Information for Investigators


The trial was stopped prematurely on the advice of the independent data monitoring committee because it was unlikely to demonstrate benefit and because of possible harm. Of a planned 340 participants, 126 (37%) were enrolled. The mean (SD) SOFA score in the landiolol group was 8.8 (3.9) compared with 8.1 (3.2) in the standard care group (mean difference [MD], 0.75 [95% CI, −0.49 to 2.0]; P = .24). Mortality at day 28 after randomization in the landiolol group was 37.1% (23 of 62) and 25.4% (16 of 63) in the standard care group (absolute difference, 11.7% [95% CI, −4.4% to 27.8%]; P = .16).


The outcomes from septic shock remain very poor. To date, therapeutic strategies using immunomodulatory or vasoactive interventions have failed to make any significant improvements. Recently, interest has grown in the use of beta-adrenergic blockade following supportive results in animal and preliminary human studies. Beta blockade represents a paradigm shift in patient management but its use arises from observations in both animal models and patients of harm induced by excessive sympathetic activation and benefit from beta-adrenergic blockade.

The Trial

This was an un-blinded study as the treatment target is physiological - the landiolol infusion should be titrated according to protocol to reduce the heart rate to between 80 and 94 beats per minute.


Adult patients in an intensive care unit (ICU) diagnosed with septic shock as defined by consensus criteria (Sepsis-3) who, having received adequate fluid resuscitation, are receiving noradrenaline treatment at >=0.1mcg/kg/min continuously for longer than 24 hours (but less than 72 hours) to maintain a predefined mean arterial pressure (usually of 65 mmHg) and continue to have a heart rate (HR) more than 94 bpm (>=95bpm).

    Inclusion Criteria

  • >18 years old
  • Being treated on a Critical Care Unit
  • Septic shock according to Sepsis-3
  • Heart rate >=95 bpm (24 hours after start of vasopressor therapy)
  • Receiving vasopressor support with noradrenaline to maintain a target blood pressure for >=24 hours
  • Noradrenaline dose of >= 0.1mcg/kg/min

    Main Exclusion Criteria

  • Noradrenaline dose <0.1 mcg/kg/min
  • >72 hours after start of vasopressor therapy
  • Having pre-existing severe cardiac dysfunction (NYHA grade 4 or more) or Untreated second or third degree heart block
  • A past history of ischaemic stroke or transient ischaemic attack (TIA) or untreated severe carotid stenosis
  • Pregnancy



Primary endpoint

Mean SOFA score whilst on ICU after randomisation (up to a maximum of 14 days).

Secondary endpoint

  • 28-day, hospital and 90-day survival, ICU and hospital length of stay
  • Individual organ failure-days in ICU survivors through measures of oxygenation, renal, hepatic and coagulation function; dose and duration of vasopressor treatment (total daily administered doses)
  • Myocardial Injury – Troponin-T, Beta Natriuretic Peptide, Creatine Kinase-MB, Arrhythmia, Changes in ECG between Randomisation and End of ICU
  • Metabolic Function – changes in plasma lactate concentration, plasma free fatty acid concentration, control of serum blood glucose, changes in insulin requirements
  • Immune Function – Plasma concentrations of cytokines, plasma C-reactive concentration protein, neutrophil phagocytic and oxidative burst activity (selected sites)


Landiolol (Rapibloc®, AOP Orphan Pharmaceuticals, Vienna, Austria) is a new ultra-short acting beta blocker that has a half-life of 2.3 to 4 minutes and is about 8 times more selective for the beta 1 receptor than esmolol. Landiolol has been used safely and successfully in septic patients with atrial fibrillation

Link to the Main Outcome Paper

We published our Main Paper in JAMA as of October 2023

Link to the Protocol Paper

We published our Protocol Paper in BMJOpen as of February 2020