Early initiation of norepinephrine in septic shock reduces mortality, claims study

Globally, septic shock is one of the most challenging problems in critical care medicine. With an increasing annual incidence in the developed world, mortality remains between 25 and 50% of those afflicted.

The pathophysiology of septic shock is complex and involves vasodilatation, relative and absolute hypovolemia, myocardial dysfunction, increased metabolic rate, and altered regional and microvascular blood flow.

Nor-epinephrine is both an alpha1- and beta1-agonist and is, therefore, able to increase vascular tone and contractility. Recent guidelines recommend nor-epinephrine as the first-line vasopressor in septic shock. The 2018 Surviving Sepsis Campaign (SSC) Bundle recommends administering broad-spectrum antibiotics, rapidly administering 30 ml/kg crystalloid for hypotension or lactate ≥ 4 mmol/L, and applying vasopressors if the patient is hypotensive during or after fluid resuscitation to maintain MAP ≥ 65 mmHg within the first hour.

It is the timing of vasopressor therapy, rather than the specific agent, that appears to be crucial, but a universally accepted recommendation on the timing to start nor-epinephrine support has not been clearly stated to date.

Also, the effect of the timing of nor-epinephrine initiation on clinical outcomes in patients with septic shock is uncertain.

Therefore, a systematic review and meta-analysis was performed by Yuting Li and associates, attached to the Department of Intensive Care Unit, The First Hospital of Jilin University, China, to evaluate the impact of the early and late start of norepinephrine support on clinical outcomes in patients with septic shock.

PubMed, Cochrane, and Embase databases were searched for randomized controlled trials (RCTs) and cohort studies from inception to the 1st of March 2020. Researchers included studies involving 929 adult patients (> 18 years) with septic shock. Septic shock was classified according to the current Third International Consensus Definitions for Sepsis and Septic Shock.

All authors reported the primary outcome of short-term mortality and comparing early versus late norepinephrine initiation with clinically relevant secondary outcomes (ICU length of stay, time to achieved target mean arterial pressure (≥ 65 mmHg), and volume of intravenous fluids within 6 h).

On analysis, the following facts emerged.

• The primary outcome of this meta-analysis showed that the short-term mortality of the early group was lower than that of the late group (odds ratio [OR] = 0.45; 95% CI, 0.34 to 0.61; P < 0.00001; χ 2 = 3.74; I 2 = 0%).
• Secondary outcomes demonstrated that the time to achieved target MAP of the early group was shorter than that of the late group (mean difference = − 1.39; 95% CI, − 1.81 to − 0.96; P < 0.00001; χ 2 = 1.03; I 2 = 0%).
• The volume of intravenous fluids within 6 h of the early group was less than that of the late group (mean difference = − 0.50; 95% CI, − 0.68 to − 0.32; P < 0.00001; χ 2 = 33.76; I 2 = 94%).
• There was no statistically significant difference in the ICU length of stay between the two groups.

"Delays in the initiation of vasopressor therapy following the first documentation of hypotension in septic shock are modestly associated with increased specific organ failure and mortality risk. We now need a large multicenter phase 3 RCT of early nor-epinephrine initiation powered for mortality and organ dysfunction. In a word, early may be better." wrote the authors.

For the full article click on the link: 10.1186/s13054-020-03204-x

Primary source: Critical Care