Effects of Very Early Start of Norepinephrine in Patients with Septic Shock: a Propensity Score-Based Analysis


Ospina-Tascón GA, Hernandez G, Alvarez I et al.

Critical Care 2020, 24 (1), pp 1-11.

Aim of Study

Sought to evaluate whether a very early start of vasopressors, even without completing the initial fluid loading, might impact clinical outcomes in septic shock.

Design and Location

Prospective propensity matched trial (Colombia)


Prospectively collected between January 2015 and February 2017 in one mixed-ICU in a university hospital in Colombia.

Adult patients > 18 years or older fulfilling the diagnostic criteria for septic shock (the presence of suspected infection accompanying organ dysfunction, the use of vasopressors, MAP < 65 mmHg, and lactate levels > 2 mmol/L ).

They were classified into very-early (VE-VPs) or delayed vasopressor start (D-VPs) categories according to whether norepinephrine was initiated or not within/before the next hour of the first resuscitative fluid load.

Then, VE-VPs patients were 1:1 propensity matched to D-VPs based on age; source of admission; chronic and acute comorbidities; and lactate, heart rate, systolic, and diastolic pressure at vasopressor start.

Decision to start vasopressor support was always taken by the physician according to their clinical judgment.

FHypo = First hypotensive event

FRLoad = First fluid load with resuscitative intention

VPs = The start of vasopressor

VE-VPs = Very early start of vasopressor. Vasopressor support initiated within the next hour or even before the FRLoad.

D-VPs = Delayed vasopressor initiation. Vasopressor support was started > 1 h after the FRLoad.

Primary Outcome

Assess the association between VE-VPs and day 28 mortality

Secondary Outcomes

  • The delay time until the start of antibiotics with respect to the first hypotension episode
  • Time intervals from FHypo, FRLoad, and VPs up to ICU admission.
  • The volume of resuscitation fluids received before VPs.
  • The volume of resuscitation fluids and dose of vasopressors at certain intervals.
  • Net fluid balance at FHypo, FRLoad, VPs, and also 8h and 24h after the start of vasopressor support.
  • General demographics – age, APACHE II, co-morbidities, and origin of the patient (ER, ward, or ITU).
  • Heart rate and arterial pressure at FHypo, FRLoad, VPs, and at 2, 4, 6, 8, and 24 h after the VPs.
  • Multiple organ dysfunction was assessed using the Sequential Organ Failure Assessment Score (SOFA).
  • Ventilator-free days.
  • Requirement of renal replacement therapy (RRT).
  • RRT-free days.
  • ICU and hospital length of stay.


Risk- adjusted Cox proportional hazard model


A total of 337 patients with sepsis requiring VP support for at least 6 h during a 24-month period.

Patients subjected to VE-VPs received significantly less resuscitation fluids at vasopressor starting (0 vs. 1500mL, p < 0.001) and during the first 8 h of resuscitation (1100 vs. 2600mL, p < 0.001).

No significant increase in acute renal failure and/or renal replacement therapy requirements

VE-VPs was related with significant lower net fluid balances 8 and 24 h after VPs.

VE-VPs was also associated with a significant reduction in the risk of death compared to D-VPs (HR 0.31, CI 95% 0.17–0.57, p < 0.001) at day 28


Very early start of vasopressor support is associated with:

  • Less use of resuscitation fluids
  • Less fluid accumulation
  • Possibly shortening of hypotension time

Very early start of vasopressors was not associated with:

  • Increased kidney injury
  • Ischemia-related adverse effects
  • Severe digital ischaemia

Might decrease mortality in patients with septic shock.

Stated Limitations from the Study

It did not evaluate whether a restrictive fluid administration (tolerating worse haemodynamic variables) may be beneficial.

Lack of control by randomization and blinding might limit the validity of conclusions, although propensity scores were constructed incorporating baseline characteristics likely influencing the decision for an early start of VP support.

Other non-identifiable potential factors might not have been included.

The small sample size introduces a risk of missing important differences at baseline, might contribute to the observed differences in mortality instead of early vasopressor introduction

Not possible to establish causal mechanisms leading to differences in clinical outcomes between the groups.

AKI, acute renal replacement therapy, and digital ischaemia were easily tracked, whilst other adverse consequences of the early use of vasopressors can’t be ruled out.

Not able to identify if the decision of the early start of vasopressors relied on some particular doctors.

Single-centre design might restrict a potential generalisation of the results.

Discussion from Journal Club Meeting (?Change of Practice)

A very early start of vasopressor support was associated with:

  • A lower amount of resuscitation fluids
  • Less fluid accumulation
  • Shortening of hypotension times
  • Potentially decreased 28-day mortality rate

Very early start of vasopressors (even before completing a pre-defined volume of fluid resuscitation) seems to be a safe intervention with potential beneficial effects on clinical outcomes.

However, many limitations to the study with some practical issues:

  • Speed of CVC insertion
  • Availabilities of ITU beds
  • Small sample size
  • Clinical judgement of clinician

Summary by Dr S Chapman. Journal Club Meeting 12 March 2020.

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