Alexander G. Logan

Suppression of Central Sleep Apnea by Continuous Positive Airway Pressure and Transplant-Free Survival in Heart Failure A Post Hoc Analysis of the Canadian Continuous Positive Airway Pressure for Patients With Central Sleep Apnea and Heart Failure Trial (CANPAP)

Background— In the main analysis of the Canadian Continuous Positive Airway Pressure (CPAP) for Patients with Central Sleep Apnea (CSA) and Heart Failure Trial (CANPAP), CPAP had no effect on heart transplant–free survival; however, CPAP only reduced the mean apnea-hypopnea index to 19 events per hour of sleep, which remained above the trial inclusion threshold of 15. This stratified analysis of CANPAP tested the hypothesis that suppression of CSA below this threshold by CPAP would improve left ventricular ejection fraction and heart transplant–free survival. Methods and Results— Of the 258 heart failure patients with CSA in CANPAP, 110 of the 130 randomized to the control group and 100 of the 128 randomized to CPAP had sleep studies 3 months later. CPAP patients were divided post hoc into those whose apnea-hypopnea index was or was not reduced below 15 at this time (CPAP-CSA suppressed, n=57, and CPAP-CSA unsuppressed, n=43, respectively). Their changes in left ventricular ejection fraction and heart transplant–free survival were compared with those in the control group. Despite similar CPAP pressure and hours of use in the 2 groups, CPAP-CSA–suppressed subjects experienced a greater increase in left ventricular ejection fraction at 3 months (P=0.001) and significantly better transplant-free survival (hazard ratio [95% confidence interval] 0.371 [0.142 to 0.967], P=0.043) than control subjects, whereas the CPAP-CSA–unsuppressed group did not (for left ventricular ejection fraction, P=0.984, and for transplant-free survival, hazard ratio 1.463 [95% confidence interval 0.751 to 2.850], P=0.260). Conclusions— These results suggest that in heart failure patients, CPAP might improve both left ventricular ejection fraction and heart transplant–free survival if CSA is suppressed soon after its initiation.

Relationship Between Overnight Rostral Fluid Shift and Obstructive Sleep Apnea in Drug-Resistant Hypertension

Obstructive sleep apnea occurs frequently in patients with drug-resistant hypertension. The factors accounting for this observation, however, are unclear. Both conditions demonstrate clinical features suggestive of extracellular fluid volume overload. The aims of this study were to examine whether the spontaneous overnight fluid shift from the legs to the upper body is associated with obstructive sleep apnea in hypertensive subjects and whether its magnitude is greater in drug-resistant hypertension. Leg fluid volume and the circumference of the calf and neck were measured before and after sleep in drug-resistant hypertensive (n=25) and controlled hypertensive (n=15) subjects undergoing overnight polysomnography. The severity of obstructive sleep apnea was greater in the drug-resistant hypertensive group than in the controlled hypertensive group (apnea-hypopnea index: 43.0±5.4 versus 18.1±4.2 events per hour of sleep; P=0.02, case-mix adjusted). In both groups, the apnea-hypopnea index strongly related to the amount of leg fluid volume displaced (R2=0.56; P<0.0001), although the magnitude of change was greater in the drug-resistant hypertensive group (346.7±24.1 versus 175.8±31.3 mL; P=0.01, propensity-score adjusted). The overnight reduction in calf circumference and increase in neck circumference were also greater in drug-resistant hypertension (both P≤0.02). In hypertensive subjects, rostral fluid displacement strongly relates to the severity of obstructive sleep apnea with its magnitude being greater in drug-resistant hypertension. Our findings support the concept that fluid redistribution centrally during sleep accounts for the high prevalence of obstructive sleep apnea in drug-resistant hypertension.

Microsphere Measurement of Intrarenal Circulation of the Dog

Distribution of cortical blood flow was measured in the dog by a technique based on radionuclide-labeled microspheres. Initially it was necessary to test possible pitfalls of this technique. Completeness of trapping in the kidney, the effect on renal function, and the notion that microsphere distribution reflects blood flow distribution in the kidney cortex were studied. Renal vein blood contained less than 0.2% of the microspheres (16.8μ diameter) found in the renal artery after an aortic injection. No impairment of CPAH (control 167±4; postinjection 179±31 ml/min), CIn (control 39.3%6; postinjection 37.6±2 ml/min), and Tm glucose (control 90.8±13; postinjection 102±24) was found using doses adequate to measure renal blood flow (5 mg/injection × 4 injections). After 4 injections of 50 mg each significant impairment of renal function was observed. Intrarenal blood flow distribution was determined during hemorrhagic hypotension. 169Yb-labeled microspheres were injected into the root of the aorta before, and 85Sr-labeled microspheres after, acute hemorrhage. Radioactivity was measured in the outer two thirds and inner one third of kidney slices. Tissue blood flow was calculated and expressed as the ratio of outer cortex to inner cortex counts. Renal blood flow was redistributed to the inner cortex after hemorrhage (ratio before, 3.00; after 1.30, P < 0.01). Finally, the results of this technique were compared to a widely used method of measuring intrarenal blood flow distribution, 133Xe washout. The first component of the washout technique correlated fairly well with total cortical flow but it was not possible to match the second component with any single anatomical area of the kidney. Limitations of the 133Xe washout are discussed.

Intrarenal Blood Flow Distribution in Canine Puppies

Extract: The present study was designed to examine the developmental changes in renal blood flow distribution in canine puppies utilizing the techniques of xenon-133 (133Xe) washout, anatomic measurements, and para-aminohippuric acid (PAH) clearances and extractions. The distribution patterns determined by analysis of the xenon washout curves were confirmed by studies of the intrarenal distribution of injected radioactive microspheres. The mean total blood flow was 1.2 ml/g kidney/min at 6 weeks of age and rose progressively to the adult value of 3.5 ml/g kidney/min at 14–16 weeks of age. The mean Component I flow, 1.7 ml/g/min at 6 weeks, increased to 4.7 ml/g/min at 14–16 weeks of age. The increase in Component I flow was associated with an increase in PAH extraction ratio. The low renal blood flow observed in the puppy less than 6 weeks of age appears to be due in large part to a small cortical volume. Anatomically, the amount of cortex/medulla ratio was less in the puppy than in the adult, and this was supported by the relatively low cortical volume of distribution noted in the washout studies. At 10 and 12 weeks of age, when the relative cortical mass approximated that found in the adult, the Component I flow rate was still low, but from age 12 weeks, Component I flow and total renal blood flow increased markedly. Renal blood flow increased during a period when cardiac output per kilogram body weight was constant and total peripheral resistance was rising.The progressive age-dependent increase that was noted in total renal blood flow was primarily due to an increase in cortical flow. The increased cortical flow was in part a consequence of cortical growth; change in sympathetic tone may also have contributed.

Effect of intensified diuretic therapy on overnight rostral fluid shift and obstructive sleep apnoea in patients with uncontrolled hypertension.

Objectives: Fluid displacement from the lower extremities to the upper body during sleep is strongly associated with obstructive sleep apnoea in hypertensive patients. The present pathophysiological study tests the hypothesis that intensified diuretic therapy will reduce the apnoea-hypopnoea index and blood pressure of uncontrolled hypertensive patients with obstructive sleep apnoea in proportion to the reduction in overnight change in leg fluid volume. Methods: Uncontrolled treated hypertensive patients underwent overnight polysomnography and measurement of overnight changes in leg fluid volume and neck circumference. Those with an apnoea-hypopnoea index at least 20 events per hour (n = 16) received metolazone 2.5 mg and spironolactone 25 mg daily for 7 days after which the daily dose was doubled for 7 additional days. Baseline testing was again repeated. Results: Intensified diuretic therapy reduced the apnoea-hypopnoea index from 57.7 ± 33.0 to 48.5 ± 28.2 events per hour (P = 0.005), overnight change in leg fluid volume from –418.1 ± 177.5 to –307.5 ± 161.9 ml (P < 0.001) and overnight change in neck circumference from 1.2 ± 0.6 to 0.7 ± 0.4 cm (P < 0.001). There was an inverse correlation between the reduction in overnight change in leg fluid volume and decrease in apnoea-hypopnoea index (r = –0.734, P = 0.001). The reduction in overnight change in leg fluid volume was also significantly correlated with the change in morning blood pressure (r = 0.708, P = 0.002 for SBP; r = 0.512, P = 0.043 for DBP). Conclusion: The findings provide further evidence that fluid redistribution from the legs to the neck during sleep contributes to the severity of obstructive sleep apnoea in hypertension and may be an important link between these two conditions.

Association between refractory hypertension and obstructive sleep apnea

Background Obstructive sleep apnea (OSA) increases the risk for mild hypertension, but its relationship to refractory hypertension (RHT) has not been systematically examined. We previously reported a high prevalence of OSA in patients with RHT, but did not have a control group with which to compare. Rapid eye movement (REM) sleep deprivation can raise blood pressure in animals. However, a potential relationship of OSA and REM sleep time with RHT has not been examined. Objective To determine whether, compared with patients with well controlled hypertension, those with RHT have a higher prevalence of OSA (apnea–hypopnea index ≥10 per hour of sleep) and shorter REM sleep time. Methods We compared the prevalence of OSA and sleep structure in 42 patients with RHT with 22 patients with controlled hypertension, matched for age, sex and BMI. Results Compared with the controlled hypertension group, the RHT group had a significantly higher prevalence of OSA (81 versus 55%, P = 0.03) and less REM sleep time (47.0 ± 4.5 versus 63.2 ± 4.9 min, P = 0.02). Multivariate analysis revealed significantly increased odds of having RHT associated with OSA independent of other risk factors (adjusted odds ratio, 3.994; 95% confidence interval, 1.191–13.388). Reduced REM sleep time was also independently associated with the presence of RHT (adjusted odds ratio, 1.025; 95% confidence interval, 1.002–1.049). Conclusion OSA and reduced REM sleep time are associated with increased odds of having RHT and, therefore, may play roles in its pathogenesis.

Intracortical Distribution of Renal Blood Flow in Hemorrhagic Shock in Dogs

The effect of acute hypotensive hemorrhage on the intracortical distribution of renal blood flow was studied in anesthetized mongrel dogs with radioactive microspheres. In the early stages of shock, when carotid artery manipulation was avoided, outer cortical blood flow fell drastically and juxtamedullary flow was relatively well preserved. Carotid artery cannulation caused a redistribution of blood flow within the kidney even before hemorrhage, presumably by stimulating the carotid sinus reflex. Subsequently, with hemorrhage there was a parallel reduction in outer cortical and juxtamedullary blood flow. 138Xe washout curves agreed with the microsphere findings. It was concluded that when the carotid artery was not disturbed, juxtamedullary blood flow was selectively preserved in the early stages of acute hypotensive hemorrhage.

Influence of Lower Body Positive Pressure on Upper Airway Cross-Sectional Area in Drug-Resistant Hypertension

We previously showed that in hypertensive patients the amount of fluid displaced from the legs overnight is directly related to the severity of obstructive sleep apnea and that the rostral fluid shift was greater in drug-resistant hypertensive patients. The findings suggested that this fluid redistribution increases upper airway collapsibility, yet more direct evidence is lacking. The present study examines the effects of graded lower body positive pressure on leg fluid volume, upper airway cross-sectional area, and neck circumference in patients with drug-resistant hypertension (n=25) and controlled hypertension (n=15). In both groups, the reduction in mean upper airway cross-sectional area and oropharyngeal junction area, assessed by acoustic pharyngometry, and the increase in neck circumference, determined by mercury strain gauge plethysmography, were related to the amount of fluid displaced from the legs (R 2=0.41, P<0.0001; R 2=0.42, P<0.0001; and R 2=0.47, P<0.0001, respectively). Displacement of leg fluid volume was significantly greater in patients with drug-resistant hypertension than in controlled hypertension (P<0.0001), and as a consequence, the former experienced greater reductions in mean upper airway cross-sectional area and oropharyngeal junction area (P=0.001 and P<0.0001, respectively). The findings support the concept that in hypertensive subjects, rostral fluid displacement may participate in the pathogenesis of obstructive sleep apnea by narrowing the upper airway and making it more susceptible to collapse during sleep. The exaggerated fluid volume displacement from the legs and upper airway response to lower body positive pressure in patients with drug-resistant hypertension provide additional evidence of an important link between drug-resistant hypertension and obstructive sleep apnea.

Renal Cortical Blood Flow, Cortical Fraction, and Cortical Blood Volume in Hypertensive Subjects

In 15 patients with essential hypertension total blood flow to a single kidney (TRBF) was measured by a constant infusion indicator-dilution technic which had previously been validated in dogs. Indocyanine green indicator-dilution curves then were used to calculate the fraction of renal flow traversing the rapid (cortical) circulation and the blood volume in this cortical compartment. TRBF ranged from 152 to 1033 ml/min/1.73m2 per kidney and was closely correlated with cortical flow (r = 0.99). The cortical fraction of TRBF ranged from 46 to 93% and varied directly with total flow (r = 0.69). Noncortical flow ranged from 12 to 85 ml/min/1.73m2 per kidney and showed no correlation with TRBF. Cortical blood volume varied from 12 to 85 ml/1.73m2 and also was closely correlated with TRBF (r = 0.93).These data suggest that diminished TRBF in hypertensive patients is due to reduction in cortical flow with preservation of noncortical (medullary) flow and reduction in cortical blood volume. The reduced cortical fraction of TRBF could be a factor in the renal functional abnormalities which occur in hypertension.

Ambulatory blood pressure monitoring: its time to move on!

The diagnosis of hypertension has traditionally relied upon repeated office or clinic blood pressure (BP) measurements taken by a health professional generally using a mercury sphygmomanometer. Increasingly, ambulatory BP monitoring is being used to expedite the diagnosis of hypertension and categorize it into different types [1]. Currently, it is only approved for reimbursement (United States) to diagnose white-coat hypertension (i.e. elevated BP in the physicians’ office or clinic and normal BP outside these settings) [2]. Ambulatory BP monitoring also provides important information on BP level during the sleep period (nocturnal hypertension, nondipping BP pattern) [3]. Several studies have shown that these parameters are important harbingers of poor cardiovascular prognosis and that nighttime pressures more accurately predict the occurrence of death and cardiovascular events than daytime pressures, independent of other confounders [4,5].