Feasibility of subacute rehabilitation for mechanically ventilated patients with COVID-19 disease: a retrospective case series.

In this case series study, we aimed to evaluate the feasibility of a subacute rehabilitation program for mechanically ventilated patients with severe consequences of COVID-19 infection. Data were retrospectively collected from seven males (age 37-61 years) who were referred for inpatient rehabilitation following the stay in the ICU (14-22 days). On admission, six patients were still supported by mechanical ventilation. All patients were first placed in isolation in a special COVID unit for 6-22 days. Patients attended 11-24 treatment sessions for the duration of rehabilitation stay (13-27 days), including 6-20 sessions in the COVID unit. The treatment included pulmonary and physical rehabilitation. The initially nonventilated patient was discharged prematurely due to gallbladder problems, whereas all six mechanically ventilated patients were successfully weaned off before transfer to a COVID-free unit where they stayed for 7-19 days. At discharge, all patients increased limb muscle strength and thigh circumference, reduced activity-related dyspnea, regained functional independence and reported better quality of life. Rehabilitation plays a vital role in the recovery of seriously ill post-COVID-19 patients. Facilities should develop and implement plans for providing multidisciplinary rehabilitation treatments in various settings to recover functioning and prevent the development of long-term consequences of the COVID-19 disease.

[Exercise capacity after mechanical ventilation because of COVID-19: Cardiopulmonary exercise tests in clinical rehabilitation]. / Inspanningscapaciteit na beademing vanwege covid-19.

OBJECTIVE: To safely and effectively train the exercise capacity of post-COVID-19 patients it is important to test for cardiopulmonary risk factors and to assess exercise limitations. The goal of this study was to describe the exercise capacity and underlying exercise limitations of mechanically ventilated post-COVID-19 patients in clinical rehabilitation. DESIGN: A retrospective cohort study. METHOD: Twenty-four post-COVID-19patients that were mechanically ventilated at ICU and thereafter admitted for clinical rehabilitation performed a symptom-limited cardiopulmonary exercise test (CPET) with breath-by-breath gas-exchange monitoring, ECG-registration, blood pressure- and saturation monitoring. In absence of a primary cardiac or ventilatory exercise limitation patients were considered to be limited primarily by decreased peripheral muscle mass. RESULTS: Twenty-three patients could perform a maximal exercise test and no adverse events occurred. Cardiorespiratory fitness was very poor with a median peak oxygen uptake of 15.0 [10.1-21.4] mlO2/kg/min (57% of predicted values). However, we observed large differences within the group in both exercise capacity and exercise limitations. While 7/23 patients were primarily limited by ventilatory function, the majority (70%) was limited primarily by the decreased peripheral muscle mass. CONCLUSION: Cardiorespiratory fitness of post-COVID-19 patients in clinical rehabilitation is strongly deteriorated. The majority of patients seemed primarily limited for exercise by the decreased peripheral muscle mass.

[Management strategy of lung protection in patients with intra-abdominal infection].

Lung protection is important in the treatment of patients with intra-abdominal infection (IAI). This article focuses on the management strategy of lung protection in IAI patients. In the implementation of IAI individual respiratory protection, good humidification and chest physical therapy, nutritional support, strict balloon management, keeping a semi-supine position, and reducing the duration and depth of analgesia and sedation are helpful to maintain effective coughing capacity and prevent silent aspiration. It is also necessary to prevent ventilator-associated lung injury in mechanical ventilation, and implement strategies of small tidal volume, limited platform pressure, diaphragmatic protection and right heart protection ventilation in acute respiratory distress syndrome (ARDS). Respiratory mechanical indicators, including airway resistance, respiratory compliance, maximum inspiratory pressure (MIP), and airway closure pressure (P0.1) can be used in IAI patients receiving mechanical ventilation for individualized assessment and monitoring of respiratory functional status. Patients with IAI who have not been treated with mechanical ventilation can use simplified bedside lung function indicators, including forced vital capacity of inhalation and exhalation, maximum inspiratory pressure and exhalation pressure, as well as volume and rate of 1s. In pulmonary rehabilitation, the protection technique of the seven-word principle of humidification, turning, patting, coughing, expansion, blowing and mobilization are implemented.

Postacute inpatient rehabilitation for COVID-19.

This case describes the successful pulmonary rehabilitation of a premorbidly independent female in the early 80s who was admitted for acute respiratory distress syndrome secondary to COVID-19 requiring 14 days of intubation. Patient was admitted to the acute rehabilitation unit 1 month after hospitalisation. Patient initially had poor endurance and was only able to ambulate with a front wheel walker for 150 feet, and also had tachycardia and decreased oxygen saturation after ambulation. During patient's rehabilitation course, therapy was focused on improving activity tolerance. Ten days after admission, patient was able to ambulate without an assistive device for 250 feet and with a rollator for over 900 feet. Patient also showed improvement in gait speed, heart rate, oxygen saturation after ambulation and incentive spirometer volume. This case demonstrates that pulmonary rehabilitation is an important component of inpatient care for patients with COVID-19 to improve functional exercise capacity and aerobic capacity.

Treatment of acute respiratory failure in the course of COVID-19. Practical hints from the expert panel of the Assembly of Intensive Care and Rehabilitation of the Polish Respiratory Society.

In 2019, a pandemic began due to infection with a novel coronavirus, SARS-CoV-2. In many cases, this coronavirus leads to the development of the COVID-19 disease. Lung damage in the course of this disease often leads to acute hypoxic respiratory failure and may eventually lead to acute respiratory distress syndrome (ARDS). Respiratory failure as a result of COVID-19 can develop very quickly and a small percent of those infected will die because of it. There is currently no treatment for COVID-19, therefore the key therapeutic intervention centers around the symptomatic treatment of respiratory failure. The main therapeutic goal is to main-tain gas exchange, mainly oxygenation, at an appropriate level and prevent the intensification of changes in the lung parenchyma. Depending on the severity of hypoxemia different techniques can be used to improve oxygenation. Medical staff dealing with COVID-19 patients should be familiar with both, methods used to treat respiratory failure and the epidemiological risks arising from their use. In some patients, conventional (passive) oxygen therapy alone is sufficient. In patients with worsening respiratory failure high flow nasal oxygen therapy (HFNOT) may be effective. The continuous positive airway pressure (CPAP) and non-invasive ventilation (NIV) methods can be used to a limited extent. With further disease progression, invasive ventilation must be used and in special situations, extracorporeal membrane oxygenation (ECMO) can also be administered. The authors of this article set themselves the goal of presenting the most current knowledge about the epidemiology and patho-physiology of respiratory failure in COVID-19, as well as the methods of its treatment. Given the dynamics of the developing pandemic, this is not an easy task as new scientific data is presented almost every day. However, we believe the knowledge contained in this study will help doctors care for patients with COVID-19. The main target audience of this study is not so much pneumonologists or intensivists who have extensive experience in the application of the techniques discussed here, but rather doctors of other specializations who must master new skills in order to help patients during the time of a pandemic.

Feasibility and Efficacy of the Pulmonary Rehabilitation Program in a Rehabilitation Center: CASE REPORT OF A YOUNG PATIENT DEVELOPING SEVERE COVID-19 ACUTE RESPIRATORY DISTRESS SYNDROME.

DETAILS OF THE CLINICAL CASE: A 51-yr-old man underwent a respiratory rehabilitation program (RRP), after being tracheostomized and ventilated due to acute respiratory distress syndrome (ARDS) from coronavirus disease-2019 (COVID-19) infection. Respiratory care, early mobilization, and neuromuscular electrical stimulation were started in the ad hoc isolation ward of our rehabilitation center. At baseline, muscle function was consistent with intensive care unit-acquired weakness and the patient still needed mechanical ventilation (MV) and oxygen support. During the first week of RRP in isolation, the patient was successfully weaned from MV, the tracheal cannula was removed, and the walking capacity was recovered. At the end of the RRP, continued in a standard department, respiratory muscles strength increased by 7% and muscle function improved as indicated by the quadriceps size enlargement of 13% and the change of the Medical Research Council sum score from 48/60 to 58/60. DISCUSSION: Providing RRP in patients with severe COVID-19 ARDS involves risks for operators and organizational difficulties, especially in rehabilitation centers; nevertheless, its continuity is important to prevent the development of permanent disabilities in previously healthy subjects. Limited to the experience of only one patient, we were able to carry out a safe RRP during the COVID-19 pandemic, promoting the complete functional recovery of a COVID-19 young patient. SUMMARY: Most patients who develop serious consequences of COVID-19 infection risk a reduction in their quality of life. However, by organizing and directing specialized resources, subacute rehabilitation facilities could ensure the continuity of the RRPs even during the COVID-19 pandemic.

Influence of quality of intensive care on quality of life/return to work in survivors of the acute respiratory distress syndrome: prospective observational patient cohort study (DACAPO).

BACKGROUND: Significant long-term reduction in health-related quality of life (HRQoL) is often observed in survivors of the acute respiratory distress syndrome (ARDS), and return to work (RtW) is limited. There is a paucity of data regarding the relationship between the quality of care (QoC) in the intensive care unit (ICU) and both HRQoL and RtW in ARDS survivors. Therefore, the aim of our study was to investigate associations between indicators of QoC and HRQoL and RtW in a cohort of survivors of ARDS. METHODS: To determine the influence of QoC on HRQoL and RtW 1 year after ICU-discharge, ARDS patients were recruited into a prospective multi-centre patient cohort study and followed up regularly after discharge. Patients were asked to complete self-report questionnaires on HRQoL (Short Form 12 physical component scale (PCS) and mental component scale (MCS)) and RtW. Indicators of QoC pertaining to volume, structural and process quality, and general characteristics were recorded on ICU level. Associations between QoC indicators and HrQoL and RtW were investigated by multivariable linear and Cox regression modelling, respectively. B values and hazard ratios (HRs) are reported with corresponding 95% confidence intervals (CIs). RESULTS: 877 (of initially 1225 enrolled) people with ARDS formed the DACAPO survivor cohort, 396 were finally followed up to 1 year after discharge. The twelve-month survivors were characterized by a reduced HRQoL with a greater impairment in the physical component (Md 41.2 IQR [34-52]) compared to the mental component (Md 47.3 IQR [33-57]). Overall, 50% of the patients returned to work. The proportion of ventilated ICU patients showed significant negative associations with both 12 months PCS (B = - 11.22, CI -20.71; - 1,74) and RtW (HR = 0,18, CI 0,04;0,80). All other QoC indicators were not significantly related to outcome. CONCLUSIONS: Associations between ICU QoC and long-term HrQoL and RtW were weak and largely non-significant. Residual confounding by case mix, treatment variables before or during ICU stay and variables pertaining to the post intensive care period (e.g. rehabilitation) cannot be ruled out. TRIAL REGISTRATION: Clinicaltrials.govNCT02637011. (December 22, 2015, retrospectively registered).

Joint Statement on the Role of Respiratory Rehabilitation in the COVID-19 Crisis: The Italian Position Paper.

Due to the exponential growth of the number of subjects affected by coronavirus disease 2019 (COVID-19), the entire Italian health care system had to respond promptly and in a very short time with the need of semi-intensive and intensive care units. Moreover, trained dedicated COVID-19 teams consisting of physicians were coming from different specialties (intensivists or pneumologists and infectiologists), while respiratory therapists and nurses have been recruited to work on and on without rest. However, due to still limited and evolving knowledge of COVID-19, there are few recommendations concerning the need in respiratory rehabilitation and physiotherapy interventions. The presentation of this paper is the result of a consensus promoted by the Italian societies of respiratory health care professionals who contacted pulmonologists directly involved in the treatment and rehabilitation of COVID-19. The aim was to formulate the more proper and common suggestions to be applied in different hospital settings in offering rehabilitative programs and physiotherapy workforce planning for COVID-19 patients. Two main areas of intervention were identified: organization and treatment, which are described in this paper to face the emergency.

Respiratory physiotherapy in patients with COVID-19 infection in acute setting: a Position Paper of the Italian Association of Respiratory Physiotherapists (ARIR).

Respiratory physiotherapy in patients with COVID-19 infection in acute setting: a Position Paper of the Italian Association of Respiratory Physiotherapists (ARIR) On February 2020, Italy, especially the northern regions, was hit by an epidemic of the new SARS-Cov-2 coronavirus that spread from China between December 2019 and January 2020. The entire healthcare system had to respond promptly in a very short time to an exponential growth of the number of subjects affected by COVID-19 (Coronavirus disease 2019) with the need of semi-intensive and intensive care units.

Effects of a physiotherapic program in patients on veno-venous extracorporeal membrane oxygenation: an 8-year single-center experience.

BACKGROUND: To date, there is no agreement on the timing to perform a physical session in patients on veno-venous extracorporeal membrane oxygenation (VV-ECMO). We aimed to assess whether early physiotherapy (within the first week from ECMO start) could affect in-ICU mortality. METHODS: Our retrospective observational study included 101 adults supported on VV ECMO from 2009 to 2016, consecutively admitted at our ECMO referral Center in Florence (Italy). Clinical data right before ECMO start were collected for all patients. The level of mobilization using the ICU mobility scale was recorded on the first session and at discharge. RESULTS: Early physiotherapy (within the first week) was more frequently initiated in patients with lower BMI (P=0.013) and it was associated with lower duration of ECMO support (P=0.03), mechanical ventilation (P=0.001) and length of stay (P=0.001). In-ICU mortality was not different between the two subgroups. CONCLUSIONS: In patients on VV-ECMO support, physiotherapy is feasible and safe and that early physiotherapy, initiated within the first week from ECMO start, is associated with shorter duration of ECMO support and ICU length of stay.

Long-term outcome after the acute respiratory distress syndrome: different from general critical illness?

PURPOSE OF REVIEW: To review the current research data on long-term outcome and health-related quality of life in survivors of the acute respiratory distress syndrome (ARDS) and to compare these findings with those from non-ARDS patients surviving critical illness. RECENT FINDINGS: Between 6 months and 2 years after discharge from ICU, survivors of ARDS present with substantial impairments of the levels of body function (muscle strength, walking capacity and/or physical activity (physical SF-36 score). In contrast to non-ARDS patients from surgical ICUs, a standardized intensified physical therapy during early course of illness in ARDS patients could not show an improvement of long-term physical function performance. Furthermore, a substantial part of further ARDS patients suffer from depression (26-33%), anxiety (38-44%) or posttraumatic stress disorder (22-24%). In general, the level of functional autonomy and daily life activities was reduced, and in one study, 6 months after ICU-discharge this level was significantly lower in ARDS patients compared with non-ARDS patients. In a recent study, 44% of ARDS survivors were jobless 1 year after critical illness, whereas half of previously employed patients returned to work within 4 months after hospital discharge. General health-related quality of life was significantly reduced compared with a matched population in all studies. SUMMARY: Surviving ARDS is associated with a long-term substantial reduction in health-related quality of life and such a reduction does not differ from findings in patients surviving other critical illness. In further research, a special attention should be paid to prevention measures of the 'post intensive care syndrome' as well as to patient important domains, which might better explain the patient's and families' demands.

Sedation and Mobilization During Venovenous Extracorporeal Membrane Oxygenation for Acute Respiratory Failure: An International Survey.

OBJECTIVES: To characterize sedation, analgesia, delirium, and mobilization practices in patients supported with venovenous extracorporeal membrane oxygenation for severe acute respiratory failure. DESIGN: Cross-sectional electronic survey administered January 2016 to March 2016. SETTING: Three-hundred ninety-four extracorporeal membrane oxygenation centers registered with the Extracorporeal Life Support Organization. SUBJECTS: Extracorporeal membrane oxygenation medical directors and program coordinators. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed responses from 209 respondents (53%), mostly from academic centers (63%); 41% respondents provide venovenous extracorporeal membrane oxygenation to adults exclusively. Following venovenous extracorporeal membrane oxygenation initiation, 97% respondents administer sedative/analgesic infusions, and the sedation target was "sedated" or "very sedated" for 59%, "calm and cooperative" for 25%, and "unarousable" for 16%. Use of daily sedation interruption and a sedation/analgesia protocol was reported by 51% and 39%, respectively. Midazolam (48%) and propofol (19%) were reported as the most frequently used sedatives; fentanyl (44%) and morphine (20%) the most frequent opioids. Use of a delirium scale was reported by 55% respondents. Physical therapy was reported by 84% respondents, with 41% initiating it within 72 hours after cannulation. Mobilization goals varied from range of motion exercises (81%) to ambulation (22%). The most frequently perceived barriers to mobilization were hemodynamic instability, hypoxemia, and dependency on venovenous extracorporeal membrane oxygenation support. CONCLUSIONS: The majority of respondents reported targeting moderate to deep sedation following cannulation, with the use of sedative and opioid infusions. There is considerable variability surrounding early physical therapy and mobilization goals for patients with acute respiratory failure supported by venovenous extracorporeal membrane oxygenation.

[Life after ARDS]. / Das Leben nach ARDS.

Patients who survive acute respiratory distress syndrome (ARDS) often suffer from long-term physical and psychological sequelae. Lung function is commonly only mildly reduced, whereas general physical activity and walking distance are often compromised. Most markedly, these patients have a high incidence of depression, anxiety, and posttraumatic stress disorder. The rate of cognitive dysfunction is as high as 70-100% at the time of hospital discharge, and remains 46-80% and 20% one year and five years post discharge, respectively. The possibility of returning to work is markedly limited. Because of these outcomes, preventative strategies must be identified to reduce the high prevalence of physical and psychological morbidity. Prevention and treatment of delirium as well as early and consequent mobilization and intensive care unit diaries are potentially beneficial.

Understanding patient outcomes after acute respiratory distress syndrome: identifying subtypes of physical, cognitive and mental health outcomes.

PURPOSE: With improving short-term mortality in acute respiratory distress syndrome (ARDS), understanding survivors' posthospitalisation outcomes is increasingly important. However, little is known regarding associations among physical, cognitive and mental health outcomes. Identification of outcome subtypes may advance understanding of post-ARDS morbidities. METHODS: We analysed baseline variables and 6-month health status for participants in the ARDS Network Long-Term Outcomes Study. After division into derivation and validation datasets, we used weighted network analysis to identify subtypes from predictors and outcomes in the derivation dataset. We then used recursive partitioning to develop a subtype classification rule and assessed adequacy of the classification rule using a kappa statistic with the validation dataset. RESULTS: Among 645 ARDS survivors, 430 were in the derivation and 215 in the validation datasets. Physical and mental health status, but not cognitive status, were closely associated. Four distinct subtypes were apparent (percentages in the derivation cohort): (1) mildly impaired physical and mental health (22% of patients), (2) moderately impaired physical and mental health (39%), (3) severely impaired physical health with moderately impaired mental health (15%) and (4) severely impaired physical and mental health (24%). The classification rule had high agreement (kappa=0.89 in validation dataset). Female Latino smokers had the poorest status, while male, non-Latino non-smokers had the best status. CONCLUSIONS: We identified four post-ARDS outcome subtypes that were predicted by sex, ethnicity, pre-ARDS smoking status and other baseline factors. These subtypes may help develop tailored rehabilitation strategies, including investigation of combined physical and mental health interventions, and distinct interventions to improve cognitive outcomes.

How to approach the acute respiratory distress syndrome: Prevention, plan, and prudence.

The acute respiratory distress syndrome (ARDS) is typically manifested by refractory hypoxemia with high mortality. A correct diagnosis is the first step to achieve better outcomes. An early intervention to manage modifiable risk factors of ARDS development and the avoidance of aggravating factors that increase disease severity and progression should be carefully addressed. A management plan is necessary at an early stage of ARDS to determine the level of intensive care. It should be carefully decided which therapeutic measures should be performed depending on the patient׳s underlying clinical condition. The clinician׳s considerate prudence is required in decisions of when to apply intensive measures for an ARDS treatment. Mechanical ventilator support should be carefully used depending on the patient׳s severity and pathological phase. Decreasing inappropriate alveolar strain through a low tidal volume under optimal positive end-expiratory pressure is key for ventilator support in ARDS. The extracorporeal membrane oxygenation applied in the experienced centers seems to improve the survival of patients with severe ARDS. A constellation of physical and psychological problems can develop or persist for up to 5 years in patients with ARDS. Therefore, an early mobilization with rehabilitation, even during an intensive care unit stay, should be seriously considered whenever feasible. Lastly, prevention of aspiration, stress ulcers, deep vein thrombosis, catheter-related infection, overhydration, and heavy sedation is essential to achieve better outcomes in ARDS.

Determinants of Quality of Life and Return to Work Following Acute Respiratory Distress Syndrome.

BACKGROUND: Acute respiratory distress syndrome (ARDS) in adults is a consequence of lung damage caused by either pulmonary or extrapulmonary disease. Survivors often suffer from an impaired health-related quality of life (HRQoL), mental and physical impairments, and persistent inability to work. METHODS: In this systematic review of the literature, we consider the determinants of HRQoL and return to work (RtW). 24 observational studies showing a statistical association between one or more determinants and HRQoL or RtW were included. Because of the heterogeneity of these studies, no statistical aggregation of the individual effect estimates was carried out; instead, the results are summarized descriptively. RESULTS: Psychopathological manifestations, in particular, are associated with impaired quality of life. In contrast, many care- and disease-related determinants had only small, non-significant effects on HRQoL and RtW. The onesecond capacity was found in all studies to be positively associated with the HRQoL. ARDS induced by sepsis seems to be a risk factor for a lower HRQoL in comparison to ARDS of other causes. A synthesis of the evidence is impeded both by the high level of heterogeneity of studies and by the high risk of selection bias in all studies. CONCLUSION: The identification of determinants of impaired quality of life after ARDS is essential for the assessment of clinically relevant interventions. In multiple studies, major significant effects were only observed when determinants the content of which was closely related to the scales of the HRQoL instruments were measured at the same time as the HRQoL.

Standardized Rehabilitation and Hospital Length of Stay Among Patients With Acute Respiratory Failure: A Randomized Clinical Trial.

IMPORTANCE: Physical rehabilitation in the intensive care unit (ICU) may improve the outcomes of patients with acute respiratory failure. OBJECTIVE: To compare standardized rehabilitation therapy (SRT) to usual ICU care in acute respiratory failure. DESIGN, SETTING, AND PARTICIPANTS: Single-center, randomized clinical trial at Wake Forest Baptist Medical Center, North Carolina. Adult patients (mean age, 58 years; women, 55%) admitted to the ICU with acute respiratory failure requiring mechanical ventilation were randomized to SRT (n=150) or usual care (n=150) from October 2009 through May 2014 with 6-month follow-up. INTERVENTIONS: Patients in the SRT group received daily therapy until hospital discharge, consisting of passive range of motion, physical therapy, and progressive resistance exercise. The usual care group received weekday physical therapy when ordered by the clinical team. For the SRT group, the median (interquartile range [IQR]) days of delivery of therapy were 8.0 (5.0-14.0) for passive range of motion, 5.0 (3.0-8.0) for physical therapy, and 3.0 (1.0-5.0) for progressive resistance exercise. The median days of delivery of physical therapy for the usual care group was 1.0 (IQR, 0.0-8.0). MAIN OUTCOMES AND MEASURES: Both groups underwent assessor-blinded testing at ICU and hospital discharge and at 2, 4, and 6 months. The primary outcome was hospital length of stay (LOS). Secondary outcomes were ventilator days, ICU days, Short Physical Performance Battery (SPPB) score, 36-item Short-Form Health Surveys (SF-36) for physical and mental health and physical function scale score, Functional Performance Inventory (FPI) score, Mini-Mental State Examination (MMSE) score, and handgrip and handheld dynamometer strength. RESULTS: Among 300 randomized patients, the median hospital LOS was 10 days (IQR, 6 to 17) for the SRT group and 10 days (IQR, 7 to 16) for the usual care group (median difference, 0 [95% CI, -1.5 to 3], P = .41). There was no difference in duration of ventilation or ICU care. There was no effect at 6 months for handgrip (difference, 2.0 kg [95% CI, -1.3 to 5.4], P = .23) and handheld dynamometer strength (difference, 0.4 lb [95% CI, -2.9 to 3.7], P = .82), SF-36 physical health score (difference, 3.4 [95% CI, -0.02 to 7.0], P = .05), SF-36 mental health score (difference, 2.4 [95% CI, -1.2 to 6.0], P = .19), or MMSE score (difference, 0.6 [95% CI, -0.2 to 1.4], P = .17). There were higher scores at 6 months in the SRT group for the SPPB score (difference, 1.1 [95% CI, 0.04 to 2.1, P = .04), SF-36 physical function scale score (difference, 12.2 [95% CI, 3.8 to 20.7], P = .001), and the FPI score (difference, 0.2 [95% CI, 0.04 to 0.4], P = .02). CONCLUSIONS AND RELEVANCE: Among patients hospitalized with acute respiratory failure, SRT compared with usual care did not decrease hospital LOS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00976833.