Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

McIntyre (2018)

(selection of studies, see exclusion table)

SR and meta-analysis of RCTs

Literature search up to February 2018

A: Lauzier 2006

B: Albanese 2005

C: Barzegar 2014

D: Chen 2017

E: Choudhury 2016

F: Fonseca Ruiz 2013

G: Gordon 2016

H: Russell 2008

I: Svoboda 2012

J: Russel 2017

K: Morelli 2009

Study design:

A: open-label RCT

B: open-label RCT

C: open-label RCT

D: single-blind RCT

E: open-label RCT

F: open-label RCT

G: 2x2 factorial double blind with hydrocortisone

RCT

H: double blind RCT

I: open-label RCT

J: double blind RCT

K: open-label RCT, 3 arms

Setting and Country:

A: Tertiary care one hospital, Canada

B: Tertiary care one hospital, France

C: Tertiary care one hospital, Iran

D: One hospital, China

E: One hospital, India

F: One hospital, Colombia

G: Multicentre, 18 ICUs, UK

H: Multicentre, Canada, US Australia

I: One hospital, Czech Republic

J: Multicentre,

Belgium, Denmark and the US

K: Tertiary care one hospital, Italy

Source of funding:

A: non-commercial

B: no funding source

C: Not stated

D: non-commercial

E: Not stated

F: Not stated

G: non-commercial

H: non-commercial

I: non-commercial

J: Ferring pharmaceuticals, patents related to the use

of vasopressin in septic shock

K: non-commercial

Inclusion criteria SR:

RCTS comparing vasopressin in combination with catecholamine vasopressors to catecholamines alone for patients with distributive shock

Exclusion criteria SR:

-

11 studies included for this analysis for the guideline

Important patient characteristics at baseline:

N, mean age

A: n=23; 55 yrs

B: n=20; 66 yrs

C: n=30; 64 yrs

D: n=57; NR

E: n=84; 48 yrs

F: n=30; 58 yrs

G: n=421; 66 yrs

H: n=802; 61 yrs

I: n=32; 73 yrs

J: n=53; 63.2 yrs

K: n=45; 66 yrs

Sex:

A: 63% Male

B: 65% Male

C: 63% Male

D: NR

E: 82% Male

F: 59% Male

G: 58% Male

H: 61% Male

I: 61% Male

J: 71% Male

K: 73% Male

APACHE score:

A: 23.2

B: 28.5

C: NR (SOFA=12)

D: NR (SOFA=14.3)

E: 19

F: 24

G: 27.1

H: 27.1

I: NR (SOFA=18)

J: 12

K: NR (SAP=60)

Groups comparable at baseline?

Yes, as far as known

Describe intervention:

A: Vasopressin 0.04–0.20 U/min

B: Terlipressin 1 mg bolus, followed by second bolus 1 mg if MAP <65 mm Hg

C: Vasopressin 0.03 u/min

D: Terlipressin (0.01-0.04U/min) and norepinephrine as needed to maintain MAP between 65 and 75 mm Hg

E: Terlipressin 1.3-5.2mcg/min over 24 h

F: Vasopressin: noradrenaline plus vasopressin at titrated doses of 0.01 U / min and increasing every 10 minutes 0.01 U / min to achieve a mean arterial pressure (MAP) of 6

G: Vasopressin up to 0.06 U/min with target MAP 65-75 mm Hg or

physician discretion

H: Vasopressin started at 0.01 U/min, titrated up to 0.03 U/min with

target MAP 65-75 mm Hg or physician discretion

I: Terlipressin 4 mg/24 h for 72 h

J: Selepressin infused at 1.25, 2.5 or 3.75 ng/kg/min until shock

resolution or a maximum of 7 days

K1: Vasopressin continuous infusion 0.03 U/min over a period of 48 hrs

versus

K2: Terlipressin continuous infusion 1.3 mcg/kg over a period of 48 hrs

Describe control:

A: Norepinephrine 0.1–2.8 mcg/kg/min

B: Norepinephrine started with 0.3 mcg/kg and increased by 0.3 mcg/kg

every 4 minutes until MAP 65 to 75 mm Hg

C: Norepinephrine adjusted to MAP > 65 mm Hg

D: Norepinephrine (>1mcg/min)

E: Norepinephrine 7.5-60mcg/min

F: Norepinephrine

G: Norepinephrine up to 12 mcg/min with target MAP 65-75 mm

Hg or physician discretion

H: Norepinephrine 5 mcg/min up to 15 mcg/min with target MAP

65-75 mm Hg or physician discretion

I: Norepinephrine as needed

J: Open label norepinephrine to achieve MAP > 65

K3: Norepinephrine titrated as needed

End-point of follow-up:

A: until IC admission

B: in-hospital data

C: 28-days

D: 28-days

E: 28-days

F: 28-days

G: 28-days

H: 90 days

I: 28-days

J: 28-days

K: in-hospital data (length of stay)

For how many participants were no complete outcome data available?

(intervention/control)

A: 0

B: 0

C: 0

D: Large numbers of post-randomization

exclusions in both arms

E: 0

F: 0

G: Modified intention to treat analysis, 9

patients randomized in vasopressin arm but

not analyzed exceed fragility threshold

H: 0, intention to

treat analysis for mortality outcome,

modified intention to treat for others

I: Two patients who died were excluded

post randomization

J: 2/19 lost to follow up in group 1

K: 0

Outcome measure-1: mortality 28-30 days

Effect measure: RR (95% CI):

A: -

B: 1.25 (0.47 to 3.33)

C: 0.71 (0.29 to 1.75)

D: 0.94 (0.43 to 2.09)

E: 0.86 (0.69 to 1.07)

F: 0.91 (0.30 to 2.75)

G: 1.13 (0.83 to 1.52)

H: 0.91 (0.76 to 1.09)

I: 0.82 (0.69 to 1.13)

J: 0.98 (0.32 to 3.03)

K: -

Pooled effect from McIntyre is not relevant, see overall forest plots in text in figures.

Outcome measure-2: IC mortality

Effect measure: RR (95% CI):

A: 0.77 (0.20 to 3.03)

K1: 0.90 (0.53 to 1.54)

K2: 1.00 (0.61 to 1.64)

Pooled effect from McIntyre is not relevant, see overall forest plots in text in figures.

Outcome measure-3: Hospital length of stay in days

Effect measure: MD (95% CI):

D: -1.73 (-5.87 to 2.41)

E: 2.30 (-0.52 to 5.12)

F: -12.10 (-23.06 to -1.14)

G: -1.00 (-5.28 to 3.28)

H: -0.60 (-4.63 to 3.43)

Pooled effect from McIntyre is not relevant, see overall forest plots in text in figures.

Outcome measure-4: IC length of stay in days

Effect measure: MD (95% CI):

C: 5.40 (-0.64 to 11.44)

D: -1.93 (-4.42 to 0.56)

E: 0.30 (-2.42 to 3.02)

G: 0.00 (-1.32 to 1.32)

H: -1.70 (-4.11 to 0.71)

K: 0.30 (-9.08 to 9.68)

Pooled effect from McIntyre is not relevant, see overall forest plots in text in figures.

Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Xiao 2016

Type of study: RCT

Setting: ICU

Country: China

Source of funding: National Natural Science

Foundation of China (grant no. 81272077), the Program for

Changjiang Scholars and Innovative Research Team in University (IRT1216), the Major State Basic Research Program

(grant no. 2012CB518101), and the Chongqing Scientific

Foundation for Distinguished Young Scholars (grant no.

cstc2011jjjq0019).

Inclusion criteria:

- ICU patients with existing sepsis;

-Patients with refractory hypotension (SBP

<90 mm Hg, MAP <65 mm Hg);

-vasoactives must be given to maintain the MAP 65 mm Hg after adequate fluid

Resuscitation

Exclusion criteria:

- age <18 y;

- complicated with left ventricular dysfunction

(cardiac index <2.2 L/min/m2 when pulmonary wedge pressure >18 mm Hg);

- with coronary heart disease;

-with apparent valvular heart disease;

- presence (or suspected) of ischemia in the mesenteric arteries or vascular

spasm diseases.

N total at baseline:

Intervention: 15

Control: 17

Important prognostic factors²:

age ± SD:

I: 63 ± 11

C: 62 ± 14

Sex:

I: 67% M

C: 71% M

Groups comparable at baseline? yes

Describe intervention (treatment/procedure/test):

Patients received enough

fluid plus intravenous infusion of norepinephrine (NE) and a small dose of Terlipressin (TP) (1.3 mg/kg/h) to maintain MAP 65 mm Hg

All patients received anesthesia and ventilator-assisted control breathing. The breathing mode was volume-controlled ventilation. According to the 2008 international

sepsis treatment guidelines, except for fluid resuscitation,

NE and NE + TP, the basic treatment measures including organ protection and antibiotics, and so on for each patient in the two groups were similar.

Describe control (treatment/procedure/test):

Patients received enough fluid plus intravenous infusion of NE to maintain the MAP ≥65 mm Hg but

≤95 mm Hg.

All patients received anesthesia and ventilator-assisted control breathing. The breathing mode was volume-controlled ventilation. According to the 2008 international

sepsis treatment guidelines, except for fluid resuscitation,

NE and NE + TP, the basic treatment measures including organ protection and antibiotics, and so on for each patient in the two groups were similar.

Length of follow-up:

Mortality: 7-day survival

Loss-to-follow-up:

Intervention:

N=0 (0%)

Reasons (describe)

Control:

N=0 (0%)

Reasons (describe)

Incomplete outcome data:

NA

Outcome measures and effect size (include 95%CI and p-value if available):

Mortality rate (7-days)

I: 5/15 =33%

C: 13/17 = 76%

Laterre 2019

Type of study: adaptive RCT phase 2b/3

Setting: 63 hospitals

Country: Belgium, Denmark, France, The Netherland and US

Source of funding: Ferring Farmaceuticals F/S

Several conflicts of interests reported by the author group

Inclusion criteria:

-+>18 yr

-proven or suspected infection and septic shock

Exclusion criteria:

-if they were receiving vasopressin or terlipressin

-if it was not possible to start study drug within 12 hours after of the use of any vasopressor treatment

-if sepsis was not the primary cause of hypotension

N total at baseline:

Intervention: 585

Control: 283

Important prognostic factors²:

age ± SD:

I:66.6 ± 12.8

C: 65.7 ± 14.6

Sex:

I: 61% M

C: 55% M

Apache II:

I:25.7 ± 7.8

C: 26.0 ± 7.7

Groups comparable at baseline? yes

Describe intervention (treatment/procedure/test):

Random assignment to 1 of 3 dosing regimens of selepressin:

1. starting infusion rate 1.7 ng/kg/min

2. starting infusion rate 2.5 ng/kg/min

3. starting infusion rate 3.5 ng/kg/min

Administered as continuous infusions titrated according to hemodynamic parameters

Describe control (treatment/procedure/test):

Placebo

Administered as continuous infusion titrated according to hemodynamic parameters

Length of follow-up:

Mortality up to 180 days

Loss-to-follow-up:

Intervention:

N=29 (5%)

Reasons: withdrawal of consent, lost to follow-up

+n=23 did not receive selepressin (died, withdrawal by investigator, not eligible)

Control:

N=3 (1%)

Reasons: withdrawal of consent, lost to follow-up

+n=17 did not receive selepressin (died, withdrawal by investigator, withdra consent not eligible)

Modified intention to treat analysis with patients that received intervention or placebo:

I: N=562

C: N=266

Incomplete outcome data:

NA

Outcome measures and effect size (include 95%CI and p-value if available):

30-day mortality N, RR (95% CI)

I: 193/562

C: 91/266

RR: 1.0 (0.82 to 1.32)

Hammond 2018

Type of study: Prospective open-label trial

Setting: One medical intensive care unit in an academic medical

center

Country:US

Source of funding: organizational grant from the American Colleges of Clinical Pharmacy Critical Care Practice & Research Network, Lenexa, Kansas

Inclusion criteria:

-Adults who presented to the emergency department or were receiving care in the ward were assessed for enrolment

-at least two systemic inflammatory response syndrome criteria

-with a suspected or

confirmed source of infection

-had MAP less than 60 mm Hg despite at least 30 ml/kg of crystalloid resuscitation within the previous 4 hours

-admitted to the 28-bed medical intensive care unit at our institution

Exclusion criteria:

-shock not caused by sepsis

-end-stage renal disease requiring long-term dialysis

-endstage hepatic disease

-were not expected to be

alive at 48 hours from septic shock diagnosis in

the opinion of the attending physician

-received a continuous infusion of a vasopressor other than norepinephrine or vasopressin before

receipt of either agent

-were enrolled in another

clinical trial

-were admitted from an outside hospital

-received a nonstudy vasopressor before

receipt of a study vasopressor

N total at baseline:

Intervention: 41

Control: 41

Important prognostic factors²:

age (median (IQR)):

I: 62 (51–74)

C: 60 (49–68)

Sex:

I: 54% M

C: 44% M

APACHE II (Mean (sd):

I: 28 (21–34)

C: 22 (18–30)

Groups comparable at baseline?

yes

Describe intervention (treatment/procedure/test):

Vasopressin initiated within 4 hours of norepinephrine

+ initial sepsis management according to the institution’s usual care measures that were aligned with recommendations from the Surviving Sepsis Campaign.

Describe control (treatment/procedure/test):

Norepinephrine monotherapy

+ initial sepsis management according to the institution’s usual care

measures that were aligned with recommendations from the Surviving Sepsis Campaign.

Length of follow-up:

28-days

Loss-to-follow-up:

Intervention:

N=0

Control:

N=0

Incomplete outcome data:

NA

Outcome measures and effect size (include 95%CI and p-value if available):

28-day mortality N, RR (95% CI)

I: 19/41 (46%)

C:21/41 (51%) p=0.66

ICU duration, days, median (IQR)

I: 4.1 (2.4–8.9)

C: 3.8 (2.1–7.4) p=0.54

Study

First author, year

Appropriate and clearly focused question?¹

Yes/no/unclear

Comprehensive and systematic literature search?²

Yes/no/unclear

Description of included and excluded studies?³

Yes/no/unclear

Description of relevant characteristics of included studies?⁴

Yes/no/unclear

Appropriate adjustment for potential confounders in observational studies?⁵

Yes/no/unclear/notapplicable

Assessment of scientific quality of included studies?⁶

Yes/no/unclear

Enough similarities between studies to make combining them reasonable?⁷

Yes/no/unclear

Potential risk of publication bias taken into account?⁸

Yes/no/unclear

Potential conflicts of interest reported?⁹

Yes/no/unclear

McIntyre (2018)

Yes

We used a selection of the included papers described in McIntyre as described

Yes

Yes

Yes

NA

Yes

Unclear

Very heterogenous treatments and populations

Yes

Yes

Study reference

(first author, publication year)

Describe method of randomisation¹

Bias due to inadequate concealment of allocation?²

(unlikely/ likely/ unclear)

Bias due to inadequate blinding of participants to treatment allocation?³

(unlikely/likely/unclear)

Bias due to inadequate blinding of care providers to treatment allocation?³

(unlikely/likely/unclear)

Bias due to inadequate blinding of outcome assessors to treatment allocation?³

(unlikely/likely/unclear)

Bias due to selective outcome reporting on basis of the results?⁴

(unlikely/likely/unclear)

Bias due to loss to follow-up?⁵

(unlikely/likely/unclear)

Bias due to violation of

intention to treat analysis?⁶

(unlikely/likely/unclear)

Xiao 2016

Patients were randomized and blindly into sole NE group

and NE + TP group

Unclear

Unlikely

Unclear

Unclear

Unlikely

Unlikely

Unlikely

Laterre 2019

Randomization was stratified by study site, need for mechanical ventilation, baseline NE requirement, and serum creatinine level. The first 200 patients were randomized in a fixed ration of one third placebo and the remainder allocated evenly among the 3 lowest doses of the 4 possible selepressin groups. Thereafter, the probability of randomization to placebo was held constant while a response-adaptive randomization algorithm determined probabilities of allocation to the selepressin groups.

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

97% of dosed patients in selepressin group completed follow-up versus 99% of dozed patients in placebo group

Unlikely

Adapted intention to treat analysis with population that received the study drug

Hammond 2018

Between November 2015 and February 2016, patients who developed septic shock were initiated on norepinephrine

monotherapy. Between March 2016 and June 2016,

patients who developed septic shock were initiated on norepinephrine at 5 lg/minute and vasopressin at 0.04 units/minute within 4 hours of each other as combination therapy.

Likely

Method of allocation was based on the month of presentation.

Unlikely

Likely

Unlikely

Unlikely

Unlikely

Unlikely