Effect of Aerosolised Colistin in Ventilator Associated Pneumonia

Study Overview
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Brief Summary
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the management of Ventilator-associated pneumonia (VAP) caused by multidrug-resistant (MDR) gram-negative bacilli (GNB) represent a real therapeutic dilemma in intensive care unit (ICU). Colistin remains an effective agent against MDR GNB. However, because of its side effects, mainly nephrotoxicity, other modalities than the intra venous (IV) route should be tried. Several recent data emphasize the interest of inhaled route. The investigators purpose was to evaluate the effectiveness and systemic toxicity of aerosolized colistin in ventilator associated pneumonia.

Detailed Description
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prospective, randomized, single-blind study comparing two groups of patients treated with aerosolised (AS) colistin versus colistin intravenously (IV). Included were patients who have mechanical ventilation over 48 hours and that have developed a VAP. A VAP was defined as a CPIS (Clinical Pulmonary Infection Score) >6. Exclusion criteria were septic shock and/or bacteraemia. Included patients were divided into two randomized groups. The 1st received colistin in AS as 4 MU by nebulisation 3 times per 24 h. The 2nd received colistin in IV as a loading dose of 9 MU followed by 4.5MU two times per 24 h. Colistin was given for 14 days or until extubation. Patients were followed for 28 days. Therapeutic efficacy was assessed by a primary outcome: the cure of VAP at day 14 of therapy and defined as resolution of clinical and biological signs of infection that means a CPIS< 6 and bacteriological eradication. Secondary outcomes: duration of mechanical ventilation, ICU stay-length and mortality at day 28. Systemic toxicity was assessed by the occurrence of acute renal failure (ARF) defined as increase of plasma creatinine more than 1.5 times its base value.

Official Title
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Efficacy and Toxicity of Aerosolised Colistin in Ventilator Associated Pneumonia: A Prospective, Randomized Trial

Conditions
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Pneumonia, Ventilator-Associated

Intervention / Treatment
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* Drug: AS colistin and imipenem
* Drug: IV colistin  and imipenem .
* Drug: AS colimycin (colistin)
* Drug: IV colimycin (colistin)
* Drug: AS colistin and imipenem
* Drug: IV colistin and imipenem


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Critically ill patients older than 18 years, with mechanical ventilation during more than 48 hours, and who have presented a Ventilator associated Pneumonia (VAP) defined as a CPIS (Clinical Pulmonary Infection Score) of more than six Exclusion Criteria: Age <18 years Pregnancy Septic shock

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: aerosolised (AS) colistin group<br>the intervention was: AS colistin and imipenem. the drug administered was colimycin (colistin) powder 1 million units (MU) by a flakon (Sanofi Winthrop Industry) at the dosage of 4 million units (MU) for 30 minutes 3 times per day for at least 14 days in addition to IV imipenem 1 g three times per day. Nebulisation was made via an ultrasonic vibrating plates nebulizer (Aeroneb Pro® Aerogen Nektar Corporation, Galway, Ireland). Inhaled colimycin® requires specific settings of the ventilator to limit turbulence inspiratory flow. The adjustment consisted in a volume controlled mode with a Tidal volume <8 ml / kg, respiratory rate at 12 cycles / min, I / E: 1/1 and an end inspiratory break > 20%. | Drug: AS colistin and imipenem<br>* colimycin (colistin) powder (1 million units (MU) by flakon) by AS route in addition to imipenem<br>* Other names: colimycin (colistin) powder (Sanofi laboratories);Drug: AS colimycin (colistin)<br>* nebulisation of colimycin (colistin) for 30 minutes 3 times per day during at least 14 days. Nebulisation was made via an ultrasonic vibrating plates nebulizer (Aeroneb Pro® Aerogen Nektar Corporation, Galway, Ireland).<br>* Other names: colimycin (colistin);Drug: AS colistin and imipenem<br>* IV imipenem 1 g three times per day.<br>* Other names: imipenem;|
| Active Comparator: intravenous (IV) colistin goup<br>the intervention was: IV colistin and imipenem. the intravenous (IV) colistin goup received IV colimycin (colistin) as a loading dose of 9 MU during 60 minutes followed by 4.5 million units 2 times per day in addition to IV imipenem 1 g three times per day. | Drug: IV colistin  and imipenem .<br>* colimycin (colistin) powder (1 MU by flakon) by intravenous route in addition to imipenem<br>* Other names: colimycin (colistin) powder (Sanofi laboratories);Drug: IV colimycin (colistin)<br>* intravenous colimycin (colistin) : 9 MU during 60 minutes followed by 4.5 million units 2 times per day<br>* Other names: colimycin (colistin) powder by intravenous route;Drug: IV colistin and imipenem<br>* IV imipenem 1 g three times per day<br>* Other names: imipenem;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| cure of VAP | a CPIS (clinical pulmonary infection score) less than 6 and bacterial eradication | day 14 of therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| occurrence of acute renal failure | an acute renal failure was defined as increase of plasma creatinine more than 1.5 times its base value. | From date of randomization until the time of the cessation of colistin, assessed up 14 days on average | 
| duration of mechanical ventilation |  | From date of randomization until the time of weaning from ventilator, an average of 14 days | 
| length of stay in intensive unit |  | from randomisation until the time of patient discharge, an average of 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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colistin, aerosol, ventilator associated pneumonia, nephrotoxicity, intravenous