Lung transplantation (LTx) is the only effective method for end-stage lung disease.^[1] On a global scale, over 4,000 lung transplants are performed annually. In recent years, the postoperative survival rate of patients has significantly improved. However, compared to patients receiving other solid organ transplants, patients receiving LTx have longer waiting time, mainly due to a lack of lung donors and transplant resources. A previous study has shown that patients waiting for heart or lung transplantation in various countries face mortality rates ranging from 5% to 30%.^[2] Early transplantation has become the most effective life-saving strategy for these patients.

During the waiting period for LTx, the patient’s condition may worsen and require supportive care, including invasive respiratory support or extracorporeal membrane oxygenation (ECMO). Currently, some countries use invasive mechanical ventilation (IMV) or ECMO as an urgent LTx (ULTx) indicator. The main purpose of ULTx is to reduce the waiting period and mortality rate of critically ill patients who are on the transplant waitlist by prioritizing the availability of lung resources.^[3,4] The allocation principle of ULTx has been applied in Germany, France, and other countries, thereby reducing mortality rates, especially in patients waiting for transplantation.^[5]

Given the serious and complex conditions, long-term invasive respiratory support and ECMO for ULTx patients pose significant challenges to clinical practice. To improve the quality of life of transplant patients, pulmonary rehabilitation is crucial. Therefore, a comprehensive analysis was conducted on the clinical experience and outcomes of ULTx patients who needed IMV and ECMO between 2018 and 2023.

Retrospectively, the electronic medical records of the LTx center were used for data extraction. From January 2018 to January 2023, a total of 14 patients were enrolled. The inclusion criteria were as follows: patients receiving ECMO and IMV, age ≥18 years old, and ULTx performed. Those with no complete or missing medical records were excluded. The oxygen support at admission included non-invasive ventilation (NIV, n=1), high-flow nasal cannula (HFNC, n=2), IMV (n=8), and oxygen storage mask (n=3). All patients needed IMV as oxygen saturation decreased during the waiting period for transplantation, leading to a rapid deterioration of their critical state. Pulmonary function tests were not conducted. Blood gas analysis showed that the oxygenation levels of all patients were <300 mmHg (1 mmHg=0.133 kPa). Clinical symptoms included chest tightness, dyspnea, exercise-induced asthma, and respiratory distress. Expert consultation was conducted to determine the necessity of ECMO while waiting for LTx, as respiratory failure could not be controlled through medication or invasive respiratory support. The Acute Physiology and Chronic Health Evaluation (APACHE) II scores were calculated from admission to the ICU to assess disease severity.

Transplant surgeons, thoracic surgeons, ICU physicians, transplant nutritionists, physical therapists, psychologists, and a specialized ECMO nursing team formed a multidisciplinary team at our transplant center. Lung transplant experts assessed the pulmonary function of patients. Nutritionists formulated personalized nutritional support plans. To enhance patient recovery, physical therapists provided personalized rehabilitation programs, and psychologists assisted the patients in managing negative psychological states during their hospital stay.

The indications for ECMO were difficulties in managing hypoxemia, hypercapnia, and right heart failure after active treatment for potential lung transplant recipients.^[6] The ECMO mode was selected in accordance with the standard protocol for administering ECMO during the perioperative period of LTx. After respiratory and circulatory functions gradually stabilized, ECMO was weaned postoperatively. The weaning strategy of ECMO depends on its modes. For veno-venous ECMO (V-V ECMO) mode, the blood flow was gradually reduced to 2.5-3.0 L/min, and then the ventilation volume was decreased. Under the same mechanical ventilation conditions, V-V ECMO can be discontinued if significant improvements are found in imaging studies, with no carbon dioxide retention and adequate oxygenation maintained. However, for the veno-arterial ECMO (V-A ECMO) mode, it is important to evaluate the recovery of lung and heart function. Common indicators for heart function recovery include maintenance of hemodynamic stability with low-dose vasopressors, a self-pulse pressure difference ≥20 mmHg, and improved bedside ultrasound indicators such as cardiac output, ventricular size, aortic velocity-time integral, and ejection fraction.

The patients who receive ULTx usually have more severe conditions than those who receive regular transplants.^[7] We developed a personalized pulmonary rehabilitation protocol tailored to the specific situation of each patient. To improve nutritional status, nutritional support was initiated before LTx. Within 24 h after admission, nurses conducted a comprehensive nutritional assessment using the Nutritional Risk Screening 2002 (NRS 2002) and weight measurements, followed by weekly monitoring. An NRS 2002 score of ≥3 indicated a higher risk of malnutrition. Nutritionists were consulted to develop a dietary plan that met the patient’s energy needs, with a protein intake of 1.2-2.0 g/(kg·d). We conducted real-time monitoring of nutrition-related indicators and recorded detailed daily nutrition. Given that patients needed mechanical ventilation waiting for transplantation, we adopted a strategy that comprised passive and active training. Passive training included limb relaxation and bed-bike training. Simultaneously, we managed patients’ physical condition in real time to prevent deterioration by changing physiological and psychological states. Therefore, the patients could receive surgical treatment in the best physical and mental state, reducing the occurrence of postoperative complications.

The recovery of lung function after ULTx largely depends on the early initiation of pulmonary rehabilitation.^[8] A five-step oxygen therapy protocol including early tracheal extubation, NIV, HFNC, nasal oxygenation, and deoxygenation was performed as follows. Step 1: As the patient’s condition improved, mechanical ventilation was immediately stopped after ECMO removal. Step 2: NIV and HFNC were administered as transitional treatments after tracheal extubation. NIV was continued for 12 to 18 h daily post-tracheal extubation to facilitate pulmonary expansion. Step 3: After 2 d, if partial pressure of CO₂ (pCO₂) exceeded 50 mmHg, NIV duration was reduced to 2-4 h. HFNC was conducted during the day, and NIV was reserved for nighttime if the pCO₂ remained within the normal range. Step 4: The treatment was gradually shifted toward full HFNC therapy. Step 5: Discontinuation of oxygen administration was initiated by gradually reducing oxygen flow and transferring the patient to a nasal cannula. In addition, pulmonary rehabilitation associated with specific oxygen support methods was employed.

A respiratory training device was used to strengthen the patients’ respiratory muscles, combined with active circulatory breathing supports to promote the development of efficient breathing patterns.^[8] After extubation, the patients were encouraged to participate in the training of respiratory function, including deep breathing, abdominal breathing, lip breathing, and cough. In a supine position with both knees semi-flexed and abdominal muscles relaxed, one hand was placed on the chest, and the other was placed on the abdomen. The hand on the chest remained stationary, while the hand on the abdomen moved rhythmically with each breath. Patients were instructed to take a deep nasal breath and hold it for 3 s, followed by pursing the lips to exhale slowly, extending the exhalation time. The set breathing rate was 6−8 breaths/min, and the ratio of inhalation to exhalation time was 1:2 or 1:3. Respiratory function training should be immediately stopped if two or more of the following conditions occur: respiratory rate >35 breaths/min, peripheral oxygen saturation (SpO₂) <90%, heart rate >130 beats/min, systolic blood pressure (SBP) >180 mmHg or <90 mmHg, signs of agitation, profuse sweating, cyanosis, altered level of consciousness, or asynchrony in chest and abdomen breathing patterns.

The sputum excretion method was selected according to guidelines.^[9] Before treatment, the patient’s respiratory function was evaluated considering factors that may affect sputum excretion. Airway clearance was found to be necessary when patients had the following conditions: (1) excessive secretions; (2) persistent sputum or an ineffective cough (as indicated by coarse wet rales in lung auscultation, decreased oxygenation/ventilation, and decreased pulmonary volume on chest X-ray); and (3) acute atelectasis or mismatched ventilation perfusion.

For patients receiving IMV, artificial airway aspiration is used. In conscious patients, they are required to learn sputum excretion. The sequential sputum excretion included the following steps. Step 1: The patient was assisted to the lateral position, followed by atomization inhalation. A manual or vibration expectoration apparatus was used to tap the patient’s chest and back. Step 2: For the patients undergoing IMV, airway suction was used. The conscious patients were instructed to breathe slowly and deeply 3-5 times (abdominal breathing), hold their breath for 1-3 s, and use their abdominal muscles to perform three sudden coughs. Step 3: Postural drainage, involving prone position training, was conducted for a minimum of 2-4 h daily. The training frequency was adjusted based on the patient’s condition, either twice daily or as needed.

Physiotherapy was promptly reinstated, commencing early mobilization as soon as the patient’s condition allowed.^[10] Each day, at the patient’s bedside, doctors, physical therapists, and responsible nurses evaluated vital signs, respiratory function, physical function, and other relevant factors before developing a personalized exercise program. Passive exercise training was employed when the patient’s muscle strength was grade 0 or 1 or when Richmond Agitation-Sedation Scale (RASS <−2). Active exercise training was carried out when the patient was conscious with muscle strength above grade 2. On the basis of muscle strength recovery, the exercise plan gradually transitioned from passive to active. Once tolerance was demonstrated, the training duration was progressively extended to 15-60 min with two sessions daily. Exercise should be immediately suspended if any of the following occurs: SpO₂ <88%, an increase in heart rate by 20%, heart rate <40 beats/min or >130 beats/min, SBP >180 mmHg, mean blood pressure <65 mmHg or >110 mmHg, and instances of increased intracranial pressure or new arrhythmia.

supplementary Table 1 shows the general information of the patients who received ULTx. This study included 12 males and 2 females, with an average age of 57.43±10.97 years, body mass index of 23.94±3.33 kg/m², APACHE II score of 21.50±3.96, and an NRS 2002 score of ≥3. One patient received a single LTx, and 13 patients received bilateral LTx.

The median waiting time for ULTx was 8.5 (interquartile range [IQR] 5.0-26.5) d. The primary diagnoses included interstitial lung disease (n=7), severe pneumonia (n=5), pulmonary interstitial fibrosis (n=2), pulmonary arterial hypertension (n=3), aspiration pneumonia (n=1), silicosis (n=2), and amyopathic dermatomyositis (n=1). Additionally, the patients presented with one or more comorbidities, such as hypertension (n=5), diabetes (n=4), hepatic/renal insufficiency (n=3), chronic hepatitis B (n=1), rib fracture (n=1), rheumatoid arthritis (n=1), asthma (n=1), and old tuberculosis (n=1).

All ULTx patients received ECMO support, with 13 undergoing V-V ECMO and one undergoing V-A ECMO, for an average duration of 7.5 (IQR 4.8-15.8) d. Following ECMO, all patients’ oxygen saturation levels remained above 95%, and no significant complications were reported during the waiting period. The median postoperative ECMO support time was 1.0 (IQR 1.0-2.0) d.

The overall average duration of IMV was 13.0 (IQR 5.8-23.3) d, with a median post-ULTx IMV duration of 5.0 (IQR 3.0-7.3) d. In addition, 12 patients discontinued mechanical ventilation early, achieving an oxygenation index of 327.83±67.37 mmHg postoperatively. After surgery, 11 patients were discharged from the ICU, with an oxygenation index of 355.45±84.23 mmHg.

The average length of ICU stay was 38.3±22.9 d following active treatment. The average postoperative hospital stay was 45.8±26.1 d, and the overall hospitalization time was 60.1±30.8 d. Septic shock and primary graft dysfunction were identified as the primary causes of mortality, resulting in two deaths within 30 d with a 30-day survival rate of 85.71%. Of the 11 patients who were discharged from the hospital, 10 survived for 3 months, and 9 were still alive by the time of this manuscript preparation. Acute respiratory failure was the primary cause of death after hospital discharge.

In the present study, patients experienced an average waiting time of 8.5 (IQR 5.0-26.5) d. All patients had oxygen saturation levels exceeding 95%. Throughout the waiting period for transplantation, no noticeable complications, such as severe bleeding or thrombosis, occurred. Patients were successfully and safely weaned from ECMO after transplantation.

Preoperative ECMO serves as a dual-purpose support system for lung transplant patients, providing both ventilation and oxygenation during the waiting period. Additionally, we adopted an awake ECMO approach to mitigate the adverse effects associated with tracheal intubation, such as pulmonary infection. This approach ensured the effective implementation of preoperative rehabilitation activities, thereby increasing the success rate of transplantation.^[11,12] In the present study, case 10 and case 14 underwent awake ECMO while awaiting LTx.

Case 10 received immediate V-A ECMO support and tracheal intubation for pulmonary hypertension induced by amniotic fluid embolism 8 d after cesarean surgery. Subsequently, extubation was successfully carried out once the patient regained consciousness, leading to improved oxygenation during the preoperative period. Case 14, with end-stage lung disease, received awake ECMO for worsening infection as a temporary measure before LTx utilizing V-V ECMO. Prompt initiation of pre-rehabilitation alleviated muscle atrophy, improved weakness, and enhanced overall physical function. It is important to recognize that although oxygenation has improved, the progression of infection may still pose a risk to patients.

One important strategy to promote the rehabilitation in LTx is early extubation, which can be safely performed intraoperatively or within a few hours after surgery. However, for patients undergoing ULTx, tracheal extubation within 72 h of surgery may pose greater challenges. Hoetzenecker et al^[13] reported a postoperative tracheal extubation time of 18 (IQR 4-33) d and a length of hospital stay of 72 (IQR 50-122) d. A previous study reported a postoperative tracheal extubation period of 10-14 d.^[3] In the present study, the extubation time was 5.0 (IQR 3.0-7.3) d, and the length of hospital stay was shorter than that in previous research. This difference may be attributed to our focus on nutrition and early mobilization throughout the perioperative period.

Although ULTx is an effective method for treating end-stage lung disease, the associated mortality rate is significantly high. In an Italian study, the recipients of ULTx had increased rates of postoperative complications and in-hospital death, with 30-day, 6-month, and 1-year survival rates of 81.8%, 76.2%, and 71.4%, respectively.^[3] Another Italian study reported an in-hospital survival of 62.5%, with a 1-year survival rate of 57.6%.^[14] A study conducted in France revealed that the recipients of ULTx faced a higher risk of early death, with a 30-day survival of 81% and a 1-year survival of 67.5%.^[11] According to research by the Scandinavian National Organ Storage and Transportation Organization, the 30- and 90-day graft survival rates were 90.6% and 87.5%, respectively.^[15] A USA study that included 119 patients receiving bridging ECMO and mechanical ventilation from 2005 to 2013 reported 6-month and 1-year survival rates of 68.1% and 61%, respectively.^[16] A German trial on LTx for the treatment of acute respiratory distress syndrome (ARDS) reported a median ventilator duration of 30 d and a one-year survival of 22%.^[17] The discrepancies in mortality rates after ULTx could be potentially attributed to differences in illness severity and inclusion criteria.^[5] The current study included patients with advanced age and severe underlying diseases and demonstrated perioperative outcomes, overall survival, and mortality that are comparable with those reported in earlier ULTx studies. This implies that with intensified and systematic supportive care, as demonstrated in this study, ULTx patients can achieve acceptable post-transplant outcomes.

The acceptable short-term survival rates in this study in the patients receiving ULTx validate that our center’s pre- and post-operative protocols are safe, feasible, and effective. A comprehensive analysis of each patient’s unique condition throughout the entire pulmonary rehabilitation process is crucial for achieving optimal rehabilitation outcomes, particularly in patients with complex underlying diseases awaiting ULTx.

Funding: None.

Ethical approval: The study was approved by ethical committee of the Second Affiliated Hospital of Zhejiang University School of Medicine.

Conflicts of interest: All authors declare that they do not have any potential conflict of interest in relation to this manuscript.

Contributors: FZ and LYC contributed equally to this study. All authors read and approved the final version of the manuscript.

All the supplementary files in this paper are available at http://wjem.com.cn.