Selective Decontamination of the Digestive Tract in Intensive Care Unit Patients

Study Overview
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Brief Summary
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Introduction- Hospital acquired infections (HAI) are a major cause of morbidity and mortality and increase health care costs. Critically ill patients are particularly susceptible to these infections and have an even higher mortality. One intervention that has gained much interest in the medical literature for reducing infection rates and deaths from HAIs is selective decontamination of the digestive tract (SDD). SDD involves the application of antibiotic paste to the mouth, throat, stomach and a short course of intravenous antibiotics. The evidence supporting the use of SDD for saving lives and preventing infections is actually quite strong. However, health care professionals in many parts of the world have refrained from using SDD due to fears of the effects of overuse of antibiotics on the frequency of infections with resistant bacteria such as multi-resistant Gram negative organisms, MRSA and Clostridium difficile. SuDDICU is a cross-over, cluster randomised trial comparing the effect of using selective decontamination of the digestive tract (SDD) plus standard care, to standard care alone on hospital mortality in patients receiving mechanical ventilation in the intensive care unit (ICU). Secondary outcomes include an ecological assessment and a long-term health economic analysis.

Detailed Description
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Design- international, multicentre, crossover, cluster randomised controlled trial (x-cRCT) of eligible patients in participating ICUs using two 12-month interventional trial periods separated by a 3-month inter-period gap. An observational ecological assessment will be conducted in all ICU patients during one week of each month during the 3-month surveillance period before the first intervention period; in all trial eligible patients during the two 12-month intervention periods; in all ICU patients during one week of each month of the final 3-months of the two intervention periods; in all ICU patients during one week of each month during the 3-month inter-period and post-trial periods. Participants- General ICUs that admit mechanically ventilated patients will be randomised in the first 12-month period to either implement the SDD protocol in addition to standard care or to continue standard care without SDD, and then to cross over to the other arm during the second 12-month period. Eligible patients are defined as: All patients who are mechanically ventilated via an endotracheal tube on admission to the ICU and who are predicted to remain ventilated beyond the end of the calendar day after the day of ICU admission, or All patients who become mechanically ventilated via an endotracheal tube during their ICU stay and who are predicted to remain ventilated beyond the end of the calendar day after the day they are first ventilated, or All patients who not already recruited but are receiving mechanical ventilation via an endotracheal tube and are expected to receive ongoing ventilation for a further 48-hours or more despite an earlier prediction that ventilation would be discontinued earlier. All patients eligible for the intervention will receive the following in addition to the usual infection control measures: 1. A six-hourly topical application of 0.5g paste, containing colistin 10mg, tobramycin 10mg and nystatin 125,000 IU, to the buccal mucosa and oropharynx A six-hourly administration of 10 mL of a suspension containing 100 mg colistin, 80 mg tobramycin and 2 x 106 IU nystatin, to the gastrointestinal tract via a gastric/post-pyloric tube A four-day course of an IV antibiotic. Patients not already receiving a therapeutic antibiotic will be prescribed cefotaxime 1g six-hourly or ceftriaxone 1g daily, with dose adjusted as appropriate for organ dysfunction. Ciprofloxacin (400mg 12-hourly) may be used as an alternative if there is a contraindication to cephalosporins (e.g. allergy). Patients already receiving an alternative IV antibiotic to treat infection will not receive this additional IV antibiotic, but will continue the prescribed antibiotic for the usual duration of therapy. Statistical considerations and sample size- SuDDICU will recruit 10 000 to 15 000 patients from 29 ICUs and will have 80% power to detect an absolute reduction in hospital mortality of 3-5% from a baseline mortality of 29%, depending on the precise number of clusters.

Official Title
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A Crossover, Cluster Randomised Controlled Trial of Selective Decontamination of the Digestive Tract in Intensive Care Unit Patients (SuDDICU)

Conditions
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Critical Illness, Sepsis, Septic Shock, Ventilator Associated Pneumonia

Intervention / Treatment
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* Drug: SDD Oral Paste
* Drug: SDD Gastric Suspension
* Drug: Intravenous Antibiotic


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Site inclusion for cluster study- A general ICU or complex of ICUs (medical, surgical, mixed) capable of treating mechanically ventilated critically ill adult patients. Patient inclusion criteria All patients who are mechanically ventilated via an endotracheal tube on admission to ICU and who are predicted to remain ventilated beyond the end of the calendar day after the day of ICU admission, or All patients who become mechanically ventilated via an endotracheal tube during their ICU stay and who are predicted to remain ventilated beyond the end of the calendar day after the day they are first ventilated, or All patients not already recruited who are receiving mechanical ventilation via an endotracheal tube and are expected to receive ongoing ventilation for a further 48 hours or more despite an earlier prediction that ventilation would be discontinued earlier. Site exclusion criteria for cluster study- Unwilling or unable to follow trial protocols. Unable to capture the minimum data set required for the study. Isolated specialty ICUs not co-located with a general ICU, such as solely cardiac, neurological/neurosurgical and burns ICUs, but such specialty patients cared for in general ICUs will be included Specialty paediatric ICUs Exclusion Criteria: Patient exclusion criteria Patients enrolled in a trial that would interact with the intervention Patients with a known allergy, sensitivity or interaction to trial topical intervention drugs Patients who are known or suspected to be pregnant Patients who are moribund and not expected to survive the next 12 hours Patients less than 16 years of age will not be enrolled in the UK

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Cluster, crossover, randomized clinical trial
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Control group- standard care<br>Standard care- In Australia there are no national guidelines so local policy is determined by each ICU. We are recommending (but not mandating) that control and SDD group management be in line with these national guidelines. We will recommend control and SDD group management is in line with current national standards of practice that may or may not include a VAP bundle. We will monitor record data regarding the nature and delivery of the control and SDD group co-interventions. | |
| Experimental: SDD intervention group<br>The intervention will entail: A six-hourly topical application of 0.5g paste, containing colistin 10mg, tobramycin 10mg and nystatin 125,000 IU, to the buccal mucosa and oropharynx A six-hourly administration of 10 mL of a suspension containing 100 mg colistin, 80 mg tobramycin and 2 x 10^6 IU nystatin, to the gastrointestinal tract via a gastric/post-pyloric tube A four-day course of an IV antibiotic. Patients not already receiving a therapeutic antibiotic will be prescribed cefotaxime 1g six-hourly or ceftriaxone 1g daily, with dose adjusted as appropriate for organ dysfunction. Ciprofloxacin (400mg 12-hourly) may be used as an alternative if there is a contraindication to cephalosporins (e.g. allergy). Patients already receiving an alternative IV antibiotic to treat infection will not receive this additional IV antibiotic, but will continue the prescribed antibiotic for the usual duration of therapy. | Drug: SDD Oral Paste<br>* A six-hourly topical application of 0.5g paste, containing colistin 10mg, tobramycin 10mg and nystatin 125,000 IU, to the buccal mucosa and oropharynx<br>* Other names: Colistin, Tobramycin and Nystatin;Drug: SDD Gastric Suspension<br>* 2. A six-hourly administration of 10 mL of a suspension containing 100 mg colistin, 80 mg tobramycin and 2 x 10 ^6 IU nystatin, to the gastrointestinal tract via a gastric/post-pyloric tube<br>* Other names: Colistin, Tobramycin and Nystatin;Drug: Intravenous Antibiotic<br>* A four-day course of an intravenous antibiotic in patients not already receiving a therapeutic antibiotic<br>* Other names: Ceftriaxone, Cefotaxime or Ciprofloxacin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hospital Mortality | all-cause mortality at time of hospital discharge | Hospital discharge [up to Day 90 after randomization] | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total antibiotic usage | Total antibiotic usage (as daily defined doses) during ICU admission in all ICU admissions. | during ICU admission | 
| The incidence of antibiotic resistant organisms in cultures from blood or other sterile sites | The incidence of antibiotic resistant organisms in cultures from blood or other sterile sites during ICU admission in all ICU admissions. | during ICU admission | 
| The incidence of antibiotic-resistant organism in non-sterile clinical and surveillance specimens | The incidence of antibiotic-resistant organism in non-sterile clinical and surveillance specimens during ICU admission in all ICU admissions | during ICU admission | 
| The incidence of C. difficile infections | The incidence of C. difficile infections during ICU admission in all ICU admissions | during ICU admission | 
| Changes in antibiotic resistance rates between study epochs (pre-trial, interperiod gap and post-trial) within groups | Changes in ARO rates between time epochs (pre-trial, trial, inter-period gap and post-trial) within groups. With control group data to give the secular trend in ARO with time and SDD group data studying the effects of SDD withdrawal from practice in the year after SDD delivery | Through out all study periods | 
| Duration of mechanical ventilation | Duration that the patient is mechanically ventilated in the ICU | Time of enrolment to ICU discharge within index hospital admission,[up to Day 90 after randomization] | 
| ICU length of stay | The length of time a patient stays in the ICU | From the time of enrolment to ICU discharge, [up to Day 90 after randomization] | 
| Hospital length of stay | The total hospital length of stay for patient | From time of enrolment to hospital discharge within the index hospital admission, [up to Day 90 after randomization] | 
| ICU Mortality | mortality at time of ICU discharge | ICU discharge [up to Day 90 after randomization] |