Gaston B. Expression and activity of pH-regulatory glutaminase in the human ..... OSA patients with moderate and severe night time hypoxia (means. SEM:.
Correspondence ERRATUM: HOUSE DUST ENDOTOXIN AND SENSITIZATION IN CHILDREN To the Editor: We wish to make a correction to our article (1). Due to an editorial error, the legend of Figure 2 incorrectly states that filled circles indicate living in the same home since birth and open circles indicate not living in the same home since birth. Instead, the legend should read “Filled circles indicate not living in the same home since birth and open circles indicate living in the same home since birth.” We have reproduced the figure and corrected legend below. Ulrike Gehring GSF–Institute of Epidemiology Neuherberg, Germany
1. Gehring U, Bischof W, Fahlbusch B, Wichmann H-E, Heinrich J. House dust endotoxin and allergic sensitization in children. Am J Respir Crit Care Med 2002;166:939–944.
in patients with acute asthma. Low end-tidal CO2 would tend to alkalinize droplets and reduce NH4⫹ trapping in the condensers (2). Although the pH of the condensate was reduced in asthma, this may be misleading, because Hunt and colleagues purged CO2 from their samples. (3 ) Rapid shallow breaths could also result in increased trapping of NH4⫹ generated in the mouth and lungs by droplets lining the tubing that connects the patients to the condensers (2). Although the authors were able to document NH4⫹ production by epithelial cells in culture wells over the course of several days, it is difficult to extrapolate these results to in vivo conditions. Most NH4⫹ formation occurs in the kidney, gastrointestinal tract, and muscles (during exercise) (3). Net production by the lungs has not been described (3) and it might be difficult to document because of inhalation of NH3 from the mouth, the arterial– venous pH gradient, and large blood flow. Because the lungs are so well perfused and ventilated, significant local gradients are unlikely, and most of the NH3 and NH4⫹ in the pulmonary secretions are probably delivered there from other organs by the pulmonary and bronchial circulations. Richard M. Effros, M.D. Medical College of Wisconsin Milwaukee, Wisconsin
1. Hunt JF, Erwin E, Palmer L, Vaughan J, Malhotra N, Platts-Mills TAE, Gaston B. Expression and activity of pH-regulatory glutaminase in the human airway epithelium. Am J Respir Crit Care Med 2002;165: 101–107. 2. Effros RM, Wahlen K, Bosbous M, Castillo D, Foss B, Dunning M, Gare M, Lin W, Sun F. Dilution of respiratory solutes in exhaled condensates. Am J Respir Crit Care Med 2002;165:663–669. 3. Huizenga JR, Gips CH, Tangerman A. The contribution of various organs to ammonia formation: a review of factors determining the arterial ammonia concentration. Ann Clin Biochem 1996;33:23–30.
Figure 2. Adjusted* logistic regression results describing the association between allergen-specific sensitization (CAP-class ⭓ 2) and ln-transformed living-room floor endotoxin (expressed per m2) related to occupancy. Results are presented as odds ratios associated with a difference of two times GSD in exposure. *Adjusted for place of residence, sex, age group, parental education, parental atopy, and pet ownership (dog and/or cat). Filled circles indicate not living in the same home since birth and open circles indicate living in the same home since birth.
DO LOW EXHALED CONDENSATE NH4ⴙ CONCENTRATIONS IN ASTHMA REFLECT REDUCED PULMONARY PRODUCTION? To the Editor: Hunt and colleagues (1) recently reported that concentrations of NH4⫹ in exhaled condensates are reduced in patients with acute asthma and suggested that this is due to impaired glutaminase activity in the epithelial cells of these patients. However, three alternative explanations must be considered: (1 ) Much of the NH4⫹ that is found in condensates is derived from the mouth (salivary concentrations are approximately 100 times and condensate concentrations approximately 10 times those in the blood) and it is transported to the condenser as gaseous NH3 (2). The remarkable 1,000-fold variability of NH4⫹ concentrations found by Hunt and colleagues in condensates of normal subjects (1) could reflect differences in oral flora with urease activity and the volume of saliva present in the mouth, which can vary considerably during the course of a day. Low NH4⫹ concentrations in asthmatic condensates may be related to reduced volumes of saliva in the mouth caused by such factors as dehydration, catecholamine levels, and panting. (2 ) Decreased NH4⫹ recovery in asthmatic condensates could also reflect low end-tidal CO2 partial pressures. These low concentrations are due to hyperventilation and increased dead space, which are frequently encountered
From the Authors: We have published our agreement (1, 2) with Dr. Effros that (1 ) there is ammonia (NH3) produced in the mouth as well as in the lower airways, and (2 ) there are buffers relevant to breath condensate pH yet to be identified. We appreciate the thought that he has put into this topic. To test the hypothesis that asthmatic hyperventilation might cause breath condensate pH changes requires a very simple experiment in humans. We performed this experiment (3). Hyperventilation affects neither breath condensate pH nor NH3 levels. Although Dr. Effros’ theory is intriguing, it simply does not square with readily measurable empiric data. Low pH is a robust marker for airways inflammation (4, 5). It is reproducible not only within our group but between groups (1, 3–5). It reflects globally the solubilities, pKa, and titratable acidity of upper and lower airway buffers (1–4). On the other hand, oral NH3 (which has a nonphysiological pKa) does not substantially affect breath condensate pH: experimentally, neither changing the oral NH3/NH4⫹ concentration nor changing the oral pH have a significant effect on our breath condensate pH values. The lower airways produce NH3—resulting in concentrations of approximately 10⫺4 M—in part as a result of epithelial glutaminase activity (1–3). Concentrations of NH3/NH4⫹ are in the range of 50 M in the breath condensate of control subjects intubated for elective surgery (3). Decreased NH3 production is necessary, but is not sufficient, to explain low breath condensate pH (1). Breath condensate proton measurement, unlike the measurement of other solutes (6), is (1 ) highly reproducible, and (2 ) informative with respect to disease activity. That is to say, it is both reliable and useful. We agree that in vitro models involving two or three buffer systems studied in nonphysiological concentrations (6) have little role in interpreting breath condensate values in vivo. The complexity of the organic and inorganic chemistry prohibits one or two variables from being interpreted in isolation. Also, breath condensate collection systems need to be efficient. It is difficult to study the effects of subtle variations in technique using collection systems that take 15 minutes or longer and tend to collect variable fractions of saliva (6). We would like to thank Dr. Effros for his theoretical constructs; indeed,
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his thought processes have been very similar to ours. The theories just need to be continuously adjusted to fit the reality of data generated in physiologically relevant experiments. Benjamin M. Gaston, M.D. John F. Hunt, M.D. University of Virginia School of Medicine Charlottesville, Virginia
1. Hunt JF, Erwin E, Palmer L, Vaughan J, Malhotra N, Platts-Mills TAE, Gaston B. Expression and activity of pH-regulatory glutaminase in the human airway epithelium. Am J Respir Crit Care Med 2002;165: 101–107. 2. Gaston B, Ratjen F, Vaughan JW, Malhotra NR, Canady RG, Snyder AH, Hunt JF, Gaertig S, Goldberg JB. Nitrogen redox balance in the cystic fibrosis airway: effects of antipseudomonal therapy. Am J Respir Crit Care Med 2002;165:387–390. 3. Vaughan JW. Gaston B, Hunt JF. Exhaled breath condensate pH and ammonia levels are not dependent on airway CO2 tension (abstr). Am J Respir Crit Care Med (In press). 4. Hunt JF, Fang K, Malik R, Snyder AH, Malhotra NR, Platts-Mills TAE, Gaston B. Endogenous airway acidification. Implications for asthma pathophysiology. Am J Respir Crit Care Med 2000;161:694–699. 5. Kostikas K, Papatheodorou G, Ganas K, Psathakis K, Panagou P, Loukides S. pH in expired breath condensate of patients with inflammatory airway diseases. Am J Respir Crit Care Med 2002;165:1364–1370. 6. Effros RM, Hoagland KW, Bosbous M, Castillo D, Foss B, Dunning M, Gare M, Lin W, Sun F. Dilution of respiratory solutes in exhaled condensates. Am J Respir Crit Care Med 2002;165:663–669.
From the Authors: We thank Dr. Jardin for his comments and interest regarding our study (1). Protective lung ventilation in patients with ARDS is a strategy devoted to minimizing both overdistention and cyclic collapse and reopening of alveolar regions. Consequently, we designed our protocol according to the method proposed by Amato and colleagues (2). Lung protection requires appropriate inspiratory driving pressure (⬍ 20 cm H2O) to reduce inspiratory stretching and moderate/high levels of positive end-expiratory pressure (PEEP) to avoid end-expiratory alveolar collapse. These two variables were independently associated with better survival (2). In our study (1), PEEP was set at 3 cm H2O above the lowest inflection point (LIP) observed in the inspiratory part of the respiratory system pressure–volume curve. Therefore, our ventilatory approach using low tidal volume (7.2 ⫾ 1.2 ml/kg), low driving pressure (18.5 cm H2O), high PEEP (14 ⫾ 1.3 cm H2O), and a mean plateau pressure in the upper recommended limit (32 cm H2O) should be considered a protective ventilatory strategy rather than a deleterious one. The ARDS Network study (3) also proved the beneficial effect on survival of low tidal volume (6 ml/kg) compared with high tidal volume (12 ml/kg). Since the design and objectives of the ARDS Network study and ours were different, it is difficult to draw clinical conclusions based on differences between ventilatory strategies. Mortality in our series of ARDS patients was 65% (1). Mortality rates in ARDS range from 31 to 71% in different studies (2–4). Significant differences in mortality rates among studies may be attributed to differences in type and strength of study designs, and to the wide variety of definitions used for this syndrome (4). Therefore, it is only possible to calculate predicted mortality using the APACHE II score if the number of patients is large and a variety of etiologies and underlying diseases is included in the analysis. Since a small number of ARDS patients were included in our physiologic study (1), it would be statistically inappropriate to predict mortality from the APACHE II score at admission (5). Ana Villagra´ Josefina Lo´pez Aguilar
RECRUITMENT MANEUVERS DURING LUNG PROTECTIVE VENTILATION IN ACUTE RESPIRATORY DISTRESS SYNDROME
Lluis Blanch Hospital de Sabadell, Corporacio´ Parc Taulı´ Sabadell, Spain
To the Editor: In a recent report, Villagra´ and colleagues (1) examined the efficacy of recruitment maneuvers in a group of acute respiratory distress syndrome (ARDS) patients during protective ventilation. When reading this paper I was concerned by the original conception of “protective ventilation” advocated by these authors. It is usually admitted that protective ventilation is a strategy that limits airway pressure to avoid alveolar overdistension. A recent example of this strategy can be found in a large cooperative study (2), where patients subjected to a protective approach had a limited airway pressure (plateau pressure: 25 ⫾ 7 cm H2O at Day 1, 26 ⫾ 7 at Day 2, 26 ⫾ 7 at Day 3). In the same study, a second group of patients was subjected to a traditional approach without airway pressure limitation (plateau pressure: 33 ⫾ 9 cm H2O at Day 1, 34 ⫾ 9 at Day 2, 37 ⫾ 9 at Day 3), to compare mortality. With a plateau pressure of 32 ⫾ 5 cm H2O, and a mean airway pressure of 20 cm H2O, airway pressures in patients with ARDS treated by Villagra and colleagues are closer to this second group (1), and one may wonder what exactly is protective in Villagra´ and colleagues’ strategy. Unfortunately, these authors did not give the mortality of their patients, which could be a strong argument demonstrating “protection,” in a group where predicted mortality can be calculated as 26% (APACHE II: 17 ⫾ 7) (1). Franc¸ois Jardin University Hospital Ambroise Pare´ Boulogne Cedex, France
1. Villagra´ A, Ochagavı´a A, Vatua S, Murias G, Ferna´ndez MDM, Aguilar JL, Ferna´ndez R, Blanch L. Recruitment maneuvers during lung protective ventilation in acute respiratory distress syndrome. Am J Respir Crit Care Med 2002;165:165–170. 2. Amato MBP, Barbas CSV, Medeiros DM, Magaldi RB, Schettino GPP, Lorenzi-Filho G, Kairalla RA, Deheinzelin D, Mun˜oz C, Oliveira R, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 1998;338:347–354. 3. The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000;342:1301–1308. 4. Roupie E, Lepage E, Wysocky M, Fagon JY, Chastre J, Dreyfuss D, Mentec H, Carlet J, Brun-Buisson C, Lemaire F, Brochard L for the SRLF Collaborative Group on Mechanical Ventilation. Prevalence, etiologies and outcome of acute respiratory distress syndrome among hypoxemic ventilated patients. Intensive Care Med 1999;25:920–929. 5. Lemeshow S, Le Gall JR. Modeling the severity of illness of ICU patients. A systems update. JAMA 1994;272:1049–1055.
SERUM LEVELS OF VASCULAR ENDOTHELIAL GROWTH FACTOR ARE ELEVATED IN PATIENTS WITH OBSTRUCTIVE SLEEP APNEA AND SEVERE NIGHT TIME HYPOXIA To the Editor:
1. Villagra´ A, Ochagavı´a A, Vatua S, Murias G, Ferna´ndez MDM, Aguilar JL, Ferna´ndez R, Blanch L. Recruitment maneuvers during lung protective ventilation in acute respiratory distress syndrome. Am J Respir Crit Care Med 2002;165:165–170. 2. The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 200;342:1301–1308.
Schulz and colleagues (1) reported on elevated serum levels of vascular endothelial growth factor (VEGF-SL) in patients with obstructive sleep apnea (OSA) and severe night time hypoxia, and that VEGF-SL correlates with the degree of nocturnal oxygen desaturations in those patients. Several aspects should be taken into account to interpret these data more accurately. As stated in the article, a methodological limitation of the presented study is that VEGF-SL, and not plasma levels of VEGF were measured. Under
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physiological conditions, virtually no soluble VEGF is present in the blood. The main transporter of VEGF in the blood stream are thrombocytes (2). Platelets contain large amounts of VEGF and a tight correlation between blood platelet counts and VEGF-SL exists, influenced further by the platelet size (3). In serum samples, VEGF released from activated platelets during the in vitro clotting process is measured. When citrated plasma samples are analyzed instead (where platelets remain intact), negligible levels of VEGF are found (4). Thus, the elevated VEGF-SL in patients with OSA and severe night time hypoxia might reflect merely platelet activation and destruction in vitro. Patients with OSA syndrome are subject to increased cardiovascular morbidity, including myocardial infarction and stroke. Platelets play an important role in the pathogenesis and triggering of acute cardiovascular syndromes. In patients with OSA syndrome, platelet activation and increased aggregability are frequently present (5, 6). Therefore, increased VEGF-SL might reflect platelet activation and subsequent release of VEGF in vivo and/or in vitro under these circumstances. Schulz and colleagues state in their article that enhanced VEGF production in OSA syndrome constitutes an adaptive mechanism to counterbalance the emergence of OSA-related cardiovascular disease (1). The measured levels do not necessarily represent an adaptive mechanism to induce new vessel formation in ischemic vascular and atherosclerotic regions. Instead they may simply constitute a marker for platelet activation in patients with severe OSA syndrome. Thus, elevated VEGF-SL in patients with OSA and severe night time hypoxia are likely to be caused by platelet activation. To further illuminate the findings of Schulz and colleagues, a more suitable control group should be considered, i.e., patients with chronic obstructive pulmonary disease or emphysema without current infection, and additionally, plasma VEGF levels should be determined. Nevertheless, the findings of Schulz and colleagues might help to elucidate the role of platelet activation in patients with OSA and severe night time hypoxia, and the potential role of VEGF blood levels in those patients, as VEGF-SL may correlate with patients at risk for stroke and myocardial infarction even under nasal continuous positive airway pressure or biphasic positive airway pressure therapy. Christian M. Ka¨hler
sleep apnea (OSA) (1). The major point of criticism is that the measurements of VEGF were carried out from serum samples and that this might merely reflect platelet activation in OSA. However, we think that it is not justified to speculate that platelets are the only possible site of VEGF release in OSA. First of all, there were no differences in platelet counts between the healthy control subjects and the OSA patients with moderate and severe night time hypoxia (means ⫾ SEM: 23.0 ⫾ 1.8 versus 22.7 ⫾ 1.3 versus 21.3 ⫾ 1.7 ⫻ 104/l). Furthermore, even if one would assume platelet activation to have occurred in the OSA patients, this phenomenon has not yet been shown to be directly related to parameters of apnea severity. In contrast, VEGF serum levels in OSA were correlated with the degree of nocturnal oxygen desaturation in our patients and with the apnea–hypopnea index in two other studies reporting similar findings (2, 3). Finally, in vitro experiments have found that the release of VEGF from platelets is not stimulated by hypoxia (4). Thus, the possibility that the VEGF induction in OSA is due to enhanced endothelial gene transcription under the influence of apnea-related intermittent hypoxia can not be excluded. We concur with Ka¨hler and colleagues that in order to resolve these issues VEGF measurements should be performed from plasma samples. Furthermore, in addition to free circulating VEGF, determinations of the circulating fraction of VEGF bound to its soluble receptor Flt-1 and of the VEGF content of platelets would be helpful to better characterize the alterations of the VEGF system in OSA. Regardless of these methodological considerations, we disagree with Dr. Ka¨hler that the VEGF levels are simply a marker of the individual cardiovascular risk in OSA. This assumption neglects the biological properties of endothelial-derived VEGF as a promoter of neoangiogenesis and of plateletderived VEGF as an inducer of wound healing at sites of vascular injury (5). Therefore, we still favor the view that the elevated VEGF levels in OSA constitute an adaptive mechanism irrespective of the exact source of VEGF release. On the other hand, it has recently been documented that VEGF might lead to atherosclerotic plaque progression (6). Thus, the pathophysiological significance of VEGF activation in OSA awaits further clarification. In a recent study by Lavie and colleagues, plasma levels of VEGF were measured in a sample of OSA patients (7). These authors showed that plasma VEGF is elevated in untreated OSA and is reduced after improvement of nocturnal hypoxia by CPAP therapy.
Jutta Wechselberger Clemens Molnar Christian Prior University of Innsbruck Innsbruck, Austria
1. Schulz R, Hummel C, Heinemann S, Seeger W, Grimminger F. Serum levels of vascular endothelial growth factor are elevated in patients with obstructive sleep apnea and severe night time hypoxia. Am J Respir Crit Care Med 2002;165:67–70. 2. Wartiovaara U, Salven P, Mikkola H, Lassila R, Kaukonen J, Joukov V, Orpana A, Ristimaki A, Heikinheimo M, Joensuu H, et al. Peripheral blood platelets express VEGF-C and VEGF which are released during platelet activation. Thromb Haemost 1998;80:171–175. 3. Gunsilius E, Gastl G. Platelets and VEGF blood levels in cancer patients. Br J Cancer 1999;81:185–186. 4. Gunsilius E, Petzer A, Stockhammer G, Nussbaumer W, Schumacher P, Clausen J, Gastl G. Thrombocytes are the major source for soluble vascular endothelial growth factor in peripheral blood. Oncology 2000; 58:169–174. 5. Bokinsky G, Miller M, Ault K, Husband P, Mitchell J. Spontaneous platelet activation and aggregation during obstructive sleep apnea and its response to therapy with nasal continuous positive airway pressure. A preliminary investigation. Chest 1995;108:625–630. 6. Sanner BM, Konermann M, Tepel M, Groetz J, Mummenhoff C, Zidek W. Platelet function in patients with obstructive sleep apnoea syndrome. Eur Respir J 2000;16:648–652. From the Authors: We thank Dr. Ka¨hler and colleagues for their comments concerning our article on vascular endothelial growth factor (VEGF) levels in obstructive
Richard Schulz Werner Seeger Friedrich Grimminger Justus-Liebig-University Gießen, Germany
1. Schulz R, Hummel C, Heinemann S, Seeger W, Grimminger F. Serum levels of vascular endothelial growth factor are elevated in patients with obstructive sleep apnea and severe nighttime hypoxia. Am J Respir Crit Care Med 2002;165:67–70. 2. Imagawa S, Yamaguchi Y, Higuchi M, Neichi T, Hasegawa Y, Mukai HY, Suzuki N, Yamamoto M, Nagasawa T. Levels of vascular endothelial growth factor are elevated in patients with obstructive sleep apneahypopnea syndrome. Blood 2001;98:1255–1257. 3. Gozal D, Lipton AJ, Jones KL. Circulating vascular endothelial growth factor levels in patients with obstructive sleep apnea. Sleep 2002;25: 59–65. 4. Koehne P, Willam C, Strauss E, Schindler R, Eckardt KU, Buhrer C. Lack of hypoxic stimulation of VEGF secretion from neutrophils and platelets. Am J Physiol 2000;279:H817–H824. 5. Weltermann A, Wolzt M, Petersmann K, Czerni C, Graselli U, Lechner K, Kyrle PA. Large amounts of vascular endothelial growth factor at the site of hemostatic plug formation in vivo. Arterioscler Thromb Vasc Biol 1999;19:1757–1760. 6. Celletti FL, Waugh JM, Amabile PG, Brendolan A, Hilfiker PR, Dake MD. Vascular endothelial growth factor enhances atherosclerotic plaque progression. Nat Med 2001;7:425–429. 7. Lavie L, Kraiczi H, Hefetz A, Ghandour H, Perelman A, Hedner J, Lavie P. Plasma vascular endothelial growth factor in sleep apnea syndrome: effects of nasal continuous positive air pressure treatment. Am J Respir Crit Care Med 2002;165:1624–1628.
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CONTINUOUS POSITIVE AIRWAY PRESSURE NORMALIZES PULMONARY ARTERY PRESSURES IN SUBJECTS WITH OBSTRUCTIVE SLEEP APNEA AND PULMONARY HYPERTENSION To the Editor: I am writing to point out that Dr. Sajkov and colleagues understate the significance of their finding that effective treatment of obstructive sleep apnea (OSA) normalizes pulmonary artery pressures in patients with OSA and pulmonary hypertension (PH) (1). Their study showed that continuous positive airway pressure (CPAP) reduces pulmonary artery pressures in patients with OSA, most of whom had normal pulmonary artery pressures at the outset. Of the five subjects who had PH and OSA, all five experienced normalization of their pulmonary artery pressures after CPAP treatment. Five out of five is statistically significant (p ⫽ 0.03). The authors have demonstrated that OSA can cause PH. In recent years, this has been an issue of considerable contention. Until now, most of the research literature has favored the premise that OSA is not a cause of PH (2), although Dr. Sajkov and his colleagues have argued otherwise (3, 4). The majority of prior research has found that day time hypoxemia and abnormal lung functioning correlates better with PH than does the severity of the OSA correlate with PH. Accordingly, many investigators have concluded that OSA does not cause PH, but rather, abnormal pulmonary functioning with resultant day time hypoxemia is more likely the cause of PH in these individuals. That OSA can cause PH has enormous implications for patients with pulmonary hypertension, especially those diagnosed with primary PH (PPH). If OSA causes PH, then a proper diagnostic evaluation to identify the etiology of PH should include a polysomnogram. Likewise, a diagnosis of PPH cannot be accurately made unless a sleep study has been performed. Many publications regarding the etiology of PH have not included polysomnograms in the evaluation of the research subjects. Of particular note, some research linking appetite suppressants and PPH did not include sleep evaluations (5). Since obese individuals use appetite suppressants, and since obesity can cause OSA, research demonstrating a relationship between appetite suppressants and PPH that fails to evaluate subjects for sleep-disordered breathing may not be worth the paper, or cyberspace, on which it is printed. If the results of Sajkov and colleagues (1) are verified by other researchers, then the field of PPH will be dramatically altered, for much of what has been “learned” in recent years may no longer be applicable or correct. Robert P. Blankfield Berea Health Center Berea, Ohio
1. Sajkov KD, Wang T, Saunders NA, Bune AJ, McEvoy RD. Continuous positive airway pressure treatment improves pulmonary hemodynamics in patients with obstructive sleep apnea. Am J Respir Crit Care Med 2002;165:152–158. 2. Wright J, Johns R, Watt I, Melville A, Sheldon T. Health effects of obstructive sleep apnoea and the effectiveness of continuous positive airways pressure: a systematic review of the research evidence. BMJ 1997;314:851–860. 3. Sajkov D, Cowie RJ, Thornton AT, Espinoza HA, McEvoy RD. Pulmo-
nary hypertension and hypoxemia in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 1994;149:416–422. 4. Sajkov D, Wang T, Saunders HA, Bune AJ, Neill AM, McEvoy RD. Daytime pulmonary hemodynamics in patients with obstructive sleep apnea without lung disease. Am J Respir Crit Care Med 1999;159: 1518–1526. 5. Abenhaim L, Moride Y, Brenot F, Rich S, Benichou J, Kurz X, Higenbottom T, Oakley C, Wouters E, Aubier M, et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med 1996;335:609–616. From the Authors: We read with interest Dr. Blankfield’s letter, in which he speculates that the causal link between obstructive sleep apnea and pulmonary hypertension, as demonstrated in our previous studies (1–3) is relevant to patients with primary pulmonary hypertension. He further argues that in order to diagnose primary pulmonary hypertension, obstructive sleep apnea should be excluded by polysomnography, and criticizes the study (4) linking appetite-suppressants and primary pulmonary hypertension for failing to exclude obesity-related obstructive sleep apnea as a cause of pulmonary hypertension. As published in our previous papers (1–3), pulmonary hypertension in patients with obstructive sleep apnea, without coexisting heart or lung disease, is only of mild severity (mean pulmonary artery pressure, range 20–31 mm Hg, average 23.6 ⫹ 1.1 mm Hg). This contrasts with patients with primary pulmonary hypertension, in which pulmonary hypertension is moderate to severe (4). Further, the majority of patients with obstructive sleep apnea, as in our studies, are men, whereas in Abenhaim and colleagues’ study (4) 66% of patients with primary pulmonary hypertension were women. Therefore, not disputing that obstructive sleep apnea should be excluded as a contributing factor before a diagnosis of primary pulmonary hypertension is established, we believe that obstructive sleep apnea alone is unlikely to explain the degree of pulmonary hypertension commonly found in patients with primary pulmonary hypertension. Dimitar Sajkov The Queen Elizabeth Hospital Adelaide, Australia R. Douglas McEvoy Repatriation General Hospital Adelaide, Australia
1. Sajkov D, Wang T, Saunders NA, Bune AJ, McEvoy RD. Continuous positive airway pressure treatment improves pulmonary hemodynamics in patients with obstructive sleep apnea. Am J Respir Crit Care Med 2002;165:152–158. 2. Sajkov D, Cowie RJ, Thornton AT, Espinoza HA, Douglas McEvoy R. Pulmonary hypertension and hypoxemia in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 1994;149:416–422. 3. Sajkov D, Wang T, Saunders HA, Bune AJ, Neill AM, Douglas McEvoy R. Daytime pulmonary hemodynamics in patients with obstructive sleep apnea without lung disease. Am J Respir Crit Care Med 1999;159: 1518–1526. 4. Abenhaim L, Moride Y, Brenot F, Rich S, Benichou J, Kurz X, Higenbottom T, Oakley C, Wouters E, Aubier M, et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med 1996;335:609–616.
