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Copyright ©ERS Journals Ltd 2002
Relationship of carbon dioxide tension in arterial blood to pulmonary wedge pressure in heart failure
Depts of Medicine of the 1 Toronto General and 2 Mount Sinai Hospitals/University Health Network, University of Toronto, Toronto, Ontario, Canada
CORRESPONDENCE: T.D. Bradley, NU 9-112 Toronto General Hospital/UHN, 200 Elizabeth Street, Toronto, ON, M5G 2C4, Canada. Fax: 416 3404197
Keywords: arterial blood gas tensions, cardiopulmonary interactions, hypocapnia
Received: February 12, 2001
Accepted July 25, 2001
The present study was supported by grants from the Canadian Institutes of Health Research (MOP-11607) and from the Heart and Stroke Foundation of Ontario. G. Lorenzi-Filho was supported by research fellowships from Fundacao de Amparo a Pesquisa do Estado de Sao Paulo, Brazil and the Dept of Medicine of the University of Toronto. E.R. Azevedo held a research fellowship from Astra Zeneca/Heart and Stroke Foundation of Canada. T.D. Bradley is a Senior Scientist of the Canadian Institutes of Health Research.
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Abstract |
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Hypocapnia contributes to the genesis of Cheyne-Stokes respiration and central sleep apnoea in patients with congestive heart failure (CHF) and is associated with increased mortality. However, the cause of hypocapnia in patients with chronic stable CHF is unknown. Since pulmonary congestion can induce hyperventilation via stimulation of pulmonary vagal afferents, the present study tested the hypothesis that in patients with CHF (carbon dioxide tension in arterial blood (Pa,CO2)) is inversely related to pulmonary capillary wedge pressure (PCWP), and that alterations in PCWP would cause inverse changes in Pa,CO2.
In 11 CHF patients undergoing diagnostic cardiac catheterization, haemodynamic variables and arterial blood gas tensions were measured simultaneously at baseline. In three patients, these measurements were repeated after coronary angiographic dye infusion and nitroglycerine infusion.
At baseline, Pa,CO2 correlated inversely with PCWP (r=–0.80, p=0.003). In the three patients in whom multiple measurements were made, acute alterations in PCWP caused inversely proportional changes in Pa,CO2.
The present study concludes that in patients with congestive heart failure, pulmonary capillary wedge pressure is an important determinant of carbon dioxide tension in arterial blood. These findings imply that hypocapnia in patients with chronic stable congestive heart failure is a respiratory manifestation of elevated left ventricular filling pressures.
In patients with congestive heart failure (CHF), hypocapnia (i.e. carbon dioxide tension in arterial blood (Pa,CO2) <40 mmHg) predisposes to ventilatory instability and leads to central apnoeas during sleep when Pa,CO2 falls below the threshold for apnoea 1, 2. Indeed, CHF patients with Cheyne-Stokes respiration and central sleep apnoea (CSR-CSA) have lower Pa,CO2 both awake and asleep, than CHF patients without CSR-CSA 1. The presence of CSR-CSA in patients with CHF is associated with increased mortality probably due to apnoea-related hypoxia, arousals from sleep and activation of the sympathetic nervous system 3, 4. In addition, hypocapnia in patients with CHF is associated with an increased prevalence of ventricular arrhythmias 5, which also predisposes to sudden death. Despite these pathophysiological associations, however, the cause of hypocapnia in CHF remains to be elucidated.
In animals, increased pulmonary venous pressure induces hyperventilation through stimulation of pulmonary vagal afferents 6. Therefore, one possible explanation for hypocapnia in CHF patients is that stimulation of pulmonary vagal afferents by high cardiac filling pressures or pulmonary congestion induces hyperventilation. However, only indirect evidence supports this possibility. For example, it has been shown that CHF patients with elevated pulmonary capillary wedge pressure (PCWP) have a significantly lower Pa,CO2 than patients whose PCWP is normal 7. Since oxygen tension in arterial blood (Pa,O2) is usually normal in such patients, hypoxia is not likely the cause of hypocapnia 1, 2, 7. Based on these observations, it was hypothesized that in patients with chronic stable CHF, Pa,CO2 would be inversely related to PCWP and that alterations in PCWP would cause inverse changes in Pa,CO2.
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Subjects
The subjects were 11 consecutive males aged between 55–70 yrs who were referred to the Heart Failure Clinic of the Mount Sinai Hospital, Toronto for diagnostic assessment of CHF, and who were undergoing diagnostic cardiac catheterization. Entry criteria included a left ventricle ejection fraction at rest of <35% measured by radionuclide angiography. One patient was in New York Heart Association functional class II and 10 were in class III. The aetiology of CHF was ischaemic in eight and idiopathic dilated cardiomyopathy in three patients. Medical therapy included diuretics in all 11 patients, angiotensin-converting enzyme inhibitors in eight, hydralazine in one, digoxin in six, and amiodarone in two. Patients with a history of respiratory disease were excluded.
Protocol
The protocol was approved by the institutional ethics committee and written informed consent was obtained from all patients. Diagnostic right and left heart catheterization, with patients awake and without sedation, was performed from the femoral approach. Right-sided heart catheterization was performed using a flotation catheter positioned in the right pulmonary artery. Prior to angiography, baseline measurements of pulmonary artery pressure, mean PCWP, and mean right atrial pressure were made using a water filled pressure transducer, and cardiac output was measured by the Fick method. An arterial blood sample was drawn simultaneously from the femoral arterial line for analysis of blood gas tensions. In the last three patients simultaneous measurements of PCWP and arterial blood gas tensions were made immediately after angiographic dye infusion, which caused an increase in PCWP, and during nitroglycerine infusion once PCWP had fallen by at least 15%. Nitroglycerine was infused at a rate of 0.8–1.0 mg·kg·min–1. Throughout the procedures, patients breathed regularly.
Statistical analysis
To assess the potential relationships between Pa,CO2 and a number of physiologically plausible determinants, a multiple stepwise linear regression analysis was carried out using Pa,O2 alveolar-arterial Pa,O2 gradient, PCWP, right atrial pressure, mean arterial blood pressure and cardiac index as independent variables. A backward stepwise regression analysis was then performed to determine which of these variables was independently related to Pa,CO2. Among the three patients in whom multiple arterial blood gas analyses were performed, repeated measures analysis of variance (ANOVA) was performed to determine whether altering PCWP caused any change in Pa,CO2 and other variables. Changes in Pa,CO2 were then plotted against changes in PCWP. A p-value <0.05 was considered statistically significant.
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Results |
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Baseline characteristics of the patients are shown in table 1
. There were significant correlations between Pa,CO2 and PCWP (r=–0.80, p=0.003) (fig. 1), cardiac index (r=–0.71, p=0.004) and right atrial pressure (r=–0.76, p=0.008). However, even though two patients were mildly hypoxic (Pa,O2 of 58 and 54 mmHg) there were no significant correlations of Pa,CO2 with either Pa,O2 (r=0.14, p=0.673) or alveolar-arterial partial pressure of O2 (PO2), gradient (r=–0.33, p=0.325). Stepwise and backward linear regressions showed that PCWP was the only variable that correlated significantly and independently with Pa,CO2. Following dye infusions, PCWP increased (from 18.7 to 21.2, from 20.4 to 28.5 and from 29.0 to 34.0 mmHg in the three subjects, respectively). During nitroglycerine infusions, PCWP consistently decreased (17.2, 18.0 and 18.0 mmHg, respectively). Pa,CO2 changed significantly in response to dye and nitroglycerine infusions (mean±sd, 39.7±2.1 mmHg at baseline, to 36.3±0.6 mmHg following dye, to 39.3±1.2 mmHg during nitroglycerine infusions, p=0.03, dye infusion different from the others). Pa,O2 were 72±16, 81±14 and 71±18 mmHg at baseline, after dye and during nitroglycerine infusions, respectively (p=0.13). Alveolar-arterial PO2 gradients were 38±17, 33±14 and 39±19 mmHg at baseline, after dye and during nitroglycerine infusions, respectively (p=0.42).
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There was a consistent inverse relationship between changes in Pa,CO2 and changes in PCWP in response to dye and nitroglycerine infusions (fig. 2
). Mean arterial blood pressures did not change significantly during the experiment (94±29 at baseline, to 102±23 after dye infusion and to 87±11 mmHg during nitroglycerine infusion respectively, p=0.17).
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Discussion |
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This study is the first in humans with CHF to demonstrate that PCWP is an independent determinant of Pa,CO2. Evidence for this was provided by two novel observations. First, among all study subjects, there was a strong inverse relationship between Pa,CO2 and PCWP. Second, when PCWP was raised by contrast dye infusion, Pa,CO2 decreased. Conversely, when PCWP was reduced by nitroglycerine infusion, Pa,CO2 increased. Changes in Pa,CO2 were inversely proportional to changes in PCWP. These data indicate that elevated left ventricular filling pressure contributes to hypocapnia in patients with CHF.
Hypocapnia plays a key role in the genesis of central apnoeas during CSR-CSA 1. Central apnoeas during CSR-CSA are triggered by abrupt increases in ventilation and falls in Pa,CO2below the threshold for apnoea, which are abolished when Pa,CO2 is raised by inhalation of a CO2 containing gas mixture during sleep 2. Hypocapnia and CSR-CSA also have adverse clinical implications in patients with CHF. They are associated with increased sympathetic nervous system activity 8, left ventricular volume 9, ventricular ectopy 5 and mortality 3, 4.
What causes hyperventilation in CHF? Hypoxia is one possibility. However, studies have consistently shown that hypocapnia in CHF patients with CSR-CSA is not related to hypoxia during normal breathing 1, 5. The present findings agree with those observations: Pa,O2 was within normal limits in all except two patients, and Pa,CO2 bore no significant relationship to Pa,O2. In patients with CSR-CSA, hypoxia resulting from central apnoeas could lead to respiratory instability through stimulation of ventilation and consequent reductions in Pa,CO2. However, it was demonstrated in the present study that inhalation of supplemental O2 sufficient to abolish apnoea-related hypoxia had no impact on either Pa,CO2 or on the frequency of central apnoeas 2. Taken together, the above observations strongly suggest that in most patients with chronic stable CHF, hypoxia is unlikely to play an important role in causing hypocapnia.
Increased chemosensitivity is another possible cause of hypocapnia in CHF. Javaheri 10 found that CHF patients with CSR-CSA had increased central chemosensitivity to CO2 compared to CHF patients without CSR-CSA. In addition, Solin et al. 11 found both increased central and peripheral sensitivity to CO2 in CHF patients with CSR-CSA. Furthermore, experimentally induced CHF has been shown to increase peripheral chemosensitivity 12. These findings indicated that the state of cardiac failure itself can alter respiratory chemosensitivity. However, none of these studies examined the potential relationship between Pa,CO2 and chemosensitivity, and between chemosensitivity and PCWP. Thus, it remains unclear whether increased chemosensitivity per se is a cause of hypocapnia in CHF.
Another possible explanation for hypocapnia in CHF is stimulation of pulmonary vagal irritant receptors by pulmonary congestion. In animals, high pulmonary venous pressures induce tachypnoea, through stimulation of pulmonary vagal afferents 6. However, the relationship between pulmonary venous pressure and Pa,CO2 was not examined. In humans with CHF, Solin et al. 13 found a weak but significant inverse relationship between Pa,CO2 and PCWP (r=–0.4). However, measurements of PCWP and Pa,CO2 were performed several days to weeks apart, and no attempt was made to determine the effect of altering PCWP on Pa,CO2. Consequently, they did not establish whether PCWP is an independent determinant of Pa,CO2.
The demonstration of a significant inverse relationship between Pa,CO2 and PCWP in patients with CHF in the present study, support the findings of Solin et al. 13. However, in the present study the findings of Solin et al. 13 are extended in several important ways. Firstly, haemodynamic measurements and arterial blood gas analyses were performed simultaneously. This probably accounts for the much stronger relationship between Pa,CO2 and PCWP that was observed compared to Solin et al. 13. Second, in contrast to Solin et al. 13, other potential influences on Pa,CO2 were controlled, including cardiac output, right atrial pressure and Pa,O2. Most importantly, however, the acute effects of altering PCWP on Pa,CO2 were examined, demonstrating that PCWP contributes to variations in Pa,CO2 independently of other potentially confounding variables, and that acute changes in PCWP caused proportional inverse changes in Pa,CO2. The demonstration that Pa,CO2 varied as a function of PCWP supported a cause-effect relationship between these two variables. However, data on the effects of altering PCWP on Pa,CO2 were obtained from only three subjects. This is because the local ethics review committee provided permission to infuse nitroglycerine to lower PCWP in only three subjects owing to the invasiveness and prolonged nature of the protocols they were undergoing (discussed later).
In order to determine what factors are associated with hypocapnia, the present authors had to include data from subjects with a wide range of Pa,CO2 including some who were normocapnic. In previous studies, the present authors showed that CHF patients with CSR-CSA have lower Pa,CO2 than subjects without CSR-CSA, but that there is some overlap 1, 14. In general, patients with CSR-CSA have all awake Pa,CO2 or <40 mmHg. Therefore, if hypocapnia is considered to be a Pa,CO2 of <40 mmHg, then six of the present patients were hypocapnic. More importantly, data from subjects with a lower Pa,CO2 of <40 mmHg fall on the regression line in figure 1
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Alterations in PCWP must have influenced Pa,CO2 through the effect of left ventricular filling pressure and pulmonary venous pressure on respiratory pattern. Indeed, Churchill and Cope 6 showed that alterations in pulmonary venous pressure in dogs caused tachypnoea. However, in the present study it was not possible to assess respiratory rate and tidal volume during cardiac catheterization studies. This is because the protocol for the present study was carried out on patients who were undergoing another complex study lasting 3–4 h during which right and left heart catheters, a coronary artery sinus catheter and an intravenous infusion line were in place. Because of the extensive instrumentation, and the prolonged nature of the studies, it was not possible to apply additional instrumentation to measure respiratory pattern.
In summary, the results presented here demonstrate that elevated left ventricular filling pressure is a determinant of hypocapnia in patients with congestive heart failure. The results also indicate that alterations in pulmonary capillary wedge pressure cause inverse changes in the carbon dioxide tension in arterial blood. This cause-effect relationship is probably mediated through stimulation of pulmonary vagal irritant receptors by pulmonary venous congestion 6. Further experiments will be required to test this hypothesis. Since hypocapnia plays a critical role in the genesis of central apnoeas in Cheyne-Stokes respiration and central sleep apnoea, one important implication of the present findings is that hypocapnia and Cheyne-Stokes respiration and central sleep apnoea are respiratory manifestations of high left ventricular filling pressures and pulmonary venous congestion in patients with congestive heart failure.
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- Naughton MT, Bernard D, Tam A. Rutherford R, Bradley TD. Role of hyperventilation in the pathogenesis of central sleep apnoeas in patients with congestive heart failure. Am Rev Respir Dis 1993;148:330–338.[Web of Science][Medline] [Order article via Infotrieve]
- Lorenzi-Filho G, Rankin F, Bies I, Merson R, Rosenberg JI, Bradley TD. Effects of inhaled CO2 and O2 on Cheyne-Stokes respiration in heart failure patients. Am J Respir Crit Care Med 1999;159:1490–1498.
[Abstract/Free Full Text] - Lanfranchi PA, Braghiroli A, Bosimini A, et al. Prognostic value of nocturnal Cheyne-Stokes respiration in chronic heart failure. Circulation 1999;99:1435–1440.
[Abstract/Free Full Text] - Sin DD, Logan AG, Fitzgerald FS, Liu PP, Bradley TD. Effects of continuous positive airway pressure on cardiovascular outcomes in heart failure patients with and without Cheyne-Stokes Respiration. Circulation 2000;102:61–66.
[Abstract/Free Full Text] - Javaheri S, Corbett WS. Association of low Pa,CO2 with central sleep apnoea and ventricular arrhythmias in ambulatory patients with stable heart failure. Ann Intern Med 1998;128:204–207.
[Abstract/Free Full Text] - Churchill ED, Cope O. The rapid shallow breathing resulting from pulmonary congestion and edema. J Exper Med 1929;49:531–537.[Abstract]
- Bradley TD, Holloway RM, McLaughlin PR, Ross BL, Walters J, Liu PP. Cardiac output response to continuous positive airway pressure in congestive heart failure. Am Rev Respir Dis 1992;145:377–382.[Web of Science][Medline] [Order article via Infotrieve]
- Naughton MT, Benard DC, Liu PP, Rutherford R, Rankin F, Bradley TD. Effects of nasal CPAP on sympathetic activity in patients with heart failure and central sleep apnoea. Am J Respir Crit Care Med 1995;152:473–479.[Abstract]
- Tkacova R, Hall MJ, Liu PP, Fitzgerald FS, Bradley TD. Left ventricular volume in patients with heart failure and Cheyne-Stokes respiration during sleep. Am J Respir Crit Care Med 1997;156:1549–1555.
[Abstract/Free Full Text] - Javaheri S. A mechanism of central sleep apnoea in patients with heart failure. N Eng J Med 1999;341:949–954.
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[Abstract/Free Full Text] - Sin D, Fitzgerald F, Parker JD, Newton G, Floras JS, Bradley TD. Risk factors for central and obstructive sleep apnoea in 450 men and women with congestive heart failure. Am J Respir Crit Care Med 1999;160:1101–1106.
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