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(Chest. 2007;131:156-163.)
© 2007 American College of Chest Physicians

Effects of Nocturnal Noninvasive Mechanical Ventilation on Heart Rate Variability of Patients With Advanced COPD*

Don D. Sin, MD, FCCP; Eric Wong, MD, FCCP; Irvin Mayers, MD, FCCP; Dale C. Lien, MD, FCCP; David Feeny, PhD; Heidi Cheung, RRT; Wen Q. Gan, MD and S. F. Paul Man, MD, FCCP

* From the Pulmonary Division, Department of Medicine (Drs. Sin, Gan, and Man), The University of British Columbia, Vancouver, BC, Canada; Pulmonary Division (Drs. Wong, Mayers, and Lien, and Mrs. Cheung), Department of Medicine, University of Alberta, Edmonton, AB, Canada; and Center for Health Research (Dr. Feeny), Northwest and Hawaii, Kaiser Permanente Northwest Region, Portland, OR.

Correspondence to: Don D. Sin, MD, FCCP, James Hogg iCAPTURE Center for Cardiovascular and Respiratory Research, St. Paul’s Hospital, 1081 Burrard St, Vancouver, BC, Canada V6Z 1Y7; e-mail: dsin{at}mrl.ubc.ca

Abstract

Background: Cardiovascular comorbidities have a negative impact on the health status and prognosis of patients with COPD. We determined whether nocturnal noninvasive (positive) mechanical ventilation (NIMV) can improve heart rate variability (HRV), decrease circulating natriuretic peptide levels, and improve functional performance of patients with very advanced COPD.

Methods: A randomized, double-blind, parallel controlled trial was conducted in 23 participants with stable but advanced COPD. Participants received standard medical therapy plus nocturnal NIMV or standard medical therapy plus sham NIMV for 3 months.

Results: After 3 months of NIMV therapy, the 24-h triangular interpolation of N-N intervals increased from 322 to 473 ms (p = 0.034), the 24-h HRV index (HRVI) increased from 21.8 to 29.9 ms (p = 0.035), nocturnal HRVI increased from 6.1 to 8.0 ms (p = 0.026), and the SD of the average N-N interval increased from 37 to 41 ms (p = 0.020). None of these indexes changed significantly in the control group. Additionally, compared with the control group, the pro-atrial natriuretic peptide levels declined significantly in the NIMV group (p = 0.013).

Conclusions: NIMV applied nocturnally over 3 months may improve HRV, reduce circulating natriuretic peptide levels, and enhance the functional performance of patients with advanced but stable COPD. While not definitive due to small sample size, these data suggest that nocturnal NIMV may reduce the impact of cardiac comorbidities in COPD patients.

Key Words: controlled clinical trial • COPD • heart rate • heart rate variability • inspiratory positive pressure ventilation • natriuretic peptides

It is well recognized that cardiovascular diseases often coexist with COPD and are a source of morbidity and mortality in COPD patients.12 In patients with mild COPD, cardiac disorders are the leading causes of hospitalization, accounting for 42 to 48% of all hospitalizations.1 Having ECG signs of previous myocardial infarction or ischemia increases the risk of mortality in COPD by 42% compared with COPD patients without such changes.3 The presence of atrial fibrillation and ventricular arrhythmias of any kind increases mortality risk by 2.27-fold and 1.91-fold, respectively, in COPD.4 Although a majority of COPD patients in the community do not have any overt signs of cardiac disease,123 many appear to have subclinical cardiac abnormalities, which may add to their overall morbidity.2

One noninvasive method of ascertaining subclinical cardiac abnormalities is by determining heart rate variability (HRV). In the community, reduced HRV predicts mortality as well as conventional risk factors. In the postinfarction setting, depressed HRV predicts all-cause mortality better than does left ventricular ejection fraction.5 More recently, circulating natriuretic peptide levels have also been associated with increased risk of all-cause mortality even in subjects without overt cardiac disease6 and may represent another method of identifying subclinical cardiac abnormalities. Intriguingly, advanced COPD has also been associated with elevated natriuretic peptide levels7 and reduced HRV89 in a severity-dependent fashion.10 Interestingly, positive pressure ventilation has been shown to have beneficial effects on HRV and natriuretic peptide levels.1112 Whether application of nocturnal noninvasive (positive) mechanical ventilation (NIMV) in COPD can improve these cardiac end points is unknown. We implemented a randomized controlled trial to determine whether nocturnal NIMV applied for 3 months can do the following: (1) improve HRV; (2) decrease circulating levels of plasma natriuretic peptides; and (3) enhance functional performance of patients with severe but stable COPD.

Materials and Methods

Subjects
We recruited study participants from specialists’ clinics at the University of Alberta Hospital. To qualify for the study, patients had to meet the following entry criteria: (1) clinical diagnosis of COPD; (2) age ≥ 40 years old; (3) ≥ 10-pack-year history of cigarette smoking; (4) FEV1/FVC ratio < 70% and postbronchodilator FEV1 < 70% of predicted. Patients were excluded if they had the following conditions: (1) coexisting medical conditions that made survival for at least 6 months unlikely; (2) refusal to participate; (3) cognitive impairment that made it impossible to obtain informed consent; (4) clinical history of left ventricular heart failure; or (5) apnea-hypopnea index ≥ 20 on a home-based sleep apnea test (Embletta PDS; Medcare; Reyjkavik, Iceland). All patients provided written informed consent. Ethics approval was obtained from the University of Alberta and the University of British Columbia Research Ethics Boards.

Study Design
We employed a randomized, double-blind, parallel-group design. Recruited patients were randomly assigned to receive either standard medical therapy for COPD plus nocturnal NIMV or standard medical therapy plus sham NIMV therapy for 3 months. Randomization occurred at a central site by one individual who was unaware of patients’ clinical status. All outcome measurements were performed and interpreted by personnel who were blinded to the treatment allocation of patients. Following randomization, participants started on either nocturnal NIMV or sham therapy. All participants spent at least 4 h of NIMV/sham training at the University of Alberta Hospital Sleep Disorders Laboratory, during which patients were properly fitted with a mask (either with a nasal mask [UltraMirage; ResMed; Posway, CA] or a full-face mask [Mirage; ResMed] depending on patient preference), and the appropriate ventilator settings were set. Patients received NIMV via a ResMed VPAP II machine with a heated humidifier (HumidAire; ResMed). The patients were initially started on an inspiratory positive airway pressure (IPAP) of 8 cm H2O and an expiratory positive airway pressure (EPAP) of 4 cm H2O. The IPAP was titrated up in increments of 2 cm H2O until the highest IPAP tolerated by the patient or 20 cm H2O was reached, whichever came first. The EPAP remained at 4 cm H2O. All the other available settings were reviewed and adjusted according to the patient’s needs and preferences. All ventilatory assist devices contained a computer chip, which activated only when negative (inspiratory) flow was detected downstream. The counter was set to zero hours at the commencement of the study. For patients with arterial oxyhemoglobin saturation of < 90% despite nocturnal NIMV, supplemental oxygen was entrained to maintain arterial oxyhemoglobin saturation of ≥ 90%. For those assigned to sham therapy (ie, control subjects), they were treated using a continuous positive airway pressure (CPAP) device (S7Elite; ResMed) set at 4 cm H2O. The other components of the protocol were exactly the same as those for the NIMV study arm. Information on the hours of use from the NIMV or the sham machines was downloaded at the end of the 12 weeks of follow-up. Downloads were performed using software (AutoScan version 3.4; ResMed). Study patients were seen in person at baseline, 1 month, and 3 months for a clinical assessment and to troubleshoot any problems with the machine. Detailed measurements of physiologic end points were conducted at baseline and at 3 months. The baseline characteristics of the two groups are summarized in Table 1 .


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  		Table 1. Baseline Characteristics of the Study Patients*

 
Measurements
Spirometry was performed with a rolling seal spirometer, according to published American Thoracic Society standards and as previously described.13 Maximal inspiratory and expiratory pressures were measured by a calibrated manometer. The best of four attempts was documented. Arterial blood gases were measured from blood obtained from the radial artery during midafternoon with the patient breathing room air. A 6-minute walk test was performed along a flat indoor hallway using standard procedures.14 During the baseline measurement, we performed two walk tests and used the average values in the analysis. All walks were performed at room air under standardized conditions at the same time of the day by the same study member blinded to the patient’s assignment.

Holter Monitoring
All of the study participants underwent 24-h Holter monitoring with an ambulatory three-channel ECG recorder with an R-R interval sampling frequency of ≥ 256 Hz (model 483 Holter SSR Digicorder; Delmar Avionics; Irvine, CA). All Holter recordings were performed off NIMV or CPAP. The data were sampled digitally and transferred to a microcomputer for the analysis of HRV. After the transfer of the ECG data to a microcomputer, the R-R interval series were edited both manually and automatically. Only recordings with at least 20 h of data and with > 85% of qualified sinus beats were included in the analysis of HRV. We used the methods recommended by the Task Force of the European Society of Cardiology and the North American Society of Pacing Electrophysiology to perform the time-series analyses. All data analyses were performed using software (Accuplus; Del Mar Avionics; Irvine, CA).15 The SD of all normal-to-normal R-R intervals and the geometric HRV indexes were computed as time domain measures from the recording period. The time domain analyses were expressed in geometric measures (HRV index [HRVI]; triangular interpolation of N-N intervals [TINN]), and in standard measures (SD of the average N-N interval [SDANN]; SD of the R-R interval for normal beats [SDNN]; square root of the mean squared differences of successive N-N intervals [RMSSD]; SD of differences between adjacent N-N [SDSD]). Geometric measures require a reasonable number of N-N intervals to construct the geometric pattern. Thus, in accordance with the task force recommendations,15 we used the entire 24-h recordings to determine TINN and HRVI. Both TINN and HRVI reflect long-term changes in HRV. For standard measures, which reflect short-term variations in HRV, the recordings were classified into daytime (from 7:30 AM to 9:30 PM) and nighttime (from midnight to 7:00 AM) periods. These data are summarized in Tables 2, 3 .


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  		Table 2. Twenty-Four-Hour Measurement of Geometric Measures and Nighttime Recordings of Standard Measures of HRV at Baseline and After 3 Months of Treatment*

 

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  		Table 3. HRV During Daytime Recordings at Baseline and After 3 Months of Treatment

 
Natriuretic Peptide Measurements
A blood sample was obtained during daytime with the subjects in a sitting position using standard venipuncture techniques. Blood specimens were centrifuged immediately, and plasma was stored at – 70°C without any freeze/thaw cycles until the natriuretic peptide levels were measured. Both N-terminal components of pro-atrial natriuretic peptide (pro-ANP) and pro-brain natriuretic peptide (pro-BNP) were measured from plasma using highly sensitive quantitative immunoassays (Biomedica; Biomedica Medizinprodukte GMBH; Vienna, Austria). All measurements were made in triplicate and averaged. The lower limits of detection for these assays were 50 pg/mL for pro-BNP and 50 fmol/mL for pro-ANP. The average interassay coefficients of variation were 11.2% for pro-BNP and 4.7% for pro-ANP. To assess the effects of NIMV on inflammatory parameters, we measured serum C-reactive protein levels at baseline and after 3 months of therapy using a highly sensitive using commercially available solid-phase sandwich enzyme-linked immunosorbent assay kits ({alpha} Diagnostics; San Antonio, TX). All samples were measured in triplicate.

Statistical Analysis
The NIMV group was defined as those who were assigned to NIMV. The control group was composed of individuals who were assigned to sham therapy and two individuals who agreed to participate but declined to use any of the machines. Continuous variables were compared between the NIMV and control groups using a Student t test, and dichotomous variables were compared using a {chi}2 test. For nonnormally distributed variables, normality was achieved through logarithmic transformation. For time trend analysis within each group, a paired t test was used to compare 3-month data to those obtained at baseline. For the intergroup comparisons, a mixed model was used to take into account within-group and between-group variances (Proc Mixed, version 9.1; SAS Institute; Cary, NC). In this model, we controlled for age, gender, and baseline percentage of predicted FEV1. A p value < 0.05 (two tailed) was considered statistically significant. Continuous variables are reported as mean ± SD, unless otherwise specified.

Results

There were 23 subjects who were enrolled in the study, but 2 subjects refused any nocturnal therapy following randomization and were excluded from the main analysis. There were no significant differences in any of the other parameters measured at baseline between the NIMV and control groups except for baseline FEV1, which was significantly higher in the group that received NIMV (p = 0.045). The mean IPAP delivered was 15.5 ± 4.2 cm H2O for the NIMV group (p < 0.001 compared to control group). The EPAP was fixed at 4 cm H2O.

HRV
Over the 3 months, the subject’s 24-h heart rate did not change significantly. In the control group, the heart rate changed by – 0.10 ± 6.8 beats/min; in the NIMV group, the heart rate changed by – 0.89 ± 5.6 beats/min (p = 0.788 for the comparison between the control and NIMV groups). After 3 months of treatment, some indexes of HRV increased significantly. Overall, compared with changes in the control group, the group that received NIMV had significant increases in the geometric measures of HRV (ie, TINN, HRVI). The 24-h TINN increased from 322 to 473 ms (p = 0.034). In the control group, the 24-h TINN did not change significantly (from 444 to 405 ms; p = 0.242). Similarly, the 24-h HRVI increased from 21.8 to 29.9 ms in the NIMV group (p = 0.035); whereas in the control group, the 24-h HRVI did not change significantly (from 27.3 to 26.1 ms; p = 0.453). The standard measures were separated into nighttime and daytime measurements. In the nighttime assessment, there was a significant increase in SDNN (p = 0.021) and SDANN (p = 0.020) at 3 months compared to baseline recordings in the NIMV group. There were no significant changes in the standard HRV measures during daytime (Table 3).

In a secondary analysis, we included the two subjects who did not receive any nocturnal therapy into the control group. The nighttime SDANN comparison, which had been insignificant in the main analysis (p = 0.191), became significant after the inclusion of the two subjects (p = 0.048). For geometric measures, the inclusion or exclusion of the two subjects made no material difference to the results.

Natriuretic Peptide Levels
In the group that received NIMV, there was a trend toward lower pro-BNP levels in plasma after 3 months of therapy compared to baseline levels (p = 0.060). Compared with the control group, the pro-ANP levels were significantly lower after 3 months with NIMV therapy (p = 0.013) [Fig 1 ].


Figure 1
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  		Figure 1. Changes in daytime plasma natriuretic peptide levels over 3 months in COPD patients treated and not treated with NIMV.

 
Six-Minute Walk Test
Compared to baseline, individuals who received NIMV were able to walk 30 m (95% confidence interval [CI], 2 to 57 m) further after 3 months. In contrast, there was no significant change in the walk distance in the control group (4 m; 95% CI, – 38 to 47 m; p = 0.820). However, the control subjects had greater walk distances at baseline (343 ± 48 m) than NIMV subjects (262 ± 100 m) and at 3 months (367 ± 59 m vs 311 ± 144 m; p = 0.311), although none of these comparisons were significant at the p = 0.05 level (Fig 2 ). There were no significant associations between changes in the 6-minute walk distance and either pro-ANP or pro-BNP levels.


Figure 2
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  		Figure 2. Change in 6-min walk distance over 3 months in COPD patients treated and not treated with NIMV.

 
Other Measurements
There were no significant changes in log-C-reactive protein levels over the 3 months in the control (p = 0.930) or the NIMV groups (p = 0.511). Daytime arterial PaCO2 values were similar before and after 3 months of therapy in the control group (p = 0.728). In the NIMV group, there was a trend toward a lower daytime PaCO2 (45.2 mm Hg vs 40.4 mm Hg; p = 0.083). There were no significant changes in FEV1 in the control group (p = 0.138) or the NIMV group (p = 0.051).

Discussion

The principal finding of this study was that nocturnal NIMV for 3 months increased some indexes of HRV at nighttime and reduced circulating natriuretic peptide levels in patients with advanced but stable COPD. These data suggest that nocturnal NIMV may be able to improve certain cardiac end points in COPD. However, due to the small sample size and lack of other cardiac performance data, these findings must be interpreted cautiously.

There have been several randomized controlled trials that have evaluated the effects of nocturnal NIMV for chronic COPD. Similar to our findings, Garrod et al16 (45 patients, 8 weeks) demonstrated a significant improvement in the mean shuttle walk test after 8 weeks of NIMV therapy. Meecham Jones et al17 showed significant improvements in daytime arterial PaO2 and PaCO2, total sleep time, sleep efficiency, overnight PaCO2, and quality of life of COPD patients with NIMV. We extend these and other findings1819 by demonstrating a possible salutary effect of NIMV on HRV and circulating natriuretic peptides in severe COPD.

Although there are many factors that govern HRV, HRV provides important information regarding autonomic influences to the heart.2021 Generally, increased HRV reflects increased vagal modulation; reduced HRV indicates the reverse. In diseased states of the heart, HRV usually decreases19; with improvements in the cardiac condition, HRV increases.22 Importantly, reduced HRV is associated with poorer prognosis. In the Framingham cohort study, for instance, a 1-SD decrement in SDNN was associated with a hazard ratio of 1.47 for new cardiac events23 and significantly increased the risk of mortality in individuals who were free of overt cardiac disease at baseline.24 In the Rotterdam Study,25 subjects in the lowest quartile of SDNN relative to those with normal HRV had an 80% age- and sex-adjusted increase in the risk for cardiac mortality (hazard ratio, 1.8; 95% CI, 1.0 to 3.2). Taken together, these data suggest that HRV is a reasonable surrogate for hard clinical end points such as cardiac morbidity in the general population. It is plausible that HRV may be a surrogate of cardiac end points in COPD; however, future work is needed to validate this notion.

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are hormones of myocardial cell origin that are produced in order to maintain circulatory homeostasis.26 ANP is secreted primarily by the atrial myocardium in response to dilation, while BNP is secreted almost exclusively by the ventricles in response to increased end-diastolic pressure or volume.2627 ANP and BNP gene expressions are up-regulated in states of pressure overload and their circulating levels correlate with patient symptoms (eg, dyspnea), sympathetic activity, endothelin and renin-angiotensin-aldosterone levels.28 Most importantly, their plasma levels predict future risk of cardiovascular events and death.29 For instance in the Framingham Offspring Study, Wang and colleagues29 showed that for each 1-SD increment in log BNP levels, mortality increased by 27% and cardiovascular events increased by 28%, independent of other cardiovascular risk factors. Similar findings were observed for ANP. In view of the evolving importance of these natriuretic peptides, our finding that nocturnal NIMV reduces these levels in COPD is likely to have clinical relevance.

How NIMV improves HRV and reduces circulating natriuretic peptides in COPD patients is unclear. In certain clinical conditions (eg, congestive heart failure), positive pressure ventilation has been demonstrated to reduce both preload and afterload,30 improve cardiac output,31 and attenuate sympathetic neural activity, leading to decreased atrial and ventricular stimulation.11 There may be other mechanisms. Future work is needed to clearly delineate these mechanisms. We also observed a statistically significant increase in the 6-min walk distance after 3 months of NIMV treatment. However, the effect was quite modest (30 m on average) and did not achieve the threshold at which patients usually notice a subjective improvement.14 Moreover, although statistically not significant, the NIMV group had shorter 6-min walk distance than the control group at baseline measurement. As such, we cannot discount the possibility that the observed improvement in the NIMV group was a "regression to the mean" effect.

The present study has certain limitations. Firstly, the overall sample size was modest; therefore, hard end points such as hospitalizations and mortality could not be evaluated. Moreover, the small sample size resulted in some imbalance in the baseline characteristics (eg, FEV1) that could have influenced the analysis. To mitigate this possibility, we used regression techniques to adjust for confounders. Nevertheless, the findings of the present study should be interpreted cautiously. Secondly, we enrolled patients with very advanced COPD; thus, these findings cannot be generalized to the milder COPD population. Thirdly, the follow-up period was short. It is not clear whether the salutary effects on the cardiac end points observed within the three months are sustainable over a longer period of time. Fourthly, although we used a "sham" therapy to blind subjects to the assignment, it was not a true placebo. As such, complete blinding may not have been present and we cannot completely eliminate the possibility of a "placebo effect," though this seems unlikely in view of the excellent compliance observed in those assigned to sham therapy. Whether the sham therapy could have effected some positive benefits in our group of patients is uncertain. CPAP alone may unload respiratory muscles during inspiration and reduce the work of breathing.32 Under such scenario, we could have underestimated the true effects of NIMV in our study.

In summary, the present study indicate that NIMV applied nocturnally over 3 months may improve HRV and reduce circulating natriuretic peptides in stable advanced COPD. These data suggest the possibility that nocturnal NIMV may reduce the impact of cardiac comorbidities, which add significantly to the overall morbidity and mortality of COPD patients.

Footnotes

Abbreviations: ANP = atrial natriuretic peptide; BNP = brain natriuretic peptide; CI = confidence interval; CPAP = continuous positive airway pressure; EPAP = expiratory positive airway pressure; HRV = heart rate variability; HRVI = heart rate variability index; IPAP = inspiratory positive airway pressure; NIMV = nocturnal noninvasive (positive) mechanical ventilation; pro-ANP = pro-atrial natriuretic peptide; pro-BNP = pro-brain natriuretic peptide; RMSSD = square root of the mean squared differences of successive N-N intervals; SDANN = SD of the average N-N interval; SDNN = SD of the R-R interval for normal beats; SDSD = SD of differences between adjacent N-N intervals; TINN = triangular interpolation of N-N intervals

This project is supported by Canadian Institutes of Health Research (clinical trials), the Institute of Health Economics, and the University of Alberta Hospital Foundation.

Dr. Sin is a Senior Scholar with the Michael Smith Foundation for Health Research and is supported by a Canadian Research Chair and a Michael Smith Health Foundation and St. Paul’s Hospital Foundation Professorship in COPD.

The authors have no conflicts of interest to disclose.

Received for publication June 6, 2006. Accepted for publication August 21, 2006.

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