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(Chest. 2005;128:145-152.)
© 2005 American College of Chest Physicians

Impaired Respiratory and Skeletal Muscle Strength in Patients Prior to Hematopoietic Stem-Cell Transplantation*

Alexander C. White, MD; Norma Terrin, PhD; Kenneth B. Miller, MD and Helen F. Ryan, MD

* From the Pulmonary, Critical Care and Sleep Division (Dr. White), Division of Hematology Oncology (Dr. Ryan), Tupper Research Institute, Department of Medicine, Institute for Clinical Research and Health Policy Studies (Dr. Terrin), Tufts-New England Medical Center, Tufts University School of Medicine; and Division of Hematology Oncology (Dr. Miller), Beth Israel Deaconess Medical Center, Boston, MA.

Correspondence to: Alexander C. White, MD, Pulmonary, Critical Care and Sleep Division, New England Medical Center, NEMC #369, 750 Washington St, Boston, MA 02111; e-mail: Awhite1{at}Tufts-NEMC.org


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: The primary aim was to determine if respiratory and skeletal muscle strength and submaximal exercise capacity were reduced in subjects prior to sibling- or unrelated-donor hematopoietic stem-cell transplantation (HSCT).

Design: Prospective observational study.

Setting: Tufts-New England Medical Center, a tertiary referral center in Boston, MA.

Patients: All patients (n = 56) undergoing either sibling- or unrelated-donor HSCT from January 1, 2002, to December 31, 2002.

Measurements: Demographic data, chemotherapy burden, pulmonary function tests (PFTs), maximal inspiratory muscle strength (PImax), maximal expiratory muscle strength (PEmax), dominant hand grip strength (GS), 6-min walk test (6MWT), and survival as of May 21, 2004.

Results: PImax was reduced to < 80% predicted in 42% of subjects and to < 60% predicted in 18% of subjects. PEmax was reduced to < 80% predicted in 89% of subjects and to < 60% of predicted in 80% of subjects. A significant correlation was observed between PImax and PEmax (r = 0.65, p < 0.0001). GS was reduced to < 80% predicted in 39% of subjects and < 60% predicted in 15% of subjects. The 6MWT was reduced to < 80% predicted in 58% of subjects and to < 60% predicted in 9.6% of subjects. Diffusing capacity of the lung for carbon monoxide (DLCO) was the only PFT that was significantly correlated with 6MWT distance (r = 0.44, p = 0.015). The mean calculated load of chemotherapy was 14.8 ± 16.5 U (± SD). The mean time elapsed from date of hematologic diagnosis to date of HSCT was 874 ± 1,109 days. The median survival of the cohort was 374 days (95% confidence interval, 177 to 665 days). Respiratory or skeletal muscle strength, 6MWT distance, or calculated burden of chemotherapy did not predict survival.

Conclusions: Respiratory and skeletal muscle strength and submaximal exercise capacity are reduced in a significant percentage of patients prior to undergoing HSCT. These observations may help explain musculoskeletal weakness that has been reported in the posttransplant period.

Key Words: hematopoietic stem-cell transplantation • muscle strength • pulmonary morbidity • walk test


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Pulmonary complications are reported to occur in up to 60% of patients undergoing hematopoietic stem-cell transplantation (HSCT).1 The spectrum of HSCT-related lung disease may involve the lung parenchyma, pleural space, and the airways.1 The diverse pulmonary pathology seen following HSCT is multifactorial and may be related to the accumulated effects of chemotherapy and radiation prior to transplant, the conditioning radiation and chemotherapy used in the preparative regimen prior to transplant, the transplant itself, and the allogeneic effect of graft-vs-host disease (GVHD).

Respiratory and skeletal muscle weakness can contribute to pulmonary morbidity in patients with underlying pulmonary disease such as COPD.2 There have been numerous studies34 performed on the changes seen in pulmonary function test (PFT) results in the HSCT population, but to our knowledge respiratory and skeletal muscle function in this population has not been studied systematically. Organ dysfunction remains a major complication of HSCT,5 and the degree to which the musculoskeletal system is affected has not been well defined. There have been only case series of clinically significant muscle weakness in patients undergoing HSCT due to either GVHD-related polymyositis678 or GVHD-related myasthenia gravis.9

We have developed the hypothesis that some of the pulmonary morbidity in the HSCT population may have its origins in the period prior to the HSCT itself. Prior to undergoing HSCT, patients may receive multiple courses of chemotherapy, radiation, or corticosteroids, all of which may cause low level lung injury and alter lung repair mechanisms. These treatments may also cause skeletal or respiratory muscle weakness that may contribute to pulmonary morbidity in the posttransplant period. Thus, patients may begin the process of HSCT with already impaired respiratory and skeletal muscle function. In the months following HSCT, the patient may be exposed to additional risk factors for muscle weakness, including corticosteroid use, bed rest-related disuse atrophy, altered nutritional status, intermittent electrolyte disorders, drug-induced muscle weakness, and GVHD-related myasthenia gravis.8910111213 The aims of this study were to determine if respiratory and skeletal muscle function and submaximal exercise capacity were impaired in subjects prior to undergoing HSCT, and to determine if changes in muscle function affected survival following the transplant.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
All patients undergoing either sibling- or unrelated-donor HSCT (sibling, n = 43; unrelated donor, n = 13) between January 1, 2002, and December 31, 2002, at Tufts-New England Medical Center (T-NEMC) were included in the study. Candidates for HSCT routinely undergo evaluation of maximal inspiratory muscle strength (PImax) and maximal expiratory muscle strength (PEmax) along with a 6-min walk test (6MWT) as part of the baseline pulmonary evaluation prior to transplant. Testing of muscle function was added to standard PFTs due to recent experience with severe skeletal muscle weakness in the posttransplant period in a patient who required mechanical ventilation.8 All PFT data, including muscle strength, are used to help decide patient suitability for transplant and to help select the conditioning regimen used for marrow ablation. The pulmonary and muscle function studies were considered part of the transplant evaluation; therefore, informed consent was not obtained other than informed consent for the transplant. The Institutional Review Board at T-NEMC approved this analysis of the de-identified data, without obtaining informed consent. In some patients, PFTs were performed at the referring hospital and did not include these additional measurements of muscle strength or exercise capacity. When possible, the additional muscle testing was obtained at T-NEMC prior to HSCT.

Demographic, Clinical, and Diagnostic Data
The following data were collected from the paper and electronic medical records of each patient: age, sex, race, body mass index (BMI), underlying hematologic diagnosis, amount of chemotherapy received prior to transplant, time elapsed from date of initial diagnosis to HSCT expressed in days, and survival as of May 21, 2004. The total load of chemotherapy received prior to HSCT was calculated from outpatient medical and pharmacy records. Standard doses of chemotherapy were assumed unless otherwise stated in the medical record. The amount of chemotherapy was quantified as the number of drugs received multiplied by the number of courses administered. A single unit of chemotherapy was defined as one drug administered for one course. For example if a patient received six cycles of "CHOP" (cyclophosphamide, doxorubicin, vincristine, and prednisone), the load was calculated to be four (the number of drugs) multiplied by six (the number of cycles) = 24 U.

Conditioning Regimen, Transplantation Procedure, and GVHD Prophylaxis
The regimen for patients undergoing a reduced-intensity HSCT was extracorporeal photopheresis for 2 days, followed by pentostatin, 4 mg/m2, by continuous infusion for 2 days, and total body irradiation 600 cGy in three fractions over 2 days followed by infusion of sibling- or unrelated-donor HSCT as previously described.14 The regimen for ablative allogeneic HSCT was cyclophosphamide (60 mg/kg) for 2 days, and total body irradiation, 1,200 cGy in six fractions over 3 days. In addition, all subjects with lymphoid malignancy received etoposide (VP16, 30 mg/kg), > 4 h after they received the cyclophosphamide. Total body irradiation was delivered with parallel-opposed lateral 24 megavolts photon beams. Patients with chronic myeloid leukemia received an additional 500-cGy splenic radiation administered in 100-cGy fractions for 5 days prior to initiation of photopheresis as previously described.15 Nonstimulated donor bone marrow was collected on day 0 by the usual procedure and infused the same day. Peripheral blood stem cells were mobilized with subcutaneous granulocyte-colony stimulating factor at 10 µg/kg for 4 consecutive days. All patients received GVHD prophylaxis with methotrexate, 15 mg/m2, on day 1, and 10 mg/m2 on day 3, and a continuous infusion of cyclosporin A as previously described.16 All patients were cared for in high-efficiency particulate air-filtered rooms.

PFTs
Spirometry, lung volumes, and diffusing capacity of the lung for carbon monoxide (DLCO) were all measured (max 229; SensorMedics; Yorba Linda, CA) according to the guidelines of the American Thoracic Society.1718 Spirometry was repeated until three measures of peak flow and vital capacity were obtained that differed by < 5%. The single best of these values was selected. Maximal voluntary ventilation (MVV) was measured by having the patient breath as hard and as fast as they can for 12 s, and this value was multiplied by a factor of 5. Lung volumes were measured using an open-circuit nitrogen washout system. DLCO was measured using the single-breath technique and was expressed as absolute DLCO, DLCO corrected for hemoglobin, DLCO corrected for alveolar volume, and DLCO adjusted for both hemoglobin and alveolar volume. The values obtained were related to standard normal values.19

Peripheral Muscle Force
Dominant hand grip strength (GS) was used as a measure of peripheral muscle force and was measured in the dominant hand with the elbow at 90° flexion, and with the arm and wrist in neutral position using a hand dynamometer (JAMAR; Sammons Preston Rolyan; Bolingbrook, IL).2021 Three reproducible measurements within 10% of each other were obtained, and the mean value was calculated. The percentage of the predicted value for GS corrected for age was obtained using published normal values.20 Values > 80% of predicted were considered normal. Abnormal values were classified as < 80% predicted or < 60% predicted.

Submaximal Exercise Capacity
The 6MWT was measured in accordance with the published American Thoracic Society guidelines.22 Predicted values for 6MWT distance were calculated for each subject using the variables height, age, and weight as previously reported.23 The percentage of predicted distance walked was calculated for each subject. Patients receiving infusions that required an IV delivery device did not undergo the walk test. Values > 80% of predicted were considered normal. Abnormal values were classified as < 80% predicted or < 60% predicted.

Respiratory Muscle Force
PImax and PEmax were measured according to a modification of the method of Black and Hyatt.24 The SensorMedics V max 229 system measures pressures using an electronic transducer instead of an aneroid manometer. The individual was seated upright, wore nose clips, and breathed through a mouthpiece. PImax was measured from residual volume, and PEmax was measured as close as possible to total lung capacity (TLC). A small leak in the tubing connected to the mouthpiece prevented negative pressure generation by the muscles of the mouth and throat during the PImax maneuver. Multiple maneuvers were performed with coaching and instruction until three measurements within 10% of each other were obtained. The mean of these three measures was calculated, and the percentage of predicted values were obtained from published normal values.25 Values > 80% of predicted were considered normal. Abnormal values were classified as < 80% predicted or < 60% predicted, as these thresholds have been shown to have some correlation with dyspnea scores.26

Statistical Analysis
All data were entered into an spreadsheet and de-identified according to federal guidelines. Data are expressed as means and SDs, except for survival data, which are expressed as medians with 95% confidence intervals (CIs). Statistical, survival, and log-rank analyses were performed using a statistical software package (Version 8; SAS Institute; Cary, NC).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Data were collected on all 56 subjects undergoing sibling- or unrelated-donor HSCT at T-NEMC from January 1, 2002, to December 31, 2002. One patient received a peripheral stem-cell transplant; for all others (n = 55), the source of hematopoietic stem cells was bone marrow. The demographic and diagnostic data for the cohort are summarized in Table 1 . The percentage of subjects in the cohort undergoing the different pulmonary and muscle function tests is shown in Table 2 . Six subjects were unable to perform the 6MWT because they were connected to an IV device. Some subjects underwent PFTs at the referring facility prior to coming to T-NEMC for HSCT. Numeric PFT data were not available on two subjects; only the written interpretation from the referring facility was available. The mean calculated load of chemotherapy for the 56 patients was 14.8 ± 16.5 U (median value, 6.5 U; 25th percentile, 3.0 U; 75th percentile, 22.5 U). The mean time elapsed from date of hematologic diagnosis to the date of HSCT was 874 ± 1,109 days (median, 354 days; 25th percentile, 185 days; 75th percentile, 987 days).


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  		Table 1. Demographic and Diagnostic Characteristics of 56 HSCT Recipients*

 

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  		Table 2. Pulmonary Function and Muscle Testing Performed in Subjects Prior to HSCT

 
PFTs
PFT data are shown in Table 3 . Significant numbers of subjects had PFT measures < 80% and 60% of predicted. This was particularly true for MVV and measures of DLCO.


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  		Table 3. Pulmonary Function Measures in Subjects Prior to HSCT*

 
Respiratory Muscle Strength
Respiratory muscle strength data were available in 38 subjects. Table 4 shows the mean and SD for PImax and PEmax, along with the numbers of subjects with values in the normal range, < 80% predicted and < 60% predicted. Of note, the mean value for PEmax was reduced to 62 ± 17% predicted, while mean values for PImax were in the normal range. Significant percentages of subjects had values for PImax and PEmax that were < 80% and 60% of predicted. There was significant correlation between PImax and PEmax (r = 0.65, p < 0.0001). The values for MVV, which reflect in part respiratory muscle strength, were also found to be abnormal, with 19 subjects (46%) having values < 80% of predicted and 4 subjects (9%) having values < 60% predicted. There was no significant correlation observed between any measure of respiratory muscle strength (either PImax or PEmax) and any measure of DLCO, time elapsed between diagnosis and HSCT, or calculated burden of chemotherapy (data not shown).


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  		Table 4. Muscle Strength and 6MWT Data in Subjects Prior to Undergoing HSCT*

 
GS
GS data were available in 38 subjects (Table 4). Overall, 15 of all subjects (39%) had GS < 80% predicted and 6 subjects (15%) had values < 60% predicted. There was no significant correlation between GS and PImax (r = 0.08, p = 0.64) and GS and PEmax (r = 0.06, p = 0.7). There was no significant correlation observed between GS and any measure of DLCO, time elapsed between diagnosis and HSCT, calculated burden of chemotherapy, BMI, or age (data not shown).

6MWT
Thirty-one subjects completed the 6MWT (Table 4). The 6MWT was not performed on 25 subjects (44%). In six subjects (11%), the 6MWT could not be performed because the patients were connected to an IV pump for medications. In 19 subjects (34%), the transplant pulmonary evaluation was performed at the referring facility and the 6MWT was not included in the evaluation. Overall, 18 of all subjects (58%) had a 6MWT < 80% predicted and 3 subjects (10%) had values < 60% predicted. There was no significant correlation observed between 6MWT and time elapsed between diagnosis and HSCT or calculated burden of chemotherapy (data not shown).

Relationship Between Selected Demographic, Static Pulmonary Function, and Muscle Strength Variables and the 6MWT
We tested the relationship between 6MWT distance and each of the variables DLCO, age, BMI, height, TLC, FEV1, GS, PImax, and PEmax. Only DLCO was significantly correlated with 6MWT distance (r = 0.439, p = 0.02). Due to the small number of outcomes (n = 31) and the lack of correlation between the majority of the variables and outcome, we were unable to develop a mathematical model to predict 6MWT distance based on these static measurements using regression techniques.

Survival Analysis
A survival analysis and log-rank analysis were performed on the entire cohort on May 21, 2004. The median survival of the cohort at the time of the analysis was 374 days (95% CI, 177 to 665 days). We were unable to predict survival based on any measures of muscle strength, 6MWT distance, or calculated burden of chemotherapy. These data are shown in Table 5 .


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  		Table 5. Estimated Mean Survival Time and Log-Rank Analysis

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We observed that weakness of respiratory and skeletal muscles and reduced exercise capacity are present in a significant percentage of patients about to undergo HSCT. These observations suggest that preexisting muscle weakness may contribute to pulmonary and general morbidity following HSCT. In addition, these findings also suggest that muscle weakness observed after HSCT81328293031 may have its origins in the pretransplant period.

Muscle weakness is defined as the reduced capacity of a rested muscle to generate a force.32 Muscle fatigue occurs when there is a loss in the capacity of a muscle group to develop force in response to a load, which is reversed by rest.32 Muscle weakness is considered a risk factor for muscle fatigue. Therefore, a reduction in respiratory muscle strength increases the risk of respiratory muscle fatigue in the setting of an increased respiratory workload.33 The respiratory muscle weakness we have observed in this study predates the HSCT and may reflect disease-related inactivity or treatment-related muscle damage.

In this study, > 40% of subjects had values for PImax that were < 80% of predicted. Almost 90% of subjects had values of PEmax that were < 80% of predicted. Thus, muscle weakness was more marked in the expiratory as compared with the inspiratory muscle groups. This may be due to either PEmax being a more sensitive indicator of muscle weakness as compared with PImax34 or expiratory muscles being more vulnerable to damage.35 The respiratory muscle pump generates the pressure gradient needed to create inspiratory airflow and ventilation and provides the motor arm of coughing and secretion clearance.36 Up to 60% of patients undergoing HSCT are at significant risk of pulmonary complications. These complications include pneumonia, engraftment syndrome, diffuse alveolar hemorrhage, pleural effusions, airflow obstruction, and the idiopathic pneumonia syndrome.1 An increase in work of breathing may occur with some of these complications, and in some patients mechanical ventilation may be needed for respiratory failure. In the HSCT population, the need for mechanical ventilation can be associated with a poor prognosis.3738 The literature on respiratory muscle function in the HSCT population comprises clinical case reports or case series,827283940 and it is not known how often respiratory muscle weakness contributes to the need for mechanical ventilation. The muscle weakness in these cases was attributed to GVHD-related myositis and in some cases responded to increased immunosuppression.831 The respiratory and skeletal muscle weakness that we have observed prior to HSCT may contribute to pulmonary-related morbidity and mortality by poor secretion clearance, atelectasis, hypoventilation, hypoxemia, and hypercapnia in the post-HSCT period.

Respiratory muscle weakness has been observed in other populations, including patients undergoing solid-organ transplantation. For example, in the COPD population,210 respiratory muscle weakness appears to be related to chronic airflow obstruction, corticosteroid use, malnutrition, and electrolyte abnormalities.2 In a small cohort of lung allograft recipients, expiratory muscle weakness and ankle dorsiflexor muscle weakness have been demonstrated and may contribute to exercise intolerance in this population.41 Finally, respiratory muscle weakness may explain the impaired tidal volume response to exercise seen in the heart transplant population.42

We used GS as a measure of skeletal muscle strength. As was seen with respiratory muscle strength, almost 40% of subjects had values that were < 80% of the predicted value. GS has been shown to be associated with upper-arm lean area and thus may be an indicator of reserve muscle mass,43 which in turn may influence outcome of hospitalization.44 In this study, we were unable to demonstrate any association between GS and either BMI or age. Further larger studies are needed to determine if GS could be used as a predictor of survival in the HSCT population.

In addition to measuring static respiratory and skeletal muscle strength, we used the 6MWT as an easily obtained measure of submaximal functional capacity. The 6MWT may be an index of the patient’s ability to perform activities of daily living.22454647 We have demonstrated that > 50% of those subjects who were able to perform the test had values for 6MWT that were < 80% of predicted. The small study size prevented the construction of a model to determine if performance on the 6MWT is related to static measurements. There have been a number of studies of cardiopulmonary exercise testing in the HSCT population,448 but to our knowledge there have been no measures of 6MWT made in this population. In a retrospective cohort study of patients with lymphoma undergoing autologous HSCT, 20% of subjects had a pulmonary limitation to exercise, with 26% having poor effort,4 raising the possibility that muscle weakness may have contributed to the reduced exercise capacity.4 A reduction in the anaerobic threshold has been reported both before and after HSCT,48 lending further indirect support to a role for muscle dysfunction in reducing the exercise capacity in the HSCT subject.

Impaired muscle strength and reduced exercise endurance prior to HSCT may be due to either muscle atrophy from reduced activity due to disease or due to muscle damage from chemotherapy and corticosteroids.4950 We were unable to demonstrate any correlation between the calculated load of the chemotherapy received and respiratory or skeletal muscle strength. We were also unable to demonstrate any correlation between time from diagnosis to HSCT and any measure of muscle strength. These negative findings may be due in part to the small sample size.

This study has some limitations. Measures of lower-extremity strength were not obtained, which may be more severely affected than upper-body strength GS in this population due to enforced immobility. This is a single-institution study, and referral bias to the HSCT program at T-NEMC may have increased the number of more debilitated patients in the cohort. We did not assess posttransplantation respiratory complications and could not determine if muscle weakness before transplant increased the risk of pulmonary complications after transplant.

In summary, these data demonstrate either respiratory or skeletal muscle weakness in a significant percentage of patients just prior to starting the preparative regimen for HSCT. In addition, almost 60% of subjects undergoing a submaximal exercise test prior to HSCT had values that were < 80% of predicted. Rehabilitation programs or novel drug treatments51 targeting patients identified to be at risk of progressive muscle weakness may help reduce morbidity following an allogeneic HSCT.


   Acknowledgements
 
We thank the staff in the pulmonary function laboratory and the coordinators on the Bone Marrow Transplant Unit at T-NEMC. We also thank our colleagues in the Pulmonary, Critical Care and Sleep Division for reviewing the article.


   Footnotes
 
Abbreviations: BMI = body mass index; CI = confidence interval; DLCO = diffusing capacity of the lung for carbon monoxide; GS = dominant hand grip strength; GVHD = graft-vs-host disease; HSCT = hematopoietic stem-cell transplantation; MVV = maximal voluntary ventilation; PEmax = maximal expiratory muscle strength; PFT = pulmonary function test; PImax = maximal inspiratory muscle strength; 6MWT = 6-min walk test; TLC = total lung capacity; T-NEMC = Tufts-New England Medical Center

Supported by National Institutes of Health grant K23HL04411.

Received for publication August 2, 2004. Accepted for publication December 9, 2005.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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