Background
Methods/Design
Study design and objective
Participating center | PI | Central Ethics committee | Reference number | Approval date |
---|---|---|---|---|
Medical University Vienna, Department of Internal Medicine II. Division of Cardiology | Gottfried Heinz, MD | Ethics Committee, Medical University Vienna | ECS 1805/2017 | 15 September 2017 |
Medical University Innsbruck, Division of Emergency Medicine and Intensive Care, Department Internal Medicine | Michael Joannidis, MD | |||
State Hospital Wiener Neustadt, Department of Anesthesiology, Emergency Medicine and General Intensive Care | Helmut Trimmel, MD, MSc | |||
University Hospital Greifswald, Department of Anesthesiology, Intensive Care, Emergency and Pain Medicine | Sebastian Rehberg, MD | Ethics Committee, University Hospital Greifswald | FFV 06/17 | 15 February 2018 |
University Hospital Munich, Department of Anesthesiology | Christian Siebers, MD | |||
University Hospital Hradec Králové, Department of Anesthesiology, Resuscitation and Intensive Medicine | Pavel Dostál, MD, PhD, MBA | Ethics Committee, University Hospital Hradec Králové | 201801 I126M | 07 November 2017 |
Masaryk Hospital, Department of Anesthesiology, Perioperative Medicine and Intensive Care | Vladimír Černý, MD, PhD, FCCM | |||
University Hospital La Sapienza, Department of Anesthesiology and Intensive Care | Andrea Morelli, MD. | Ethics Committee, University Hospital La Sapienza | 4846 | 08 February 2018 |
Azienda Ospedaliero Universitaria Pisana, Department of Anesthesiology and Resuscitation 5 | Fabio Guarracino, MD | |||
Azienda Ospedaliero Universitaria Pisana, Department of Anesthesiology and Resuscitation 6 | Francesca Pratesi, MD | |||
University School of Medicine Pisa, Department of Anesthesiology and Transplant Intensive Care Unit | Gianni Biancofiore, MD | |||
University Hospital Modena, Department of Anesthesia and Intensive Care | Massimo Girardis, MD | Approval pending |
Study population
Inclusion criteria 1. Informed consent 2. Age ≥ 18 years 3. Confirmed septic shock: a. Confirmed or suspected infection b. Acute increase of ≥ 2 points on SOFA Score c. Need for continuous vasopressor therapy to maintain a mean arterial pressure (MAP) of > 65 mmHg despite adequate fluid resuscitation d. Blood lactate > 2 mmol/L (18 mg/dL)a 4. Tachycardia and/or tachyarrhythmia with heart rate ≥ 95 bpm 5. Norepinephrine infusion rate ≥ 0.2 μg/kg/min at the time of study inclusion 6. Patients must have undergone a hemodynamic optimization period of at least 24 h but a maximum of 36 h, during which period they received continuous vasopressor treatment and standard treatment for septic shock according to the SSCG 2016 guidelines aPresence of blood lactate > 2 mmol/L (18 mg/dL) and increase of ≥ 2 points on SOFA score are mandatory for the diagnosis of septic shock, but must not necessarily be present at the time of study inclusion Exclusion criteria: 1. Any form of compensatory tachycardia 2. β-blocker treatment within 72 h before randomization 3. Sick sinus syndrome, or second or third degree AV block 4. Patients with any form of cardiac pacing 5. A known serious cardiovascular condition such as ischemic stroke or transient ischemic attack within the last six months, or pre-existing heart failure NYHA class III or IV 6. Cardiogenic shock 7. MAP < 65 mmHg 8. Known pulmonary hypertension 9. Known terminal illness other than septic shock with expected patient’s survival < 28 days 10. Known presence of an advanced condition to withhold life-sustaining treatment 11. Patients for whom a “Do Not Resuscitate” (DNR) order exists 12. Known sensitivity to any component of the study medication (e.g. landiolol, mannitol) 13. Participation in a clinical drug trial within 30 days before randomization 14. Any condition that, in the investigator’s opinion, makes the individual unsuitable for study participation (to be documented) 15. Pregnant or breast-feeding patients 16. Untreated pheochromocytoma |
Randomization, blinding, and treatment allocation
Study drug
Treatments
Landiolol group
Control group
Patient assessments
Endpoints
Primary endpoint: • HR response (i.e. HR = 80–94 bpm) and maintenance thereof and no increase in vasopressor requirements during the first 24 h after treatment start Secondary endpoints: • Change in vasopressor requirements over the study period (dose and duration) • HR response (i.e. HR = 80–94 bpm) during the first 24 h after treatment start • 28-day mortality (all cause) • ICU mortality (all cause) • Duration of ICU stay (survivors/non-survivors) • Duration of hospital stay (survivors/non-survivors) • SOFA score (as long as the patient is treated with vasopressors) on days 1, 2, 3, 4, 7, 10, 13, 16, 19, 22, 25, and 28 • Daily inotropic requirements (as long as the patient is treated with vasopressors) Safety endpoints: • Incidence rate of bradycardic episodes requiring intervention • Incidence of adverse events (AE) • Incidence of serious adverse events (SAE) |