Rethinking Septic Shock Management: Potential of Early Vasopressin Use to Enhance Patient Outcomes

Vasopressin timing, patient selection, optimal vasopressin use in septic shock, and potential mortality benefits in selected patient populations.

Septic Shock Overview and Current Treatments

Septic shock is a severe, life-threatening response to infection, characterised by systemic inflammation, tissue hypoperfusion, and persistent, severe hypotension despite adequate fluid resuscitation. It results in high morbidity and mortality rates and is a major cause of mortality in intensive care units (ICUs) globally, necessitating prompt, targeted interventions to manage shock and mitigate damage from inadequate tissue perfusion (Singer et al. 2016).

According to the Surviving Sepsis Campaign (SSC) guidelines, the recommended treatment to address hypotension in septic shock includes adequate fluid resuscitation and vasopressor support to maintain a mean arterial pressure (MAP) above 65 mmHg. Norepinephrine (NE) is the first-line vasopressor recommended due to its strong vasoconstrictive effects (Evans et al. 2021). However, reliance on norepinephrine and other catecholamines presents certain disadvantages, as adverse effects have been observed not only on the heart (tachycardia, tachyarrhythmia, myocardial ischaemia) but also on the lungs, the coagulation, the immune system, the metabolism and others (Vincent and De Backer 2013; Dünser and Hasibeder 2013; Stolk et al. 2020).

Therefore, the SSC guidelines suggest adding vasopressin to norepinephrine to achieve the target MAP of 65mmHg or to reduce norepinephrine dosages. While the guidelines mention a norepinephrine dose of 0.25-0.5 µg/kg/min as a potential cut-off to start adding vasopressin, there are still many uncertainties regarding optimal timing (Evans et al. 2021).

In recent years, three retrospective observational studies have investigated predictors for a response to the addition of vasopressin, examining arterial pH and lactate concentration, as well as the association of catecholamine doses and lactate concentration at vasopressin initiation with in-hospital mortality (Sacha et al. 2018; Sacha et al. 2021; Bauer et al. 2022).

Improving Patient Outcomes by Improving Vasopressin Response Rates

Studies indicate that patients who respond to the addition of vasopressin (defined as a reduction in catecholamine dose with MAP ≥ 65 mmHg six hours after vasopressin initiation) have significantly better outcomes, such as lower mortality, reduced need for renal replacement therapy, and decreased catecholamine doses (Sacha et al. 2018; Bauer et al. 2022). Thus, a key target may be to increase the number of responders.

The two key predictors of vasopressin response in these studies were:

• Lower lactate levels at vasopressin initiation: Responders had significantly lower lactate concentrations than non-responders (5.4 ± 4.8 vs. 4.0 ± 3.6 mmol/L; P < 0.001) (Sacha et al. 2018).

• Arterial pH and acidaemia: Patients with an arterial pH below 7.40 were less likely to respond haemodynamically to vasopressin. Vasopressin’s efficacy appears to diminish in acidaemic conditions, with outcomes worsening for each 0.1 unit decrease in arterial pH below 7.4 at vasopressin initiation (Bauer et al. 2022).

Thus, adding vasopressin to norepinephrine at low lactate levels and high arterial pH levels could optimise patient outcomes.

Additional Associations Regarding Timing of Vasopressin Initiation With In-Hospital Mortality

Another study evaluated the associations of catecholamine dose and lactate concentration at vasopressin initiation with in-hospital mortality.

The findings suggested that initiating vasopressin at a lower norepinephrine-equivalent dose was associated with a higher likelihood of survival with best outcomes when vasopressin was initiated at 10 μg/min. Up to 60 μg/min, each additional 10 μg/min increase in norepinephrine-equivalent dose at the time of vasopressin initiation was associated with 20.7% higher in-hospital mortality.

Similarly, initiating vasopressin at lower lactate levels was associated with a higher likelihood of survival with best outcomes when vasopressin was initiated at 2.3 mmol/L. Each 1 mmol/L increase in lactate concentration at the time of vasopressin initiation was associated with 18.4% higher in-hospital mortality (Sacha et al. 2021).

Clinical Implications and Recommendations

The results of these three studies collectively suggest that considering vasopressin as an early adjunct to norepinephrine for patients with septic shock could be beneficial to patient outcomes especially when:

• Catecholamine requirements are low to moderate: Initiation at lower norepinephrine-equivalent doses appears to maximise vasopressin’s haemodynamic benefits.
• Lactate levels are low: Starting vasopressin when lactate levels are low may offer the best outcomes, as high lactate indicates more severe shock that may not respond as favourably.
• Arterial pH levels are high (≥7.4)

This body of research highlights the need for further studies to refine guidelines on vasopressin timing and patient selection, as current practices are based largely on observational findings and retrospective analyses. Controlled studies will be essential to establish precise criteria for optimal vasopressin use in septic shock and confirm its potential mortality benefits in selected patient populations.

Key Points

• Septic shock is a severe, life-threatening response to infection, characterised by systemic inflammation, tissue hypoperfusion, and persistent, severe hypotension.

• According to the Surviving Sepsis Campaign (SSC) guidelines, the recommended treatment to address hypotension in septic shock includes adequate fluid resuscitation and vasopressor support.

• Three recent retrospective observational studies have investigated predictors for a response to the addition of vasopressin.

• Studies indicate that patients who respond to the addition of vasopressin have lower mortality, reduced need for renal replacement therapy, and decreased catecholamine doses.

• The results of these studies suggest that vasopressin as an early adjunct to norepinephrine for patients with septic shock could be beneficial to patient outcomes.

Disclaimer

Point-of-view articles are the sole opinion of the author(s) and are part of the ICU Management & Practice Corporate Engagement or Educational Community Programme.