Responses to constant work rate bicycle ergometry exercise in primary pulmonary hypertension: the effect of inhaled nitric oxide.

OBJECTIVES: The purpose of this study was to investigate the responses of patients with primary pulmonary hypertension (PPH) to constant work rate exercise and to examine the effect of nitric oxide (NO) inhalation. BACKGROUND: Maximal exercise tolerance is reduced in PPH, but gas exchange responses to constant work rate exercise have not been defined. We hypothesized that increased pulmonary vascular resistance in PPH would reduce the rate of rise of minute oxygen consumption in response to a given work rate. Because NO may lower pulmonary vascular pressures in PPH, we also postulated that inhaled NO might ameliorate gas exchange abnormalities. METHODS: Nine PPH patients and nine matched normal subjects performed 6-min duration constant work rate cycle ergometry exercise (33.9+/-13.4 W). Patients performed two experiments: breathing air and breathing air with NO (20 ppm). Preexercise right ventricular systolic pressure was assessed by Doppler echocardiography. Normal subjects performed the air experiment only. Gas exchange and heart rate responses were characterized by fitting monoexponential curves. RESULTS: In PPH patients, resting right ventricular systolic pressure fell after NO inhalation (from 83.8+/-16.9 to 73.9+/-21.6 mm Hg, p<0.01, analysis of variance with Tukey correction), but not after breathing air alone (from 88.0+/-20.8 to 86.7+/-20.6 mm Hg, p = NS). Nitric oxide did not affect any of the gas exchange responses. Minute oxygen consumption was similar by the end of exercise in patients and normals, but increased more slowly in patients (mean response time [MRT]: air, 63.17+/-14.99 s; NO, 61.60+/-15.45 s) than normals (MRT, 32.73+/-14.79, p<0.01, analysis of variance, Tukey test). Minute oxygen consumption kinetics during recovery were slower in patients (MRT air: 82.50+/-29.94 s; NO, 73.36+/-15.87 s) than in normals (MRT, 34.59+/-7.11 s, p<0.01). Heart rate kinetics during exercise and recovery were significantly slower in patients than in normals. CONCLUSIONS: The cardiac output response is impaired in PPH. Nitric oxide lowered pulmonary artery pressure at rest, but failed to improve exercise gas exchange responses.

Exhaled nitric oxide during exercise in primary pulmonary hypertension and pulmonary fibrosis.

STUDY OBJECTIVES: Nitric oxide (NO), a potent vasodilator, is present in the exhaled air of humans. We wished to quantify NO production in patients with abnormalities of the pulmonary circulation. PARTICIPANTS: Nine patients with primary pulmonary hypertension (PPH), six with pulmonary fibrosis (PF), and 20 normal volunteers were studied. INTERVENTIONS: All subjects were studied at rest and during continuous incremental (ramp) cycle ergometry exercise. All patients with PPH and nine matched normal volunteers also performed constant exercise at equal absolute work rates. MEASUREMENTS AND RESULTS: The concentration of NO was measured continuously in mixed expired air, and the rate of NO production (VNO) calculated. Peak exercise capacity was markedly impaired in both patient groups. VNO was similar at rest in the PPH patients (142 +/- 84 nL/min) and the normal subjects (117 +/- 45 nL/min), but lower in the PF patients (66 +/- 13 nL/min; p < 0.05; analysis of variance with Bonferonni correction). While VNO in normal subjects more than doubled by peak exercise to 268 +/- 85 nL/min, there was no significant rise with exercise in either patient group (PPH, 155 +/- 81 nL/min; PF, 91 +/- 67 nL/min). Constant work rate exercise induced a significant rise in VNO in the normal subjects (rest, 101 +/- 68 nL/min; exercise, 147 +/- 87 nL/min; p < 0.001) but no significant change in the PPH patients (rest, 127 +/- 111 nL/min; exercise, 68 +/- 65 nL/min). CONCLUSIONS: We conclude that the low resting VNO in PF may be due to loss of normal functional pulmonary capillary bed. The increase in VNO seen in normal subjects may be associated with dilatation and recruitment of the pulmonary capillary bed during exercise, and failure to increase VNO during exercise in disease states may reflect an inability to recruit the capillary bed.

Effects of insulin infusion on plasma phosphate in diabetic patients.

A clinical association between insulin therapy and hypophosphatemia has frequently been made but a dose-response relationship has not been reported. Furthermore, the rapidity by which hypophosphatemia may be induced following an increment in plasma-free insulin concentration is not well defined. Therefore this study compared the effects of different rates of insulin infusion on the changes in plasma phosphate concentration in ketotic, hyperglycemic diabetic man. Sixteen prospective studies were performed in four insulin-dependent ketotic diabetic subjects. Insulin was infused according to one of four different protocols: high dose (1.0 U/kg/hr), low dose (0.1 U/kg/hr), very low dose (0.01 U/kg/hr) and control (saline only). Plasma phosphate, glucose, and free insulin concentrations were measured sequentially during the 60 min infusion periods. We observed that plasma phosphate concentrations declined significantly only with low-dose and high-dose insulin infusions. The magnitude and rapidity of fall of the mean phosphate concentration were greatest with high-dose insulin infusion. Significant hypophosphatemia can be observed within 30 min following the onset of insulin therapy.

Aerobic work capacity in patients with chronic fatigue syndrome.

OBJECTIVE: To determine the aerobic work capacity of patients with the chronic fatigue syndrome and compare it with that of two control groups, and to assess the patients' perception of their level of activity before and during illness. DESIGN: A symptom limited exercise treadmill test with on line gas analysis and blood sampling was used. Subjects were assessed by one investigator, who was blind to the group which they were in. SETTING: Department of medicine, Royal Victoria Hospital, Belfast. SUBJECTS: 13 Patients (10 women, three men) who fulfilled the diagnostic criteria for chronic fatigue syndrome. Two control groups of similar age, sex, and body weight: 13 normal subjects (10 women, three men) and seven patients (five women, two men) with the irritable bowel syndrome. MAIN OUTCOME MEASURES: Aerobic work capacity as assessed by several variables such as length of time on treadmill, heart rate, and biochemical measurements; Borg score; and visual analogue scores of perceived level of physical activity. RESULTS: The patients with the chronic fatigue syndrome had a reduced exercise capacity compared with that of the other subjects, spending a significantly shorter time on the treadmill. They had a significantly higher heart rate at submaximal levels of exertion and at stage III exertion had significantly higher blood lactate concentrations. Using a Borg score, they showed a significantly altered perception of their degree of physical exertion with a mean score of 8.2 compared with 6.6 and 5.3 for the normal subjects and patients with the irritable bowel syndrome respectively. Using a visual analogue scale they indicated that they had a greater capacity for activity before illness than had the patients with the irritable bowel syndrome, but the scores were not significantly different between the two groups. Both groups of patients indicated reduced activity at the time of testing. Normal controls and patients with the irritable bowel syndrome aspired to a greater level of activity than their current level, but the patients with the chronic fatigue syndrome aspired to a level similar to that which they had had before their illness. CONCLUSIONS: Patients with the chronic fatigue syndrome have reduced aerobic work capacity compared with normal subjects and patients with the irritable bowel syndrome. They also have an altered perception of their degree of exertion and their premorbid level of physical activity.

Chronic fatigue syndrome.

Chronic Fatigue Syndrome appears to represent a spectrum of disorders in which a variety of pathophysiological mechanisms may operate. While the initiating event in the majority of patients is a pyrexial illness, possibly due to enterovirus infection, evidence of persisting infection or inflammatory changes in muscle and/or brain remain unconvincing. CFS patients display a definite reduced aerobic work capacity compared to normal control subjects, but this may reflect a state of deconditioning resulting from prolonged physical inactivity. They also have an altered perception of their level of exertion and premorbid fitness. The characteristic fluctuation in symptoms, with periods of relapses and partial remissions, may indicate that some central disorder of sensory perception is operational. It may be that a primary sleep disorder results in a reduced sensory threshold for afferent stimuli from muscle. This could well account for many of the subjective symptoms which patients experience. Much more research is clearly necessary if we are to achieve a better understanding of this distressing and at present enigmatic disorder.

Ventilation during exercise in chronic heart failure.

The ventilatory response to exercise in patients with chronic heart failure (CHF) is greater than normal for a given work or metabolic rate (VO2). The factors that determine the ventilatory response to exercise are: 1) the CO2 production (VCO2), 2) the arterial CO2 set-point (arterial PCO2 (PaCO2) at rest), 3) the physiological dead space/tidal volume ratio (VD/VT), and 4) the change in PaCO2 during exercise. This report illustrates how each of these factors might influence the ventilatory response to exercise in CHF patients. Thirty-one CHF patients (New York Heart Association, Classes 2 and 3) were studied, 18 from Harbor-UCLA Medical Center (cycle-ergometer exercise) and 13 from Queen's University at Belfast (treadmill exercise). A group of healthy subjects matched for size, age and gender served as control subjects. Minute ventilation (VE) was 48, 88 and 43% greater in the CHF groups compared to the control population at 6 min of the 25w and 60w cycle and low level (2.5 km h-1 and 5% grade) treadmill exercise, respectively. VO2 kinetics were slower in CHF patients than the control group, the slowing being proportional to the lactate increase. However, the increase in VO2 above rest at 6 min of exercise was approximately the same for CHF and control subjects. VCO2 at 6 min increased in the CHF patients by 7% and 34% for 25 and 60 watts cycle and 19% for treadmill exercise, respectively, compared to the control group. Because PaCO2 was not measured in this study, neither CO2 set-point nor the VD/VT could be individually calculated. Because end-tidal PCO2 will decrease when PaCO2 decreases or VD/VT increases, the combined effect of PaCO2 change and increase in VD/VT could be assessed from the difference between the patient and the control group. Since PETCO2 was significantly reduced in the patient population at the end of 60w cycle exercise (32 versus 41 mm Hg), either the VD/VT was increased and/or the PaCO2 was reduced. Because the resting PaCO2 is generally normal in CHF patients, the increase in the ventilatory response to exercise in patients with CHF can best be accounted for by three physiological mechanisms: 1) an increase in VCO2 secondary to CO2 release from bicarbonate as it buffers lactic acid, 2) the reduction in PaCO2 secondary to the lactic acidosis-induced hyperventilation, and 3) an increase in the fraction of breath that is wasted (dead space). Mathematically, these factors interact so that relatively small changes in each cause large changes in VE.

Gas exchange responses to continuous incremental cycle ergometry exercise in primary pulmonary hypertension in humans.

In patients suffering from primary pulmonary hypertension (PPH), a raised pulmonary vascular resistance may limit the ability to increase pulmonary blood flow as work rate increases. We hypothesised that oxygen uptake (VO2) may not rise appropriately with increasing work rate during incremental cardiopulmonary exercise tests. Nine PPH patients and nine normal subjects performed symptom-limited maximal continuous incremental cycle ergometry exercise. Mean peak VO2 [1.00 (SD 0.22) compared to 2.58 (SD 0.64) l x min(-1)] and mean VO2 at lactic acidosis threshold [LAT, 0.73 (SD 0.17) compared to 1.46 (SD 0.21 x 1) ml x min(-1)] were much lower in patients than in normal subjects (both P<0.01, two-way ANOVA with Tukey test). The mean rate of change of VO2 with increasing work rate above the LAT [5.9 (SD 2.1) compared to 9.4 (SD 1.3) ml x min(-1) x W(-1), p<0.01)] was also much lower in patients than in normal subjects [apparent delta efficiency 60.3 (SD 38.8)% in patients compared to 31.0 (SD 4.9)% in normal subjects]. The patients displayed lower mean values of end-tidal partial pressure of carbon dioxide than the normal subjects at peak exercise [29.7 (SD 6.8) compared to 42.4 (SD 5.8) mm Hg, P<0.01] and mean oxyhaemoglobin saturation [89.1 (SD 4.1) compared to 93.6 (SD 1.8)%, P<0.05]. Mean ventilatory equivalents for CO2 [49.3 (SD 11.4) compared to 35.0 (SD 7.3), P<0.05] and O2 [44.2 (SD 10.7) compared to 29.9 (SD 5.1), P<0.05] were greater in patients than normal subjects. The sub-normal slopes for the VO2-work-rate relationship above the LAT indicated severe impairment of the circulatory response to exercise in patients with PPH. The ventilatory abnormalities in PPH suggested that the lung had become an inefficient gas exchange organ because of impaired perfusion of the ventilated lung.

Dapsone-induced methhaemoglobinaemia: a source of diagnostic confusion.

Arterial desaturation as measured using pulse oximetry may not reflect cardiorespiratory disease; other possible causes, including certain drugs, should be sought. Within the literature, examples exist of dapsone-induced methaemoglobinaemia causing diagnostic confusion, particularly where respiratory disease is a feature. Few cases have been reported that demonstrate the potential of relatively low levels of methaemoglobinaemia to upset pulse oximetry readings. We describe three examples of dapsone-induced methaemoglobinaemia emphasising the potential for low-grade methaemoglobinaemia to cause diagnostic confusion. Widespread use of the pulse oximeter indicates this problem may occur more regularly, hence there is a need for increased awareness.

Exhaled nitric oxide during incremental and constant workload exercise in chronic cardiac failure.

BACKGROUND: Nitric oxide (NO) is present in exhaled breath and produced by the pulmonary vascular endothelium as a potent vasodilator. Exercise is normally associated with pulmonary vasodilatation and a decrease in pulmonary vascular resistance to accommodate the increase in cardiac output. If production of NO is impaired in patients with chronic congestive cardiac failure (CCF), this might contribute to their exercise intolerance. PATIENTS AND METHODS: We quantified NO production (V NO) in 12 patients with chronic stable CCF and 12 controls, at rest and during incremental cardiopulmonary exercise on a treadmill, and at a later date during constant workload exercise. RESULTS: Patients had reduced V NO compared with controls during incremental exercise [381 (180) vs. 777 (275) nL min-1; mean (SD); P < 0.0001] but at constant workload V NO was similar between the two groups [353 (124) vs. 389 (189) nL min-1; P = 0.25]. Plasma levels of nitrate, the stable end-product of NO production, were significantly higher in patients [resting value 46.1 (21.6) vs. 23.0 (10.0) microM; P = 0.004] and were not influenced by exercise. CONCLUSION: Impaired NO-mediated pulmonary vasodilatation does not appear to contribute to exercise limitation in CCF. Alternatively, the lower NO production observed during maximal exercise in the patient group compared with controls may reflect a reduced incremental response of a system that is already abnormally activated in heart failure.

Non-invasive measurement of cardiac output and ventricular ejection fractions in chronic cardiac failure: relationship to impaired exercise tolerance.

1. The role of cardiac output limitation in the pathophysiology of exercise in patients with chronic failure remains undefined. During steady-state submaximal exercise, oxygen uptake is similar in patients and control subjects, but it is not known if cardiac output is also similar. We wished to determine if the reduced exercise tolerance of patients with chronic cardiac failure during such exercise is related to reduced cardiac output, or to peripheral factors. 2. Ten male patients with stable chronic failure and ten age-matched male normal controls were studied at rest and during exercise. Each subject performed a familiarization exercise test, a symptom-limited maximal exercise test and two submaximal exercise tests. Cardiac output was measured by a carbon dioxide rebreathing method. We also measured oxygen consumption, ventilation, Borg score of perceived exertion and venous lactate concentration, and ejection fractions. 3. As expected, patients had lower peak oxygen consumption [median (range) 1.18 (0.98-1.76) versus 1.935 (1.53-2.31) l/min; P < 0.001], lower peak venous lactate concentration but a similar overall level of perceived exertion. At the same submaximal workload, patients and control subjects had similar oxygen consumption [0.67 (0.59-0.80) versus 0.62 (0.52-0.82) l/min] and cardiac output [6.92 (5.79-9.76) versus 7.3 (5.99-10.38) l/min] but the patients had a greater perceived level of exertion [Borg score: 4 (1-6) versus 3 (1-5); P < 0.005], higher venous lactate concentration [1.6 (1-3.3) versus 1.14 (0.7-1.7) mmol/l; P < 0.05] and higher heart rate [106 (89-135) versus 87 (69-112) beats/ min; P < 0.005]. 4. During submaximal exercise at a similar absolute workload, patients with cardiac failure have a similar oxygen uptake and cardiac output but greater anaerobiosis and increased fatigue when compared with normal subjects. These findings appear to relate predominantly to changes that occur in the periphery rather than abnormalities of central cardiac function.

Comparative physiological study of arbutamine with exercise in humans.

Pharmacological stress testing may be used in the diagnosis of coronary artery disease when there are contra-indications to the use of conventional exercise protocols. The responses to such testing using arbutamine and to conventional treadmill exercise were compared in eight patients. Respiratory gas analysis and cardiovascular observations were performed during both tests. For an equivalent increment in heart rate, both protocols increased systolic blood pressure and serum lactate. Minute ventilation and oxygen consumption also rose during both protocols, but much more so with exercise. The end-tidal partial pressure of CO(2) [35.1 (S.D. 3. 1) to 30.8 (6.6) mmHg] and the dead space/tidal volume ratio (V(D)/V(T)) [0.37 (0.09) to 0.33 (0.08)] fell significantly during arbutamine infusion, but the respiratory exchange ratio did not change during either protocol. Oxygen pulse, a marker of stroke volume, did not change significantly after arbutamine, but rose markedly after exercise [arbutamine, 3.9 (1.1) to 3.37 (0.7) ml. min(-1).beat(-1); exercise, 4.7 (1.4) to 16.1 (4.6) ml.min(-1). beat(-1) (P<0.0001 compared with baseline); difference between peak responses: P<0.0001]. We conclude that arbutamine simulates some of the physiological responses to exercise, although a number of these responses are less marked than during conventional exercise, in particular cardiac output (oxygen pulse). An increase in ventilation is produced, possibly due to direct stimulation of arterial chemoreceptors. These data suggest that the main action of arbutamine is to increase central drive rather than to establish peripheral demand.

Oxygen consumption is increased relative to work rate in patients with McArdle's disease.

BACKGROUND: Patients with McArdle's disease suffer exercise incapacity as a result of myophosphorylase deficiency, and for a given work rate have excessive circulatory and ventilatory responses. We hypothesized that the rate of increase of oxygen consumption with work rate (DeltaVO2-DeltaWR slope) would also be elevated in such patients as a result of these excessive responses. PATIENTS AND METHODS: Five patients with McArdle's disease and five matched controls carried out a maximal incremental cardiopulmonary exercise test. Controls then carried out a second test matched to the maximal test of a paired patient. Venous blood was sampled at rest, peak exercise and recovery. RESULTS: During the matched test, the DeltaVO2-DeltaWR slope was higher in the patients than in the controls [19.9 (15.0-24.6) vs. 11.7 (9.2-13.5) mL min(-1) W(-1); mean (range); P = 0.022], and the peak-achieved VO2 was also greater in the patient group [1201 (890-1575) vs. 918 (599-1248) mL min(-1); P = 0.003]. A similar pattern was observed for heart rate [173 (165-182) vs. 108 (105-134) b.p.m.; P = 0.001] and plasma norepinephrine levels [12.6 (9.2-19.9) vs. 2.9 (2.2-4.9) nmol l(-1); P = 0.003]. CONCLUSION: There is an increased rate of rise in VO2 relative to work rate during exercise in patients with McArdle's disease. There is also a greater rise in catecholamines, which may be the result of a physiological response to substrate starvation, and is likely to contribute to the increase in VO2.

Effect of thoracotomy and lung resection on exercise capacity in patients with lung cancer.

BACKGROUND: Resection is the treatment of choice for lung cancer, but may cause impaired cardiopulmonary function with an adverse effect on quality of life. Few studies have considered the effects of thoracotomy alone on lung function, and whether the operation itself can impair subsequent exercise capacity. METHODS: Patients being considered for lung resection (n = 106) underwent full static and dynamic pulmonary function testing which was repeated 3-6 months after surgery (n = 53). RESULTS: Thoracotomy alone (n = 13) produced a reduction in forced expiratory volume in one second (FEV1; mean (SE) 2.10 (0.16) versus 1.87 (0.15) l; p<0.05). Wedge resection (n = 13) produced a non-significant reduction in total lung capacity (TLC) only. Lobectomy (n = 14) reduced forced vital capacity (FVC), TLC, and carbon monoxide transfer factor but exercise capacity was unchanged. Only pneumonectomy (n = 13) reduced exercise capacity by 28% (PVO2 23.9 (1.5) versus 17.2 (1.7) ml/min/kg; difference (95% CI) 6.72 (3.15 to 10.28); p<0.01) and three patients changed from a cardiac limitation to exercise before pneumonectomy to pulmonary limitation afterwards. CONCLUSIONS: Neither thoracotomy alone nor limited lung resection has a significant effect on exercise capacity. Only pneumonectomy is associated with impaired exercise performance, and then perhaps not as much as might be expected.

Neuroendocrine changes in chronic cardiac failure.

Numerous hormonal and neuroendocrine changes have been described in patients with chronic cardiac failure. These affect the balance of vasodilator and vasoconstrictor factors in favour of the latter, to the detriment of the circulation. Whether this is a reaction to central cardiac (haemodynamic) abnormalities, or is an integral part of the syndrome of heart failure, remains to be determined. Catecholamine levels are increased, especially in severe heart failure, and contribute to the vasoconstriction and probably also to lethal ventricular arrhythmias. The renin-angiotensin-aldosterone system (RAAS) is also activated, causing fluid retention and further vasoconstriction. In the earlier stages, some of this increase may be iatrogenic due to the use of loop diuretics or inhibitors of angiotensin converting enzyme, but there is evidence for independent RAAS activation in more severe grades of heart failure. The role of vasoconstrictor peptides such as neuropeptide Y and endothelin is briefly considered. Counterbalancing these are vasodilator peptides, in particular atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP). The possibility of therapeutic interventions to increase circulating natriuretic hormone levels is discussed.