Is very early extubation after lung transplantation feasible?☆

Article Outline

• Abstract
• Methods
• Results
• Discussion
• References
• Copyright

Abstract 

Objective: To evaluate donor graft function, intraoperative blood consumption, and oxygenation and hemodynamic stability in patients undergoing lung transplantation. Design: Prospective pilot study. Setting: University hospital. Participants: Forty-three patients undergoing lung transplantation from January 1999 to June 2001. Interventions: Hemodynamic monitoring, early extubation, and noninvasive ventilation criteria. Measurements and Main Results: The 31 nonearly extubated patients showed a lower PaO₂/fraction of inspired oxygen (F_IO₂), a higher mean pulmonary arterial pressure, extravascular lung-water index (EVLWI) and vasoactive drug support (norepinephrine), and more blood products consumption than 12 early extubated patients at the end of surgery. Seven of 12 early extubated patients did not show any signs of respiratory failure after tracheal extubation; they were alert and able to perform deep breathing exercise and coughing. In the other 5 patients, hypoxemia, hypercapnia, and an increase of respiratory rate >30 breaths/min were observed. The intermittent application of noninvasive pressure ventilation by face mask avoided endotracheal intubation. Conclusion: The use of a short-acting anesthetic drug, appropriate intraoperative extubation criteria, epidural analgesia, and postoperative noninvasive ventilation make early extubation of lung-transplanted patients possible and effective. Copyright 2003, Elsevier Science (USA). All rights reserved.

Keywords:  Lung transplantation, early extubation, noninvasive ventilation

The last 5 years have seen growing interest in fast-track surgery—a combination of anesthesiology and surgical techniques that reach the goal of reducing postoperative intubation time, intensive care unit (ICU) length of stay, and hospital length of stay. Cost containment, better use of personnel, and reduction of postoperative complication of prolonged mechanical ventilation and prolonged length of stay in the ICU are cited as advantages in support of early extubation.¹, ²

The timing of tracheal extubation in patients undergoing long intraoperative procedures is controversial. It requires a change of strategies of all staff managing these patients.³, ⁴ Advances in selection and management of lung transplantation (LTX) recipients have improved surgical success and quality of life.⁵ It is necessary to assess successful allograft implantation and lung function.⁶ The postreperfusion lung syndrome after cardiopulmonary bypass (CPB) and the ischemia-reperfusion syndrome of the pulmonary graft can lead to respiratory failure and hemodynamic instability that require supportive measures such as positive-pressure ventilation.⁷ Mechanical ventilation may be associated with early lung and bronchial anastomoses complications. The use of immunosuppressive therapy to prevent rejection in recipients of solid-organ transplants increases morbidity and mortality associated with pulmonary infection. Nosocomial pneumonia is a frequent complication of mechanical ventilation and is an important factor in determining outcome of respiratory failure. Approximately 5% of patients undergoing renal, hepatic, cardiac, or pulmonary transplantation developed pneumonia in the period after surgery, which has an associated crude mortality of 37%.⁸ To extubate early lung-transplanted patients, the following extubation criteria were evaluated: donor graft function, intraoperative blood consumption, and oxygenation and hemodynamic stability.

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Methods 

From January 1999 to June 2001, 43 patients undergoing LTX were studied. Twelve of these recipients, (2 single and 10 bilateral sequential LTx), mean age of 30.2 ± 15.2 years and mean body surface area (BSA) of 1.54 ± 0.3 m² affected by cystic fibrosis (n = 10) and emphysema (n = 2), were extubated in the operating room. The other 31 recipients (9 single and 22 bilateral sequential LTX), mean age of 35 (14) years and mean BSA of 1.60 (0.3), were affected by cystic fibrosis (n = 16), emphysema (n = 4), pulmonary fibrosis (n = 5), obliterans bronchiolitis (n = 3), bronchiectasis (n = 2), and pulmonary microlithiasis (n = 1) were not extubated in the operation room.

Monitoring consisted of 2-lead electrocardiography (EKG) (90305; Spacelabs, Redmond, WA); pulse oximetry and end-tidal carbon dioxide (N180 and N1000; Nellcor, Pleasanton, CA); radial and femoral arterial pressure (90305; Spacelabs; PiCCO System; Pulsion Medical System, Munich, Germany); and pulmonary arterial catheter (Intellicath; Baxter, Irvine, CA) for measurement of pulmonary arterial pressure, central venous pressure, pulmonary capillary wedge pressure, body temperature (90305 SpaceLabs), continuous venous oxygen saturation (Vigilance; Baxter, Irvine, CA), continuous thermal cardiac output (Vigilance), and arterial pulse contour continuous cardiac output (PiCCO System). In all patients, transesophageal echocardiography (Power Vision 8000; Toshiba Corporation, Tochigi Ken, Japan) was used intraoperatively and inspiratory O₂ fraction was analyzed (Servo Ventilator 900 D; Siemens Elema, Solna, Sweden). Preoperatively, an epidural catheter (T4-T6) was inserted for postoperative pain relief, and a test with lidocaine 2%, 2 mL, was performed.

Anesthesia was induced with propofol (0.5-1 mg/kg) and/or midazolam (0.05-0.1 mg/kg) and alfentanil (10-15 μg/kg) in 100% O₂ and maintained with sevoflurane (0.8%-1.2%) and continuous remifentanil intravenous infusion (0.1-0.5 μg/kg/min) in 100% O₂. As a neuromuscular blocking agent, rocuronium bromide was used. To control hemodynamic changes, pharmacologic options consisted of: dobutamine (5-15 μg/kg/min), norepinephrine (0.1-3 μg/kg/min), intravenous prostaglandin E1 (PGE₁) (20-300 ng/kg/min), ephedrine (5-10 mg/bolus), inhaled nitric oxide (iNO) (10-20 ppm), and aerosolized prostacyclin (10 ng/kg/min).

Before the start of the study, guidelines for early extubation were written (Table 1). Preoperative criteria for extubation excluded emergency procedures and patients with major coexisting disease. Intraoperative criteria were evaluated after new organ reperfusion and at the end of surgery and included absence of major adverse events during surgery (CPB, cardiac arrest), no lung reperfusion injury after new lung/s implantation and good graft function (PaO₂/fraction of inspired oxygen [F_IO₂] >350 mmHg, PaCO₂ <60 mmHg), few blood products units transfused (packed red cells <4 U or <800 mL; fresh-frozen plasma <10 U or <1,500 mL), hemodynamic stability with or without minimal vasoactive drugs support (intravenous PGE₁, <20 ng/kg/min, dobutamine <10 μg/kg/min, iNO <20 ppm, Norepinephrine <0.1 μg/kg/min), volumetric parameters measured with the PiCCO system within normal range (intrathoracic blood volume index [ITBVI] = 800-1,000 mL/m²), and body temperature >36°C.

Table 1. Intraoperative criteria for early extubation: Evaluated after lung implantation and at the end of surgery in mechanically ventilated patients; and criteria for application of postoperative noninvasive ventilation

Abbreviations: CPB, cardiopulmonary bypass; F_IO₂, fraction of inspired oxygen; PRC, packed red cells; FFP, fresh-frozen plasma; PGE₁, prostaglandin E_I; iNO, inhaled nitric oxide; ITBVI, intrathoracic blood volume index; RR, respiratory rate.

If criteria for early extubation were present, the remifentanil infusion rate was progressively decreased and suspended 15 minutes after extubation. At the end of surgery, after changing the endobronchial tube to a single-lumen tube to check bronchial anastomoses and to perform bronchial toilette, fiberoptic bronchoscopy and a chest radiograph were done. Weaning from mechanical ventilation was performed through pressure support ventilation mode (Servo Ventilator 900 D; Siemens, Solna, Sweden) with positive end-expiratory pressure (PEEP) = 5 cm H₂O, trigger = −1 to −2 mmHg, and pressure support = 10 to 20 cm H₂O to obtain an exhaled tidal volume >600 mL and an exhaled minute volume >10 mL/kg with a respiratory rate (RR) <30 breaths/min. At the end of surgery, postoperative analgesia was administered with an epidural bolus of 8 mL of lidocaine 1% followed by a bupivacaine 0.1% continuous infusion (5 mL/h). Inhalation of iNO (10-20 ppm) was continued until extubation. Administration of intravenous PGE₁ (20 ng/kg/min) was maintained during the early postoperative period. Extubation was performed when patients were awake and orientated and when their respiratory pattern included tidal volume ≥8 mL/kg, RR <30 breaths/min, and PaO₂/F_IO₂ ≥300 mmHg. After tracheal extubation, if necessary (PaO₂/F_IO₂ <180 mmHg and/or PaCO₂ ≥70 mmHg and/or RR >30 breaths/min), patients were assisted with delivery of artificial, noninvasive ventilation (NIV) (Table 1). NIV was intermittently applied for a period of 30 to 40 minutes, in sitting patients, through a full face mask secured with elastic straps to the face. Pressure support ventilation (from 10-20 cm H₂O) was slowly increased to obtain a larger exhaled tidal volume, a RR <30 breaths/min, and patient comfort. Ventilatory settings were adjusted based on continuous pulse oximetry and on measurement of arterial blood gases analyses.

Hemodynamic, volumetric, oxygenation data, vasoactive drugs infusion rate, and blood products transfused were collected at the end of surgery (FINAL) in mechanical ventilation in the 12 early extubated patients (EE) and in the 31 not early extubated patients (Not EE).

In the EE patients, hemodynamic, volumetric, and oxygenation data were measured in 3 phases in the group of 7 patients who did not require NIV (EE-Not NIV) and in 4 phases in the group of 5 patients who required NIV (EE-NIV). In the EE-Not NIV group, data were collected at the end of surgery on mechanical ventilation (FINAL), 30 minutes after extubation in spontaneous breathing (SB₃₀), and 60 minutes after extubation (SB₆₀). In the EE-NIV group, data were measured at the end of surgery on mechanical ventilation (FINAL), 30 minutes after tracheal extubation in spontaneous breathing (SB₃₀), during noninvasive ventilation (30 minutes after the beginning of NIV application − NIV), and in spontaneous breathing 120 minutes after extubation (30 minutes after NIV discontinuation − SB₁₂₀). Postoperative analgesia, sedation, and motor blockade were respectively evaluated with the Numeric Ordinal Scale (modified by Keele); Ramsay Score; and Bromage Scale immediately, 30 minutes, and 60 minutes after tracheal extubation.

All values are reported as mean and SD. Statistical analysis of hemodynamics, volumetrics, oxygenation, and vasoactive infusion rate at the end of surgery (FINAL) and age, BSA, lung/s ischemia time, anesthesia time (from induction to extubation), blood products transfused during LTX of the EE group and the Not EE group were analyzed with an unpaired t-test. Hemodynamic, volumetric, and oxygenation data between different phases of early extubated patients (EE-Not NIV and EE-NIV) at the end of surgery and after extubation were analyzed with an analysis of variance test and Bonferroni post hoc test. A p value <0.05 was considered statistically significant.

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Results 

All patients were successfully transplanted. Patient age and BSA were similar in the EE and Not EE groups. In 11 of 31 patients in the Not EE group, CPB was used. During LTX, less FFP and packed red cells units were transfused in EE compared with Not EE patients (p < 0.05) (Table 2). In the EE and Not EE groups, mean anesthesia time (547 ± 111 minutes v 586 ± 138 minutes), mean ischemia time of the first LTX (273 ± 48 minutes v 302 ± 67), and mean ischemia time of the second LTX (390 ± 72 minutes v 400 ± 73 minutes, respectively) were not statistically different. At the end of surgery, in the FINAL phase, a higher PaO₂/F_IO₂ and a lower mean pulmonary arterial pressure, extravascular lung-water index (EVLWI), and norepinephrine infusion rate (p < 0.05) were observed in the EE group (Table 2). EE patients were extubated in the operating room 49 ± 29 minutes after bronchoscopy. Thirty and sixty minutes after the extubation the degree of Numeric Ordinal Verbal Scale was 0-1, without motor blockade (degree 0, Bromage Scale). All patients were well oriented and able to cough and to do active movements (degree 0, Ramsay Score).

Table 2. Hemodynamic, volumetric, and oxygenation data; vasoactive drug infusion rate; and blood substitutes administered during surgical procedures

NOTE. Data are reported as mean (SD); Collected at the end of lung transplantation during mechanical ventilation (FINAL).

Abbreviations: HR, heart rate; mAP, mean arterial pressure; mPAP, mean pulmonary arterial pressure; CI, cardiac index; F_IO₂, fraction of inspired oxygen; ITBVI, intrathoracic blood volume index; EVLWI, extravascular lung water index; iNO, inhaled nitric oxide; ivPGE₁, intravenous prostaglandin E₁, PRC, packed red cells; FFP, fresh-frozen plasma.

In the EE-Not NIV group (7 patients), an RR <30 breaths/min with stable pulse oximetry, confirmed by blood gas analysis, were observed soon after extubation and during postoperative stay in the operating room (Table 3). Only a decrease in PaO₂/F_IO₂ between FINAL and SB₃₀ phase and between FINAL and SB₆₀ phase was noted (Fig 1).

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• Fig. 1. 

  PaO₂/F_IO₂ and PaCO₂ in early extubation patients without noninvasive mechanical ventilation (EE-Not NIV) during mechanical ventilation (FINAL) and during spontaneous breathing 30 minutes (SB₃₀) and 60 minutes after extubation (SB₆₀). Data are reported as mean ± SD. *p < 0.05 between FINAL and SB₃₀. °p < 0.05 between FINAL and SB₆₀.

No other statistically significant differences were observed among hemodynamic, volumetric, and oxygenation data analyzed.

Table 3. Hemodynamic, volumetric, and oxygenation data of 7 early extubation patients without noninvasive mechanical ventilation (EE-Not NIV) collected during mechanical ventilation (FINAL), and during spontaneous breathing 30 minutes (SB₃₀) and 60 minutes after extubation (SB₆₀)

NOTE. Data are reported as mean (SD).

Abbreviations: HR, heart rate; mAP, mean arterial pressure; mPAP, mean pulmonary arterial pressure; CI, cardiac index; ITBVI, intrathoracic blood volume index; EVLWI, extravascular lung water index.

In the EE-NIV (5 patients) group after extubation (SB₃₀ phase), tachypnea (>30 breaths/min), a decreasing of PaO₂/F_IO₂, and an increasing of PaCO₂ were observed as compared with the FINAL phase. All these parameters improved during the NIV phase (Table 4, Figs 2 and 3).

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• Fig. 2. 

  PaO₂/F_IO₂ and PaCO₂ in early extubation patients with invasive ventilation (EE-NIV) during mechanical ventilation (FINAL), during spontaneous breathing 30 minutes after extubation (SB₃₀), 30 minutes after NIV application (NIV), and with spontaneous breathing 120 minutes after extubation (30 minutes after NIV discontinuation − SB₁₂₀). Data are reported as mean ± SD. *p < 0.05 between FINAL and SB₃₀. §, p < 0.05 between FINAL and NIV. °p < 0.05 between FINAL and SB₁₂₀.

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• Fig. 3. 

  PaO₂/F_IO₂ and PaCO₂ in individual early extubation patients with noninvasive ventilation (EE-NIV) with spontaneous breathing 30 minutes after extubation (SB₃₀), 30 minutes after NIV application (NIV), and with spontaneous breathing 120 minutes after extubation (30 minutes after NIV discontinuation − SB₁₂₀).

After NIV discontinuation, a reduction of PaO₂/F_IO₂ was noted, but it increased if compared with the SB₃₀ phase. In SB₁₂₀ phase, decreases of RR and PaCO₂, compared with SB₃₀ phase after extubation, were also observed. No differences in hemodynamic and volumetric data were noted among phases. The postoperative length of stay in the operating room after extubation was 115 ± 55.5 minutes: 156 ± 54 minutes in the EE-NIV group and 84 ± 36 minutes in the EE-Not NIV group.

Table 4. Hemodynamic, volumetric, and oxygenation data of 5 early extubation patients with noninvasive mechanical ventilation (EE-NIV) collected during mechanical ventilation (FINAL), during spontaneous breathing 30 minutes after extubation (SB₃₀), 30 minutes after NIV application (NIV), and with spontaneous breathing 120 minutes after extubation (30 minutes after NIV discontinuation − SB₁₂₀)

NOTE. Data are reported as mean (SD).

Abbreviations: HR, heart rate; mAP, mean arterial pressure; mPAP, mean pulmonary arterial pressure; CI, cardiac index; ITBVI, intrathoracic blood volume index; EVLWI, extravascular lung water index.

The ICU length of stay of early extubated patients was 12 to 36 hours. In all patients, no cardiovascular or respiratory complication occurred in the early postoperative period. One cardiac tamponade occurred 5 days after transplantation and was treated with percutaneous pericardiocentesis. Two patients died, 1 from massive myocardial infarction after 20 days and 1 from sepsis after 2 years.

Nine patients in the Not EE group died in the late postoperative period, whereas the ICU length of stay of the other 22 patients ranged from 96 hours to 25 days. Three patients in the Not EE group died in the late postoperative period 21 days, 3 months, and 8 months after LTX.

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Discussion 

In the past decade, advancements in immunosuppressive therapy, organ preservation techniques, and selection and management of recipients have improved the outcome of patients undergoing LTX.⁵ Potential intraoperative problems during this procedure include prolonged surgery, hemodynamic and metabolic perturbations, use of cardiopulmonary bypass, major blood loss, and graft dysfunction. Over the years, however, the improvement of surgical technique has reduced times of surgery, intraoperative bleeding, and lung tissue damage, and anesthesiologists have become better able to control intraoperative hemodynamic and respiratory changes.

Fast-track surgery has increased interest in other areas of cardiothoracic anesthesia practice.⁹ With modification to a balanced anesthetic regimen using rapid-acting narcotics, inhalation anesthetics, and propofol, early extubation has been shown to improve shunt fraction and postoperative complications, decreasing postoperative recovery,¹ and not to increase perioperative cardiorespiratory or sympathoadrenal morbidity and mortality in cardiac surgery.²

In lung-transplant patients, prolonged mechanical ventilation after surgery ensures better lung graft expansion and oxygenation, with lower risk of atelectasis, during the early postoperative period, which may be marked by cardiovascular instability and acute lung injury. However, accentuated lung impedance because of lung inflation increases right ventricular workload, and positive-pressure ventilation may exacerbate lung injury.¹⁰ The endotracheal tube increases patient discomfort and stress and may also cause injuries of the tracheal mucosa, inducing inflammation, edema, and submucosal hemorrhage, with the risk of others complications, such as tracheal stenosis.¹¹ Prolonged mechanical ventilation may carry associated risks of barotrauma, hemodynamic instability, and bronchial anastomosis leak and requires the use of sedatives that may inhibit gastrointestinal motility.⁷ In mechanically ventilated patients, endotracheal intubation is the single predisposing factor for developing nosocomial bacterial pneumonia and infection.¹² However, after single-lung transplantation, continued ventilation of 2 lungs with very different mechanics and gas exchanging characteristics may pose other problems.

In spontaneously breathing patients, reduced intrapleural pressure improves venous return, increasing cardiac end-diastolic volume and cardiac output and reducing pulmonary pressure, and improving splanchnic perfusion.⁴, ¹³ Early extubation allows accelerated recovery of mental status, mobilization, and oral intake of food. Thus, spontaneous ventilation may be beneficial in selected and hemodynamically stable transplanted patients.

Early extubation protocols have been used successfully in other large surgical procedures to identify low risk populations to facilitate early extubation and to improve favorable outcome.¹⁴, ¹⁵, ¹⁶ Intraoperative cardiovascular stability and donor graft function are the most important criteria determining perioperative morbidity and mortality in LTX. In this study population, the norephinephrine infusion rate was lower at the end of surgery in early extubated patients, and was decreased before extubation (Table 2). In the Not EE group, it was necessary to administer norepinephrine to all patients; mPAP was lower in the EE group (Table 2). Graft dysfunction, secondary to ischemia-reperfusion injury or acute rejection, is one of the early complications after LTX and leads to pulmonary edema, decreased graft function, pulmonary hypertension, and right ventricular failure. The treatment includes positive-pressure mechanical ventilation and pulmonary inodilators, if necessary, for inotropic support and diuretics.¹⁷ In patients extubated in the operating room, a higher PaO₂/F_IO₂ and a lower EVLWI are signs of good graft function (Table 2). EVLWI quantifies the extravascular lung water and is evidence of lung capillary leak and correct fluid management. In this study, intrathoracic blood volume index (ITBVI) was used to evaluate cardiac preload and to avoid excessive fluid administration. In all EE patients, ITBVI in the FINAL phase and after extubation was maintained around 800 mL/m², which represents the lowest value of normality. The coupling of ITBVI and EVLWI is really useful to manage these patients.

Early extubation criteria and an anesthetic technique performed with continuous remifentanil infusion in combination with low-dose inhalation anesthetics resulted in early recovery and tracheal extubation with a mean time of 50 minutes after endobronchial tube exchange when patients are deeply anesthetized.

After tracheal extubation, a decrease in PaO₂/F_IO₂ was observed compared with the mechanical ventilation phase (Table 3, Final-SB₃₀). In 7 patients, PaO₂/F_IO₂ was greater than 180 mmHg (with F_IO₂ = 0.4-0.5) and increased in the following hour (Fig 1). There were no signs of respiratory distress, and the patients were alert and pain free, able to perform deep-breathing exercises, and coughing.

In lung transplant surgery, the extensive thoracic incision and the placement of chest tubes result in postoperative pain and impairment of ventilation. In a recent editorial, Myles⁶ reported that early extubation in lung-transplant patients requires the use of short-acting anesthetics drugs, restoration of normothermia, and effective postoperative analgesia with minimal sedation and respiratory depression. Epidural analgesia used in this series achieved all these objectives, leading to earlier patient mobilization and aggressive chest physiotherapy.

In 5 patients, hypoxemia and/or hypercapnia were observed soon after extubation associated with tachypnea >30 breaths/min (Table 4). Blood gas values remained unchanged after deep breathing. There were no signs of pulmonary edema on the chest radiograph. Because of possible complications of endotracheal intubation, this study tried to support these patients' pulmonary function through noninvasive ventilation. Westerlind et al⁷ described the use of continuous positive airway pressure (CPAP) to correct hypoxemia and maintain lung expansion following extubation after LTX. CPAP is as effective as deep breathing and incentive spirometry and may not depend on the patient's effort.¹⁸ It is suggested to restrict the use of CPAP for prevention and treatment of postoperative pulmonary complications to those patients who are unable to perform deep-breathing exercises or to comply with incentive spirometry.¹⁹, ²⁰ CPAP usually increases PaO₂ but does not change PaCO₂ (that may also increase). NIV (ie, the delivery of assisted breaths without an invasive artificial airway) is as safe and effective as conventional therapy delivered through an endotracheal tube in improving gas exchange, either PaO₂ or PaCO₂, in patients with acute exacerbations of chronic obstructive pulmonary disease and with acute hypoxemic respiratory failure.²¹, ²², ²³ When NIV is used to avoid endotracheal intubation, the incidence of bacterial pneumonia is extremely low.²⁴ It is a feasible technique applied both continuously and intermittently, which allows the maintenance of speech and swallowing with good patient acceptance. NIV is a tool for correcting the increased work of breathing and for avoiding intubation. The combination of external PEEP and pressure support ventilation offsets the auto-PEEP level and reduces the work of breathing that the respiratory muscle must perform to produce the tidal volume.²⁵ In a recent randomized study, early application of NIV in a group of solid-organ transplant recipients was associated with a significant reduction in the rate of endotracheal intubation, fatal complications, and ICU mortality.²⁶

In the present study population during NIV, an increase of oxygenation and decreases of PaCO₂ and respiratory rate were found when compared with SB₃₀ phase (Table 4, NIV phase). This improvement in gas exchange went on also after NIV was suspended, in SB₁₂₀ phase (Fig. 2, Fig. 3, SB₁₂₀ phase). NIV is not free from risks, such as gastric inflation, vomiting, patient ventilation mismatch, airway obstruction for copious secretions, and inability to cooperate (tolerance of facial mask). When NIV is applied intermittently, these complications can be minimized.

The high PaCO₂ values after extubation and in SB₁₂₀ phase (Table 3, Table 4) are frequent in lung-transplant recipients in the early postoperative period. This hypercapnia is not associated with respiratory depression and lung injury, but it seems to depend on alterations in respiratory pattern regulation. Usually it reaches normal values within 24 to 48 hours after extubation. No patient of this study population was reintubated in the ICU.

In conclusion, the use of short-acting anesthetic drugs, postoperative analgesia, and NIV make early extubation in the operating room of lung-transplant patients with hemodynamic and oxygenation stability feasible and effective. Further studies are necessary to improve criteria selection of patients to be enrolled in this program and to evaluate if this new approach can lead to a reduction of postoperative complications and ICU and hospital length of stay in lung-transplant patients.

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