CPAP Reduces Hypoxemia After Cardiac Surgery (CRHACS Trial). A randomized controlled trial

Transcription

1 CPAP Reduces Hypoxemia After Cardiac Surgery (CRHACS Trial). A randomized controlled trial Backgrounds Postoperative pulmonary complications are most frequent after cardiac surgery and lead to increased morbidity and mortality. Moreover these complications result in a prolonged length of stay in intensive care unit and in the hospital 1. The major cause that contributed to deterioration of pulmonary function and oxygenation is atelectasis and occurs up to 54-92% after cardiac surgery 2,3. During invasive mechanical ventilation atelectasis can be prevented by the use of positive end-expiratory pressure (PEEP), but after extubation, if atelectasis are still present, a deterioration of pulmonary gas exchanges might develop 4. Continuous positive airway pressure (CPAP) is a method to apply non-invasively a level of PEEP in spontaneous breathing patients. CPAP may prevent the collapse of alveolar unit, increases the FRC and the oxygenation and reduces the breathing workload and cardiac preload 5 7. Although several studies have demonstrated the efficacy of CPAP to reduce atelectasis and improve oxygenation after both abdominal 7,8 and cardiac surgery 2,5, only one study confirm that the oxygen improvement with CPAP actually reduce the need of intubation and mechanical ventilation in patients undergoing abdominal surgery 7. After cardiac surgery, there are several factors that can contribute to the development of post-operative pulmonary dysfunctions: the cardiopulmonary by pass, post-operative diaphragmatic dysfunction, pain, immobilization 9. 1

2 The cardiopulmonary by pass determines a systemic inflammatory response, that can involved the lungs and even few hours of mechanical ventilation may exacerbate cytokines levels and deteriorate lung function 10,11. This mechanism can increase the risk of hypoxemia after extubation and of re-intubation, prolonging mechanical ventilation and increasing mortality rate. The application of a precocious CPAP after extubation may prevent gas exchange deterioration and reduce the risk of re-intubation. Hypotesis We want to test the hypothesis that the application of a continuous positive airway pressure (CPAP) after extubation in patients undergoing cardiac surgery can reduce hypoxemia and re-intubation rate. Primary end point: to reduce the rate of re-intubation. Secondary end point: to reduce the incidence of atelectasis, pneumonia, sepsis, the mortality rate, the intensive care unit (ICU) and hospital length of stay. Methods Design multi-center open label randomized controlled study. Centers participating the study San Giovanni Battista, University Hospital of Torino (coordinator center, prof. V.M. Ranieri), S. Croce e Carle Hospital of Cuneo (dr. A. Locatelli), Ospedali Riuniti of Bergamo (dr. L. Lorini), University Hospital of Pisa (dr. F. Guerracino), S. Orsola Hospital of Bologna (prof. G. Frascaroli), San Gerardo Hospital of Monza (prof. R. Fumagalli), Niguarda Ca' Granda Hospital of Milano (prof. R Fumagalli); Monzino Hospital of Milano (dr. L. Salvi), Umberto I Hospital of Roma (prof. L Tritapepe), Research and Health Foundation "Giovanni Paolo II" of Campobasso (prof. M. Rossi), ISMETT/UPMC Institute of Palermo (dr. A. Arcadipane); University Hospital Federico II of Napoli (dr. E. De Robertis). 2

3 Inclusion criteria patients undergoing cardiac surgery on cardiopulmonary bypass, PaO 2 /FiO 2 < 200 after extubation, extubation time < 24 h. Exclusion criteria patients < 18 years old, extracorporeal membrane oxygenation, severe cardiac dysfunction (FE<25%), mechanical ventilation before the intervention, severe COPD (patients on oxygen therapy, with a FEV1< 50%), heart or lung transplantation, lack of consent. All patients after extubation will undergo a trial in spontaneous breathing with a Venturi mask, with a FiO 2 of 50%, for 15 minutes. If the PaO 2 /FiO 2 will be < 200 the patients will be randomized into one of the following groups: Treatment Group (CPAP-Helmet) the patient will receive CPAP treatment with Helmet (StarMed S.r.l.), at a PEEP level of 10 cmh 2 O and a FiO 2 adjusted to maintain SpO 2 >95%, for six hours. After three hours of treatment a blood gas analysis will be evaluated and the patient will proceed with the treatment for three more hours. At the end of the six hours, the patient will repeat a spontaneous breathing trial with a Venturi mask at FiO 2 = 50%, for 15 minutes and than a blood gas analysis will be repeated: if the PaO 2 /FiO 2 will be < 200 the patient will received a second treatment with CPAP; if PaO 2 /FiO 2 will be >200, the patient will stop the treatment. Control Group (Oxygen therapy) the patient will maintain spontaneous breathing, with a system for oxygen delivery at a FiO 2 adjusted to maintain SpO 2 >95%, for six hours. After three hours of treatment a blood gas analysis will be evaluated and the patient will proceed with the treatment for three more hours. At the end of the six hours, the patient will do a trial for 15 minutes and after that a blood gas analysis will be repeated: if the PaO 2 /FiO 2 will be < 200 the patient will go on with the control treatment; if PaO 2 /FiO 2 will be >200, the patient will stop the treatment. All patients will be evaluated for re-intubation rate, hypoxia, atelectasis, pneumonia, sepsis and for the outcome at 30 days. 3

4 Criteria for re-intubation Immediate re-intubation will be required, when any of the following events will be present: respiratory or cardiac arrest, respiratory failure with loss of consciousness, psychomotor agitation inadequately controlled by sedation, massive aspiration, persistent inability to remove secretions and severe hemodynamic instabilit 12. In addition respiratory failure, within 72 hours from extubation, was defined as the presence and persistency of two of the following criteria 13 : (1) espiratory acidosis (ph < 7.35 or PaCO 2 > 45 mmhg); (2) arterial saturation of O 2 < 90% or PaO 2 < 60 mmhg with an inspired oxygen fraction > 50%; (3) respiratory rate > 35 breaths/minute; (4) decreased consciousness agitation or diaphoresis; (5) clinical signs suggestive of respiratory muscle fatigue and/or increased work of breathing, such as the use of respiratory accessory muscles, paradoxical motion of the abdomen, or retraction of the intercostal spaces. Collection of the data All data will be collected on a web case report form (CRF). Each center will have a personal access (username and password) to its own page, to enroll their patients and enter the following data: Pre-operative data Age, Gender, EUROscore, ACEFscore, Co-morbidities (severe COPD, hypertension, diabetes, smocking), Left Ventricular Function (LVF), dialysis, preoperative creatinine; Intra-operative data Surgical procedures (CABG, valvular surgery, aortic surgery), anesthesia drugs, BGA before induction of anesthesia, type of anesthesia, duration of intervention, duration of cardiopulmonary by pass (CPB), duration of the aorta cross clamp, CPB temperature, hematocrit (the lowest value), blood transfusions, fluid balance; Post-operative data PaO 2 /FiO 2 and BGA at extubation time and every three hours until the treatment ends, Thorax X-Ray, re-intubation, hemodynamic parameters (mean arterial pressure, central venous pressure), diuresis, fluid balance, type and dose of 4

5 catecholamine, SOFA score, atelectasis, pneumonia, day of discharge from ICU and from the hospital, 30 day mortality; Outcome data Duration of mechanical ventilation, day of discharge from ICU and from the hospital, re-admission to ICU, in-hospital mortality at 30 days. Statistics Sample size Based on previous published data 4,5 and on the retrospective evaluation of a multicenter study on patients undergoing cardiac surgery and developing post-operative hypoxemia, the predictive re-intubation rate has been estimated of 10%. This study has been designed to enroll 480 patients for group, to demonstrate at least a relative 50%of reduction (from 10% to 5%) in the re-intubation rate, with a 5% risk of type I error and a power of 80%. Interim analysis: we expect to perform an interim analysis for the evaluation of the efficacy of the treatment at the enrolment of the 50% of the sample size. The method of OBrien and Fleming will be used to control the inflation of the type I error. Type I error 0,05 Observed Rate 0,10 Expected Rate 0,05 Power (%) 80 N per group 480 Data analysis Statistical analysis will be conduct according to the intention to treat principles, analysing the whole sample size of the randomized patients. The baseline data will be described per arm using the most appropriate statistical methods and they will be express as mean and standard deviation or median and interquartile range or rate, according to the type of variable. The primary end point will be express as re-intubation rate and a Chi square 5

6 test will be used to evaluate the difference between the two groups. A Student-t test for independent data and a Wilcoxon Mann Whitney U test will be used to analyze the variables of the secondary end points. The mortality will be described with the Kaplan Meyer method and the evaluation for the comparison between the two groups will be performed by the Log Rank test. Randomization Patients will be randomized centrally, using a block randomization scheme with a web interface. The randomization will be done per centre and EURO score. Each centre will have a personal access (username and password) to the web page to randomize its own patients at the moment of the enrolment. Safety Potential risks This study is finalized to show the clinical effects of CPAP after cardiac surgery to prevent post-operative hypoxemia and re-intubation. During the study all patients of both groups will receive all standard therapy with the addiction of the effect of CPAP in the treatment group. CPAP is a well-known support already tested in different clinical context, and it is considered safe without increasing risks for patients. Advantage of the study CPAP is an additional support to standard therapy for the prevention and treatment of the post operative hypoxemia and it can reduce the re-intubation rate after cardiac surgery, reducing the duration of mechanical ventilation and the length of stay in intensive care unit. 6

7 Adverse events Any event which results in death or it will be life-threatening or require prolongation of the hospitalization will be defined as adverse event. These events even if they will not be correlated to the treatment they will be reported to the coordinator center, to the ethic committee and to the administration department of each center. 7

8 References [1] Rochelle Wynne and Mari Botti. ``Postoperative pulmonary dysfunction in adults after cardiac surgery with cardiopulmonary bypass: clinical significance and implications for practice.'' eng. In: Am J Crit Care 13.5 (2004), pp [2] Patrick Pasquina et al. ``Continuous positive airway pressure versus noninvasive pressure support ventilation to treat atelectasis after cardiac surgery.'' eng. In: Anesth Analg 99.4 (2004), pp [3] L Magnusson et al. ``Atelectasis is a major cause of hypoxemia and shunt after cardiopulmonary bypass: an experimental study.'' eng. In: Anesthesiology 87.5 (1997), pp [4] A. Tenling et al. ``Atelectasis and gas exchange after cardiac surgery.'' eng. In: Anesthesiology 89.2 (1998), pp [5] Alexander Zarbock et al. ``Prophylactic nasal continuous positive airway pressure following cardiac surgery protects from postoperative pulmonary complications: a prospective, randomized, controlled trial in 500 patients.'' eng. In: Chest (2009), pp [6] D. Kindgen-Milles et al. ``Nasal continuous positive airway pressure: A method to avoid endotracheal reintubation in postoperative high-risk patients with severe nonhypercapnic oxygenation failure.'' eng. In: Chest (2000), pp [7] Vincenzo Squadrone et al. ``Continuous positive airway pressure for treatment of postoperative hypoxemia: a randomized controlled trial.'' eng. In: JAMA (2005), pp [8] M. Lang et al. ``Outcome and resource utilization in gastroenterological surgery.'' eng. In: Br J Surg 88.7 (2001), pp [9] Y. G. Weiss et al. ``Postcardiopulmonary bypass hypoxemia: a prospective study on incidence, risk factors, and clinical significance.'' eng. In: J Cardiothorac Vasc Anesth 14.5 (2000), pp

9 [10] John G. Laffey, John F. Boylan, and Davy C. H. Cheng. ``The systemic inflammatory response to cardiac surgery: implications for the anesthesiologist.'' eng. In: Anesthesiology 97.1 (2002), pp [11] Enrico Zupancich et al. ``Mechanical ventilation affects inflammatory mediators in patients undergoing cardiopulmonary bypass for cardiac surgery: a randomized clinical trial.'' eng. In: J Thorac Cardiovasc Surg (2005), pp [12] Miquel Ferrer et al. ``Noninvasive ventilation during persistent weaning failure: a randomized controlled trial.'' eng. In: Am J Respir Crit Care Med (2003), pp [13] Andres Esteban et al. ``Noninvasive positive-pressure ventilation for respiratory failure after extubation.'' eng. In: N Engl J Med (2004), pp