Original Clinical ScienceçGeneral
Sleep-Related Breathing Disorders and Lung Transplantation Ana R. Hernandez Voth,1 Pedro D. Benavides Mañas,1 Alicia De Pablo Gafas,2 and María J. Díaz de Atauri Rodríguez3 Aim. Sleep-related breathing disorders (SRBD) are common in patients with lung transplantation (LT); however, there are few data
about its prevalence, and none about its pathogenesis or evolution. The SRBD events consist mainly obstructive, central, and mixed apnea, as well as hypopneas. The aim of this study was to describe the prevalence of SRBD before the LT, and its evolution after a period of 1 year follow-up. Methods. Prospective, observational, descriptive, and analytical study of the SRBD and its evolution in 20 LT patients. The group was studied before and at 6 and 12 months after the LT; in each phase, standard polysomnography was performed, and anthropometric, pathologic, clinical, and pharmacological data were collected. Results. Prevalence of obstructive sleep apnea syndrome was 38% before the LT, 86% at 6 months, and 76% at 12 months after LT. There was a significant increase of weight, body mass index, neck circumference, blood pressure during the first year of follow-up, especially at 6 months after LT. We also observed an increase in the number of central and mixed apneas during the follow-up, although not as remarkable as obstructive apneas. There was no correlation between immunosuppressant studied drugs and any of the studied variables. Conclusions. We have observed a significant prevalence of obstructive sleep apnea syndrome in patients in waiting list for LT, and LT has an important influence in the evolution of the disorder. In our series, LT has somehow affected the stability of upper airway and ventilatory mechanics. (Transplantation 2015;99: e127–e131)
S
leep-related breathing disorders (SRBD) are commonly observed in lung transplantation (LT)1 patients; however, there is limited published information regarding their prevalence and no studies about pathogenesis, evolution, and treatment in this population. Sleep-related breathing disorders are common in patients with terminal chronic respiratory failure2 and respiratory failure may even potentiate SRBD, thus increasing the severity of the obstructive sleep apnea syndrome (OSAS) as oxygenation worsens.3 Lung transplantation has been consolidated as an important therapeutic strategy for chronic respiratory failure, and as a result of the latest advances in surgical techniques, intensive care, and immunosuppressive drugs, patients with LT Received 26 June 2014. Revision requested 11 July 2014. Accepted 4 November 2014. 1
have increasing life expectancies.1 In addition to the main known causes of mortality in LT recipients, such as rejection and infections,4 and given their increasing survival rates, the patients have now an increased probability of developing chronic secondary effects, such as obesity and arterial hypertension (AH). The association of both of these chronic disorders with SRBD has been studied in the general population,5 but not in the LT recipient population. Previous studies6 analyzed the prevalence of SRBD in patients on the LT waiting list, or several months after and at different progression times of the transplant. The first objective of this study was to describe the prevalence of SRBD in patients with chronic terminal respiratory failure who were on waiting list for LT; the second objective was to analyze the evolution of SRBD during a follow-up period of 1 year after the LT.
Department of Pneumology, 12 de Octubre University Hospital, Madrid, Spain.
2
MATERIALS AND METHODS
3 Department of Pneumology, Sleep Disorders Unit, CIBERES, 12 de Octubre University Hospital, Madrid, Spain.
(1) Study design: prospective, observational, descriptive, and analytical study of SRDB in patients before and after LT. (2) Population: population consisted in all patients who had undergone a LT in our center, have had a polisomnography (PSG) before the LT and who underwent a PSG at 6 and 12 months after LT (n = 21). A standard PSG was performed in all LT waiting list patients except for: (a) Patients receiving noninvasive mechanical ventilation, such as bilevel positive airway pressure as a bridge to lung transplant (7 patients). (b) Patients who joined the waiting list presenting urgent clinical conditions requiring orotracheal intubation and noninvasive mechanical ventilation (2 patients).
Department of Pneumology, Lung Transplantation Unit, 12 de Octubre University Hospital, Madrid, Spain.
The authors declare no funding or conflicts of interest. Correspondence: Ana R. Hernandez Voth, Hospital Universitario 12 de Octubre, Av. De Córdoba s/n. Madrid, 28041, Spain. ([email protected]) A.R.H.V. participated in research design, in the writing of the article and performance of the research. P.D.B.M. participated in research design and performance of the research. A.D.P.G. participated in research design and writing of the paper. M.J. D.d.A.R. participated in research design and writing of the paper. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0041-1337/15/9909-e127 DOI: 10.1097/TP.0000000000000600
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FIGURE 1. Diagram of the patient selection process. Pre LT, before lung transplantation; NIMV, noninvasive mechanical ventilation; post LT, after lung transplantation.
(c) Patients whose clinical condition required an urgent lung transplant, consequently, there was no time to perform a PSG according to protocol (11 patients). After excluding these patients, 85 had been positively assessed and included in the LT waiting list and pre-LT PSG were performed. Within the group, 44 patients were excluded given the fact that after data compilation, they had not undergone LT or they had not fulfilled the 12 months follow-up previously agreed on the objectives since the LT. In the case of the remaining 41 patients, PSG could not be performed in 13 of them at 6 months, and in 7 at 12 months, due to severe clinical conditions in both cases which made it difficult to perform the PSG according to protocol. Finally, 21 patients at follow-up at 6 months and 12 months after LT took place without SRBD diagnose before admittance in the waiting list and with pre-LT, at 6 and 12 months post-LT PSG (Figure 1). Informed consent was obtained from all patients before their participation in this study. (3) Study period: From March 2009, when we had our first LT and PSG case, through December 2012, when we had our last PSG at 12 months follow-up. Study phases: All of the studied variables were analyzed in three phases: –Phase I: before the LT (pre-LT) –Phase II: 6 months after transplantation (6 months post-LT) –Phase III: 12 months after transplantation (12 months post-LT) (4) Sleep studies: sleep studies were conducted using a standard PSG at the Multidisciplinary Sleep Unit of the 12 de Octubre University Hospital. An Alice 5 (Phillips) 12 channels polysomnography was used. Each PSG was manually analyzed by qualified personnel from the unit using the SEPAR7 and AASM8 guidelines. Obstructive sleep apnea syndrome was defined as an AHI greater or equal to 10 events per hour of sleep and was considered severe if AHI is 30 or higher. (5) Immunosuppressive drugs protocol: all patients received induction immunosuppression with Basiliximab and maintenance treatment with steroid drugs, a calcineurin (Cyclosporine or Tacrolimus), and a purine inhibitor (Azathioprine or Mycophenolate). Treatment with steroids bolus was indicated in patients with a diagnosis of acute graft rejection and was followed by a later progressive decrease to the usual previous dosage.
(6) Measurements: the follow-up took place at the Multidisciplinary Sleep and Lung Transplant Units of the 12 de Octubre University Hospital. The study was divided into a pre-LT phase, a phase at 6 months after LT, and another phase at 12 months after LT. At each phase, in addition to obtaining and analyzing the PSG, the following data were obtained: –Anthropometric data: age, sex, weight, height, BMI (weight/ height2), and cervical perimeter –Clinical data: underlying lung pathology before the LT, home oxygen needs, and measurements of systolic and diastolic arterial pressure. Symptoms suggesting respiratory disorders during sleep were gathered via the Epworth Sleepiness Scale questionnaire,5 and a score greater than 10 was considered as excessive daytime sleepiness. –PSG data: the total sleep time and percentage of sleep time for each phase, AHI, ODI, and the proportion of sleep time with an oxyhemoglobin saturation lower than 90% (TC90). –Pharmacological data: the total accumulated and daily mean doses of the immunosuppressive medications administered after the LT (steroids, tacrolimus, cyclosporine, mycophenolate, azathioprine, everolimus) were quantified. The doses of these medications were registered in phases II and III of the study (7) Statistical analysis: for the numeric variables, arithmetic means with standard deviations and medians with ranges were TABLE 1.
General characteristics of the studied population Age
Sex Male Female LT indication COPD Interstitial Lund disease Cystic fibrosis Primary pulmonary hypertension LT modality Bilateral Unilateral
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53.7 (± 10.8)
13 (62%) 8 (38%) 10 (42%) 7 (33%) 2 (10%) 2 (10%) 12 (57%) 9 (43%)
Voth et al
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TABLE 2.
Evolution of the studied clinical and sleep variables Analyzed variables
Before LT
Weight (mean ± SD), kg Body mass index (mean ± SD) Neck circumference (mean ± SD), cm Systolic blood pressure (mean ± SD), mm Hg Diastolic blood pressure (mean ± SD), mm Hg Apnea/hypopnea index, median (range) TC90, median (range) ODI, median (range) SpO2 minimum (mean ± SD) Epworth sleepiness scale score (mean ± SD) Total sleep time (mean ± SD), min Sleep efficacy (mean ± SD), % Sleep efficiency (mean ± SD), % Arousal index (mean ± SD) Obstructive apneas, median (range) Central apneas, median (range) Mixed apneas, median (range) Hypopneas, median (range)
6 mo after LT
60.4 ± 10.7 22.4 ± 3.7 37.05 ± 3.3 114.5 ± 13.6 71.3 ± 8.3 7 (0-40) 1 (0-100) 1 (0-23) 84.3 ± 9.6 6.9 ± 2.9 291.7 ± 84.6 29.5 ± 10.8 68.3 ± 18.7 39.5 ± 15.4 3 (0-129) 0 (0-2) 0 (0-3) 27 (0-137)
12 mo after LT a
63.9 ± 12.3 24.1 ± 4.1 a 38.3 ± 3.5 a 124.9 ± 19.1 a 77.6 ± 11.7 a 20 (6-89) a 2 (0-57) 11 (1-85) a 82.3 ± 8.9 6.85 ± 2.9 360.2 ± 61.8 a 27.95 ± 13.2 82.15 ± 13.3 a 48.6 ± 22.1 32 (2-549) a 0 (0-45) a 0 (0-42) a 69 (14-178) a
65.7 ± 11.7 b 24.8 ± 4.1 bc 39.2 ± 3 b 124.1 ± 16 76.5 ± 11.1 23 (3-93) b 2 (0-81) 13 (1-100) b 81.4 ± 8.6 5.9 ± 3.6 333.2 ± 74.9 27.2 ± 11.9 81.8 ± 17.9 b 40.1 ± 17.6 28 (0-264) b 1 (0-37) b 1 (0-50) b 52 (4-329) b
a
Statistically significant difference between pre-LT and 6 months after LT (P < 0.05). Statistically significant difference between pre-LT and 12 months after LT (P < 0.05). Statistically significant difference between 6 and 12 months after LT (P < 0.05). TC90, proportion of total sleep time of oxihemoglobin saturation under 90%. b c
calculated for variables with normal and non-normal distributions, respectively. The data were analyzed using nonparametric statistical tests (McNemar test, Mann-Whitney U test, and Wilcoxon test). The statistical program used was SPSS 17.0 (SPSS Inc., Chicago, IL). A P value less than 0.05 was considered statistically significant.
RESULTS A diagram of the patient selection process and final simple is shown in Figure 1. Population general characteristics are shown in Table 1. The evolution of the clinical variables and the PSG parameters for each phase of this study are presented in Table 2.
(1) Phase I. Pre-LT: a 38% prevalence of OSAS (8 patients) was observed; 1 patient was diagnosed with severe OSAS. Five patients had a diagnosis of chronic obstructive pulmonary disease (COPD), and 3 patients had usual interstitial pneumonia (UIP). Two patients had AH controlled with pharmacological treatment. All sleep studies done in pre-LT phase were performed using continuous oxygen therapy, according to the terminal respiratory distress situation in all patients. (2) Phase II. 6 months after LT: compared with the pre–lung transplant phase, a statistically significant increase was observed in systolic arterial pressure (P = 0.008), weight (P = 0.03), body mass index (BMI) (P = 0.01), and cervical perimeter (P = 0.002). Apnea hypopnea index (AHI) and oxyhemoglobin desaturation index (ODI) also increased
FIGURE 2. Evolution of Apnea Hypopnea Index and Oxyhemoglobin Desaturation Index in lung transplantation recipients.
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significantly during this phase (P = 0.001 both) (Figure 2). At this phase, the frequency of OSAS increased to 86% (18 patients) (Figure 3), 8 of whom were classified as having severe OSAS. Eight patients retained the diagnosis of OSAS from phase I of the study (the total number of patients who were diagnosed with OSAS in phase I), and 9 patients developed the disorder de novo during this phase. The diseases before the LT were COPD in 9 patients (50%), UIP in 6 patients (33.3%), and cystic fibrosis (CF) in 2 patients (11.1%). The LT was single in 8 cases (44.4%) and double in 10 patients (55.5%). Obstructive sleep apnea syndrome was diagnosed in 10 of the 11 double LT patients and in 8 of the 9 single LT patients, with no significant differences between the types of LT and the development of OSAS. (3) Phase III. 12 months after LT: compared with phases I and II, the elevation of the systolic arterial pressure found in phase II was sustained. Weight, BMI, and neck perimeter (P = 0.004, P = 0.004, and P = 0.006, respectively) also maintained the elevation observed in the previous phase. The prevalence of AHI and ODI also remained elevated (Figure 2). In phase III, we observed a tendency toward maintaining the frequency of OSAS in comparison with the previous phase (Figure 3); 16 patients were diagnosed with OSAS (76%), 9 of them had severe OSAS. Of the 8 patients with OSAS in phase I, 7 continued presenting the disorder in phase III; of the 9 patients who developed OSAS during phase II, 7 continued presenting the disorder during phase III. Two new cases of OSAS were observed at 12 months after LT. The diseases before LT in these patients were COPD in 8 patients, UIP in 6 patients, CF in 1 case, and primary pulmonary arterial hypertension in another one. Nine patients received a double LT, and 7 patients received a single LT. Obstructive sleep apnea syndrome was diagnosed in 9 of 11 of the double LT patients and in 7 of the 9 single LT patients, with no significant differences between the LT types and the development of OSAS.
With these results of high frequency of OSAS and increases in AHI at 6 months after LT in asymptomatic patients, we decided to adopt an expectant attitude and to continue with the followup. At 12 months, patients remained asymptomatic but the high frequency of OSAS persisted, so we decided to initiate treatment with continuous positive airway pressure (CPAP) in the following cases: patients with severe OSAS before the transplant
FIGURE 3. Frequency of obstructive sleep apnea syndrome in lung transplantation recipients.
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(1 patient), patients with severe OSAS at 6 months that persisted at 12 months after LT (3 patients), and patients with severe OSAS at 12 months after LT (4 patients). A total of 8 patients (38%) was treated and maintained an adherence similar to our general non-LT patients, with the exception of 1 patient who voluntarily refused treatment because of poor tolerance. Although we did not observe any statistically significant relationships between the development of OSAS and AH after LT, we observed post-LT AH in 5 patients, 4 of them had developed severe OSAS. No statistically significant relationships were found in phases II and III between the accumulated or daily doses of immunosuppressive drugs and any of the studied variables. No significant correlations were observed between accumulated or daily steroid doses and weight, BMI, cervical circumference, or AHI. We have included cases of elevation in one or both hemidiaphragms because of diaphragmatic paralysis or paresis. The diagnosis was carried out using image methods (chest x-ray and thoracic ultrasound). No diaphragmatic alterations were found because of LT in the studied stages (at 6 months and 12 months after LT) within the group of patients. Also, after the LT and during an extra period of follow-up, we have recorded bronchiolitis obliterans syndrome development in 7 patients (33%). Two of them had pre-LT OSAS, 4 had developed OSAS at 6 months, and 1 developed OSAS at 12 months. No relevant statistical correlations were found between both conditions in any of the study phases, always considering the limitation in the sample size. DISCUSSION According with the results of this study, the prevalence of SRBD is increased in patients with terminal respiratory failure (38%), and the LT affects its progression in an important manner (86% at 6 months, and 76% at 6 and 12 months after LT). The largest and perhaps most important published study to analyze the association between SRBD and LT was conducted by Malouf et al,2 who described statistically significant data regarding improvement in nocturnal oxygenation and increases in BMI after LT. They did not, however, find a significant difference in the AHI when comparing the pre-LT and post-LT groups. Subsequently, Naraine et al1 studied SRBD in a cohort of 24 patients with LT and described a prevalence of 63%; specifically 38% had OSAS and 25% had central apneas syndrome. Pascual et al6 observed a poor sleep quality in patients in the waiting list for LT; however, they did not describe a higher incidence of nocturnal oxyhemoglobin desaturation or more respiratory events than expected in the general population. They attributed these findings to the fact that the sleep studies included the use of oxygen therapy. In our study, SRBD would not have been suspected based on the clinical data reported by the patients. Excessive daytime sleepiness, as measured with the Epworth scale, demonstrated a low level of predictability; thus, we considered this tool to be of limited routine use to clinically suggest or rule out the suspicion of OSAS in patients with terminal chronic respiratory failure. We also did not find a significant correlation between other clinical/demographic factors and the presence of OSAS, as described by other authors.1 It is interesting that at 6 months after LT, we observed the greater frequency of OSAS, with the same prevalence as before the LT and the addition of new cases. This suggests that
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the reception of the lung graft improves patients' daytime and nighttime oxygenations, but it might somehow affect the stability of the upper airway and the ventilation mechanism. Analyzing the factors that could influence the increased number and severity of OSAS patients during the first 6 months after LT, it is worth mentioning that the phenomena in the airway are fundamentally of obstructive nature. No case of central sleep apnea was related to the influence of medication in central nervous system, as described by other authors.1 In the general population, SRBD are closely related to obesity.9 The clear tendency toward a worsening AHI with weight gain has been well described; however, this longitudinal relationship is consistent with a bidirectional causal association between obesity and SRBD. In other words, the SRBD may result from obesity and promote greater weight gain at the same time because of the high stress levels and low daytime energy associated with chronic unstructured sleep.10 In our series of patients, the increase in AHI during the first year after LT was directly and significantly related to weight gain and increased cervical circumference. However, although a causal relationship between steroid use and weight gain has been described in both the general population and solidorgan recipients,11–14 we have not found a significant correlation with the mean daily or accumulated steroid doses or with any other immunosuppressant drug regularly used by these patients. Another aspect studied as a causal factor of SRBD in patients with LT is chronic pulmonary denervation caused by the absence of the afferent vagal neurological stimulus.15 This theory has not been supported and assumes that the SRBD would occur only in bilateral LT recipients. In our study, we did not observe any relationship that seemed causal between the type of transplant (unilateral or bilateral) and the frequency or evolution of SRBD. In contrast, it is noteworthy that despite observing a higher frequency of OSAS after the first year post-LT compared with the pre-LT phase, the tendency appears to be toward a decrease in the frequency of OSAS after the beginning of the sixth month. Other variables, such as AHI, BMI, weight, and cervical circumference, increased in a much more accelerated manner during the first phase of the study (i.e., during the first 6 months after LT) compared with that during the second phase (the next 6 months). Thus, it is important to continue to follow-up these patients to accurately evaluate whether the long-term tendency is toward the resolution of the disorder. Arterial pressure values also increased, at least during the first half of the first year. This increase coincides with the increase in AHI, weight gain, and cervical diameter. In transplant patients, the development of AH tends to be attributed to well-established pharmacological causes or the equally common development of renal insufficiency.1 Although, in our series, AH could be attributed to the use of immunosuppressive drugs, we observed a clear correlation between the AHI and severe OSAS; therefore, we cannot rule out that the development of OSAS contributes at least in part to the development of AH. Logan et al16 suggest that the treatment of OSAS with CPAP in patients on the waiting list for LT significantly decreases arterial pressure values, which suggests that CPAP might also benefit LT recipients.1 Principal limitation of this study is that the small sample size does not allow us to demonstrate in a statistically significant manner the results and associations shown here.
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Another limitation is that the measurements of arterial pressure at the 6 months after LT were conducted under antihypertensive treatment in several patients; therefore, we cannot form a direct and artifact-free relationship between AHI and arterial pressure. Despite these limitations, this is the first published study, as far as we know, about the analysis of SRBD in LT patients beginning in the pretransplant phase. The study was conducted in a protocolized manner following the evolution times of the LT, which could more accurately support the calculation of prevalence and the development of new cases of SRBD in the evolution of LT patients. In conclusion, we observed that a high frequency of OSAS develops throughout the evolution of the LT, reaches a peak toward 6 months after transplantation, and decreases at the end of the first posttransplant year; however, OSAS maintains a frequency greater than that found before the transplant. The incidence of OSAS has been significantly associated with weight gain, BMI, and cervical circumference. Finally, there is a high prevalence of SRBD in patients with terminal chronic respiratory failure who are evaluated for LT and no reliable data that could allow us to establish a pretest clinical suspicion. For this reason, we consider it important to conduct both sleep studies and SRBD-oriented questionnaires for all patients on the LT waiting list. REFERENCES 1. Naraine VS, Bradley TD, Singer LG. Prevalence of sleep disordered breathing in lung transplant recipients. J Clin Sleep Med 2009;5:441. 2. Malouf MA, Milrose MA, Grunstein RR, et al. Sleep-disordered breathing before and after lung transplantation. J Heart Lung Transplant 2008;27:540. 3. Romem A, Iacono A, McIlmoyle E, et al. Obstructive sleep apnea in patients with end-stage lung disease. J Clin Sleep Med 2013;9:687. 4. Christie JD, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: twenty-seventh official adult lung and heart-lung transplant report–2010. J Heart Lung Transplant 2010;29:1104. 5. O'Connor GT, Caffo B, Newman AB, et al. Prospective study of sleepdisordered breathing and hypertension: the Sleep Heart Health Study. Am J Respir Crit Care Med 2009;179:1159. 6. Pascual N, Jurado B, Rubio JM, et al. Respiratory disorders and quality of sleep in patients on the waiting list for lung transplantation. Transplant Proc. 2005;37:1537–1539. 7. Luz Alonso-Alvarez M, et al. Consensus document on sleep apneahypopnea syndrome in children (full version). Sociedad Espanola de Sueno. El Area de Sueno de la Sociedad Espanola de Neumologia y Cirugia Toracica(SEPAR). Arch Bronconeumol. 2011;47(Suppl 5):0, 2. 8. AARC-APT (American Association of Respiratory Care-Association of Polysomnography Technologists) clinical practice guideline. Polysomnography. Respir Care 1995;40:1336. 9. Young T, Shahar E, Nieto FJ, et al. Predictors of sleep-disordered breathing in community-dwelling adults: the Sleep Heart Health Study. Arch Intern Med. 2002;162:893–900. 10. Newman AB, et al. Progression and regression of sleep-disordered breathing with changes in weight: the Sleep Heart Health Study. Arch Intern Med 2005;165:2408. 11. Singer LG, Brazelton TR, Doyle RL, et al. Weight gain after lung transplantation. J Heart Lung Transplant 2003;22:894. 12. Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea: a population health perspective. Am J Respir Crit Care Med. 2002; 165:1217–1239. 13. Holley JL, Shapiro R, Lopatin WB, et al. Obesity as a risk factor following cadaveric renal transplantation. Transplantation 1990;49:387. 14. Augustine SM, Baumgartner WA, Kasper EK. Obesity and hypercholesterolemia following heart transplantation. J Transpl Coord 1998;8:164. 15. Shea SA, Horner RL, Banner NR, et al. The effect of human heart-lung transplantation upon breathing at rest and during sleep. Respir Physiol 1988;72:131. 16. Logan AG, Tkacova R, Perlikowsk SM, et al. Refractory hypertension and sleep apnoea: effect of CPAP on blood pressure and baroreflex. Eur Respir J 2003;21:241
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Sleep-Related Breathing Disorders and Lung Transplantation Ana R. Hernandez Voth,1 Pedro D. Benavides Mañas,1 Alicia De Pablo Gafas,2 and María J. Díaz de Atauri Rodríguez3 Aim. Sleep-related breathing disorders (SRBD) are common in patients with lung transplantation (LT); however, there are few data
about its prevalence, and none about its pathogenesis or evolution. The SRBD events consist mainly obstructive, central, and mixed apnea, as well as hypopneas. The aim of this study was to describe the prevalence of SRBD before the LT, and its evolution after a period of 1 year follow-up. Methods. Prospective, observational, descriptive, and analytical study of the SRBD and its evolution in 20 LT patients. The group was studied before and at 6 and 12 months after the LT; in each phase, standard polysomnography was performed, and anthropometric, pathologic, clinical, and pharmacological data were collected. Results. Prevalence of obstructive sleep apnea syndrome was 38% before the LT, 86% at 6 months, and 76% at 12 months after LT. There was a significant increase of weight, body mass index, neck circumference, blood pressure during the first year of follow-up, especially at 6 months after LT. We also observed an increase in the number of central and mixed apneas during the follow-up, although not as remarkable as obstructive apneas. There was no correlation between immunosuppressant studied drugs and any of the studied variables. Conclusions. We have observed a significant prevalence of obstructive sleep apnea syndrome in patients in waiting list for LT, and LT has an important influence in the evolution of the disorder. In our series, LT has somehow affected the stability of upper airway and ventilatory mechanics. (Transplantation 2015;99: e127–e131)
S
leep-related breathing disorders (SRBD) are commonly observed in lung transplantation (LT)1 patients; however, there is limited published information regarding their prevalence and no studies about pathogenesis, evolution, and treatment in this population. Sleep-related breathing disorders are common in patients with terminal chronic respiratory failure2 and respiratory failure may even potentiate SRBD, thus increasing the severity of the obstructive sleep apnea syndrome (OSAS) as oxygenation worsens.3 Lung transplantation has been consolidated as an important therapeutic strategy for chronic respiratory failure, and as a result of the latest advances in surgical techniques, intensive care, and immunosuppressive drugs, patients with LT Received 26 June 2014. Revision requested 11 July 2014. Accepted 4 November 2014. 1
have increasing life expectancies.1 In addition to the main known causes of mortality in LT recipients, such as rejection and infections,4 and given their increasing survival rates, the patients have now an increased probability of developing chronic secondary effects, such as obesity and arterial hypertension (AH). The association of both of these chronic disorders with SRBD has been studied in the general population,5 but not in the LT recipient population. Previous studies6 analyzed the prevalence of SRBD in patients on the LT waiting list, or several months after and at different progression times of the transplant. The first objective of this study was to describe the prevalence of SRBD in patients with chronic terminal respiratory failure who were on waiting list for LT; the second objective was to analyze the evolution of SRBD during a follow-up period of 1 year after the LT.
Department of Pneumology, 12 de Octubre University Hospital, Madrid, Spain.
2
MATERIALS AND METHODS
3 Department of Pneumology, Sleep Disorders Unit, CIBERES, 12 de Octubre University Hospital, Madrid, Spain.
(1) Study design: prospective, observational, descriptive, and analytical study of SRDB in patients before and after LT. (2) Population: population consisted in all patients who had undergone a LT in our center, have had a polisomnography (PSG) before the LT and who underwent a PSG at 6 and 12 months after LT (n = 21). A standard PSG was performed in all LT waiting list patients except for: (a) Patients receiving noninvasive mechanical ventilation, such as bilevel positive airway pressure as a bridge to lung transplant (7 patients). (b) Patients who joined the waiting list presenting urgent clinical conditions requiring orotracheal intubation and noninvasive mechanical ventilation (2 patients).
Department of Pneumology, Lung Transplantation Unit, 12 de Octubre University Hospital, Madrid, Spain.
The authors declare no funding or conflicts of interest. Correspondence: Ana R. Hernandez Voth, Hospital Universitario 12 de Octubre, Av. De Córdoba s/n. Madrid, 28041, Spain. ([email protected]) A.R.H.V. participated in research design, in the writing of the article and performance of the research. P.D.B.M. participated in research design and performance of the research. A.D.P.G. participated in research design and writing of the paper. M.J. D.d.A.R. participated in research design and writing of the paper. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0041-1337/15/9909-e127 DOI: 10.1097/TP.0000000000000600
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FIGURE 1. Diagram of the patient selection process. Pre LT, before lung transplantation; NIMV, noninvasive mechanical ventilation; post LT, after lung transplantation.
(c) Patients whose clinical condition required an urgent lung transplant, consequently, there was no time to perform a PSG according to protocol (11 patients). After excluding these patients, 85 had been positively assessed and included in the LT waiting list and pre-LT PSG were performed. Within the group, 44 patients were excluded given the fact that after data compilation, they had not undergone LT or they had not fulfilled the 12 months follow-up previously agreed on the objectives since the LT. In the case of the remaining 41 patients, PSG could not be performed in 13 of them at 6 months, and in 7 at 12 months, due to severe clinical conditions in both cases which made it difficult to perform the PSG according to protocol. Finally, 21 patients at follow-up at 6 months and 12 months after LT took place without SRBD diagnose before admittance in the waiting list and with pre-LT, at 6 and 12 months post-LT PSG (Figure 1). Informed consent was obtained from all patients before their participation in this study. (3) Study period: From March 2009, when we had our first LT and PSG case, through December 2012, when we had our last PSG at 12 months follow-up. Study phases: All of the studied variables were analyzed in three phases: –Phase I: before the LT (pre-LT) –Phase II: 6 months after transplantation (6 months post-LT) –Phase III: 12 months after transplantation (12 months post-LT) (4) Sleep studies: sleep studies were conducted using a standard PSG at the Multidisciplinary Sleep Unit of the 12 de Octubre University Hospital. An Alice 5 (Phillips) 12 channels polysomnography was used. Each PSG was manually analyzed by qualified personnel from the unit using the SEPAR7 and AASM8 guidelines. Obstructive sleep apnea syndrome was defined as an AHI greater or equal to 10 events per hour of sleep and was considered severe if AHI is 30 or higher. (5) Immunosuppressive drugs protocol: all patients received induction immunosuppression with Basiliximab and maintenance treatment with steroid drugs, a calcineurin (Cyclosporine or Tacrolimus), and a purine inhibitor (Azathioprine or Mycophenolate). Treatment with steroids bolus was indicated in patients with a diagnosis of acute graft rejection and was followed by a later progressive decrease to the usual previous dosage.
(6) Measurements: the follow-up took place at the Multidisciplinary Sleep and Lung Transplant Units of the 12 de Octubre University Hospital. The study was divided into a pre-LT phase, a phase at 6 months after LT, and another phase at 12 months after LT. At each phase, in addition to obtaining and analyzing the PSG, the following data were obtained: –Anthropometric data: age, sex, weight, height, BMI (weight/ height2), and cervical perimeter –Clinical data: underlying lung pathology before the LT, home oxygen needs, and measurements of systolic and diastolic arterial pressure. Symptoms suggesting respiratory disorders during sleep were gathered via the Epworth Sleepiness Scale questionnaire,5 and a score greater than 10 was considered as excessive daytime sleepiness. –PSG data: the total sleep time and percentage of sleep time for each phase, AHI, ODI, and the proportion of sleep time with an oxyhemoglobin saturation lower than 90% (TC90). –Pharmacological data: the total accumulated and daily mean doses of the immunosuppressive medications administered after the LT (steroids, tacrolimus, cyclosporine, mycophenolate, azathioprine, everolimus) were quantified. The doses of these medications were registered in phases II and III of the study (7) Statistical analysis: for the numeric variables, arithmetic means with standard deviations and medians with ranges were TABLE 1.
General characteristics of the studied population Age
Sex Male Female LT indication COPD Interstitial Lund disease Cystic fibrosis Primary pulmonary hypertension LT modality Bilateral Unilateral
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53.7 (± 10.8)
13 (62%) 8 (38%) 10 (42%) 7 (33%) 2 (10%) 2 (10%) 12 (57%) 9 (43%)
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TABLE 2.
Evolution of the studied clinical and sleep variables Analyzed variables
Before LT
Weight (mean ± SD), kg Body mass index (mean ± SD) Neck circumference (mean ± SD), cm Systolic blood pressure (mean ± SD), mm Hg Diastolic blood pressure (mean ± SD), mm Hg Apnea/hypopnea index, median (range) TC90, median (range) ODI, median (range) SpO2 minimum (mean ± SD) Epworth sleepiness scale score (mean ± SD) Total sleep time (mean ± SD), min Sleep efficacy (mean ± SD), % Sleep efficiency (mean ± SD), % Arousal index (mean ± SD) Obstructive apneas, median (range) Central apneas, median (range) Mixed apneas, median (range) Hypopneas, median (range)
6 mo after LT
60.4 ± 10.7 22.4 ± 3.7 37.05 ± 3.3 114.5 ± 13.6 71.3 ± 8.3 7 (0-40) 1 (0-100) 1 (0-23) 84.3 ± 9.6 6.9 ± 2.9 291.7 ± 84.6 29.5 ± 10.8 68.3 ± 18.7 39.5 ± 15.4 3 (0-129) 0 (0-2) 0 (0-3) 27 (0-137)
12 mo after LT a
63.9 ± 12.3 24.1 ± 4.1 a 38.3 ± 3.5 a 124.9 ± 19.1 a 77.6 ± 11.7 a 20 (6-89) a 2 (0-57) 11 (1-85) a 82.3 ± 8.9 6.85 ± 2.9 360.2 ± 61.8 a 27.95 ± 13.2 82.15 ± 13.3 a 48.6 ± 22.1 32 (2-549) a 0 (0-45) a 0 (0-42) a 69 (14-178) a
65.7 ± 11.7 b 24.8 ± 4.1 bc 39.2 ± 3 b 124.1 ± 16 76.5 ± 11.1 23 (3-93) b 2 (0-81) 13 (1-100) b 81.4 ± 8.6 5.9 ± 3.6 333.2 ± 74.9 27.2 ± 11.9 81.8 ± 17.9 b 40.1 ± 17.6 28 (0-264) b 1 (0-37) b 1 (0-50) b 52 (4-329) b
a
Statistically significant difference between pre-LT and 6 months after LT (P < 0.05). Statistically significant difference between pre-LT and 12 months after LT (P < 0.05). Statistically significant difference between 6 and 12 months after LT (P < 0.05). TC90, proportion of total sleep time of oxihemoglobin saturation under 90%. b c
calculated for variables with normal and non-normal distributions, respectively. The data were analyzed using nonparametric statistical tests (McNemar test, Mann-Whitney U test, and Wilcoxon test). The statistical program used was SPSS 17.0 (SPSS Inc., Chicago, IL). A P value less than 0.05 was considered statistically significant.
RESULTS A diagram of the patient selection process and final simple is shown in Figure 1. Population general characteristics are shown in Table 1. The evolution of the clinical variables and the PSG parameters for each phase of this study are presented in Table 2.
(1) Phase I. Pre-LT: a 38% prevalence of OSAS (8 patients) was observed; 1 patient was diagnosed with severe OSAS. Five patients had a diagnosis of chronic obstructive pulmonary disease (COPD), and 3 patients had usual interstitial pneumonia (UIP). Two patients had AH controlled with pharmacological treatment. All sleep studies done in pre-LT phase were performed using continuous oxygen therapy, according to the terminal respiratory distress situation in all patients. (2) Phase II. 6 months after LT: compared with the pre–lung transplant phase, a statistically significant increase was observed in systolic arterial pressure (P = 0.008), weight (P = 0.03), body mass index (BMI) (P = 0.01), and cervical perimeter (P = 0.002). Apnea hypopnea index (AHI) and oxyhemoglobin desaturation index (ODI) also increased
FIGURE 2. Evolution of Apnea Hypopnea Index and Oxyhemoglobin Desaturation Index in lung transplantation recipients.
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significantly during this phase (P = 0.001 both) (Figure 2). At this phase, the frequency of OSAS increased to 86% (18 patients) (Figure 3), 8 of whom were classified as having severe OSAS. Eight patients retained the diagnosis of OSAS from phase I of the study (the total number of patients who were diagnosed with OSAS in phase I), and 9 patients developed the disorder de novo during this phase. The diseases before the LT were COPD in 9 patients (50%), UIP in 6 patients (33.3%), and cystic fibrosis (CF) in 2 patients (11.1%). The LT was single in 8 cases (44.4%) and double in 10 patients (55.5%). Obstructive sleep apnea syndrome was diagnosed in 10 of the 11 double LT patients and in 8 of the 9 single LT patients, with no significant differences between the types of LT and the development of OSAS. (3) Phase III. 12 months after LT: compared with phases I and II, the elevation of the systolic arterial pressure found in phase II was sustained. Weight, BMI, and neck perimeter (P = 0.004, P = 0.004, and P = 0.006, respectively) also maintained the elevation observed in the previous phase. The prevalence of AHI and ODI also remained elevated (Figure 2). In phase III, we observed a tendency toward maintaining the frequency of OSAS in comparison with the previous phase (Figure 3); 16 patients were diagnosed with OSAS (76%), 9 of them had severe OSAS. Of the 8 patients with OSAS in phase I, 7 continued presenting the disorder in phase III; of the 9 patients who developed OSAS during phase II, 7 continued presenting the disorder during phase III. Two new cases of OSAS were observed at 12 months after LT. The diseases before LT in these patients were COPD in 8 patients, UIP in 6 patients, CF in 1 case, and primary pulmonary arterial hypertension in another one. Nine patients received a double LT, and 7 patients received a single LT. Obstructive sleep apnea syndrome was diagnosed in 9 of 11 of the double LT patients and in 7 of the 9 single LT patients, with no significant differences between the LT types and the development of OSAS.
With these results of high frequency of OSAS and increases in AHI at 6 months after LT in asymptomatic patients, we decided to adopt an expectant attitude and to continue with the followup. At 12 months, patients remained asymptomatic but the high frequency of OSAS persisted, so we decided to initiate treatment with continuous positive airway pressure (CPAP) in the following cases: patients with severe OSAS before the transplant
FIGURE 3. Frequency of obstructive sleep apnea syndrome in lung transplantation recipients.
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(1 patient), patients with severe OSAS at 6 months that persisted at 12 months after LT (3 patients), and patients with severe OSAS at 12 months after LT (4 patients). A total of 8 patients (38%) was treated and maintained an adherence similar to our general non-LT patients, with the exception of 1 patient who voluntarily refused treatment because of poor tolerance. Although we did not observe any statistically significant relationships between the development of OSAS and AH after LT, we observed post-LT AH in 5 patients, 4 of them had developed severe OSAS. No statistically significant relationships were found in phases II and III between the accumulated or daily doses of immunosuppressive drugs and any of the studied variables. No significant correlations were observed between accumulated or daily steroid doses and weight, BMI, cervical circumference, or AHI. We have included cases of elevation in one or both hemidiaphragms because of diaphragmatic paralysis or paresis. The diagnosis was carried out using image methods (chest x-ray and thoracic ultrasound). No diaphragmatic alterations were found because of LT in the studied stages (at 6 months and 12 months after LT) within the group of patients. Also, after the LT and during an extra period of follow-up, we have recorded bronchiolitis obliterans syndrome development in 7 patients (33%). Two of them had pre-LT OSAS, 4 had developed OSAS at 6 months, and 1 developed OSAS at 12 months. No relevant statistical correlations were found between both conditions in any of the study phases, always considering the limitation in the sample size. DISCUSSION According with the results of this study, the prevalence of SRBD is increased in patients with terminal respiratory failure (38%), and the LT affects its progression in an important manner (86% at 6 months, and 76% at 6 and 12 months after LT). The largest and perhaps most important published study to analyze the association between SRBD and LT was conducted by Malouf et al,2 who described statistically significant data regarding improvement in nocturnal oxygenation and increases in BMI after LT. They did not, however, find a significant difference in the AHI when comparing the pre-LT and post-LT groups. Subsequently, Naraine et al1 studied SRBD in a cohort of 24 patients with LT and described a prevalence of 63%; specifically 38% had OSAS and 25% had central apneas syndrome. Pascual et al6 observed a poor sleep quality in patients in the waiting list for LT; however, they did not describe a higher incidence of nocturnal oxyhemoglobin desaturation or more respiratory events than expected in the general population. They attributed these findings to the fact that the sleep studies included the use of oxygen therapy. In our study, SRBD would not have been suspected based on the clinical data reported by the patients. Excessive daytime sleepiness, as measured with the Epworth scale, demonstrated a low level of predictability; thus, we considered this tool to be of limited routine use to clinically suggest or rule out the suspicion of OSAS in patients with terminal chronic respiratory failure. We also did not find a significant correlation between other clinical/demographic factors and the presence of OSAS, as described by other authors.1 It is interesting that at 6 months after LT, we observed the greater frequency of OSAS, with the same prevalence as before the LT and the addition of new cases. This suggests that
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the reception of the lung graft improves patients' daytime and nighttime oxygenations, but it might somehow affect the stability of the upper airway and the ventilation mechanism. Analyzing the factors that could influence the increased number and severity of OSAS patients during the first 6 months after LT, it is worth mentioning that the phenomena in the airway are fundamentally of obstructive nature. No case of central sleep apnea was related to the influence of medication in central nervous system, as described by other authors.1 In the general population, SRBD are closely related to obesity.9 The clear tendency toward a worsening AHI with weight gain has been well described; however, this longitudinal relationship is consistent with a bidirectional causal association between obesity and SRBD. In other words, the SRBD may result from obesity and promote greater weight gain at the same time because of the high stress levels and low daytime energy associated with chronic unstructured sleep.10 In our series of patients, the increase in AHI during the first year after LT was directly and significantly related to weight gain and increased cervical circumference. However, although a causal relationship between steroid use and weight gain has been described in both the general population and solidorgan recipients,11–14 we have not found a significant correlation with the mean daily or accumulated steroid doses or with any other immunosuppressant drug regularly used by these patients. Another aspect studied as a causal factor of SRBD in patients with LT is chronic pulmonary denervation caused by the absence of the afferent vagal neurological stimulus.15 This theory has not been supported and assumes that the SRBD would occur only in bilateral LT recipients. In our study, we did not observe any relationship that seemed causal between the type of transplant (unilateral or bilateral) and the frequency or evolution of SRBD. In contrast, it is noteworthy that despite observing a higher frequency of OSAS after the first year post-LT compared with the pre-LT phase, the tendency appears to be toward a decrease in the frequency of OSAS after the beginning of the sixth month. Other variables, such as AHI, BMI, weight, and cervical circumference, increased in a much more accelerated manner during the first phase of the study (i.e., during the first 6 months after LT) compared with that during the second phase (the next 6 months). Thus, it is important to continue to follow-up these patients to accurately evaluate whether the long-term tendency is toward the resolution of the disorder. Arterial pressure values also increased, at least during the first half of the first year. This increase coincides with the increase in AHI, weight gain, and cervical diameter. In transplant patients, the development of AH tends to be attributed to well-established pharmacological causes or the equally common development of renal insufficiency.1 Although, in our series, AH could be attributed to the use of immunosuppressive drugs, we observed a clear correlation between the AHI and severe OSAS; therefore, we cannot rule out that the development of OSAS contributes at least in part to the development of AH. Logan et al16 suggest that the treatment of OSAS with CPAP in patients on the waiting list for LT significantly decreases arterial pressure values, which suggests that CPAP might also benefit LT recipients.1 Principal limitation of this study is that the small sample size does not allow us to demonstrate in a statistically significant manner the results and associations shown here.
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Another limitation is that the measurements of arterial pressure at the 6 months after LT were conducted under antihypertensive treatment in several patients; therefore, we cannot form a direct and artifact-free relationship between AHI and arterial pressure. Despite these limitations, this is the first published study, as far as we know, about the analysis of SRBD in LT patients beginning in the pretransplant phase. The study was conducted in a protocolized manner following the evolution times of the LT, which could more accurately support the calculation of prevalence and the development of new cases of SRBD in the evolution of LT patients. In conclusion, we observed that a high frequency of OSAS develops throughout the evolution of the LT, reaches a peak toward 6 months after transplantation, and decreases at the end of the first posttransplant year; however, OSAS maintains a frequency greater than that found before the transplant. The incidence of OSAS has been significantly associated with weight gain, BMI, and cervical circumference. Finally, there is a high prevalence of SRBD in patients with terminal chronic respiratory failure who are evaluated for LT and no reliable data that could allow us to establish a pretest clinical suspicion. For this reason, we consider it important to conduct both sleep studies and SRBD-oriented questionnaires for all patients on the LT waiting list. REFERENCES 1. Naraine VS, Bradley TD, Singer LG. Prevalence of sleep disordered breathing in lung transplant recipients. J Clin Sleep Med 2009;5:441. 2. Malouf MA, Milrose MA, Grunstein RR, et al. Sleep-disordered breathing before and after lung transplantation. J Heart Lung Transplant 2008;27:540. 3. Romem A, Iacono A, McIlmoyle E, et al. Obstructive sleep apnea in patients with end-stage lung disease. J Clin Sleep Med 2013;9:687. 4. Christie JD, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: twenty-seventh official adult lung and heart-lung transplant report–2010. J Heart Lung Transplant 2010;29:1104. 5. O'Connor GT, Caffo B, Newman AB, et al. Prospective study of sleepdisordered breathing and hypertension: the Sleep Heart Health Study. Am J Respir Crit Care Med 2009;179:1159. 6. Pascual N, Jurado B, Rubio JM, et al. Respiratory disorders and quality of sleep in patients on the waiting list for lung transplantation. Transplant Proc. 2005;37:1537–1539. 7. Luz Alonso-Alvarez M, et al. Consensus document on sleep apneahypopnea syndrome in children (full version). Sociedad Espanola de Sueno. El Area de Sueno de la Sociedad Espanola de Neumologia y Cirugia Toracica(SEPAR). Arch Bronconeumol. 2011;47(Suppl 5):0, 2. 8. AARC-APT (American Association of Respiratory Care-Association of Polysomnography Technologists) clinical practice guideline. Polysomnography. Respir Care 1995;40:1336. 9. Young T, Shahar E, Nieto FJ, et al. Predictors of sleep-disordered breathing in community-dwelling adults: the Sleep Heart Health Study. Arch Intern Med. 2002;162:893–900. 10. Newman AB, et al. Progression and regression of sleep-disordered breathing with changes in weight: the Sleep Heart Health Study. Arch Intern Med 2005;165:2408. 11. Singer LG, Brazelton TR, Doyle RL, et al. Weight gain after lung transplantation. J Heart Lung Transplant 2003;22:894. 12. Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea: a population health perspective. Am J Respir Crit Care Med. 2002; 165:1217–1239. 13. Holley JL, Shapiro R, Lopatin WB, et al. Obesity as a risk factor following cadaveric renal transplantation. Transplantation 1990;49:387. 14. Augustine SM, Baumgartner WA, Kasper EK. Obesity and hypercholesterolemia following heart transplantation. J Transpl Coord 1998;8:164. 15. Shea SA, Horner RL, Banner NR, et al. The effect of human heart-lung transplantation upon breathing at rest and during sleep. Respir Physiol 1988;72:131. 16. Logan AG, Tkacova R, Perlikowsk SM, et al. Refractory hypertension and sleep apnoea: effect of CPAP on blood pressure and baroreflex. Eur Respir J 2003;21:241
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