Background
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 [
1‐
3]. Patients with septic shock can be identified with a clinical construct of sepsis with persisting hypotension requiring vasopressors to maintain mean arterial pressure (MAP) ≥ 65 mmHg and having a serum lactate level > 2 mmol/L (18 mg/dL) despite adequate volume resuscitation [
4]. 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 [
5].
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 [
6‐
9]. Besides relative and absolute hypovolemia, decreased vascular tone is one of the major characteristics of septic shock causing hypotension [
10]. Norepinephrine is both an alpha1- and beta1-agonist and is therefore able to increase vascular tone and contractility [
11]. Recent guidelines recommend norepinephrine as the first-line vasopressor in septic shock [
12].
So far, most studies have focused on the rational use of different types of vasopressors [
13‐
15]. However, it is the timing of vasopressor therapy, rather than the specific agent, that appears to be crucial [
16]. Studies comparing different agents have not clarified the optimal agents, and none have addressed the optimal timing [
15,
17]. The present data show that the time from the onset of septic shock to initial norepinephrine administration is an important determinant of survival, but a recommendation on the timing to start norepinephrine support was not clearly stated [
18].
Since the optimal timing of the initiation of norepinephrine remains unknown and whether the benefits or harm of norepinephrine introduction even preceding fluid resuscitation has not been still answered, we conducted a meta-analysis which extracted results from published randomized controlled trials (RCTs) and cohort studies to evaluate the impact of early and late start of norepinephrine support on clinical outcomes in patients with septic shock.
Discussion
This systematic review and meta-analysis of five studies including 929 patients compared early and late norepinephrine initiation in patients with septic shock. We found that the overall short-term mortality was about 29.3%, and the short-term mortality of the early group was lower than that of the late group. Secondary outcomes showed that the time to achieved target MAP of the early group was shorter than that of the late group. The survival benefit of early and effective resuscitation is confirmed in septic shock patients [
31]. This meta-analysis demonstrated that the significant mortality benefit with early initiation of a norepinephrine is likely secondary to earlier achievement and maintenance of adequate perfusion pressures, preventing the onset and/or progression of organ dysfunction [
32]. This is also in line with another study suggesting that shorter hypotension times are associated with better outcomes in septic shock [
33]. The patients with septic shock receiving vasopressors early or late depend on the patient’s response to initial fluid resuscitation and the judgment of the physicians. If clinicians delay starting vasopressors because of a lack of critical care bed availability, then they probably should not delay. Managing a patient on a general ward, without vasopressors, hoping that in time blood pressure will improve and thus not require critical care, may lead to worse outcomes for patients [
34]. Since the timing to start norepinephrine is crucial, one of the recommendations was to administer norepinephrine in the initial phase of septic shock even when hypovolemia is not completely corrected by fluid administration [
35]. In addition, a low value of diastolic arterial pressure (e.g., < 40 mmHg) is strongly suggestive of a markedly depressed arterial tone and should prompt initiation of norepinephrine urgently [
36].
Secondary outcomes demonstrated that the volume of intravenous fluids within 6 h of the early group was less than that of the late group. Fluid overload is a common complication during septic shock resuscitation. Two recent studies also showed that early use of norepinephrine is associated with less fluid administration and improved outcomes [
37,
38]. Positive cumulative fluid balance is an independent factor of mortality in septic shock patients: the higher the positive fluid balance, the poorer the outcome [
39‐
41]. A recent large cohort study of 23,513 patients with severe sepsis and septic shock showed that administration of more than 5 L of fluid during the first day is associated with a significantly increased risk of death [
42]. The mechanisms by which excessive fluid administration may worsen outcome include peripheral tissue edema with risks of multiple organ dysfunction, pulmonary edema with risks of profound hypoxemia, degradation of endothelial glycocalyx [
43] with risks of increased vascular permeability, marked increase in venous pressures with risks of decrease in organ perfusion pressure [
44], and hemodilution [
45]. Early use of norepinephrine decreases the use of fluid replacement, possibly by constricting the dilated vascular bed, and shortens resuscitation duration [
46]. In addition, our meta-analysis showed that there was no statistically significant difference in the ICU length of stay between the two groups. Delay in vasopressor initiation was not predictive of ICU length [
47].
Early norepinephrine use in septic shock can increase cardiac output through an increase in cardiac preload and/or contractility and improve microcirculation and tissue oxygenation [
36]. However, the use of vasopressors is not without consequences. Risk of well-known adverse reactions, such as arrhythmias, may have been increased for patients with prolonged exposure to vasopressors, potentially adding to the increased mortality rate. Another main argument is that high doses of exogenous norepinephrine may have deleterious consequences such as myocardial cell injury, oxidative stress, and alteration of sepsis-associated immunomodulation [
48]. Splanchnic hypoperfusion is also an important concern when norepinephrine is given early. No matter what, norepinephrine remains the primary vasopressor in septic shock, and the existing evidence suggests that it remains a safe and effective first-line medication for septic shock.
At present, there is no uniform definition of “early” or “late” norepinephrine initiation in patients with septic shock, and the five studies included in our meta-analysis have different definitions of the early and late groups. We listed a table (Table
3) to illustrate each author’s definition of the early and late groups. The recent Hour-1 Bundle supported by the SSC recommends starting vasopressors within the first hour of resuscitation if initial fluid loading does not restore minimum MAP [
5]. Indeed, norepinephrine infusion can be safely started before ICU admission, even in intermediate care without intensivist supervision. Delays in 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 norepinephrine initiation powered for mortality and organ dysfunction. In a word, early may be better.
This meta-analysis and the five included studies have several characteristics. First, the effect of the timing of norepinephrine initiation on short-term mortality is different in the five included studies. Therefore, the meta-analysis of different studies with different conclusions adds to the significance of this study. Second, although the primary outcomes of the five studies are inconsistent, the secondary outcomes, including the time to achieved target MAP and ICU length of stay, are consistent. This will reinforce the secondary outcomes of this meta-analysis.
Our meta-analysis has several limitations. First, the number of included studies is small. Further randomized clinical studies should be conducted in order to confirm the results. Second, many of the secondary outcomes such as ICU length of stay, time to achieved target MAP, or volume of intravenous fluids within 6 h were not included in all of the studies examined in this meta-analysis. Third, organ dysfunction is also a very important clinical outcome. However, few included studies had shown this data. Fourth, although we had performed a subgroup analysis of RCTs and cohort studies, there was still substantial heterogeneity among the included studies. Very heterogeneous populations were included in both randomized and observational studies. In addition, inclusion/exclusion criteria and comorbidities were widely different among included studies which supposed a limitation to interpret results. Therefore, our findings should be interpreted with caution.
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