Vasopressin is often used as a second line agent to Noradrenaline in septic shock. The usual approach to sepsis is commencement of fluids and if a mean arterial pressure (MAP) >65, is not achieved rapidly,  to commence Noradrenaline. If unable to reach the target MAP, a second agent, usually Vasopressin, is added. The evidence for this is weak. (15 minute read)

This study looked at outcomes related to the timing of vasopressin initial (1). Guidelines recommend commencing Vasopressin when the dose of Noradrenaline is in the range of 0.25-0.5mcg/kg/min(2).

Is there an effect on patient outcomes, if we reach higher Noradrenaline doses, before Vasopressin is commenced? It may result in a delay in achieving an appropriate MAP, resulting in a worst prognosis.(3)

The Question this paper aimed to answer
“We hypothesized that vasopressin initiation is associated with lower mortality when adults with septic shock are treated with low doses of NE.”

 What They Did

This was a retrospective observational cohort study. It used a database of over 40,000 patients at the Beth Israel Deaconess Medical Center.

 Inclusion Criteria:

• Patients >18yo
• Admitted to ICU
• Had received NorArdenaline and Vasopressin with Noradrenaline initiated before Vasopressin, no more than 48 hours.

 N= 1817

• Group 1 had low dose NorAdrenaline (<0.25mcg/kg/min) (N=613 (33.74%))
• Group 2 had high dose of NorAdrenaline (>25mcg/kg/min)(N=1204(66.26%))

 Propensity Score Matching was used as there was a significant difference in severity of illness in the two groups. The result was that 535 patients per group, with similar characteristics and disease severity, were chosen.    

Primary Outcome

28 day mortality after diagnosis of septic shock

Secondary Outcomes

• Haemodynamic response to Vasopressin
• Duration of Noradrenaline and Vasopressin
• Duration of mechanical ventilation-free days
• IV fluid and urine in days 1 and 2 after initiation of vasopressin
• Duration of ICU and hospital stays.

What they Found

The mean dose of NorAdrenaline at the time of commencement of Vasopressin was:

• 14 + 0.07 mcg/kg/min in the low dose NorAdrenaline Group
• 41 + 0.28 mcg/kg/min in the High Dose NorAdrenaline Group

Primary Outcome: 28 Day Mortality was lower in the lower dose NorAdrenaline Group (49.2% vs 59.4% (CI 0.518-0.840, p<0.001)

Secondary Outcomes: There was no significant difference to haemodynamic response to Vasopressin, duration of Vasopressin, ICU or hospital stay the two groups. The low dose NorAdrenaline grouo received a shorter duration of NorAdrenaline, less fluid and had a longer duration of ventilator-free days.

 My Take on this

This is a retrospective, single centre study, making it difficult to apply the outside the study environment. It is also a data registry trial, which can sometimes result in less than applicable results. It is unclear if the sicker patients received the higher doses of NorAdrenaline.

The results are not consistent with a meta-analysis (4), which showed no reduction in short term mortality with early initiation of Vasopressin. The VASST Trial (6) (subgroup analysis), did find that there was improved survival in patients with less severe shock when vasopressin was added earlier.

Noradrenaline is primarily and alpha1 and beta1 receptor agonist, with little beta 2 or alpha 2 activity. At doses < than 2 mcg/min, the beta1 effects are prominent resulting in increase in cardiac output. At  doses > 3 mcg/min, the alpha1 effects are more prominent resulting in vasoconstriction with venous:arterial activity relatively equal.

 High doses with significant vasoconstriction and increased systemic vascular resistance may:

• decrease in end-organ perfusion
• increase pulmonary vascular resistance
• increase afterload and thus increase myocardial work done
• cause a reflex bradycardia, resulting in a decrease in cardiac output.

However it has also been shown to increase cardiac output by increasing pre-load, in adequately fluid resuscitated patients, decrease the amount of fluid needed, thus avoiding over load and probably the most important part of its use, reaching MAP >65 earlier.

I’ll continue early use of NorAdrenaline early, following a modest fluid resuscitation. However as dosage increases, I will consider commencement of Vasopressin ( the evidence is weak). I believe it's more about the timely achievement of MAP and thus organ perfusion. 

References

• Xu J et al. Timing of vasopressin initiation and mortality in patients with septic shock:analysis of the MIMIC-III and MIMIC-IV databases. BMC Infectious Diseases (2023) 23:199 pp 1-10
• Evans L, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021;47:1181–247.
• Wieruszewski PM, Khanna AK. Vasopressor choice and timing in vasodilatory shock. Crit Care. 2022;26:76.
• Guerci P, Belveyre T, Mongardon N, Novy E. When to start vasopressin in septic shock: the strategy we propose. Crit Care. 2022;26:125
• Yao R, Xia D, Wang L, Wu G, Zhu Y, Zhao H, et al. Clinical efficiency of Vasopressin or its analogs in comparison with catecholamines alone on patients with septic shock: a systematic review and Meta-analysis. Front Pharmacol. 2020;11:563

6. Russell J et al. Vasopressin versus Norepinephrine Infusion in patients with Septic Shock. NEJM. February 28 2008 358;9 pp 877-887