What is the Optimal Timing for Vasopressin in Patients with Septic Shock?

If the targeted perfusion objectives are not achieved using moderate dosages of the primary vasopressor, determining whether to introduce an additional vasopressor or increase the existing one should involve weighing the potential advantages (enhanced cardiac output, blood pressure, and perfusion) against the associated risks (elevated probability of arrhythmia and digital ischemia) for each strategy. To date, clinical trials aiming at identifying which patients could benefit the most of early association of NE + AVP are lacking and are urgently needed.

Current Guidelines on the Timing of Vasopressin in Septic Shock

In patients experiencing septic shock, current guidelines propose a weak endorsement to incorporate vasopressin (AVP) into the norepinephrine treatment when the norepinephrine dosage nears 0.25 to 0.5 μg/kg/min. This weak recommendation is based on the observed reduction in the need for catecholamine vasopressors when vasopressin is added to the treatment regimen. However, it is important to note that the clinical outcomes have been inconsistent across various meta-analyses, which contributes to the weak recommendation.

In the VANISH trial, the investigators compared the impact of early vasopressin and norepinephrine in 409 septic shock patients on kidney failure. The results showed no substantial difference in the number of days without kidney failure between those treated with vasopressin and those treated with norepinephrine. However, the vasopressin group had a lower usage of renal replacement therapy. No significant differences were observed in mortality rates or serious adverse events between the two groups [1].

The Vasopressin in Septic Shock Trial (VASST) was a study that compared the addition of vasopressin to norepinephrine with norepinephrine alone in the treatment of septic shock patients. This trial aimed to determine whether the use of vasopressin, in conjunction with norepinephrine, could reduce mortality rates compared to the use of norepinephrine alone. No significant differences were found between the vasopressin and norepinephrine groups in 28-day or 90-day mortality rates, or in the overall rates of serious adverse events. However, one of the key findings from the trial was that patients who were receiving lower doses of norepinephrine (less than 15 μg/min or 0.25 μg/kg/min) at the time of enrollment experienced lower mortality rates when they were also randomized to receive vasopressin. This suggests that the combination of vasopressin and norepinephrine might be more effective in treating septic shock in patients who are on lower doses of norepinephrine [2].

In a systematic review and meta-analysis of 23 randomized clinical trials involving 3,088 patients, researchers examined the association of vasopressin plus catecholamine vasopressors compared to catecholamine vasopressors alone in patients with distributive shock, a condition usually caused by excessive vasodilation due to severe infection. The study found that the addition of vasopressin to catecholamine vasopressors was associated with a lower risk of atrial fibrillation, which is common with catecholamines and linked to adverse events such as increased mortality and length of hospital stay. The findings for secondary outcomes, such as mortality and requirement for renal replacement therapy, were not consistent, with some trials at low risk of bias showing no significant differences in these outcomes [3].

At what dose of norepinephrine would you start vasopressin in the management of septic shock?

• 0.2-0.3 mcg/kg/min
• 0.3-0.5 mcg/kg/min
• >0.5 mcg/kg/min

In another meta-analysis of four trials involving 1,453 patients, researchers investigated the potential benefits and harms of vasopressin therapy in adults with septic shock. The study found no significant effect of vasopressin on 28-day mortality or serious adverse events. However, vasopressin resulted in more digital ischemia but fewer arrhythmias. The rates of mesenteric ischemia and acute coronary syndrome were similar between groups. While vasopressin reduced the requirement for renal replacement therapy (RRT), the finding was not robust in sensitivity analyses, and no significant interactions were found in predefined subgroups. Overall, vasopressin therapy appears safe, with a different side effect profile from norepinephrine, but the reduced RRT finding should be interpreted cautiously. Future trials should focus on long-term outcomes and cost-effectiveness analyses related to potential reduced RRT use [4].

Predicted in-hospital mortality with norepinephrine-equivalent dose at vasopressin initiation

Recent Evidence for timing of Vasopressin Use in Septic Shock

More recently, another retrospective study was done at multiple hospitals within the Cleveland Clinic Health was published in critical care medicine [5]. The study aimed to determine the association of catecholamine dose, lactate concentration, and timing from shock onset at vasopressin initiation with in-hospital mortality. The retrospective, observational study included 1,610 adult patients who met the criteria for septic shock and received continuous infusion vasopressin as an adjunct to catecholamine vasopressors. The results showed that the odds of in-hospital mortality increased by 20.7% for every 10 μg/min increase in norepinephrine-equivalent dose up to 60 μg/min at the time of vasopressin initiation. However, no association was detected when the norepinephrine-equivalent dose exceeded 60 μg/min. A significant interaction between the timing of vasopressin initiation and lactate concentration was observed for the association with in-hospital mortality. Higher norepinephrine-equivalent dose and higher lactate concentration at vasopressin initiation were each associated with higher in-hospital mortality in patients with septic shock who received vasopressin [5].

Another retrospective observational cohort study investigated the optimal timing for vasopressin initiation in septic shock patients using the MIMIC-III v1.4 and MIMIC-IV v2.0 databases. Patients were stratified based on norepinephrine (NE) dose at vasopressin initiation, either low (NE<0.25 µg/kg/min) or high (NE ≥ 0.25 µg/kg/min). The study found that initiating vasopressin at low doses of NE was associated with reduced 28-day mortality, shorter NE duration, less intravenous fluid volume on the first day, more urine on the second day, and longer mechanical ventilation-free and CRRT-free days. No significant differences were observed in hemodynamic response, vasopressin duration, or ICU or hospital length of stay. The results suggest that vasopressin initiation when using low-dose NE is associated with improved 28-day mortality in septic shock patients [6].

Like any other retrospective study, confounding factors should be taken into consideration in this investigation of the optimal timing for vasopressin initiation in septic shock patients. Although the teo mentioned studies found that initiating vasopressin at low doses of NE was associated with reduced 28-day mortality and other positive outcomes, it is important to account for potential confounders that could influence the results. Further prospective studies would help to confirm these findings and provide more robust evidence for clinical practice.

Conclusion

In conclusion, incorporating vasopressin into norepinephrine treatment for septic shock has a weak recommendation due to inconsistent clinical outcomes across studies. Vasopressin therapy appears safe, with a different side effect profile from norepinephrine. It appears that starting vasopressin at lower dose of norepinephrine maybe associated with a better outcome. I would probably aim to start vasopressin at a dose of 0.2-0.25 μg/kg/min. Clinicians should weigh advantages and risks when adjusting vasopressor treatments to achieve targeted perfusion objectives.

REFERENCES:

1. Gordon AC, Mason AJ, Thirunavukkarasu N, et al. Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical Trial. JAMA. 2016;316(5):509–518. doi:10.1001/jama.2016.10485

2. Russell JA, Walley KR, Singer J, Gordon AC, Hébert PC, Cooper DJ, Holmes CL, Mehta S, Granton JT, Storms MM, Cook DJ, Presneill JJ, Ayers D; VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008 Feb 28;358(9):877-87. doi: 10.1056/NEJMoa067373. PMID: 18305265.

3. McIntyre WF, Um KJ, Alhazzani W, Lengyel AP, Hajjar L, Gordon AC, Lamontagne F, Healey JS, Whitlock RP, Belley-Côté EP. Association of Vasopressin Plus Catecholamine Vasopressors vs Catecholamines Alone With Atrial Fibrillation in Patients With Distributive Shock: A Systematic Review and Meta-analysis. JAMA. 2018 May 8;319(18):1889-1900. doi: 10.1001/jama.2018.4528. PMID: 29801010; PMCID: PMC6583502.

4. Nagendran M, Russell JA, Walley KR, Brett SJ, Perkins GD, Hajjar L, Mason AJ, Ashby D, Gordon AC. Vasopressin in septic shock: an individual patient data meta-analysis of randomised controlled trials. Intensive Care Med. 2019 Jun;45(6):844-855. doi: 10.1007/s00134-019-05620-2. Epub 2019 May 6. PMID: 31062052.

5. Sacha GL, Lam SW, Wang L, Duggal A, Reddy AJ, Bauer SR. Association of Catecholamine Dose, Lactate, and Shock Duration at Vasopressin Initiation With Mortality in Patients With Septic Shock. Crit Care Med. 2022 6. Apr 1;50(4):614-623. doi: 10.1097/CCM.0000000000005317. PMID: 34582425.

6. Xu J, Cai H, Zheng X. Timing of vasopressin initiation and mortality in patients with septic shock: analysis of the MIMIC-III and MIMIC-IV databases. BMC Infect Dis. 2023 Apr 3;23(1):199. doi: 10.1186/s12879-023-08147-6. PMID: 37013474; PMCID: PMC10071631.