Should we initiate vasopressors earlier in patients with septic shock: A mini systemic review

Table 1 Basic characteristics of studies on early initiation of vasopressors included in the systematic review

No.	Ref.	Study design and period	No.of patients/early/late group	Agents	Time 0	Definition for early initiation	Primary outcome reported	Primary outcome	Other points	Comments
1	Beck et al[31], 2014, Canada	Multicenter, retrospective cohort study 1996-2008	6514/-/-	NE, Dopamine, Phenyleph-rine, VP, Epinephrine			Survival to hospital discharge	A weak correlation between vasopressor delay and hospital mortality (adjusted OR 1.02/h, P < 0.001)	The significance was found between the delay to vasopressor initiation (> 14 h post hypotension) and the occurrence of organ failure	1 Markedly delayed initiation of vasopressor (> 14 h after hypotension) in septic shock patients is associated with a small increase in mortality risk. 2 Delays in vasopressor initiation is only weakly associated with mortality, while delays in antimicrobial is more higher
2	Bai et al[61], 2014, China	Two centers, retrospective cohort study, Jan. 2011-Dec. 2012	213/86/127	NE	Septic shock onset	NE administered within 2 h after onset of septic shock	28 d mortality	The early group was lower than the late group, 29.1% vs 43.3%, P < 0.001	1 Duration of NE was significantly shorter in the early-NE group (2.6 ± 0.6 d vs 2.9 ± 1.0 d, P = 0.001). 2 Serum lactate levels at 2, 4, 6 and 8 h after septic shock onset were significantly lower in the early-NE group (P < 0.05)	1 Early administration (within 2 h after the septic shock onset) of NE in septic shock patients is associated with an increased survival rate. 2 Early NE initiation can increase MAP, shorten the duration of hypotension and, improve vital organ perfusion and decrease serum lactate levels
3	Permpikul et al[39], 2019, Thailand	Single center, RCT, Oct. 2013-Mar. 2017	310/155/155	NE	ED arrival	Median time from emergency room arrival to NE administration was 93 min	Shock control rate	Early NE administration resulted in significant higher shock control rate than standard treatment, 76.1% vs 48.8%, P < 0.001	1 Achievement of target MAP (> 65 mmHg), urine output (> 0.5 mL/kg) and lactate clearance (> 10%) were all significantly higher in the early-NE group (all P < 0.05). 2 There was no difference between groups for the rates of mechanical ventilator support or RRT. 3 patients in the early-NE group had a lower rate of cardiogenic pulmonary edema (14.4% vs 27.7%, P = 0.004) and new-onset arrhythmia (11% vs 20%, P = 0.03)	This study confirms that the early use of NE, can enable septic shock patients to benefit in short-term endpoints, such as shock control rate, urine output and lactate clearance, represented both macro- and micro-circulation restoration
4	Colon et al[62], 2019, United States	Single center, retrospective cohort study Jan. 2017-Jul. 2017	119/76/43	Vasopress-ors	Initial hypotension	Received vasopressor within 6 h from initial hypotension	30 d mortality	Vasopressor initiation after 6 h from shock onset is associated with a significant increase in 30 d mortality, 25% vs 51.1%, P < 0.01	1 Logistic regression analysis: administration of vasopressors after 6 h from hypotension were independently associated with increased 30 d mortality. 2 The time to target MAP was shorter in the early vasopressor group (1.5 h vs 3 h, P < 0.01)	1 Demonstrates that there is a mortality benefit with early use of vasopressor. 2 Early administration of vasopressor in septic shock patients (< 6 h from initial hypotension) is associated with decreased mortality, that is likely secondary to faster achievement of MAP goals
5	Elbouhy et al[63], 2019, Egypt	Single center, RCT Jan. 2017-Dec. 2018	101/57/44	NE	ED admission	NE infusion started after 25 (20-30) min from ED admission, simultaneous administration of crystalloid fluids	In-hospital survival	Early NE in septic shock improved in-hospital survival, 71.9% vs 45.5%, P = 0.007	1 MAP of 65 mmHg was achieved after 2 h in the early group compared to 3 h in the late group (P = 0.003). 2 Post-resuscitation serum lactate level was 2 mmol/L in the early group and 2.9 mmol/L in the late group (P = 0.037). 3 Acute kidney injury developed in 24 of the early group (42%) compared to 23 of the late group (52%) (P = 0.3). 4 Patients in the early group were resuscitated by significantly lower volume of fluids, 25 mL/kg compared to 32.5 mL/kg in the late group (P = 0.000). 5 The in-hospital survival rate in the early group was 71.9% compared to 45.5% in the late group (P = 0.007)	1 They found that early use of NE initiated simultaneously with fluids was associated with earlier achievement of target MAP, earlier lactate clearance with earlier achievement of lactate < 2 mmoL/L and consequently higher in-hospital survival. 2 The significantly lower volume required for fluids resuscitationin the early-NE than in the late-NE group
6	Ospina-Tascón et al[64], 2020, Colombia	Single center, prospective cohort study, Jan.2015-Feb.2017	186/93/93	NE, VP	First resuscitative fluid load	Vasopressor support initiated within the next hour or even before the first fluid load with resuscitative intention (FRLoad)	Association between early vasopressor and 28 d mortality	Early vasopressor was associated with a significant reduction in the risk of death compared to delayed vasopressor (HR 0.31, 95%CI 0.17-0.57, P < 0.001) at day 28	1 Patients in the early vasopressor group received less resuscitation fluids in the first 8 h of resuscitation (P < 0.001). 2 There were no significant differences regarding the maximal dose of NE, steroids and VP use, or requirement of RRT. 3 No cases of severe digital or severe vasopressor-induced splanchnic ischemia were documented	1 Early vasopressor support is associated with less use of resuscitation fluids, less fluid accumulation, and shortening of hypotension time. 2 Early vasopressor was not associated with increased kidney injury or ischemia-related adverse effects, and it might decrease mortality in patients with septic shock
7	Yeo et al[65], 2021, Korean	Multicenter, prospective observational study Sep. 2019-Feb. 2020	298/149/149	NE, VP, epinephrine, dopamine	First resuscitative fluid load	Vasopressor was initiated within 1 h of the first resuscitative fluid load	28 d mortality	Vasopressor initiation within 1 h was associated with higher 28 d mortality, 47.7% vs 33.6%, P = 0.013	1 Volume of fluid given within the initial 6 h was significantly lower in the early group (P = 0.046). 2 The total SOFA score on day 3 in ICU was significantly lower in the late group than that in the early group (P = 0.045). Lactate levels were significantly lower on day 3 in the late group than that in the early group (P = 0.014)	1 Use of a vasopressor within 1 h of the first fluid loading was related to higher mortality in patients with septic shock. 2 Less fluid was administered to the early group, but inadequate fluid resuscitation exhibited worse organ function and lactate clearance 3 d after septic shock onset
8	Jouffroy et al[50], 2022, France	Multicenter, retrospective study, Apr. 2016-Dec. 2020	478/143/335	NE	Prehospital	Patients with prehospital NE administration (early NE)	30 d mortality	Prehospital NE infusion (early NE) is associated with a decrease in 30 d mortality	N/A	A strength of this study is that NE administration is started within 1 h after septic shock onset and before the completion of the fluid resuscitation
9	Xu et al[7], 2022, United States	Single center, retrospective observational cohort study 2008-2019	2862/1431/1431	NE	Septic shock onset	Receiving NE within the first 3 h	28 d mortality	Early group had lower 28 d mortality, 30.0% vs 37.8%, P < 0.001	Patients in the early-NE initiation group had a significantly shorter duration of ICU and hospital stay, shorter duration of supportive NE and invasive mechanical ventilation, lower incidence of acute kidney injury, and lower proportion of organ failure progression than patients in the delayed NE initiation group	NE initiation within the first 3 h, regardless of preload dependency, was associated with longer survival time and shorter duration of supportive NE and invasive mechanical ventilation and may delay or partially reverse rapid onset organ failure
Sum	USA 2, other countries 1	2 RCTs	11081/2190/2377	NE 5	Shock onset 3, ED arrival 2, First fluid 2, Prehospital 1	Within 2, 3 and 6 h after shock, Within 0, 0.5, 1 h of fluid start, Prehospital	28 d mortality 4 and 30 d mortality 2 hospital survival 2	Mortality was lower in early group in 7 studies; mortality in early group was 28.1%-47.7%, in control group was 33.6%-54.5%

ED: Emergency department; MAP: Mean arterial pressure; NE: Norepinephrine; RRT: Renal replacement therapy; SOFA: Sequential organ failure assessment; ICU:Intensive care unit; VP: Vasopressin; N/A: Not applicable.

Table 2 Basic characteristics of studies on early combination with another vasopressor included in the systematic review

No.	Ref.	Study design and period	No. of patients	Agents	Time 0	Definition for early combination	Primary outcome reported	Primary outcome	Other points	Comments
1	Reardon et al[56], 2014, United States	Single center, retrospective study Jan. 2010-Dec. 2011	71, 35 (early)/36 (late)	VP	Catecholami-ne initiation	VP was initiated within 6 h of catecholamine therapy	Impact of VP on catecholamine dose and duration	No difference in dose and duration of catecholamine or VP therapy between the 2 groups	1 There was a significant difference in incidence of new-onset arrhythmias between the early VP and late groups (P < 0.001). 2 There was a trend toward worsening troponin T and CK-MB in the late VP group	1 Early VP therapy was associated with no difference in total catecholamine requirements but decreased incidence of new-onset arrhythmias. 2 There was also a trend toward improvement in cardiac biomarkers in the early VP group
2	Hammond et al[11], 2018, United States	Single center, prospective trial Nov. 2015-Jun. 2016	82, 41 (VP)/41 (NE)	VP	NE initiation	VP was initiated within 4 h of NE	Time to target MAP	Early VP to NE achieved target MAP faster than those receiving initial NE alone (P = 0.058)	-	Early concomitant VP and NE achieved and maintained a target MAP faster than initial NE alone, particularly in those in whom absolute or relative VP deficiency is suspected or confirmed
3	Hammond et al[13], 2019, United States	Single center, retrospective cohort study, May 2014-Oct. 2015	93, 48 (VP)/48 (NE)	VP	NE initiation	VP was initiated within 4 h of NE	Time to target MAP	Early VP to NE achieved target MAP sooner than later or no initiation (P = 0.023)	1 Changes in SOFA at 76 h since septic shock onset, the early VP saw a significant decrease of 4 compared to a decrease of 1 for NE alone (P = 0.012). 2 Early VP were discharged from the hospital 10 d sooner than those in the NE alone (14.3 vs 25.2 d, P = 0.014). 3 Incidence and duration of RRT were comparable between groups (17% vs 25% and 6.7 vs 11.2 d, respectively)	Early VP in combination with NE achieved a target MAP faster than the NE alone and may be more likely to resolve organ dysfunction at 72 h, although the in-hospital and 28-d mortalities were similar between groups, patients who survived benefited from earlier achievement and maintenance of goal MAP
4	Khanna et al[66], 2017, International	Multicenter, RCT May. 2015-Jan 2017	321/163/158	ATII	NE initiation	> 0.2 μg/kg/min of NE	Response to MAP at 3 h	More patients in the ATII response to MAP at 3 h (69.9% vs 23.4%, P < 0.001)	1 At 48 h, mean doses of background vasopressors were consistently less in the AT II group. 2 At 48 h, the mean improvement in the cardiovascular SOFA score was greater in the ATII group (-1.75 vs -1.28, P = 0.01). 3 No difference between the two groups for serious adverse reactions. 4 No difference between the two groups for 28 d mortality	1 Demonstrates the safety and efficacy of widespread clinical use of ATII. 2 ATII reduces the need for catecholamines in patients with catecholamine-resistant vasodilatory shock (CRVS), while reducing the cardiovascular injury it causes
5	Bellomo et al[49], 2020, International	Multicenter, Retrospective study	255/127 (low)/119 (high)	ATII	NE initiation	> 0.2 μg/kg/min of NE	Renin kinetic changes and their prognostic value in CRVS	In patients with higher renin concentrations, ATII significantly reduced 28-d mortality compared with placebo (P = 0.012)	1 Baseline serum renin concentration was above the upper limits of normal in 194 of 255 (76%) patients with a median renin concentration of 172.7 pg/mL. 2 At 3 h after initiation of ATII therapy, there was a 54.3% reduction in renin compared with a 14.1% reduction with placebo (P < 0.0001)	Serum renin concentrations are significantly higher in CRVS and may identify patients in whom early combination with ATII has a beneficial effect on clinical outcome
Sum	United States 3, International 2	RCT 1, Retrospective study 3	822, 414/402	VP 3, ATII 2	Vasopressors initiation 5	Within 4, 6 h of catecholamine, > 0.2 μg/kg/min of NE	Time to target MAP 2	1 VP, Achieved target MAP faster 2, No difference 1. 2 ATII response to MAP 1 reduced mortality 1

ATII: Angiotensin-II; CRVS: Catecholamine-resistant vasodilatory shock; MAP: Mean arterial pressure; NE: Norepinephrine; RRT: Renal replacement therapy; SOFA: Sequential organ failure assessment; VP: Vasopressin.