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

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.