Patients and setting
The study was performed in the ICU of the University Hospital “Maggiore della Carità” (Novara, Italy) between January 2011 and December 2013, according to the principles outlined in the Declaration of Helsinki. The ICU is a closed fourteen-beds unit, attended around the clock by physicians all certified and trained in Anesthesiology and Critical Care. The protocol was approved by the local Ethics Committee i.e., Comitato Etico Interaziendale A.O.U. “Maggiore della Carità”, ASL BI, ASL NO, ASL VC, ASL VCO (Corso Mazzini n. 18, 28100 Novara; Protocol 145/CE; Study n. CE 21/11), and written informed consent to participate in the study and to publish results was obtained for all the patients according to the Italian regulations. In our routine care, irrespective of the cause of intubation and mechanical ventilation, tracheotomy is considered after 7 days of invasive mechanical ventilation for the patients for whom extubation is considered unlikely to occur in the following 3–5 days. If there is uncertainty or disagreement at this regard, the patient is re-evaluated after 2–3 additional days. Tracheotomy is performed, anyway, within 14 days after initiation of invasive mechanical ventilation in all patients. At the time of the study, there were no formal protocols for either weaning or disconnection from the ventilator. The weaning strategy for tracheotomized patients was based on the application of pressure support ventilation with progressive reduction of positive end-expiratory pressure (PEEP) and support level; the decision of disconnecting the patient was left to the discretion of the attending physician in charge.
Patients who met the following inclusion criteria were considered eligible: 1) diagnosis at ICU admission of neurosurgical and neurological disease, 2) presence of a tracheotomy performed in our ICU; 3) age >18 years, 4) no need for continuous intravenous sedative infusion and/or controlled mechanical ventilation, 5) ability to trigger the ventilator, 6) no scheduled surgery in the following 72 h. The only exclusion criteria were the preexisting decision to limit life support and the inclusion in other research protocols.
After enrolment, patients were assigned to the intervention or control group following a previously generated random sequence held by an investigator not involved in the study enrolment, who indicated in sealed, opaque numbered envelops the group of assignment. The trial was registered at the Australian New Zealand Clinical Trials Registry (ACTRN12612000372886).
Study protocol and measurements
Routine care was no different between the two groups. Active humidification was used for all patients both during mechanical ventilation and during spontaneous breathing, while tracheal suctioning and mechanically assisted cough devices were applied when needed. All patients randomized to treatment were screened every morning to assess readiness for SBT by the attending physicians. The criteria for readiness were 1) normal sodium blood values, 2) core temperature <38.5 °C during the previous 8 h, 3) pH ≥ 7.35, 4) a ratio of partial pressure arterial oxygen and fraction of inspired oxygen (PaO2/FiO2) ≥200 mm Hg with a PEEP ≤5 cm H2O, 5) FiO2 ≤0.4, 6) heart rate ≤125 beat/min, 7) systolic blood pressure (SBP) ≥90 mmHg without epinephrine or norepinephrine infusion and with dopamine infusion ≤5 µg/kg/min.
The patients who passed the screening underwent a 30 min SBT through the circuit of a flow-triggered ventilator, set to deliver 2 cm H2O of continuous positive airway pressure, with a FiO2 of 0.4. The trial was interrupted and mechanical ventilation resumed whenever one of the following occurred: 1) respiratory rate >35/min, 2) signs of evident respiratory distress (diaphoresis, accessory muscles recruitment, thoraco-abdominal paradox), 3) peripheral oxygen saturation (SpO2) <90 %, 4) SBP <90 mmHg or >180 mmHg, 5) heart rate >140/min.
At the end of the trial, the patients who had a respiratory rate/tidal volume ratio (RR/VT) ≤105 and PaO2/FiO2 ≥200 mm Hg with a pH ≥ 7.35 were immediately disconnected from the ventilator. Conversely, if the RR/VT exceeded 105 or the arterial blood gas analysis criteria were not met, mechanical ventilation was resumed. Patients randomized to the control group, as routine use in the ICU, were evaluated every day by the attending physicians who discontinued mechanical ventilation based on clinical judgment; all the information collected for the intervention group were also available.
Irrespective of the group of randomization, patients were considered successfully weaned off if they did not meet criteria for resuming mechanical ventilation within 48 h. Criteria for ventilation resumption were 1) emergency, such as respiratory or cardiac arrest, and gasping for air, 2) neurologic deterioration [a decrease of more than 2 points of Glasgow Coma Scale (GCS)], 3) hemodynamic instability (i.e., need for continuous infusion of epinephrine, norepinephrine or vasopressin, or dopamine >5 µg/kg/min to maintain SBP >90 mmHg), despite adequate filling, 4) respiratory distress, as assessed by the combination of SpO2 <90 %, respiratory rate >35/min, and visible accessory muscle recruitment or thoraco-abdominal paradox, despite administration of oxygen.
Statistical analysis
Lacking data on tracheotomized patients, we used the sample size of 280 patients (140 per group to detect a decrease in failure i.e., reconnection to the ventilator within 48 h, from 15 to 5 % with 80 % power at the 5 % two-sided level of significance) previously adopted for intubated patients [8]. Normally distributed variables were compared by two-tailed Student’s t test, non-parametric variables were compared by Mann–Whitney test, whereas proportions and rates by Fisher’s exact test, as indicated. Data were analyzed according to intention-to-treat analysis.