The Effects of Gut Micribiota Disruption on the Immune Response After Open Heart Surgery (REMEDI)

Radboud University Medical Center

Status: Unknown

Conditions: Coronary Artery Disease; Systemic Inflammatory Response Syndrome; Postoperative Shock; Extracorporeal Circulation; Complications

Treatments: Drug: Fluconazole Oral Product; Drug: Vancomycin Oral; Drug: Placebos; Drug: Ciprofloxacin Pill; Drug: Metronidazole Oral

Study type: Interventional

Funder types: Other

Identifiers

NCT03939273

2019-000964-54 (EudraCT Number)

The REMEDI trial

Details and patient eligibility

About

In this randomized, double-blind, placebo-controlled study, the investigators will assess whether preoperative disruption of the gut microbiota by a course of broad spectrum antibiotics will attenuate the postoperative systemic inflammatory response after on-pump cardiac surgery

Full description

During cardiac surgery, the use of cardiopulmonary bypass and extracorporeal circulation, operative trauma, and ischemia-reperfusion injury can induce a profound systemic innate immune response. This response contributes to postoperative morbidity and mortality, as increased proinflammatory cytokine levels are associated with several postoperative complications. Commensal microbiota in the gut can modulate systemic immune responses. The investigators hypothesize that reduction of systemic immune activation by disruption of the microbiome may be beneficial in patients undergoing cardiac surgery.

The objective of this trial is to assess the anti-inflammatory effects of disruption of the intestinal microbiota with broad-spectrum antibiotics in patients with systemic inflammation following cardiac surgery and to assess the effects on clinical outcomes in these patients.

To this end, subjects will be randomized into one of two treatment arms and will receive either active treatment or a placebo during the seven days prior to surgery. Active treatment consists of a seven day course of oral ciprofloxacin 500 mg twice a day, oral vancomycin 500 mg thrice per day, oral metronidazole 500 mg thrice per day and a six day course of oral fluconazole 200 mg once per day. Placebo treatment is randomly allocated in a double blind fashion in a 1:1 proportion to the active treatment. Stool samples will be obtained prior to and directly after study treatment to assess the effects on the richness and diversity of the gut microbiota. During and after surgery, plasma levels of circulating cytokines will be measured to assess the effects of microbiota disruption on the inflammatory response.

Enrollment: 80 estimated patients

Sex: All

Ages: 18 to 99 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Age > 18 years
• Scheduled for elective on-pump cardiac surgery.
• Written informed consent to participate in this trial prior to any study-mandated procedure

Exclusion criteria

• Use of any antibiotic or antifungal therapies within 30 days prior to surgery

• History of inflammatory bowel disease

• History of bowel resection and / or short bowel syndrome

• Pre-operative creatinine clearance < 50 ml/min

• Severe hepatic impairment

• Immune compromised

  • Solid organ transplantation
  • Known HIV
  • Pregnancy
  • Use of immunosuppressive drugs

• Emergency surgery

• Haematological disorders

  • Disorders from myeloid and / or lymphoid origin
  • Leucopenia

• Known hypersensitivity to any of the investigational and/or non-investigational products or their excipients.

• Treatment with investigational drugs or participation in any other intervention clinical trial within 30 days prior to study drug administration

• Inability to personally provide written informed consent

• Suspected of not being able to comply with the trial protocol

• Use of vitamin K antagonists

• Use of tricyclic antidepressants

• Use of other drugs which have potential dangerous interactions with study treatment

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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80 participants in 2 patient groups, including a placebo group

Active group

Active Comparator group

Description:

A preoperative seven day course of oral ciprofloxacin 500 mg twice a day, oral vancomycin 500 mg thrice per day, oral metronidazole 500 mg thrice per day and a six day course of oral fluconazole 200 mg once per day.

Treatment:

Drug: Fluconazole Oral Product

Drug: Ciprofloxacin Pill

Drug: Metronidazole Oral

Drug: Vancomycin Oral

Control group

Placebo Comparator group

Description:

A preoperative seven day course of placebo, consisting of pills and capsules identical in appearance and number to the active group

Treatment:

Drug: Placebos