Impact of humidification and gas warming systems on ventilatorassociated

Transcription

1 Online Data Supplement Impact of humidification and gas warming systems on ventilatorassociated pneumonia. Jean-Claude Lacherade, M.D. 1, Marc Auburtin, M.D. 2, Charles Cerf, M.D. 3, Andry Van de Louw, M.D. 3, Lilia Soufir, M.D. 1, Yves Rebuffat, M.D. 4, Saïda Rezaiguia, M.D. 3, Jean-Damien Ricard, M.D. 2, François Lellouche, M.D. 1, Christian Brun- Buisson, M.D. 1, Laurent Brochard, M.D. 1 1 Medical ICU, Créteil (France); 3 Surgical ICU, 4 Neuro-surgical ICU, Henri Mondor Hospital, Words: (text only)

2 MATERIALS and METHODS Study Design The study was conducted in five intensive care units (ICUs) located in two French university-affiliated teaching hospitals (Hôpital Henri Mondor, Creteil and Hôpital Bichat-Claude Bernard, Paris). Three of these were surgical ICUs and two were medical ICUs. During the study period, all patients hospitalized in these ICUs, aged more than 18 years and expected to require mechanical ventilation (via a nasotracheal, orotracheal, or tracheostomy tube) for more than 48 hours were eligible to be randomly assigned to receive airway humidification via either a heat and moisture exchanger (HMEF) or a heated water humidifier (HH). Patients already ventilated for more than 24 hours, patients having contraindications to the use of a HMEF (hemoptysis, severe hypothermia), or of a HH (active tuberculosis), patients admitted after cardiac arrest, patients already enrolled in another clinical trial and patients with early decision to limit active therapy, were not included. A randomization list in blocks of six, stratified by participating ICU, was generated from a computer, and treatment allocation was concealed using sequentially numbered opaque sealed envelopes. The HMEF was the hygroscopic DAR-Hygrobac (DAR SpA, Mirandola, Italy) device. The HH was the Fisher-Paykel MR 730 device (Fisher and Paykel Ltd, Auckland, New Zealand), including warming of the inspiratory and expiratory circuits; the reservoir was filled with sterile irrigation water. 1

3 Heat moisture exchanger devices (placed between the y-connector of the ventilator tubing and the tracheal tube) were routinely changed at 48 hours interval. The ventilator circuits were not changed in any group of randomization during the duration of ventilation for a given patient, as recommended (E1, E2). For all patients requiring a transport out of the ICU, a HMEF system was placed on the ventilator circuit for the time of transportation, irrespective of the randomization group. The protocol was approved by the ethics committee of the French Society of Intensive Care Medicine (SRLF). Because both systems were already routinely used without clear guidelines in these ICUs, consent was waived. Information about the study was provided to patients or family. Diagnosis of Ventilator-associated pneumonia (VAP) Included patients were screened daily for the occurrence of VAP. Episodes of pneumonia diagnosed within 48 hours of ventilation were not considered as ventilatorassociated. Screening for VAP was maintained until the first episode of VAP, or 48 h after weaning from the ventilator, death, or the 28 th day of mechanical ventilation, whichever occurred first. In the event of unsuccessful weaning (ventilatory support needed again less than 48 h after extubation), patients were kept in the study as described above. A clinical suspicion of VAP was based on the presence of a recent and persistent infiltrate on chest X-ray and two of the following criteria: fever (>38.3 C) or hypothermia (<36.5 C), leucocytosis (> /l) or leucopenia (< /l), and purulent tracheal secretions. Confirmation of pneumonia required a positive quantitative culture of either a protected telescoping catheter (PTC) or of broncho- 2

4 alveolar lavage. Protected telescoping catheters samplings were obtained blindly via the endotracheal tube, or via bronchoscopy as previously described (E3); bronchoalveolar lavage were obtained via bronchoscopy using a standard lavage with successive instillation of three aliquots of 50 ml warmed isotonic saline and reaspiration (E4); the second sample was used for culture. Samples were obtained before any change or introduction of new antibiotics. The diagnosis of VAP was confirmed when the quantitative culture of a protected distal sample or of a bronchoalveolar lavage respectively grew >10 3 colony-forming units (CFU/ml) or >10 4 CFU/ml of at least one microorganism. Microbiologists were unaware of the randomization arm during the trial. VAP occurring between the 3 rd and 7 th day of mechanical ventilation was considered as early-onset pneumonia, and those occurring later as late-onset pneumonia. The incidence density of VAP in each group (per 1000 mechanical ventilation-days) was calculated as the ratio between the number of VAP and the sum of days exposed to mechanical ventilation (i.e., the whole duration of ventilation for patients without VAP or the duration of ventilation until the first episode of VAP). Microorganisms causing VAP were recorded. Data collection and definitions The following parameters were recorded prospectively for each patient: age, sex, organ failure at admission, diagnostic category (medical, planned post-operative admission, emergency post-operative admission), Simplified Acute Physiology Score II (SAPS II) (E5) at the 24 th hour after admission, major comorbidities (chronic obstructive pulmonary disease, hemopathy, other malignancy, immunosuppressive 3

5 treatment, HIV infection), parameters at initiation of the mechanical ventilation (PaO2/FiO2 ratio and Logistic Organ Dysfunction score) (E6). During the course of ventilation, the following was recorded : maximal inspired oxygen fraction (for at least 6 consecutive hours), need for positive end-expiratory pressure (PEEP), highest level of PEEP required, duration of mechanical ventilation prior to pneumonia, total duration of mechanical ventilation (until death or weaning), need for tracheostomy, duration of ICU stay and outcome at ICU discharge. Other potential risk factors for VAP were recorded daily during the follow-up: intravenous sedation, paralytic agents, stress ulcer prophylaxis, enteral feeding, ability to maintain semirecumbent position of the trunk above 30 degrees, position of endotracheal tube (nasal or oral), position of gastric tube (nasal or oral), need for reintubation, transport out of ICU, antibiotic therapy, use of corticosteroids. The safety of the humidification systems was assessed by recording episodes of endotracheal tube occlusion. Outcome measures The primary end-point was the comparison of the VAP rate between the two groups of randomization (HME and HH). Secondary outcome variables included the duration of mechanical ventilation before the occurrence of VAP, the ICU mortality rate, the duration of mechanical ventilation, the duration of ICU stay, and the tracheostomy rate. 4

6 Statistical Analysis For the main end-point, we estimated the sample size necessary to provide a 80% chance to detect a relative reduction of 40% in the VAP rate between the two study groups, based on a previous report by Kirton et al. (E7). A 25 % incidence of VAP was expected to occur in the HH group. Based on these assumptions, 250 patients were needed in each group. An interim analysis was performed after 250 patients to examine the overall rate of VAP; because this rate was higher than expected, the sample size was recalculated to include 185 patients per group. Comparisons between groups were done using Student s t-test for continuous variables and the chi-square statistic for categorical variables. A multivariate logistic regression analysis was performed including VAP as the dependent variable, and group of randomization and other pertinent variables which differed between the groups (with p value below 0.20 in the univariate analysis) as potentially independent variables. The time to occurrence of VAP was also analyzed by the Kaplan-Meier method and tested with a log-rank test. RESULTS Flow diagram of the study: A flow diagram of the study protocol is presented in Figure E1.During the study period, 1147 patients received mechanical ventilation in the five participating ICUs patients were expected to require mechanical ventilation less than 48 hours. Among the 589 remaining patients, 219 patients were not included: 99 patients 5

7 already under mechanical ventilation for more than 24 hours, 20 patients admitted after cardiac arrest (asystole or pulseless electrical activity), 2 patients already enrolled in another clinical trial, early decision to limited active therapy done for 6 patients, 1 patient with bacillary tuberculosis and 91 patients because of an unavailability of HH systems or of investigators. Finally, 370 patients could be included, 186 in the HMEF arm and 184 in the HH arm. One patient in the HMEF group was secondary excluded because of early decision to limit active therapy including the lack of specific diagnostic procedure for pneumonia. The mean number of included patients per center participating to the trial was Number and type of samples obtained. A clinical suspicion of pneumonia occurred in 74 (40%) and 77 (42%) patients in the HMEF and HH group, respectively, and a similar number of samples (106 and 112) were obtained in each group. There was no difference in the type of sample (bronchoscopic or non-bronchoscopic) obtained in each group (Table E1), although a slight majority of samples were obtained non-bronchoscopically in both groups. Among bronchoscopic samples, there was a trend to more BAL being used in the HH group compared to the HEMF group (30 vs. 18, P=0.1) and to more BAL being positive in the former (15/30 vs. 5/18, P=0.25). The proportion of non-bronchoscopic samples positive for pneumonia (58/125; 46%) was however similar to that of bronchoscopic samples (42/93; 45%). Reintubation Reintubation occurred mostly in patients with unsuccessful weaning (ventilatory support needed again within 48 hours after extubation). These patients were kept in the study until the first episode of VAP, or 48 h after weaning from the ventilator, 6

8 death, or the 28 th day of mechanical ventilation, whichever occurred first. Twenty-one of the 58 patients (36.2%) reintubated during the follow-up developed VAP, as compared 25.4% VAP rate in patients not reintubated. REFERENCES E1. Kollef, M. H The prevention of ventilator-associated pneumonia. N Engl J Med 340(8): E2. Cook, D., J. D. Ricard, B. Reeve, J. Randall, M. Wigg, L. Brochard, and D. Dreyfuss Ventilator circuit and secretion management strategies: a Franco- Canadian survey [In Process Citation]. Crit Care Med 28(10): E3. Pham, L. H., C. Brun-Buisson, P. Legrand, A. Rauss, F. Verra, L. Brochard, and F. Lemaire Diagnosis of nosocomial pneumonia in mechanically ventilated patients. Comparison of a plugged telescoping catheter with the protected specimen brush. Am Rev Respir Dis 143(5 Pt 1): E4. Fartoukh, M., B. Maitre, S. Honore, C. Cerf, J. R. Zahar, and C. Brun-Buisson Diagnosing pneumonia during mechanical ventilation: the clinical pulmonary infection score revisited. Am J Respir Crit Care Med 168(2): E5. Le Gall, J. R., S. Lemeshow, and F. Saulnier A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study. Jama 270(24): E6. Le Gall, J. R., J. Klar, S. Lemeshow, F. Saulnier, C. Alberti, A. Artigas, and D. Teres The Logistic Organ Dysfunction system. A new way to assess organ dysfunction in the intensive care unit. ICU Scoring Group. Jama 276(10): E7. Kirton, O. C., B. DeHaven, J. Morgan, O. Morejon, and J. Civetta A prospective, randomized comparison of an in-line heat moisture exchange filter and heated wire humidifiers: rates of ventilator- associated early-onset (communityacquired) or late-onset (hospital- acquired) pneumonia and incidence of endotracheal tube occlusion. Chest 112(4):

9 Table E1 Samples obtained and positivity rates in the two groups HMEF HH p value Number of patients Patients with clinically suspected pneumonia No. samples obtained Non-bronchoscopic samples Protected telescoping catheter 66 (30) 59 (28) 0.17 Bronchoscopic samples Protected telescoping catheter 22 (12) 23 (10) 1.0 8

10 Broncho-alveolar lavage 18 (5) 30 (15) 0.1 *p value for comparison between HMEF and HH groups. Numbers in brackets indicate number of positive samples 9

11 Figure E1: Flow chart of the study 1147 patients requiring mechanical ventilation Duration of mechanical ventilation suspected < 48 hours n=558 Duration MV really < 48 hours n= 481 Duration MV < 72 hours n= 44 Duration MV < 96 hours n= 33 Patients already ventilated for more than 24 hours n= 99 Cardiac arrest n= 20 Early decision of withdrawal n=6 Inclusion in another clinical study n=2 Active tuberculosis n=1 Unavailability of HH systems or of investigators n= patients included in the trial Secondary withdrawal n=1 369 patients included in the data analysis 10