Physiologic changes following lung transplantation

INTRODUCTION — Important physiologic changes occur over the months to years following lung transplantation. Some changes affect all lung transplant recipients; others may be dependent upon the type of lung transplant surgery performed (single lung transplantation (SLT), bilateral sequential or double lung transplantation (BLT), heart-lung transplantation (HLT), and living donor lobar transplantation (LDLT)), or on the pre-transplant diagnosis (eg, chronic obstructive pulmonary disease [COPD], interstitial lung disease, cystic fibrosis, pulmonary hypertension).

The effect of lung transplantation on long-term general respiratory physiology will be presented here. Other outcome measures, such as survival and quality of life, are discussed separately. (See "Lung transplantation: An overview" and "Heart-lung transplantation in adults".)

ANATOMIC CHANGES — In the process of donor lung retrieval, the vagus and sympathetic nerves, pulmonary and bronchial blood vessels, and lymphatics are interrupted. Although the pulmonary artery and pulmonary veins are reanastomosed to those of the recipient, the bronchial arteries that supply the airways are usually not revascularized. The recipient phrenic, vagus, and recurrent laryngeal nerves are sometimes injured during the operative procedure, more commonly during heart-lung transplantation or when cardiopulmonary bypass is needed.

Postoperative respiratory function of the recipient will reflect these changes in addition to any lung injury that occurs related to the procedure. If a single lung is transplanted, postoperative function will reflect the combination of donor lung and diseased recipient lung. A discussion of the different surgical procedures is provided separately. (See "Lung transplantation: Procedure and postoperative management".)

GENERAL PHYSIOLOGIC CHANGES — Lung transplantation alters many components of respiratory physiology. Some changes result from the surgical procedure, such as denervation of the transplanted lung, interrupted cough reflex, and reduced gastroesophageal motility.

Airway reactivity — Mild airway hyperresponsiveness, particularly in response to certain bronchoprovocations, is common among lung and heart-lung transplant recipients. However, it is generally not a clinically significant problem. Nevertheless, this abnormality may be associated with an increased risk of developing bronchiolitis obliterans syndrome (BOS).

Bronchial hyperresponsiveness in response to exercise, isocapnic hyperventilation, and inhalation of histamine and distilled water has been studied in lung transplant recipients. Small studies have found that neither exercise nor isocapnic hyperventilation provokes a significant decrement in forced expiratory volume in one second (FEV₁); distilled water inhalation challenge stimulated only a modest response in a minority of HLT recipients [1-3].

Methacholine challenge tests have yielded conflicting results. Hyperresponsiveness to methacholine has been confirmed in some, but not all studies [2-5]. When present, hyperresponsiveness was attributed to denervation hypersensitivity of airway smooth muscle muscarinic receptors [3,4,6]. Response to methacholine does not appear to correlate with time since transplantation, post-transplantation FEV₁, or airway inflammation [3,7]. In one study, patients with a positive methacholine challenge at three months were more likely to have gastroesophageal reflux disease, acute rejection (temporal relationship with challenge test not specified), and hospitalization within 30 days of discharge post-transplant [5].

Although bronchial hyperreactivity is nonspecific, early bronchial hyperresponsiveness to methacholine has been associated with a higher likelihood of developing BOS [8-10] or CLAD [5]. (See "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome".)

Cough reflex and mucociliary clearance — Two important lung defenses, the cough reflex and mucociliary clearance, are impaired following transplantation. These changes probably influence susceptibility to respiratory infection and the consequences of aspiration.

The afferent limb of the cough reflex from the transplanted lung is interrupted during organ procurement. Coughing can be stimulated from a remaining native lung or from sites in the respiratory tract proximal to the airway anastomosis. HLT recipients show a markedly decreased response to inhalation of nebulized distilled water despite the preservation of the laryngeal cough response [11].

Reduced airway clearance may be a risk factor for sequelae of aspiration (eg, lung injury and infection) in that prolonged contact time leads to greater likelihood of lung or airway injury. This problem has been demonstrated by the presence of bile acids in the bronchoalveolar lavage (BAL) of some transplant recipients, which appeared to be a risk factor for bronchiolitis obliterans syndrome [12].

Mucociliary clearance appears to be modestly decreased in the transplanted lung, but the mechanism has not been fully elucidated. Mucociliary transport depends upon the interaction between cilia and the overlying layer of mucus [13]. Both epithelial damage and ciliary dysfunction may contribute to poor clearance [14,15], but mucus secretion is also influenced by neurologic control. It is possible that post-transplant alterations in the quantity or the composition of mucus change its rheologic properties and retard clearance.

Control of breathing — Control of breathing is subtly altered after heart-lung and lung transplantation, but the changes are not clinically significant. The ventilatory response to hypercapnia has been variable [16-21]. In one series of patients with obstructive lung disease, hypercapnia, and a blunted response to CO₂ rebreathing before transplantation, hypercapnia and decreased ventilatory response to CO₂ persisted during the first week after single lung transplantation (SLT) or bilateral lung transplantation (BLT), but resolved by three weeks [20].

Both normal and mildly blunted responses to hypercapnia have been reported later in the postoperative period [17-19]; however, the ventilatory response to isocapnic hypoxia remains normal [17]. (See "Control of ventilation".)

Prior to lung transplantation, patients with advanced lung disease adapt their breathing patterns (frequency, tidal volume, proportion of time spent in inspiration) to compensate for their underlying lung disease. After lung transplantation, the breathing patterns during rest and exercise of transplant recipients with chronic obstructive pulmonary disease (COPD), cystic fibrosis, and pulmonary fibrosis are similar to those of healthy subjects [22], suggesting that lung disease-based adaptations in breathing pattern are reversible with lung transplantation [22].

Oropharyngeal dysphagia, gastroesophageal reflux, and gastroparesis — A spectrum of oropharyngeal and gastroesophageal disorders develops following lung transplantation. The pathogenesis is likely related to injury to the vagus, recurrent laryngeal, and superior laryngeal nerves at the time of surgery, or may be related to preoperative disease or the effects of transplant medications [23-25].

Swallowing impairments are common in the early postoperative period but may not be clinically evident. Postoperative development of swallowing difficulty was examined in a retrospective series of 263 lung transplant recipients [26]. Swallowing impairments were suspected on clinical swallowing examination by a speech pathologist in 57 percent of patients, who were subsequently referred for instrumental endoscopic or radiographic evaluation. Over 70 percent of the referred patients had laryngeal penetration or tracheal aspiration as assessed by fiberoptic endoscopic or video fluoroscopic swallowing studies, mostly due to silent aspiration without any protective mechanism (eg, cough). In addition, vocal cord paresis was frequently identified (25 percent) when a formal swallowing evaluation was performed. Similarly, in a lung transplant program where all recipients routinely undergo modified barium swallow study, 22 of 42 (52 percent) patients had atypical laryngeal penetration and/or aspiration, and 75 percent of those with abnormal studies had silent aspiration [27]. In another study of 297 lung recipients who underwent routine bedside and instrumental assessments, 67 percent had deep laryngeal penetration or aspiration on instrumental testing; nearly half of these patients had a normal bedside examination [28].

The mechanism of oropharyngeal dysphagia is probably multifactorial, including gastroesophageal reflux (GERD), recurrent and superior laryngeal (sensory) nerve injury, and local trauma from endotracheal intubation and intraoperative transesophageal echocardiogram. The clinical predictors of impaired postoperative swallowing are unclear, although number and duration of intubations as well as total time spent in the ICU were associated with speech-language pathology referral [29]. In a follow-up study, patients with a normal swallowing evaluation had improved survival, although oropharyngeal dysphagia was not an independent risk factor for BOS [30]. Our practice is to refer all newly transplanted patients with prolonged or recurrent endotracheal intubation for speech-language pathology assessment prior to commencing oral feeding.

Gastroesophageal dysfunction is common in patients with end-stage lung disease prior to lung transplantation. In one study of patients awaiting lung transplant, gastroesophageal reflux symptoms, esophageal dysmotility, abnormal pH probe testing, and delayed gastric emptying were reported in approximately 72, 33, 38, and 44 percent, respectively [31]. Pretransplant GERD may affect early outcomes after lung transplantation. Among 32 lung transplant recipients with objective evidence of GERD prior to transplantation, FEV₁ and survival at 18 months were decreased compared with 82 transplant recipients without GERD [32]. In a series of small retrospective cohort studies from a single center, reflux episodes and decreased bolus clearance detected on pre-transplant impedance monitoring were superior to pH measurement in predicting early allograft injury (acute cellular rejection and lymphocytic bronchiolitis) after lung transplantation [33]. These parameters were also associated with early hospital readmissions [34]. The same authors suggested that pre-transplant and early post-transplant (<6 month) antireflux surgery would improve outcome after lung transplantation by preventing the development of early graft injury [35]. Parameters detected on pre-transplant impedance monitoring and their impact on the development on chronic lung allograft dysfunction has not been fully explored.

Gastroesophageal dysfunction appears to be further increased following lung transplant surgery and is associated with CLAD. As examples [31,36-41]:

●GERD has been noted in 50 to 65 percent of transplant recipients [36-38,41]. In a cohort of 23 transplant recipients, 35 percent had GERD before transplant; this increased to 65 percent post-transplant (based on 24 hour pH probe analysis) [37]. GERD was not associated with esophageal or gastric dysmotility. A lower prevalence (48 percent) of GERD was found in a study of 45 transplant recipients, although patients were tested later in their post-transplant course [38].

●In a study of gastric emptying, delayed emptying was noted in 50 percent of pre-transplant patients, 74 percent of recipients at three months post-transplant, and 63 percent at 12 months [42]. In another study, delayed gastric emptying was noted in 39 of 43 lung transplant recipients at three months post-transplant and 17 of 21 at six months [31].

●Bile acids were found in BAL fluid in about half of 50 lung transplant recipients [31]. This finding was confirmed in another series; in addition, while pepsin was generally present in BAL from lung transplant recipients, 70 percent of the patients with BOS had bile acid in their BAL fluid compared to 31 percent of stable patients [38]. Furthermore, bile acid aspiration is associated with an increased rate of decline in FEV₁, progression of BOS >1, and decreased survival despite the use of azithromycin [43] (see "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome"). In a nested case-control study comparing BAL fluid three months post-transplant in lung recipients with and without GERD (confirmed by esophageal probe), 25 patients with GERD had higher levels of the bile acid taurocholic acid (TCA) in BAL fluid compared with 51 subjects without GERD, and BAL TCA levels declined after antireflux surgery [44].

●Pepsinogen A4, a precursor to pepsin secreted specifically in the stomach, was detected in large airway bronchial wash (LABW) in 7 of 61 samples from lung transplant recipients [45]. LABW PGA4 was associated with LABW bile acid levels and an increased risk of CLAD in 200 lung transplant recipients [45].

●Significantly higher BAL bile acid levels, neutrophilia, and IL-8 levels were detected in 12 lung transplant recipients with chronic Pseudomonas aeruginosa colonization, compared to 12 noncolonized controls [46]. This finding highlights a possible association between reflux, aspiration, and chronic bacterial airway colonization. Pepsinogen A4 was also associated with positive BAL cultures requiring treatment [45].

●Nonacid or weakly acidic reflux, as detected by impedance-pH testing, also appears common among lung transplant recipients [38,47]. In one study of 24 lung transplant recipients, the volume of reflux and an increase in nocturnal weakly acidic reflux events, even in the face of normal total reflux events, appeared to correlate with the presence of bile acids in BAL fluid [47].

Some programs have adopted an approach of early fundoplication post-transplant with the goal of preventing chronic lung allograft dysfunction [48,49]. However, there have been no randomized controlled trials of this approach, and uncontrolled cohort studies are susceptible to bias since less robust patients would not be offered fundoplication. Published observational studies are mixed, with some showing no evidence that fundoplication alters the trajectory of lung function decline or incidence of CLAD [50,51]. Moreover, pre-transplant gastroesophageal reflux may normalize after transplantation without intervention, and other patients may develop new gastroesophageal reflux after transplantation [52]. Thus, pre-transplant testing may not be a reliable basis for intervention. Esophageal motility tends to improve after transplantation, perhaps due to normalization of lung size and intrathoracic mechanics [52]. Our program’s current approach to asymptomatic patients is to reserve fundoplication for patients with severe post-transplant gastroesophageal reflux associated with declining lung function.

Respiratory and skeletal muscle function — Skeletal and respiratory muscle dysfunction are both observed in lung transplant recipients. The etiology is likely multifactorial; the principal mechanisms include deconditioning, critical care neuropathy, glucocorticoid related myopathy, and injury to the phrenic nerve.

●Leg muscle weakness, a consistent finding in lung transplant patients, appears to be independent of the underlying pre-transplant diagnosis and type of surgery [53-57]. A systematic review found that quadriceps strength ranged from 49 to 86 percent predicted in pre-lung transplant patients to 51 to 72 percent in the early postoperative period and 58 to 101 percent beyond three months post-transplant [58]. Furthermore, in a longitudinal retrospective study the initial increase in six-minute walk distance following lung transplantation was not continued between 6 to 12 months post-transplant; 58 percent of lung transplant recipients did not achieve the 82 percent predicted distance at 12 months. FEV₁ and quadriceps, or grip strength at discharge were predictive of reaching this value [59].

In a randomized controlled trial, a three-month rehabilitation program improved quadriceps force and other measures of physical fitness and functional capacity in uncomplicated lung transplant recipients over age 40 [60]. With rehabilitation, leg muscle strength can equal [61] or exceed [60] pre-transplant values.

●In addition, lung transplantation had a more profound effect on exercise tolerance in female patients and their muscle strength recovered more slowly despite intensive rehabilitation [62]. These findings suggest that deconditioning is not the only factor in the development of skeletal muscle weakness.

●A report of 12 patients found that the cumulative dose of glucocorticoids was an independent predictor of quadriceps atrophy, but not diaphragm or abdominal muscle weakness [53]. In contrast, another study found both diaphragmatic and leg weakness after a brief course of high dose glucocorticoids, as given to treat acute rejection [63]. (See "Glucocorticoid-induced myopathy".)

●The reported incidence of diaphragmatic paralysis due to phrenic nerve injury following lung transplantation has ranged from 3 to 30 percent [64-66]. In one series, phrenic nerve injury occurred more often in heart-lung than in single or double lung transplant recipients [65]. (See "Noninfectious complications following lung transplantation", section on 'Phrenic nerve and diaphragmatic dysfunction'.)

●In contrast, diaphragmatic strength improves after lung transplantation in most patients with COPD. This is related to a decrease in lung volumes and the restoration of a more normal diaphragmatic configuration rather than an increase in strength [67,68].

In addition, abnormal skeletal muscle oxidative capacity and calcineurin inhibitor therapy, as suggested by experimental studies, may contribute to ongoing muscle weakness in transplant recipients [69-72].

Sleep-disordered breathing — The incidence of sleep-disordered breathing (SDB) is increased in lung transplant recipients. As examples:

●In one series of 49 transplant recipients, 23 had obstructive sleep apnea (OSA) on polysomnography [73]. In another series of 24 recipients, 15 had SDB; nine of these patients had OSA while six had central sleep apnea [74]. In a separate cross-sectional study of 77 stable recipients, 43 percent had OSA and 6.5 percent had central sleep apnea, with OSA being more common in subjects with COPD or IPF as the indication for transplant [75]. In a prospective study of 219 consecutive lung transplant recipients who underwent routine testing at one-year post-transplant, moderate to severe SDB was detected in 126 patients (57.5 percent), of whom 93 (74 percent) had OSA [76]. A subset of patients who had pretransplant testing showed a significant increase in the apnea-hypopnea index post-transplant.

●SDB and nocturnal desaturation were not observed in two smaller series of heart-lung transplantation (HLT) recipients, although one study noted an increased breathing frequency during sleep, particularly among patients with restrictive pulmonary function tests (PFTs) [16,77].

●A prospective study of 20 patients studied pretransplant and at six-months and one-year post-transplant showed a prevalence of obstructive sleep apnea (OSA) of 38 percent pre-transplant, 86 percent at six months, and 76 percent at 12 months post-transplant. The median apnea-hypopnea index (AHI) increased from 7 pre-transplant to 20 at six months post-transplant. Although obstructive apneas were predominant, central and mixed apneas were also observed [78].

Potential contributing factors for sleep-disordered breathing following lung transplantation, include pharyngeal muscle dysfunction, glucocorticoid-induced central fat deposition, increased body mass index (BMI), pretransplantation sleep-disordered breathing, and abnormal pulmonary function [79-81]. In addition, lung transplantation may impair the reflexes that maintain upper airway patency during sleep and sedation, thus resulting in upper airway obstruction [73]. (See "Pathophysiology of upper airway obstruction in obstructive sleep apnea in adults".)

Patients with pulmonary arterial hypertension may exhibit nocturnal periodic breathing, similar to Cheyne-Stokes respiration; reversal of periodic breathing was reported in a patient with pulmonary hypertension following lung transplantation [82]. Possible contributing factors to central sleep apnea in lung transplant recipients include lung denervation affecting the control of breathing, altered chemoreceptor sensitivity, and changes in respiratory drive due to transplant related medications [74].

PULMONARY FUNCTION TESTING — After lung transplantation, pulmonary function tests (PFTs) typically reflect the pretransplant lung disease, the type of surgical procedure (eg, single, bilateral, heart-lung, or living lobar transplantation), and development of complications such as infection, acute lung allograft rejection, airway complications, or chronic lung allograft dysfunction.

Spirometry — Over the first few months after transplantation, forced vital capacity (FVC) and forced expiratory volume in one second (FEV₁) usually improve, generally reaching a plateau by one year although the best post-transplant values might be achieved at different time points for FEV₁ and for FVC [83]. At this point, the postoperative values approach the recipient's predicted value (as determined by age, height, and sex). As examples:

●In a retrospective review of bilateral lung transplantation (BLT) and single lung transplantation (SLT) for chronic obstructive pulmonary disease (COPD), post-transplant spirometry was obtained in 130 patients; the majority of improvement occurred in the first three months following SLT and BLT; slight further improvement continued up to 12 months after SLT and up to about 24 months in a few patients after BLT [84].

●In a retrospective review of 178 bilateral lung transplant recipients, the median time to best baseline lung function after transplant was 440 days (interquartile range 143 to 921) with a highly variable trajectory. The mean FEV₁ achieved was 90 percent predicted and FVC 90 percent predicted. However, 42 percent of patients did not achieve normal FEV₁ or FVC post-transplant and this was associated with decreased post-transplant survival [85]. A separate retrospective study of 217 BLT recipients found that 51 percent achieved normal spirometry (FEV₁/FVC ≥0.7 and FEV₁ and FVC ≥80% predicted) within the first 12 months post-transplant, while 64 percent achieved normal baseline spirometry at a range of 27 to 1889 days post-transplant. Abnormal baseline or 12-month spirometry was associated with reduced survival and CLAD [86].

●In a retrospective review of 33 heart-lung transplant (HLT) recipients, vital capacity (VC) and FEV₁ were 100 percent of predicted two months after transplant [87].

Approximately 50 percent of bilateral lung transplant recipients have a flow volume loop pattern with a midvital capacity expiratory to inspiratory flow ratio (Ve50/Vi50) greater than 1, a supranormal expiratory flow with a ratio of Ve50/FVC ≥1.5/sec, and an absence of identifiable causes of extrathoracic obstruction [88]. This pattern is associated with implantation of relatively larger donor lungs compared with the predicted volume of the recipient thorax. It is hypothesized that the mismatch in size could lead to increased lung elastic recoil or decreased airway resistance.

Declines in the FEV₁ following lung transplantation may be a manifestation of acute or chronic rejection, infection, airway stenosis or other issues. When all other causes have been ruled out, an otherwise unexplained decline in FEV₁ is indicative of chronic lung allograft dysfunction (CLAD), which may have a primarily obstructive (bronchiolitis obliterans syndrome [BOS]), restrictive (restrictive allograft syndrome [RAS]) or mixed phenotype. CLAD phenotypes are identified based upon a combination of spirometry, total lung capacity, and chest CT appearance [89]. (See "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome" and "Chronic lung allograft dysfunction: Restrictive allograft syndrome".)

Lung volumes — Several studies have examined the time course and patterns of changes in lung volumes after lung transplant.

Characteristics of the recipient thoracic cage, as determined by the recipient's predicted or pretransplant TLC, appear to be the major determinant of TLC and VC in SLT, BLT, and HLT [90-93]. In one study of 32 heart-lung transplant recipients, for example, the total lung capacity one year after surgery approached the recipients' pretransplant value, independent of the size of the donor lungs [90].

However, some studies have found slightly different correlations [93-95]. As an example, in a series of 71 standard, size matched (often slightly over sized) transplantations, postoperative TLC correlated with the recipients' pre-transplant value and donor predicted TLC [94]. In contrast, in size reduced (eg, split-lung, segmental resection, lobectomy) and living lobar transplantation, the post-transplant lung volumes were more dependent on donor lung volumes [94]. Total lung capacity in size reduced lung transplantation and FVC in living donor lung transplantation (LDLT) can usually be estimated based on donor lung volumes adjusted to the number of segments implanted [94,95].

The relative contribution of the rib cage and abdominal compartments to end-inspiratory and end-expiratory chest wall volumes during exercise is similar in lung transplant recipients and healthy controls [22]. In contrast, patients with end-stage lung disease have substantially smaller increases in inspiratory lung volumes (both ribcage and abdominal compartments) when comparing rest and peak exercise values.

Additional factors that may affect the static and dynamic lung volumes in the post-transplant period include [89]:

●Graft related airflow obstruction (eg, infection, acute rejection, BOS, anastomosis stenosis, dehiscence, and malacia, and also disease recurrence)

●Native lung related airflow obstruction (hyperinflation, disease progression)

●Restrictive ventilatory limitation without decrease of the FEV₁/VC ratio (chronic postoperative pain, increased body mass index, respiratory muscle weakness, rib fracture, pleural effusion, disease recurrence)

●Development of RAS, a form of CLAD, is associated with a decline in total lung capacity (in addition to forced vital capacity) and high-resolution computed tomography (HRCT) findings of ground glass opacities, intra- and interlobular septal thickening, traction bronchiectasis, and peripheral consolidation [96-99]. In contrast, patients with BOS have an obstructive pattern on spirometry and the HRCT shows air trapping and bronchiectasis [89]. (See 'Spirometry' above and "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome".)

Gas transfer — Changes in diffusing capacity (DLCO) after lung transplantation are affected by the recipient's underlying lung disease and whether the transplant is an SLT or BLT [100]. As an example, DLCO improved by 50 percent in patients with interstitial lung disease who received an SLT, compared with 150 and 300 percent in emphysema patients who received SLT and BLT, respectively [100]. In a study of 1259 bilateral lung transplant recipients, the median time to peak DLCO after transplantation was 354 days (range 181 to 737 days) and recipients attained a mean of 80 percent predicted DLCO (standard deviation 21 percent) [101].

Following heart-lung transplant, the distribution of perfusion and ventilation are normal and arterial blood gases are typically normal by eight weeks post-transplant [102]. DLCO is reported to be normal to mildly reduced [103,104].

Exercise function — In the absence of complications, heart-lung and lung transplant recipients experience improved functional capacity; however, a persistent exercise limitation remains regardless of the type of surgery or the underlying lung disease [56,105-116]. Other solid organ transplant recipients exhibit a similar pattern of impairment [117-119].

The physiologic changes in response to exercise are characterized by:

●Reduced (40 to 60 percent predicted) peak oxygen consumption VO₂

●Early onset of anaerobic threshold (at submaximal VO₂)

●Normal gas exchange

●Adequate heart rate reserve

●Sufficient cardiac output to maintain the workload reached

●Absence of ventilatory or cardiac limiting factors

Oxygenation remains normal during peak incremental and steady state exercise in HLT and BLT patients as well as in SLT patients with obstructive lung disease [107,108,111,120,121]. However, mild exercise desaturation may be seen in SLT recipients with restrictive parenchymal or pulmonary vascular disease [106,107].

The pattern of exercise limitation is most compatible with skeletal muscle dysfunction [54,69,122]. Impaired oxidative capacity (O₂ uptake and utilization) may be due to pre-transplant deconditioning, muscle atrophy and/or adverse effects of immunosuppressive drugs (eg, glucocorticoids).

Physiologic measurements during high-altitude mountain expeditions have demonstrated the feasibility and safety of high-altitude exercise in stable, trained lung transplant recipients compared with healthy controls [123,124].

Operation specific changes — The specific transplant procedure, whether SLT, BLT, HLT or LDLT, influences the post-transplant pulmonary function test results.

With SLT, static and dynamic lung volumes depend to some extent on the physiologic properties of the remaining native lung:

●In one study of patients with pulmonary fibrosis, vital capacity following SLT increased from a mean preoperative value of 43 percent to 69 percent of predicted at one year [125].

●In SLT recipients with obstructive lung disease, the FEV₁ can rise to 50 to 57 percent of predicted and mild elevation of TLC persists [115,126-129]. After SLT for obstructive lung disease, approximately 80 percent of both the ventilation and perfusion are distributed to the transplant allograft [106]. In contrast, following SLT for restrictive lung disease, a similar pattern of perfusion is seen, but only 60 to 70 percent of the total ventilation is directed to the transplanted lung [106,125].

Following BLT, the original pathological process has little impact upon the pulmonary function of the graft. FEV₁, FVC and TLC are generally in the low normal range at six to nine months post transplantation with an average FEV₁ of 78 to 85 percent predicted and FVC of 66 to 92 percent predicted [115,126,127,130]. Following HLT, pulmonary function testing shows a mild restrictive ventilatory pattern [103].

Lung volumes in LDLT recipients usually progressively increase up to 12 months post transplantation, similar to SLT and BLT patients [95,131]. In LDLT, allograft FVC can be estimated based on the donor lung FVC and the number of pulmonary segments implanted and correlates well with the recipients' measured post-transplant values [95]. Maximum workload at peak exercise, maximum heart rate, peak VO₂, oxygen consumption at anaerobic threshold, and the ability to maintain O₂ saturation were similar in LDLT and cadaveric bilateral transplant recipients [131].

Despite the transplantation of significantly less lung tissue, pulmonary function with LDLT appears to approximate that observed with deceased donor BLT by six months post-transplant. In one study comparing two transplantation procedures (LDLT versus deceased donor BLT), the first and third post-transplant month values were significantly lower in the LDLT group, but by six months there was no difference between them [131]. This was true even after the subgroup analysis of recipients with less than two years and more than two years survival. Forced vital capacity increased to a mean of 63.6 percent of predicted, FEV₁ to the mean of 64.5 percent of predicted by six months post transplantation.

DISEASE SPECIFIC CHANGES — The underlying lung disease for which transplantation is performed and the type of transplantation procedure influence postoperative respiratory physiology. Disease specific survival following the various lung transplant procedures is discussed separately. (See "Lung transplantation: Disease-based choice of procedure".)

COPD/emphysema — Single lung (SLT) and bilateral lung (BLT) transplantation are performed for patients with chronic obstructive pulmonary disease (COPD)/emphysema. With both procedures, forced vital capacity (FVC) and forced expiratory volume in one second (FEV₁) increase compared with pretransplant values. However, some differences in post-transplantation respiratory function after SLT compared with BLT have been observed [84,127,132,133]. As an example, a retrospective review comparing spirometry results after BLT and SLT found that FVC was about 10 percent higher at one and five years following BLT, and FEV₁ was about 15 to 20 percent higher at the same time points [134]. Similar results were found in a smaller series that also found a 30 percent increase in the distance walked in six minutes (six-minute walk test [6MWT]) [84].

In an observational study of patients with COPD, physical activity as measured by a pedometer was significantly greater (6642 versus 1407 steps) among 47 lung transplant recipients compared with 15 lung transplant candidates; lower extremity strength and FEV₁ were also improved [135].

A small study of SLT in 19 patients with emphysema found that donor lung volume was slightly more than half what was expected based on donor predicted values [136]. The reduction in lung volume was predominantly related to a lower chest wall volume and partially related to continued hyperinflation of the emphysematous native lung. A decrease in inspiratory muscle strength appeared to contribute to the decreased chest wall volume.

There is no statistical difference between a left versus a right SLT in terms of pulmonary function test results and graded exercise results. A trend towards a greater increase of FEV₁ and FVC with right SLT has been observed and is most likely due to the larger size of the right lung [137].

Cystic fibrosis — BLT is the procedure of choice in chronic suppurative lung diseases such as cystic fibrosis (CF); however, occasionally heart-lung transplantation (HLT) or living donor lobar transplantation (LDLT) are performed.

Following BLT or HLT for cystic fibrosis, the FEV₁ generally increases to 70 to 80 percent of predicted for the recipient and remains stable in the absence of other complications [138-144]. LDLT recipients are reported to have lung function comparable to that of BLT recipients of deceased donor lungs at one year post transplant [131].

Hemodynamic analysis at one year following LDLT revealed normal pulmonary artery pressures and pulmonary vascular resistance [145]. This demonstrates the ability of two lobes to accept the entire cardiac output.

Interstitial lung diseases — Both single and bilateral lung transplantation are employed in patients with interstitial lung diseases (ILD); in one study there was no statistical difference in pulmonary function test results after transplantation when the two methods were compared [146]. There was a trend towards slightly increased mean FEV₁ in BLT recipients, but there was no significant difference in terms of exercise capacity.

Post-transplant vital capacity (VC) in transplant recipients closely correlates with the predicted normal VC of the donor after left SLT. In contrast, VC may be the same or smaller than the predicted normal VC of the recipient in right SLT [93,109]. This may be explained by the ability of the left hemithorax to accommodate a larger donor organ by the descent of the diaphragm to a normal position and by the shift of the mediastinum to the right.

Pulmonary arterial hypertension — Bilateral lung transplantation is the procedure of choice for patients with pulmonary arterial hypertension (PAH); heart-lung transplantation is performed on rare occasions (eg, compromised left ventricle function). (See "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)".)

The main physiologic changes that specifically apply to patients with PAH are hemodynamic and are mostly related to the type of transplant surgery [127,147-152]:

●Cardiac index, mean pulmonary artery pressure, and pulmonary vascular resistance usually return to normal after HLT or BLT.

●Mean pulmonary artery pressure and pulmonary vascular resistance decrease significantly after SLT. However, improvement in the hemodynamic outcome parameters remains inferior to BLT or HLT [153].

●SLT may be complicated by ventilation/perfusion mismatch and hypoxemia in the setting of acute rejection or donor lung infection, when ventilation usually shifts to the native lung [147-150,154,155].

Following BLT, a sudden decrease in pulmonary artery pressure may lead to a decrease in the cavity of the hypertrophied right ventricular (RV) resulting in ventricular outflow obstruction. This somewhat unusual complication can be diagnosed by transesophageal echocardiography; once this is recognized, cessation of inotropic agents may lead to hemodynamic improvement [156]. Left ventricular dysfunction can also transiently occur in the setting of restored RV function, likely due to a compliance disorder of the small left ventricle (LV) and paradoxical ventricular septal movements [151].

Reverse remodeling of the right ventricle has been shown to occur after lung transplantation for PAH. In general, patients demonstrate significant and sustained improvements in right ventricular function by echocardiography [127,148,150,157,158]. In addition, tricuspid regurgitation improves and flattening of the intraventricular septum disappears. These findings were demonstrated in a cohort of 14 patients with PAH who had normal RV size at three months after BLT [158]. However, improvements in right ventricular hypertrophy may not occur immediately post-transplant [148]. Instead, RV hypertrophy regresses as part of the long-term reverse remodeling process.

Secondary pulmonary hypertension — Patients with secondary pulmonary hypertension (SPH) experience modest and heterogeneous improvements in hemodynamics after lung transplantation, with patients with more severe SPH experiencing greater improvements [159,160]. One group reported improved right ventricular function after transplantation in only two of six patients with SPH [157]. In contrast, a larger study of 45 patients with SPH demonstrated a significant decrease in pulmonary arterial pressure in transplant recipients with both low and high preoperative SPH [160]. In this study, more severe SPH was not associated with adverse outcome despite the more frequent use of cardiopulmonary bypass, greater reperfusion lung injury, and greater dependence on nitric oxide and oxygen [160], suggesting that single lung transplantation may be acceptable for patients with SPH.

SUMMARY AND RECOMMENDATIONS

●Types of post-transplant physiologic change – A variety of physiologic changes occur following lung transplantation; some affect all lung transplant recipients, while others may be dependent on the type of lung transplant surgery performed (single lung transplantation [SLT], bilateral lung transplantation [BLT], heart-lung transplantation [HLT], and living donor lobar transplantation [LDLT]), or on the pre-transplant diagnosis. (See 'Introduction' above.)

●Anatomic changes – When donor lungs are transplanted, vagal and autonomic nerves, and also pulmonary, bronchial, and lymphatic vessels are all interrupted. One of the interrupted nerves is the afferent limb of the cough reflex; coughing can be stimulated from a remaining native lung or from sites in the respiratory tract proximal to the airway anastomosis, but may be blunted in the transplanted lung. (See 'Anatomic changes' above.)

●Oropharyngeal and gastroesophageal consequences – Following lung and heart-lung transplantation, gastroesophageal reflux symptoms, esophageal dysmotility, and delayed gastric emptying are frequent. Swallowing impairments are also common in the early postoperative period. As a consequence of gastroesophageal dysmotility, aspiration of gastric and bile acids may occur and contribute to acute rejection and chronic lung allograft dysfunction (CLAD). (See 'Oropharyngeal dysphagia, gastroesophageal reflux, and gastroparesis' above.)

●Respiratory and skeletal muscle function – Diaphragmatic strength improves after lung transplantation in most patients with chronic obstructive pulmonary disease (COPD), however diaphragmatic paralysis may occur in 3 to 30 percent of transplant recipients, more commonly those receiving HLT. Skeletal muscle strength is reduced in most transplant recipients, probably due to deconditioning and effects of immunosuppressive medications post-transplant. Rehabilitation is effective at improving strength. (See 'Respiratory and skeletal muscle function' above.)

●Changes in pulmonary function – Forced vital capacity (FVC) and forced expiratory volume in one second (FEV₁) usually improve over the first three months following SLT and BLT; slight further improvement occurs up to about 24 months after BLT. (See 'Pulmonary function testing' above.)

●Exercise tolerance – In the absence of complications, lung transplant recipients experience improved functional capacity; however, a persistent exercise limitation remains regardless of the type of surgery or the underlying lung disease. In part, this is caused by skeletal muscle dysfunction from deconditioning and medications. (See 'Exercise function' above.)

●Pulmonary vascular changes – Following BLT or HLT for pulmonary arterial hypertension (PAH), cardiac index, mean pulmonary artery pressure, and pulmonary vascular resistance usually return to normal. After SLT for PAH, mean pulmonary artery pressure and pulmonary vascular resistance decrease significantly, but cardiac index is less likely to improve. (See 'Disease specific changes' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Roland G Nador, MD, who contributed to an earlier version of this topic review.