin receptors. V1a receptors have been identified in arterial vessels; their activation induces vasoconstriction by increasing cytoplasmic ionised calcium via the phosphatidylinositol bisphosphate cascade, which is the most significant effect of argipressin.
During vasopressin infusion, a linear blood pressure response can be observed in patients with vasodilatory shock (septic shock, vasoplegic shock and SIRS (systemic inflammatory response syndrome)). Specifically, a significant correlation has been demonstrated between changes in baseline corrected mean arterial pressure (MAP) and the vasopressin dose. A comparably significant linear relationship has been demonstrated between vasopressin doses and an increase in peripheral resistance, as well as a reduction in norepinephrine requirements.
On initiation of vasopressin treatment, with a parallel reduction in catecholamines, a decrease in heart rate was observed in patients with septic shock. In a study in human volunteers investigating the effect of vasopressin infusion after lisinopril, heart rate decreased from 67±6.5 to 62±4.5 beats per minute (P <0.05). Suppression of heart rate and cardiac index (CI) can be expected only within the dose range of 0.1 IU/min and higher.
Clinical efficacy
Clinical evidence for the efficacy of argipressin in the stated indication of hypotension in catecholamine-refractory septic shock is based on the analysis of several clinical trials and publications. This analysis included a total of 1,588 patients with septic shock who had to date been treated with vasopressin under controlled conditions.
The largest investigation of vasopressin in septic shock was a multicentre, randomised, double-blind clinical trial (the VASST study), in which a total of 778 patients with septic shock were randomised to receive either low-dose vasopressin (0.01 to 0.03 IU/min) or norepinephrine (5 to 15 μg/min) as an adjunct to open-label vasopressor administration. Patients aged 16 years or older were considered for inclusion if they had fluid-resistant septic shock, defined as an inadequate response to 500 ml of normal saline or a need for vasopressors or low-dose norepinephrine. Patients had to have received ≥5 μg/min of norepinephrine or its equivalent for at least six consecutive hours during the preceding 24 hours and to have received at least 5 μg/min during the final hour before randomisation, or >15 μg/hour of norepinephrine equivalent for three consecutive hours. The primary endpoint was death from any cause, assessed 28 days after initiation of the study drug. There was no significant difference between the vasopressin group (35.4%) and the norepinephrine group (39.3%) (95% confidence interval -2.9% to +10.7%, p = 0.26). Similarly, no significant difference was recorded in mortality at 90 days (43.9% and 49.6% respectively, p = 0.11).
In a recent double-blind randomised study (VANISH) comparing norepinephrine with early administration of argipressin (up to 0.06 IU/min), mortality was 30.9% in the argipressin group and 27.5% in the norepinephrine group. One or more serious adverse events were observed in 10.7% of patients treated with argipressin and 8.3% of patients treated with norepinephrine. Significantly less renal replacement therapy was required in the argipressin group compared with the norepinephrine group (25.4% vs. 35.3%).
Effects on the QT and QTc interval
Experimentally high doses of vasopressin have been shown to induce ventricular arrhythmias in animals. Within the anticipated dose range and route of administration (chronic infusion), prolongation of the QT and QTc interval has not been described. Isolated cases of Torsade de pointes tachycardia have been described in patients treated with vasopressin for the management of bleeding oesophageal varices at doses more than ten times higher than the recommended levels, but no conclusions can be drawn regarding torsadogenic potential.
Paediatric population
In a double-blind randomised placebo-controlled study (Choong et al., 2009) involving 69 paediatric patients with vasodilatory shock (aged 4-14 years, 54 with septic shock), 35 patients were treated with vasopressin (initial dose 0.0005 U/kg/min increased up to 0.002 U/kg/min) and 34 patients with placebo. There was no difference between vasopressin and placebo in the primary efficacy parameters (time to achieve haemodynamic stability without vasoactive treatment, 49.7 hours in the vasopressin group and 47.1 hours in the placebo group), and in secondary efficacy parameters such as ventilator-free days; 10 patients (30.3%) died in the vasopressin group and 5 (15.6%) in the placebo group. It is unclear to what extent this outcome was related to baseline differences.
⚠️ Warnings
This medicinal product must not be confused with other medicinal products containing argipressin expressed in a different unit of strength (for example "Pressor Units", PU).
Argipressin must not be administered as a bolus in the treatment of catecholamine-refractory shock.
Argipressin may only be administered under strict and continuous monitoring of haemodynamic and organ-specific parameters.
Therapy with argipressin should be initiated only when adequate perfusion pressure cannot be maintained despite adequate volume substitution and the administration of catecholaminergic vasopressors.
Argipressin should be used with particular caution in patients with cardiac or vascular disease. The administration of high doses of argipressin for other indications has been reported to cause myocardial and intestinal ischaemia, myocardial and intestinal infarction, and reduced perfusion of the extremities.
In rare cases, argipressin may cause water intoxication. Early signs such as drowsiness, lethargy and headache must be recognised in time to prevent terminal coma and convulsions.
Argipressin should be used with caution in epilepsy, migraine, asthma, heart failure or any condition in which a rapid increase in extracellular water may pose a threat to an already overloaded system.
In the paediatric population, the benefits have not been shown to outweigh the risks. The use of argipressin in this indication in children and neonates is not recommended (see section 5.1).
This medicinal product contains less than 1 mmol sodium (23 mg) per ml, that is to say essentially "sodium-free".
