Summary

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.

Hypothesis

We hypothesise that a reduction in heart rate using landiolol infusion in patients with septic shock and tachycardia improves organ failure as measured by the Sequential Organ Failure Assessment (SOFA) score during the 14 days after study drug administration through a reduction in cardiac and immune dysfunction.

The Trial

This is 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.

Population

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 an ICU
• 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

Trial Outcomes

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 of adrenaline, dobutamine, phosphodiesterase inhibitors)
• 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

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

 

Enquiries:

 
Email: STRESS-L@warwick.ac.uk

Address:
Warwick Clinical Trials Unit
Warwick Medical School
University of Warwick
Gibbet Hill Road
Coventry
CV4 7AL