Carbon Monoxide Poisoning, or Carbon Monoxide Protection?

Carbon Monoxide Poisoning, or Carbon Monoxide Protection?

stress. In the current study, CO levels changed within hours of the stress, could be measured easily with a venous blood draw (and possibly could be m...

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stress. In the current study, CO levels changed within hours of the stress, could be measured easily with a venous blood draw (and possibly could be measured in exhaled breath10), and were affected by treatment. Other biomarkers, such as tumor necrosis factor-␣ and C-reactive protein, which are thought to reflect the damaging effects of apnea, have been inconsistent in their utility in OSA, as these markers have multiple influences.11 These data suggest several future directions. For the scientist, some questions include: what stress influences CO in OSA patients, and is it repetitive arousal, hypoxemia, or some other factors? Does CO level predict long-term cardiovascular morbidity? Is a low CO level a marker of low cardiovascular risk, or instead is it a reflection of impaired protective responses in a patient who is at increased risk of cardiovascular morbidity? While the HO gene is thought to be relatively conserved, polymorphisms in the promoter region have been associated with variable HO-1 expression and associated with higher risks of cardiopulmonary disease. In the current study, there was wide unexplained variability in CO production among patients with OSA. Are these differences due to promoter polymorphisms or other factors? How should CO be measured (by exhaled breath, serum CO level, or hemoglobin-bound CO)? And when should it be measured (during sleep or on awakening, or do elevations persist for some time)? For clinicians, assuming that the CO level has prognostic value, is it a viable biomarker that should be measured to assess disease burden? Does it reliably reflect the response to treatment? And finally, will exogenous CO one day be a therapy (as has been suggested for other pulmonary diseases) to prevent cardiovascular disease in those with OSA, perhaps in patients nonadherent to CPAP therapy?12 We congratulate Kobayashi et al for fueling the fire on the CO discussion. ACKNOWLEDGMENT: The authors thank Drs. Rebecca Baron, Augustine Choi, and Mark Perrella for their insightful comments and discussion.

Robert L. Owens, MD Susie Yim-Yeh, MD Atul Malhotra, MD, FCCP Boston, MA Dr. Owens is a fellow in the Divisions of Pulmonary, Critical Care, and Sleep Medicine, Brigham and Women’s Hospital. Dr. Yim-Yeh is affiliated with the Sleep Disorders Research Program, Brigham and Women’s Hospital. Dr. Malhotra is affiliated with the Divisions of Pulmonary, Critical Care, and Sleep Medicine, Brigham and Women’s Hospital, and Harvard Medical School. Dr. Malhotra is funded by the National Institute of Health (grants P50 HL060292, RO1-HL73146, and AG024837) and the Established Investigator Award from the American Heart Association. Drs. Owens and Yim-Yeh have reported to the ACCP that no significant conflicts of interest exist with any companies/organi-

zations whose products or services may be discussed in this article. Dr. Malhotra has received consulting and/or research grants from Respironics, Itamar Medical, Restore Medical, NMT Medical, Inspiration Medical, Apnex Medical, Sepracor, Cephalon, and Pfizer. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Robert L. Owens, MD, Pulmonary & Critical Care and Sleep Medicine Fellow, Brigham and Women’s Hospital, Sleep Disorders Research Program, 221 Longwood Ave, Boston, MA 02115; e-mail: [email protected] DOI: 10.1378/chest.08-1728

References 1 Horvath I, Donnelly LE, Kiss A, et al. Raised levels of exhaled carbon monoxide are associated with an increased expression of heme oxygenase-1 in airway macrophages in asthma: a new marker of oxidative stress. Thorax 1998; 53:668 – 672 2 Yasuda H, Yamaya M, Nakayama K, et al. Increased arterial carboxyhemoglobin concentrations in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005; 171: 1246 –1251 3 Fredenburgh LE, Perrella MA, Mitsialis SA. The role of heme oxygenase-1 in pulmonary disease. Am J Respir Cell Mol Biol 2007; 136:158 –165 4 Kobayashi M, Miyazawa N, Murakami S, et al. Circulating carbon monoxide level is elevated after sleep in patients with obstructive sleep apnea. Chest 2008; 134:904 –910 5 Morse D, Choi AM. Heme oxygenase-1: from bench to bedside. Am J Respir Crit Care Med 2005; 172:660 – 670 6 Meyer J, Prien T, Van Aken H, et al. Arterio-venous carboxyhemoglobin difference suggests carbon monoxide production by human lungs. Biochem Biophys Res Commun 1998; 244:230 –232 7 Minamino T, Christou H, Hsieh CM, et al. Targeted expression of heme oxygenase-1 prevents the pulmonary inflammatory and vascular responses to hypoxia. Proc Natl Acad Sci U S A 2001; 78:8798 – 8803 8 Yet SF, Perrella MA, Layne MD, et al. Hypoxia induces severe right ventricular dilatation and infarction in heme oxygenase-1 null mice. J Clin Invest 1999; 103:R23–R29 9 Chin K, Ohi M, Shimizu K, et al. Increase in bilirubin levels of patients with obstructive sleep apnea in the morning: a possible explanation of induced heme oxygenase-1. Sleep 2001; 24:218 –223 10 Petrosyan M, Perraki E, Simoes D, et al. Exhaled breath markers in patients with obstructive sleep apnoea. Sleep Breath 2008; 12:207–215 11 Romero-Corral A, Sierra-Johnson J, Lopez-Jimenez F, et al. Relationships between leptin and C-reactive protein with cardiovascular disease in the adult general population. Nat Clin Pract Cardiovasc Med 2008; 5:418 – 425 12 Ryter SW, Morse D, Choi AM. Carbon monoxide and bilirubin: potehtial therapies for pulmonary/vascular injury and disease. Am J Respir Cell Mol Biol 2007; 36:175–182

The “Obesity Paradox” Is Smoking/Lung Disease the Explanation? studies indicate that overweight and obeM any sity are extremely prevalent in Westernized

societies, and during recent decades, the preva-


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lence has been markedly increasing, especially in the United States.1 If current trends continue, obesity will soon overtake cigarette smoking as the leading cause of preventable death in the United States.1 Substantial evidence documents the “heavy” cardiovascular (CV) burden of obesity. Overweight/obesity is a strong risk factor for the development and progression of hypertension, dyslipidemia (especially elevated triglycerides and low levels of high-density lipoprotein cholesterol), metabolic syndrome, and type 2 diabetes mellitus, and increases systemic inflammation (eg, high levels of C-reactive protein).1–3 Although hypertension is a strong risk factor for left ventricular hypertrophy, obesity contributes to left ventricular hypertrophy and other ventricular structural abnormalities independent of arterial pressure.1,2 Although all of these factors contribute to atherosclerosis and coronary heart disease (CHD), obesity is probably an independent risk factor.1–3 Additionally, obesity has adverse affects on both systolic and diastolic ventricular function, and is associated with an increased risk of heart failure (HF).1,4 Therefore, the prevention and treatment of overweight/obesity are major societal concerns. Despite the association of obesity with CV risk factors and increased CV risk, numerous studies1– 6 have now documented a strong “obesity paradox,” in which obese patients with CV disease, including hypertension, CHD, and, especially, HF have a better prognosis than do their lean counterparts. In a large study2 of patients who had been referred for echocardiography with normal systolic function, we have also demonstrated a strong obesity paradox. The reasons for this surprising paradox have been difficult to elucidate. Potential contributors have included nonpurposeful weight loss prior to study entry (due to unrecognized non-CV diseases), obese patients presenting earlier due to increased dyspnea due to non-CV causes, such as deconditioning and restrictive lung disease, and reduced expression of atrial natriuretic peptides, which has been documented in cases of obesity.1– 6 Although some have also suggested7 that part of the explanation of the obesity paradox may be the limitations of the body mass index (BMI) to define at-risk obesity, suggesting that other measures such as waist circumference, waist/ hip ratio, or percentage of body fat determinations would be more accurate, we have demonstrated that a higher percentage of body fat predicted better prognosis in patients with HF8; preliminary data from our institution have suggested the same regarding CHD and mortality. In the current issue of CHEST (see page 925), Galal and colleagues9 assessed 4.4-year mortality in 2,392 patients with peripheral arterial disease (PAD)

from the Netherlands who had undergone major vascular surgery and had a high risk of mortality during follow-up. That study demonstrated a powerful obesity paradox in patients with PAD, with progressive reductions in mortality in normalBMI, overweight, and obese groups of patients compared with an underweight group of patients. Although lower BMI was an independent predictor of higher mortality in the entire population, the increased risk in the underweight patients was almost completely explained statistically by a high prevalence of moderate-to-severe COPD. Nevertheless, adjusting for the severity of COPD did not abolish the relationship between BMI and mortality in the overweight and obese groups. The contributions of the study by Galal et al9 are noteworthy, particularly regarding extending the obesity paradox to patients with PAD as well as documenting the contribution of COPD to this paradox, especially in underweight PAD patients. Nevertheless, the fact that the underweight patients had higher mortality and more COPD is of no major surprise, and many studies1,2,4 – 6 have documented higher mortality rates among underweight persons. Importantly, this population may be different than other populations, such as cohorts of hypertensive, CHD, and HF patients, in that smoking, as the authors state, appears to be an especially potent contributor to PAD.1,9 Nevertheless, other studies5 have also attempted to correct for smoking as a risk factor, and still lower BMI is an independent predictor of higher risk. Likewise, even in the present study,9 which corrects for smoking status as well as COPD, lung disease did not completely explain this paradox in the subgroups of overweight and obese patients, who had the best prognosis. Considering this surprising paradox, how should clinicians proceed at present? In fact, some experts9,10 have even questioned the safety and efficacy of purposeful weight loss in patients with CV diseases. However, we and others have reported1,3– 6,11 that purposeful weight loss improves left ventricular systolic and diastolic function, reduces CHD risk factors, and is associated with the most favorable CV prognosis. Certainly, efforts to increase physical activity and overall physical fitness in our society are desperately needed, as many studies12 have clearly demonstrated that a reduced level of fitness is a powerful predictor of mortality and increased fitness is protective in patients with obesity and other CV risk factors. As we continue to investigate the mechanisms for this puzzling obesity paradox, the “weight” of evidence clearly supports purposeful weight loss, particularly with therapies that do not reduce lean body

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CHEST / 134 / 5 / NOVEMBER, 2008


mass, such as exercise training in addition to caloric restriction, for the primary and secondary prevention of CV diseases. Carl J. Lavie, MD, FCCP Hector O. Ventura, MD Richard V. Milani, MD New Orleans, LA Dr. Lavie is Medical Director, Cardiac Rehabilitation and Prevention, Director, Exercise Laboratories, Ochsner Medical Center. Dr. Ventura is Chairman of Graduate Medical Education, and Director of Advanced Heart Failure and Transplantation, Ochsner Medical Center. Dr. Milani is Vice Chairman, Department of Cardiovascular Diseases, Ochsner Medical Center. The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Carl J. Lavie, MD, FCCP, Medical Director, Cardiac Rehabilitation and Prevention, Director, Exercise Laboratories, Ochsner Medical Center, 1514 Jefferson Hwy, New Orleans, LA 70121-2483; e-mail: [email protected] DOI: 10.1378/chest.08-1673

References 1 Lavie CJ, Milani RV. Obesity and cardiovascular disease: the Hippocrates paradox? J Am Coll Cardiol 2003; 42:677– 679 2 Lavie CJ, Milani RV, Ventura HO, et al. Disparate effects of left ventricular geometry and obesity on mortality in patients with preserved left ventricular ejection fraction. Am J Cardiol 2007; 100:1460 –1464 3 Lavie CJ, Morshedi-Meibodi A, Milani RV. Impact of cardiac rehabilitation on coronary risk factors, inflammation, and the metabolic syndrome in obese coronary patients. J Cardiometab Syndr 2008; 3:136 –140 4 Lavie CJ, Mehra MR, Milani RV. Obesity and heart failure prognosis: paradox of reverse epidemiology? Eur Heart J 2005; 26:5–7 5 Lavie CJ, Artham SM, Milani RV, et al. The obesity paradox: impact of obesity on the prevalence and prognosis of cardiovascular diseases. Postgrad Med 2008; 120:34 – 41 6 Lavie CJ, Milani RV, Ventura HO. Obesity, heart disease, and favorable prognosis: truth or paradox? Am J Med 2007; 120:825– 826 7 Romero Corral A, Lopez-Jimenez F, Sierra-Johnson J, et al. Differentiating between body fat and lean mass: how should we measure obesity? Nat Clin Pract Endocrinol Metab 2008; 4:322–333 8 Lavie CJ, Osman AF, Milani RV, et al. Body composition and prognosis in chronic systolic heart failure: the obesity paradox. Am J Cardiol 2003; 91:891– 894 9 Galal W, van Gestel Y, Hoeks SE, et al. The obesity paradox in patients with peripheral arterial disease. Chest 2008; 134: 925–930 10 Allison DB, Zannolli R, Faith MS, et al. Weight loss increases and fat loss decreases all-cause mortality rates: results from two independent cohort studies. Int J Obes Relat Metab Disord 1999; 23:603– 611 11 Eilat-Adar S, Eldar M, Goldbourt U. Association of intentional changes in body weight with coronary heart disease event rates in overweight subjects who have an additional coronary risk factor. Am J Epidemiol 2005; 161:352–358

12 Blair SN, Church TS. The fitness, obesity, and health equation: is physical activity the common denominator? JAMA 2004; 292:1232–1234

Prophylaxis of VentilatorAssociated Pneumonia Changing Culture and Strategies to Trump Disease “Failure is success if you learn from it.” Malcolm Forbes

lacement of an endotracheal tube (ETT) inP creases a patient’s risk of pneumonia 6-fold to

20-fold by providing bacteria colonizing the oropharynx a convenient, one-way path around the ETT cuff into the lower respiratory tract.1– 4 Crude mortality rates for ventilator-associated pneumonia (VAP) range from 20 to 60% with an estimated cost of $40,000 per episode.1,2 Many of these poor outcomes result from system failures that are preventable with changes in hospital culture.2,3,5 A crucial target for VAP prophylaxis is reducing the number of pathogenic bacteria colonizing the oropharynx and entering the lower respiratory tract.3 One strategy is the use of oropharyngeal decontamination with disinfectants, such as chlorhexidine or combinations of topically applied antibiotics, with and without systemic antibiotics.2– 4 The use of this approach has been limited due to concerns over inducing bacterial resistance.2– 4 A second strategy, which is shown in Figure 1, is to prevent the entry of oropharyngeal bacteria into the trachea by use of a specially designed ETT having a suction port above the cuff for continuous aspiration of subglottic secretions (CASS).3,6,7 In this issue of CHEST (see page 938), Bouza and coworkers6 present data from a large, well-executed clinical trial of 690 patients undergoing major cardiac surgery who were randomized to use an ETT capable of CASS or a conventional ETT. VAP was diagnosed by clinical and radiologic criteria, and was confirmed by endotracheal aspirates with ⱖ 104 organisms per milliliter. This is the largest study to evaluate CASS, and the focus was on a high-risk population that was more homogeneous than most ICU patients. The greatest benefit of CASS was observed in the 95 patients who received ventilation for ⬎ 48 h. In these patients, the use of CASS significantly reduced the rates of VAP (27% vs 48%, respectively; p ⬍ 0.04), especially VAP due to Haemophilus influenzae; decreased the duration of ventilation (median duration, 3 vs 7 days, respectively; p ⬍ 0.02); shortened the length of ICU stay (median


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