Natriuretic Peptide-Driven Fluid Management during Ventilator Weaning: A

Transcription

1 Natriuretic Peptide-Driven Fluid Management during Ventilator Weaning: A Randomized Controlled Trial Armand Mekontso Dessap, Ferran Roche-Campo, Achille Kouatchet, Vinko Tomicic, Gaetan Beduneau, Romain Sonneville, Belen Cabello, Samir Jaber, Elie Azoulay, Diego Castanares-Zapatero, Jerome Devaquet, François Lellouche, Sandrine Katsahian, Laurent Brochard. ONLINE DATA SUPPLEMENT PATIENTS AND METHODS Patients Patients admitted to the participating ICUs were screened daily to see if they met the inclusion and non-inclusion criteria. Inclusion criteria were endotracheal mechanical ventilation for at least the past 24 hours, SpO 2 90% with FiO 2 50% and PEEP 8 cmh 2 O, haemodynamic stability without vasopressor therapy or fluid bolus (rapid infusion of at least 500 ml of macromolecules or 1000 ml of saline) during the past 12 hours (with dopamine 10 γ/kg/min and dobutamine 10 γ/kg/min being allowed), sedation stopped or decreased over the past 48 hours (analgesia possibly continued), stable neurological status with Ramsay score 5, body temperature >36.0 C and <39.0 C, and informed consent signed by the patient or a close relative. Permanent non-inclusion criteria were pregnancy or lactation, age <18 years, known allergy to furosemide or sulphonamides, tracheostomy on inclusion, hepatic encephalopathy, cerebral oedema, acute hydrocephalus, myasthenia gravis, acute idiopathic polyradiculoneuropathy, decision to withdraw life support, and prolonged cardiac arrest with a poor neurological prognosis. Temporary non-inclusion criteria were extubation 1

2 scheduled on the same day, persistent acute right ventricular failure [as defined by a dilated right ventricle (end diastolic right ventricle / left ventricle area ratio >0.6) associated with septal dyskinesia using echocardiography (E1) or the concomitant presence of a mean pulmonary artery pressure > 25 mmhg, a central venous pressure higher than pulmonary artery occlusion pressure and a stroke volume index < 30 ml/m 2 using pulmonary artery catheter (E2)], renal insufficiency (defined as any of the following: need for renal replacement therapy, plasma urea >25 mmol/l, plasma creatinine >180 µmol/l, creatinine clearance <30 ml/min, greater than 25% increase in plasma creatinine over the past 24 hours), injection of iodinated contrast agent in the past six hours, blood sodium >150 meq/l, blood potassium <3.5 meq/l, or metabolic alkalosis with arterial ph >7.50). When inclusion was delayed because of a temporary non-inclusion criterion, enrolment could be performed after correction of the abnormal value. Study protocol Patients ventilated in volume-assist or pressure-control mode were eligible for inclusion only if a pressure-support (PS) test was positive. The PS test consisted in changing the ventilator mode to PS, without changing FiO 2 or PEEP. PS was set at 10 cmh 2 O initially then adjusted to obtain an expired tidal volume 6 ml/kg of predicted body weight and a respiratory rate 35/min. The maximum inspiratory pressure (PS level plus PEEP) allowed to reach these objectives was 30 cmh 2 O. The test was stopped in the event of respiratory distress or haemodynamic instability (heart rate increase >30/min versus baseline, systolic blood pressure <80 mmhg or >160 mmhg, respiratory rate >40/min). The test was considered positive if, after 30 minutes with no change in the inspiratory pressure level, the patient remained clinically stable with a respiratory rate 35/min and an expired tidal volume 6 ml/kg of predicted body weight, without desaturation (SpO 2 90% with 2

3 FiO 2 50% and PEEP 8 cmh 2 O). In patients already ventilated with PS at the time of inclusion, the positivity criteria of the PS test were checked. Randomisation and masking Patients fulfilling the inclusion and non-inclusion criteria and having a positive PS test were ventilated using the AWS, starting with similar PS and PEEP levels to those used during the PS test. Patients were then immediately assigned to one of two groups (BNPguided fluid management or standard management based on clinical acumen) via independent centralised block randomisation, with stratification on the centre and underlying disease. Three subgroups were pre-defined for stratification: i) presence of known chronic obstructive pulmonary disease (COPD), ii) presence of known left ventricular systolic dysfunction (LVD, ejection fraction <45%), and iii) absence of both disorders. Patients with both disorders were classified in the COPD subgroup. The main purpose of stratification was to ensure a homogeneous distribution of COPD and LVD in the two arms. Careful attention was paid to minimising changes in diuretic therapy practices caused by the research protocol during weaning in the control group. All randomised patients were ventilated using the AWS during weaning and followed up until discharge from the hospital or day 60 after randomisation. B-type natriuretic peptide (BNP) assay A blood sample was collected each morning for a BNP assay in all randomised patients ventilated using the AWS. BNP was assayed using a rapid immunofluorescence test and a bedside measuring device (Triage BNP Test, Biosite, Jouy-en-Josas, France). To ensure reliability of the assay, i) device calibration was checked daily; ii) the assay cassette was removed from the refrigerator at least one hour before blood collection; and iii) the 3

4 assay was carried out immediately after blood sample collection. Two devices were supplied per centre: the first, which was used in the BNP-guided group, displayed the BNP result; the second did not show the result in visual display or print form and was used in the control group. All BNP devices were calibrated weekly using a quality control, as recommended by the manufacturer. Fluid and electrolyte management In the control group, the clinicians were blinded to the BNP assay results, and all treatments, including diuretics, were carried out according to standard practice. BNP results were uploaded from the device memory at study completion. In the BNP-guided group, on days with a BNP level 200 pg/ml, fluid intake was restricted (baseline infusion 500 ml/24 hours, parenteral nutrition 1000 ml/24 hours, no saline solutions apart from nutrition and drugs) and furosemide was administered (as intravenous bolus doses of 0 to 30 mg every 3 hours, to achieve a target urine output of 4.5 to 9 ml/kg/3 hours) (see appendix). The 200 pg/ml threshold was chosen based on a previous study showing that BNP levels were higher in patients who failed weaning from mechanical ventilation than in successfully weaned patients.(e3) Fluid intake restriction and diuretic administration according to BNP levels were continued for at least 24 hours after extubation in the BNP-guided group. Sodium, potassium, urea, creatinine, and arterial blood gases were monitored daily in all patients. Recommendations were given to prevent and/or treat possible adverse events related to diuretic treatment in the BNP-guided group, as detailed hereafter. When urine output exceeded 36 ml/kg/12 hours or blood potassium was <4.0 meq/l while receiving diuretics, blood electrolytes were checked within the next 12 hours. In the event of metabolic alkalosis with furosemide, acetazolamide was added (250 mg every 8 hours if ph >7.45 or 500 mg every 8 hours if ph >7.50) in the absence of contraindications (history of 4

5 hypersensitivity to acetazolamide or sulphonamides; severe hepatic, renal, or adrenal insufficiency; or history of renal lithiasis). If blood potassium was <4.5 meq/l during diuretic therapy, supplemental potassium was given ( 4 g/day if blood potassium was <4 0 meq/l or 3 g/day if blood potassium was between 4.0 and 4.4 meq/l). Magnesium supplements ( 1.5 g/day) were given routinely during diuretic treatment. If plasma urea doubled during diuretic treatment, the diuretic was suspended. In this case or in the event of oliguria (urine output <6 ml/kg/12 hours) despite maximum-dose diuretic therapy, echocardiography was considered to enable dobutamine therapy (starting at 5 micrograms/kg/min) in the event of LVD (ejection fraction <45%). An additional increase in the diuretic dosage was considered only in the absence of renal function deterioration (need for renal replacement therapy, greater than 50% plasma creatinine increase, or doubling of plasma urea). If blood sodium exceeded 150 meq/l, hypotonic solutions could be given to increase the daily fluid intake above 500 ml (no salt intake). If iodinated contrast agent injection was expected to be needed, an infusion of 500 ml or more of 0.9% saline was recommended and diuretic administration was suspended six hours before and six hours after the infusion. The other conditions requiring furosemide discontinuation were as follows: metabolic alkalosis with arterial ph >7.55, blood potassium <3.0 meq/l, blood sodium >155 meq/l, renal function deterioration (same definition as above), urine output > 9 ml/kg/3 hours, and hypotension requiring fluid bolus or vasopressor therapy. When diuretic treatment was stopped because of one of these abnormal findings, it could be reinstituted after correction of the abnormal value, in accordance with the inclusion and noninclusion criteria. The first furosemide dose after re-institution was half the last dose administered. Ventilatory management 5

6 During ventilation using the AWS, sedation was stopped whenever possible, whereas analgesia could be continued, with a target Ramsay score of 2 3. The AWS (SmartCare TM ) has been described elsewhere (E4-8). Briefly, it is a closed-loop knowledge-based system that interprets clinical data in real time and provides continuous adjustment of the level of PS delivered to intubated patients, with the goal of keeping the patient within a zone of respiratory comfort. Respiratory comfort is defined primarily as a respiratory rate within the range of 15 to 30 breaths/min (up to 34 in patients with neurologic disease), a tidal volume above a minimum threshold (250 or 300 ml depending on the weight), and an endtidal CO 2 level below a maximum threshold (55 or 65 mmhg depending on the presence of COPD). Average measurements of these parameters are made every 2 to 5 minutes and the level of PS is periodically adapted by the system in steps of 2 to 4 cm of water. The system automatically tries to reduce the PS level to a minimal value and initiates the equivalent of a spontaneous breathing trial when predetermined thresholds of PS are reached in a state of normal ventilation with PEEEP 5 cm H 2 O. Upon successful completion of the equivalent of a spontaneous breathing trial, the ventilator issues a directive stating that the patient is "ready for separation from ventilator". If the PEEP level at AWS initiation was >5 cmh 2 O, the level was set manually to no more than 5 cmh 2 O as soon as possible, to allow the system to perform separation trials.(e8) If the PEEP decrease caused SpO 2 to drop below 90%, the adjustment was postponed then re-attempted every 12 hours. When the AWS declared the patient ready for separation, extubation was performed as soon as possible, after checking for the other required extubation criteria, namely, SpO 2 90% with FiO 2 40% and PEEP 5 cmh 2 O, haemodynamic stability, Ramsay Score 3 with continuous sedation stopped or minimal (analgesic medication could be continued), audible cough (spontaneously or during 6

7 aspiration), need for fewer than three endotracheal suctionings during the last four hours, and no scheduled procedure requiring sedation or scheduled surgery. Assist-control ventilation was resumed during ventilation using the AWS in case of respiratory worsening with a respiratory rate >40/min or hypoxaemia (FiO 2 >60% and PEEP >8 cmh 2 O required to obtain SpO 2 90%). BNP was no longer assayed in controlled mode ventilation. When the daily PS test became positive again, the patient was switched back to ventilation using the AWS and managed according to his or her randomisation group. The diagnosis of ventilator-associated pneumonia was based on the following usual criteria: systemic signs of infection, new or worsening infiltrates on the chest roentgenogram, purulent tracheal secretions, and bacteriologic evidence of pulmonary parenchymal infection (chiefly from distal airway sampling using a protected telescoping catheter or bronchoscopy).(e9) Non-invasive ventilation was allowed after extubation if deemed necessary by the attending physician. Re-intubation criteria were as follows: respiratory distress (with SpO 2 <85%, respiratory rate >35/min or ph<7.30), shock (systolic blood pressure<90 mmhg despite 1000 ml fluid bolus, or requirement for vasopressor therapy), or coma (Glasgow Coma Scale <8 or having decreased by 2 points compared to the score immediately after extubation). In the event of respiratory distress requiring re-intubation, the patient was not re-ventilated using the AWS. Last, a general recommendation was made to investigators to wait until day 10 after randomisation before deciding to perform tracheotomy, if at all possible. End points The primary end point was the time from randomisation to successful extubation (patient alive and without re-intubation 72 hours after extubation). Secondary end points included time to first extubation, time to successful weaning from invasive and non-invasive 7

8 ventilation (defined as the time from randomisation to completion of 72 hours of unassisted spontaneous breathing without non-invasive ventilation for 3 hours per day), ventilator-free days calculated as the number of days without mechanical ventilation within 60 days after randomisation (patients who died or were dependent on mechanical ventilation for more than 60 days had zero ventilator-free days), ICU and hospital lengths of stay, ICU and hospital deaths, and mortality on day 60 after randomisation. Statistical analysis We estimated the sample size needed to detect an at least 40% decrease in weaning duration in the BNP-guided fluid management group compared to the control group, with an α risk of 5% and a β risk of 10% (power of 90%). In a previous multicentre trial, weaning duration in patients ventilated using the AWS was 4 4±4 0 days.(e8) Assuming a slightly higher standard deviation equal to the mean (4 4), and considering that the use of nonparametric tests might require up to 15% additional subjects,(e10) a sample size of 150 patients per group was deemed necessary. The data were analysed using SPSS Base 18 (SPSS Inc, Chicago, IL, USA) and R (The R Foundation for Statistical Computing, Vienna, Austria). We used the chi-square or Fisher exact test to compare categorical variables between study groups and the Mann-Whitney test to compare continuous variables, including the primary end point. The primary end point was also analysed in the three predefined subgroups (COPD, LVD, and neither). We also used the Kaplan-Meier method to assess the effect of BNP-guided fluid management on the cumulative probability of successful extubation. Because the proportional hazards assumption was not met during the 60-day follow-up, we used the Breslow-Gehan-Wilcoxon test to assess differences between groups (E11). This test allows weighting of time points by the number of cases at risk at each time point (E12). Lastly, the effect of BNP-guided fluid management on the cumulative 8

9 incidence of successful extubation was assessed while considering need for continuous sedation as a competing event, according to the Gray model (E13, 14). Two-sided p values <0.05 were considered significant. 9

10 Table E1: Algorithm for dosing diuretics according to BNP levels in the intervention group Initial dose of furosemide (mg) Urine output (ml/kg/3 hours) Subsequent doses of furosemide (mg) < >9 0 Example for a patient of 70 kg Initial dose of furosemide (mg) 3-hour urine output (ml) Subsequent doses of furosemide (mg) < >

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