Kirk Kee

Loop Gain As a Means to Predict a Positive Airway Pressure Suppression of Cheyne-Stokes Respiration in Patients with Heart Failure

RATIONALE Patients with heart failure (HF) and Cheyne-Stokes respiration or periodic breathing (PB) often demonstrate improved cardiac function when treatment with continuous positive airway pressure (CPAP) resolves PB. Unfortunately, CPAP is successful in only 50% of patients, and no known factor predicts responders to treatment. Because PB manifests from a hypersensitive ventilatory feedback loop (elevated loop gain [LG]), we hypothesized that PB persists on CPAP when LG far exceeds the critical threshold for stable ventilation (LG = 1). OBJECTIVES To derive, validate, and test the clinical utility of a mathematically precise method that quantifies LG from the cyclic pattern of PB, where LG = 2π/(2πDR - sin2πDR) and DR (i.e., duty ratio) = (ventilatory duration)/(cycle duration) of PB. METHODS After validation in a mathematical model of HF, we tested whether our estimate of LG changes with CPAP (n = 6) and inspired oxygen (n = 5) as predicted by theory in an animal model of PB. As a first test in patients with HF (n = 14), we examined whether LG predicts the first-night CPAP suppression of PB. MEASUREMENTS AND MAIN RESULTS In lambs, as predicted by theory, LG fell as lung volume increased with CPAP (slope = 0.9 ± 0.1; R(2) = 0.82; P < 0.001) and as inspired-arterial PO(2) difference declined (slope = 1.05 ± 0.12; R(2) = 0.75; P < 0.001). In patients with HF, LG was markedly greater in 8 CPAP nonresponders versus 6 responders (1.29 ± 0.04 versus 1.10 ± 0.01; P < 0.001); LG predicted CPAP suppression of PB in 13/14 patients. CONCLUSIONS Our novel LG estimate enables quantification of the severity of ventilatory instability underlying PB, making possible a priori selection of patients whose PB is immediately treatable with CPAP therapy.

Prevalence of depression in patients referred with snoring and obstructive sleep apnoea.

Depression and obstructive sleep apnoea are two common entities, with common symptoms that make identification of either condition difficult. Our aim was to examine, within a group of patients referred with snoring and obstructive sleep apnoea, (i) the prevalence of depression with the 14‐question Hospital Anxiety and Depression Scale (HADS), (ii) the correlation between the two lead depression symptoms from the Mini‐International Neuropsychiatric Interview (MINI) and HADS, and (iii) the relationship between depression symptoms with physiological markers of OSA.

Sleep apnoea in heart failure: To treat or not to treat?

Heart failure (HF) and sleep apnoea are common disorders which frequently coexist. Two main types of apnoea occur: one is obstructive which, through recurring episodes of snoring, hypoxaemia, large negative intra‐thoracic pressures and arousals from sleep leading to downstream inflammatory and autonomic nervous system changes, is thought to be a causative factor to the development of systemic hypertension and HF. The other type of apnoea, Cheyne–Stokes respiration with central sleep apnoea (CSR‐CSA), is characterized by an oscillatory pattern of ventilation with a prevailing hyperventilation‐induced hypocapnia, often in the absence of significant hypoxaemia and snoring, and is thought to be a consequence of advanced HF‐related low cardiac output, high sympathetic nervous system activation and pulmonary congestion. CSR‐CSA may be a compensatory response to advanced HF. Rostral fluid shift during sleep may play an important role in the pathogenesis of both obstructive sleep apnoea (OSA) and CSA. Studies of positive airway pressure (PAP) treatment of OSA and CSA in HF have shown short‐term improvements in cardiac and autonomic function; however, there is no evidence of improved survival. Loop gain may provide useful marker of continuous PAP (CPAP) responsiveness in patients with central apnoea. A greater understanding of the pathophysiology of the interaction between obstructive and central apnoea and the various types of HF, and the mechanisms of therapies, such as PAP, is required to develop new strategies to overcome the disabling symptoms, and perhaps improve the mortality, that accompany HF with sleep apnoea.

Increased Dead Space Ventilation Mediates Reduced Exercise Capacity in Systolic Heart Failure.

RATIONALE Patients with chronic heart failure have limited exercise capacity, which cannot be completely explained by markers of cardiac dysfunction. Reduced pulmonary diffusing capacity at rest and excessively high ventilation during exercise are common in heart failure. We hypothesized that the reduced pulmonary diffusing capacity in patients with heart failure would predict greater dead space ventilation during exercise and that this would lead to impairment in exercise capacity. OBJECTIVES To determine the relationship between pulmonary diffusing capacity at rest and dead space ventilation during exercise, and to examine the influence of dead space ventilation on exercise in heart failure. METHODS We analyzed detailed cardiac and pulmonary data at rest and during maximal incremental cardiopulmonary exercise testing from 87 consecutive heart transplant assessment patients and 18 healthy control subjects. Dead space ventilation was calculated using the Bohr equation. MEASUREMENTS AND MAIN RESULTS Pulmonary diffusing capacity at rest was a significant predictor of dead space ventilation at maximal exercise (r = -0.524, P < 0.001) in heart failure but not in control subjects. Dead space at maximal exercise also correlated inversely with peak oxygen consumption (r = -0.598, P < 0.001), peak oxygen consumption per kilogram (r = -0.474, P < 0.001), and 6-minute-walk distance (r = -0.317, P = 0.021) in the heart failure group but not in control subjects. CONCLUSIONS Low resting pulmonary diffusing capacity in heart failure is indicative of high dead space ventilation during exercise, leading to excessive and inefficient ventilation. These findings would support the concept of pulmonary vasculopathy leading to altered ventilation perfusion matching (increased dead space) and resultant dyspnea, independent of markers of cardiac function.

Heart failure and sleep-disordered breathing: mechanisms, consequences and treatment

Purpose of review This review examines the recently published articles pertaining to sleep-disordered breathing (SDB) and heart failure. Recent findings The recent findings can be classified into pulmonary, upper airway and treatment trials. Pulmonary complications of heart failure include loss of surfactant, increased pulmonary dry weight and reduced lung volume, which are likely to increase plant gain and thus predispose to central sleep apnea with Cheyne–Stokes respiration. Upper airway narrowing in normal individuals has been shown to occur with lower limb compression and the supine body position, thus suggesting that rostral fluid shifts may narrow the upper airway and aggravate obstructive sleep apnea. Extrapolating this to congestive heart failure (CHF), it is possible that CHF fluid status may impact upon obstructive sleep apnea severity. Following the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnoea and Heart Failure trial, further SDB intervention studies have been reported using adaptive servo-ventilation. Although encouraging, small, short-term studies are discussed, however long-term randomized trials with objective cardiac outcomes are still lacking. Summary The relationship between CHF and SDB is likely to be bidirectional, CHF impacting on SDB severity and vice versa. Identification of SDB in the CHF population appears to be important as it is probably associated with greater mortality, but whether SDB intervention significantly influences CHF survival still remains to be determined.

Control theory prediction of resolved Cheyne-Stokes respiration in heart failure.

Cheyne–Stokes respiration (CSR) foretells deleterious outcomes in patients with heart failure. Currently, the size of therapeutic intervention is not guided by the patients underlying pathophysiology. In theory, the intervention needed to resolve CSR, as a control system instability (loop gain >1), can be predicted knowing the baseline loop gain and how much it falls with therapy. In 12 patients with heart failure, we administered an inspiratory carbon dioxide fraction of 1–3% during CSR (n=95 interventions) as a means to reduce loop gain. We estimated the loop gain on therapy (LGtherapy), using the baseline loop gain (using hyperpnoea length/cycle length) and its expected reduction (18% per 1% inspired carbon dioxide), and tested the specific hypothesis that LGtherapy predicts CSR persistence (LGtherapy >1) versus resolution (LGtherapy <1). As predicted, when LGtherapy >1.0, CSR continued during therapy in 23 out of 25 (92%) trials. A borderline loop gain zone (0.8<LGtherapy<1) yielded an unpredictable outcome, while LGtherapy <0.8 consistently yielded CSR resolution (37 out of 37 trials). A threshold of LGtherapy=0.9 determined outcome in 76 out of 95 (80%) trials. We establish proof-of-concept that control theory provides predictive insight into CSR resolution in heart failure. Thus, we now have a means to calculate the size of interventions needed to ameliorate CSR on a patient-by-patient basis. Control theory predicts the magnitude of therapeutic intervention needed to resolve Cheyne-Stokes respiration http://ow.ly/Vpuj301PRUq

Ventilation heterogeneity is increased in patients with chronic heart failure

In the healthy lung, ventilation is distributed heterogeneously due to factors such as anatomical asymmetry and gravity. This ventilation heterogeneity increases pathologically in conditions such as asthma, chronic obstructive lung disease, and cystic fibrosis. In chronic heart failure, lung biopsy demonstrates evidence of peripheral lung fibrosis and small airways narrowing and distortion. We hypothesized that this would lead to increased ventilation heterogeneity. Furthermore, we proposed that rostral fluid shifts when seated patients lie supine would further increase ventilation heterogeneity. We recruited 30 ambulatory chronic heart failure patients (57 ± 10 years, 83% male, left ventricular ejection fraction 31 ± 12%) as well as 10 healthy controls (51 ± 13 years, 90% male). Heart failure patients were clinically euvolemic. Subjects underwent measurement of ventilation heterogeneity using the multiple‐breath nitrogen washout technique in the seated position, followed by repeat measurements after 5 and 45 min in the supine position. Ventilation heterogeneity was calculated using the lung clearance index (LCI), Sacin and Scond which represent overall, acinar, and small conducting airway function, respectively. Lung clearance index (9.6 ± 1.2 vs. 8.6 ± 1.4 lung turnovers, P = 0.034) and Scond (0.029 ± 0.014 vs. 0.006 ± 0.016/L, P = 0.007) were higher in the heart failure patients. There was no difference in Sacin (0.197 ± 0.171 vs. 0.125 ± 0.081/L, P = 0.214). Measures of ventilation heterogeneity did not change in the supine position. This study confirms the presence of peripheral airway pathology in patients with chronic heart failure. This leads to subtle but detectable functional abnormalities which do not change after 45 min in the supine position.

Maximal exercise does not increase ventilation heterogeneity in healthy trained adults

The effect of exercise on ventilation heterogeneity has not been investigated. We hypothesized that a maximal exercise bout would increase ventilation heterogeneity. We also hypothesized that increased ventilation heterogeneity would be associated with exercise‐induced arterial hypoxemia (EIAH). Healthy trained adult males were prospectively assessed for ventilation heterogeneity using lung clearance index (LCI), Scond, and Sacin at baseline, postexercise and at recovery, using the multiple breath nitrogen washout technique. The maximal exercise bout consisted of a maximal, incremental cardiopulmonary exercise test at 25 watt increments. Eighteen subjects were recruited with mean ± SD age of 35 ± 9 years. There were no significant changes in LCI, Scond, or Sacin following exercise or at recovery. While there was an overall reduction in SpO2 with exercise (99.3 ± 1 to 93.7 ± 3%, P < 0.0001), the reduction in SpO2 was not associated with changes in LCI, Scond or Sacin. Ventilation heterogeneity is not increased following a maximal exercise bout in healthy trained adults. Furthermore, EIAH is not associated with changes in ventilation heterogeneity in healthy trained adults.

Characteristics of Patients Who Progress from Bridging to Long Term Oxygen Therapy: From Bridging to Long Term Oxygen

Patients with persistent hypoxia following an acute hospital admission may be discharged with ‘bridging’ domiciliary oxygen as per criteria defined by the Thoracic Society of Australia and New Zealand. The need for continuous long‐term oxygen therapy (LTOT) is then reassessed at a clinic review 1–2 months later.

Reply: Dyspnea in Heart Failure: A Multiheaded Beast

a pulmonary vasculopathy in patients with heart failure is problematic, as they cite no histologic studies supporting such a finding. Although the reduced diffusing capacity observed in patients with chronic heart failure is likely due to a thickened alveolar capillary barrier (2), there is a better explanation for the increased exercise physiologic dead space, unrelated to the decreased diffusing capacity (3). A comprehensive review of the prognostic importance of the V : E/VCO2 measurement in patients with heart failure (4, 5) included a discussion of the physiological factors responsible for the observed elevation in exercise dead space, mentioning both increased ventilation–perfusion heterogeneity and reductions in late-exercise tidal volume. Although increased ventilation–perfusion heterogeneity would certainly contribute to an increased exercise dead space, the few multiple inert gas elimination studies performed on patients with heart failure have not revealed an appreciable increase in V : A/Q : heterogeneity relative to findings in normal subjects (2). However, an early model of pulmonary gas exchange described by John West demonstrated that in the presence of normal extent of V : A/Q : heterogeneity, an increase in the overall V : A/Q : ratio increases the physiologic dead space measurement. During exercise, patients with severe heart failure and a very high V : E/VCO2 may reach 6 to 10 L of alveolar ventilation per liter of cardiac output, an increase adequate to explain the increased physiologic dead space measurement (3). The validity of separation of patients by Kee and colleagues (1) into high dead space and low dead space groups was dependent on an adjustment to end-tidal PCO2 to serve as a surrogate for arterial PCO2 in the Bohr-Enghoff dead space calculation. The equation used from the data of Jones and colleagues (6) is based on submaximal exercise data acquired on five fit young men and includes a negative correction for tidal volume. In this study, the adjusted values to represent arterial CO2 would therefore be smaller for subjects with larger exercise tidal volumes, leading to a lower dead space calculation. The only significant difference in Kee and colleagues’ Table 4 (1) describing the characteristics of low dead space and high dead space subjects was sex, which in this instance is most likely related to smaller lung size in women. To what extent the equation proposed by Jones and colleagues (6) reliably estimates PaCO2 in maximally exercising older patients with heart failure is uncertain, given the differences in V : A/Q :