Friday, February 13, 2009

Non-Smokers Are More Prone to Pulmonary Oedema Than Smokers During Acute Coronary Syndrome

Introduction:
Patients of acute coronary syndrome (ACS) often get admitted in the coronary care unit (CCU) with varied degree of left ventricle dysfunction, low cardiac output, low tissue perfusion and cardiogenic shock. These patients are thus vulnerable to develop backpressure changes on pulmonary bed presenting as the pulmonary oedema[1-3] and the associated ventilation perfusion mismatch.[4,5] These changes predispose patients to varied degree of hypoxaemia, metabolic acidosis and the compensatory respiratory alkalosis.[6] These factors together are likely to cast changes in the arterial blood gas (ABG) depending upon the extent of cardiac insult and the compensatory response. As smoking is a predisposing factor to coronary artery disease,[7] a significant number of ACS patients might be chronic smokers as well. Short-term better outcome of active smokers 'smokers paradox' during ACS has been reported.[8,9] Based on the data of national registry, the paradox was correlated with younger age, more men smokers and with fewer cardiovascular risk factors such as hypertension or diabetes.[8,9] However, the phenomenon was not fully explained by the measured covariates. Chronic smoking is associated with airway-alveolar changes in smokers[10] than in the non-smoker. We hypothesise that the smoking related lung changes might show different clinical presentation during ACS than that of non-smoker. As we have not come across any such report after extensive literature search, we prospectively compared clinical presentation of ACS patients in terms of being chronic smoker or the non-smokers.

Patients included were aged from 48 to 82 years (median 60 years). Patients in two study groups were demographically similar in terms of their age, gender, distribution, weight, height and body surface area . The non-smoker patients (group 1) had significantly (p <> 0.05). However, non-smokers (group 1) had significant (p < 0.01) tachycardia (101 ± 26 bpm) and the lower urine output at similar creatinine levels than the smokers (group 2) .
In the background of maintaining target SpO2 (≥ 95%) by oxygen inhalation and active respiratory support, the difference between PaO2 in two groups was statistically insignificant (p > 0.05), but the calculated PaO2/FiO2 ratio (201 ± 44) in non-smokers was significantly (p < 0.0001) lower than in the smokers (296 ± 110). Although blood pH was normal in both the groups, the significant (p < 0.001) metabolic acidosis (bicarbonate; 19 ± 4.3 mmol/l, base deficit; -5.1 ± 4.8, and higher lactate; 2.1 ± 0.72 mmol/l) was noteworthy amongst non-smokers with compensatory hypocarbia (28 ± 2.9 mmHg) than the smokers (PaCO2- 38 ± 5.7 mmHg and HCO3- 24 ± 4.9 mmol/l) . Incidence of active respiratory support (29%) and inotropes used (32%) was significantly lower in smokers (group 2) than in non-smokers (group 1) during ACS. Although the in-hospital mortality was higher in non-smokers (21%) than in the smokers (11%), the difference could not attain statistical significance .
The post hoc analysis for observed difference between the mean values of PaO2/FiO2 in two groups for the small sample size revealed power (1-beta) 99% for the two tailed α-probability (0.05) and the power of observed difference in rate of respiratory support for the two groups was 93% at alpha error probability 80% for the sample size in our study.

Discussion:
The present study demonstrates that during similar degree of ACS, the non-smoker patients developed higher degree of pulmonary oedema (higher chest x-ray score, AaDpO2 and lower PaO2/FiO2), metabolic acidosis (higher lactate levels and base deficit) with compensatory hypocarbia than the smokers. Risk estimates suggested that the non-smokers were three times more at risk for active respiratory support to maintain SpO2 > 95% and the inotropes to maintain mean arterial pressure (MAP) ≥ 60 mmHg than the smokers during ACS.
Normally, there is continuous exchange of liquid, colloid and solutes between the vascular bed and interstitium.[13,14] Studies have shown that during ACS, patients develop depressed myocardial contractility with segmental motion abnormalities[2,15] and the back pressure effect on lung vasculature.[3] The increased left atrial pressure model for cardiogenic oedema on rat demonstrated increased fluid flux from the lung vasculature with decreased reabsorption[16] thus predisposing patients to pulmonary oedema during ACS. Lymphatic drainage plays a significant role to control extracellular fluid accumulation.[17] Pulmonary oedema, however, will develop once the lymphatic drainage is overwhelmed by the fluid accumulation in the interstitial compartment and the alveoli.[18,19] A redistribution of the pulmonary flow with prominent pulmonary vasculature in upper lobes of the lungs with increasing left atrium (LA) pressure and the pulmonary oedema is reported approximately at 22-25 mmHg of wedge pressure.[16] Chest x-ray score has a strong correlation between the extravascular lung water and the left ventricular dynamics after MI.[4,18-21] Although we did not measure LA pressure, we observed higher chest x-ray scores and hypoxaemia in our patients during ACS. However, the chest x-ray scores being higher in non-smokers suggested a higher degree of pulmonary oedema in non-smokers than in the smokers during similar degree of cardiac insult.
Besides backpressure changes during ACS, the anatomical shape of alveoli also plays an important role in the accumulation of liquid in alveoli. The small radius of curvature at the corners puts-in greater local recoil pressure and more negative interstitial pressure than at the greater radii of curvature of alveoli. The resultant readily transfer of liquid at the junctions of smaller radii alveoli and the compliant loose interstitial space will favour fluid accumulation in normal lungs of non-smokers[22] and the oedema. The oedema in due course will result in hypoxaemia, associated poor tissue oxygen delivery, lactic acidosis and the compensatory hypocapnoea. As hypocapnoea per se is also reported to be injurious to the lungs,[23] non-smokers with significant hypocapnoea than smokers during ACS will perpetuate more to the lung injury and the extra lung water accumulation than the smokers, who had hypercarbia. The hypercarbia in smokers is related to lung changes affecting gas exchange because of gas trapping, mismatched ventilation perfusion with large areas of dead space ventilation and inefficient carbon dioxide elimination.[24]
Chronic smoking, associated with loss of alveolar shape and size because of fibrosis, shall make these patients less prone to accumulate fluid in interstitial compartment and the alveoli. These alveolar changes in turn shall also distort parenchymal vasculature and sequel pulmonary hypertension,[25] in turn stimulating lymphatic drainage and the greater tolerance for higher pulmonary artery (PA) pressure and decreased lung water accumulation. The Smokers are reported with reduced diffusing capacity of the lung for carbon monoxide (Dlco)[26] as a result of the loss of alveolar-capillary surface area[27] and the reduced expiratory flow, particularly at these low lung volumes, reduces the breathing reserve to make them vulnerable for hypoxaemia and hypercarbia. However, the hypoxaemia in smokers is exquisitely sensitive to low concentrations of oxygen supplementation.[24] We too found a significantly higher arterial oxygen levels in smokers on oxygen supplementation than in non-smokers.
It has also been reported that the functional residual capacity is reduced during ACS, and the closing capacity moves higher into the tidal volume range leading to larger low (V/Q) regions and hypoxaemia, despite no change in closing volume.[5] So, both smokers and non-smokers are vulnerable to develop hypoxaemia, but improvement was more in smokers on O2 inhalation than in non-smokers. Thus, the existing literature formed a basis to explain the observed higher degree of pulmonary oedema in non-smokers than in the smokers during ACS.
Although the number of patients in this cohort was small, it has prospectively analysed the observations in the randomly selected patients and the post hoc power analysis revealed 99% power for the detected difference in hypoxaemia. Besides smaller size, the in-hospital mortality was also higher in our patients than the advanced centres and it could be related to the lack of advanced investigative and therapeutic modalities such as coronary angiography and the angioplasty to match the treatment profile. However, for a similar kind of therapeutic facilities and protocol, the lower mortality in smokers than in the non-smokers was significant and comparable with the studies reporting 'smoker's paradox' for the in-hospital mortality for the comparable age group.[8]
The role of smoking in the short-term prognosis is still not very clear and some investigators have shown that the habitual smokers suffering from ACS tend to be younger, male, with less diffuse coronary artery disease and the fewer comorbidities compared with non-smokers.[8,28,29] In our study also, the smokers were predominantly male but did not differ significantly in terms of age (smokers - 62 ± 11.1 years vs. non-smokers - 63 ± 11.0 years) or the comorbidities. All large-scale randomised trials powered to detect significant differences because of the large number of the participants have failed to address the reason for the smoker's paradox. However, we are able to demonstrate a phenomenon not studied so far could also be an added significant factor for the reported 'smoker's paradox'. As we did not measure pulmonary artery wedge pressure and the prior to ACS lung function test reports were not available in first time admitted patients or patients were incapable of performing lung function test in CCU, it should taken as the limitation in our study. In our cohort, some of the observation like tachycardia in non-smokers was related to the frequent need of inotropes in non-smokers than in smokers. Our observation of higher haematocrit in smokers is related to hypercarbic state in these patients.
In summary, the term 'smoker's paradox' for better early outcome in cigarette smoking patients during ACS does not seem to be fully justifying, as smoking predisposes patients to hypercoagulable state, impaired endothelium-dependent dilatation[30] and excessive catecholamine secretion induced life threatening cardiac arrhythmias.[31] It can lead to a misunderstanding by the public for smoking. In the wake of observed greater risk of pulmonary oedema in non-smokers, our conclusion stands that an early active respiratory support in non-smokers presenting with ACS. To fully understand the outcome of this study, a detailed physiological study on gas exchange needed to be performed.

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