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Eur Respir J 2013; 41: 217–223 DOI: 10.1183/09031936.00074312 CopyrightßERS 2013

SERIES ‘‘PHYSIOLOGY IN RESPIRATORY MEDICINE’’ Edited by R. Naeije, D. Chemla, A. Vonk Noordegraaf and A.T. Dinh-Xuan Number 1 in this Series The transpulmonary pressure gradient for the diagnosis of pulmonary vascular disease

Robert Naeije*, Jean-Luc Vachiery#, Patrick Yerly# and Rebecca Vanderpool*

ABSTRACT: The transpulmonary pressure gradient (TPG), defined by the difference between AFFILIATIONS *Dept of Physiology, Faculty of mean pulmonary arterial pressure (Ppa) and left atrial pressure (Pla; commonly estimated by Medicine, Free University Brussels, pcw pulmonary wedge pressure: P ) has been recommended for the detection of intrinsic and pulmonary vascular disease in left- conditions associated with increased pulmonary venous #Dept of Cardiology, Erasme pressure. In these patients, a TPG of .12 mmHg would result in a diagnosis of ‘‘out of proportion’’ University Hospital, Free University pulmonary . This value is arbitrary, because the gradient is sensitive to changes in Brussels, Brussels, Belgium. and both recruitment and distension of the pulmonary vessels, which decrease the CORRESPONDENCE upstream transmission of Pla. Furthermore, pulmonary flow is pulsatile, with systolic Ppa R Naeije and mean Ppa determined by and arterial compliance. It may, therefore, be Dept of Physiology Faculty of Medicine preferable to rely on a gradient between diastolic Ppa and Ppcw. The measurement of a diastolic Free University of Brussels pa pcw P /P gradient (DPG) combined with systemic and cardiac output allows for a 808 Lennik Road step-by-step differential diagnosis between pulmonary vascular disease, high output or high left- 1070-Brussels heart filling pressure state, and . The DPG is superior to the TPG for the diagnosis of ‘‘out of Belgium proportion’’ pulmonary hypertension. E-mail: [email protected]

Received: KEYWORDS: , pulmonary capillary wedge pressure, , May 10 2012 pulmonary hypertension, pulmonary vascular compliance, pulmonary vascular resistance Accepted after revision: July 26 2012 First published online: Aug 30 2012 ulmonary hypertension is defined by a hypertension may not always agree with clinical mean pulmonary arterial pressure (Ppa) context. P o25 mmHg at rest [1, 2]. The diagnosis of The degree of pulmonary hypertension that is the pulmonary vascular disease relies on: invasive passive consequence of increased Pla due to measurements of mean Ppa 25 mmHg; a pulmon- o advanced left heart failure can be observed in ary capillary wedge pressure (Ppcw); f15 mmHg; a cardiac transplantation. In patients with purely pulmonary vascular resistance (PVR) 3 Wood o passive pulmonary hypertension, the mean Ppa units; and a transpulmonary pressure gradient would decrease along with decreased Pla, while in (TPG) o12 mmHg [1, 2]. The TPG is the difference those with ‘‘out of proportion’’ pulmonary hyper- between mean Ppa and left atrial pressure (Pla). Pla is tension the mean Ppa would remain unchanged, or usually estimated by Ppcw. The TPG is thought to be decrease proportionally less than Pla.Thiswas particularly useful to diagnose ‘‘out of proportion examined in 20 previously reported patients with pulmonary hypertension’’ in patients with left heart pre- and post-operative haemodynamic measure- failure or mitral stenosis [1]. ‘‘Out of proportion’’ ments [3]. Before transplantation the mean¡SE was: infers that mean Ppa is higher than expected from an 43¡2 mmHg for Ppa;29¡2 mmHg for Ppcw, -1 -5 -2 upstream transmission of Pla, because of increased 604¡60 dyn?s ?cm ?m for PVRi;14¡1 mmHg tone and/or structural changes. However, a TPG- for TPG. After transplantation: the mean¡SE was derived diagnosis of ‘‘out of proportion’’ pulmonary 25¡2 mmHg for Ppa;12¡1 mmHg for Ppcw, European Respiratory Journal Print ISSN 0903-1936 c For editorial comments see page 7. Online ISSN 1399-3003

EUROPEAN RESPIRATORY JOURNAL VOLUME 41 NUMBER 1 217 SERIES: PHYSIOLOGY IN RESPIRATORY MEDICINE R. NAEIJE ET AL.

-1 -5 -2 452¡50 dyn?s ?cm ?m for PVRi;and12¡1 mmHg for TPG. to flow; like the height of a waterfall. Pla then becomes an In this series of patients, transplantation was followed by a apparent outflow pressure and Pc the effective outflow pressure proportional decrease in mean Ppa and Ppcw (by, on average, of the pulmonary circulation, while the PVR equation remains 18 mmHg and 17 mmHg, respectively) suggestive of purely valid provided Pla is replaced by Pc. When Pla is higher than Pc, passive pulmonary hypertension. Yet the initial TPG was, on the vessel opens and the driving pressure for flow becomes Ppa average, .12 mmHg, with a range of values from 6–20 mmHg. minus Pla, the effective outflow pressure of the pulmonary Since transplantation did not always normalise mean Ppa,thedata circulation is Pla and the usual PVR equation can be used. taken from 12 out of the 20 patients in whom mean Ppa decreased A Pc higher than Pla is typically observed in West’s zones I and to below the value of 25 mmHg were re-examined. The pre- II in the upper parts of normal vertical [6]. Diseases operative TPG was .12 mmHg (range 12–20 mmHg) in six of the associated with increased pulmonary vessel tone and/or patients. Thus, in this limited series of patients, a TPG .12 mmHg alveolar pressure (PA) are associated with an increase in Pc.In did not predict ‘‘out of proportion’’ pulmonary hypertension these patients, mean Ppa becomes less sensitive or even better than flipping a coin. How is this possible? insensitive to changes in flow or Pla, and calculated PVR rapidly decreases with increased cardiac output [7]. The presence of a HOW LEFT ATRIAL PRESSURE AFFECTS MEAN closing pressure in the pulmonary circulation can be identified PULMONARY ARTERIAL PRESSURE by a gradient between Pla and the extrapolated pressure The normal relationship between mean Ppa and Pla is described intercept of the linear adjustment of a multiple mean Ppa–Q by the PVR equation rearranged as: mean Ppa5PVR6Q+Pla, coordinates measured at constant Pla. Further proof is brought where Q is pulmonary blood flow. The inherent assumptions of about by the demonstration of a functional dissociation between the PVR equation are that the TPGT–Q relationship is linear, Pc and Pla on mean Ppa–Pla relationships in experimental crosses a zero pressure/zero flow value, and is, therefore, preparations in which flow is kept constant; this is discussed independent of the absolute value of Pla. Many studies have further by NAEIJE [3]. A typical experiment in an intact animal shown that the TPG–Q relationship may be reasonably well preparation of oleic acid injury, as a model of the acute described by a linear approximation over a limited range of respiratory distress syndrome, is shown in figure 1 [8]. In this physiological flows, but that its extrapolated pressure intercept is animal, the extrapolated intercept of linear mean Ppa–Q plots most often positive, and that the slope of the mean Ppa–Pla revealed a Pc higher than Pla, and Pla had to be increased above relationship is less than the unity [4]. that value to be transmitted upstream to mean Ppa.

It has long been known that PVR decreases with increases in Q The ‘‘waterfall model’’’ of the pulmonary circulation does not or Pla. This has been initially explained by a pulmonary take into account the natural distensibility of the pulmonary circulation model of parallel collapsible vessels with a distribu- vessels. A sufficient number of mean Ppa–Q coordinates, .4–5, tion of closing pressures (Pc) [5]. In each of these vessels, flow is show a slight curvilinearity, which is ignored by linear determined by a pressure gradient between Ppa and Pc adjustment procedures. This curvilinearity is explained by the whenever there is a Pc .Pla.APla lower than Pc is irrelevant fact that a high flow distends pulmonary resistive vessels, and is a) 30 b) 30 Pla=6 mmHg Q=3 L·min-1·m-2 OA Base

20

20 mmHg mmHg pa pa P P

10

0 10 0123456 01020 Q L·min-1·m-2 Pla mmHg

FIGURE 1. a) Mean pulmonary arterial pressure (Ppa) as a function of cardiac output (Q) at constant left atrial pressure (Pla) and b) Ppa as a function of Pla at constant Q, in an animal before (base) and after induction of acute lung injury by the injection of oleic acid (OA). Before OA, Ppa–Q plots presented with an extrapolated pressure intercept equal to Pla and any increase in Pla was transmitted upstream to Ppa. After OA, Ppa–Q plots presented with an extrapolated pressure intercept higher than Pla,andPla was not transmitted upstream to Ppa below a pressure equal to that value. These observations suggest that OA-induced pulmonary hypertension is caused by an increase in the closing pressure of the pulmonary circulation. Data from [8].

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an important cause of decreased slope of mean Ppa–Q relation- de-recruitment has to be taken into account in low cardiac ships, or PVR along with increasing flow. High flow linear output or high alveolar pressure states. The slope of the mean adjustments of multipoint mean Ppa–Q relationships are, there- Ppa–Pla relationship decreases with pulmonary vascular disten- fore, associated with spurious increase in Pc estimated from sion, but may increase in de-recruited lungs. In that case, an extrapolated pressure intercepts [9]. increased TPG may falsely suggest pulmonary or remodelling. This difficulty is overcome by a mathematical model of the pulmonary circulation fitting multipoint mean Ppa–Q plots by There is thus no good rationale for a stable cut-off value of an equation relating mean Ppa, Pla, Q, total PVR at rest (R0) and 12 mmHg for the TPG as the measurement is sensitive to Pla- a distensibility coefficient (a) [9]: dependent changes in pulmonary vascular recruitment and

5 1/5 distension mean Ppa 5 ([(1 + aPla) + 5aR0(Q)] - 1)/a (1) HOW LEFT ATRIAL PRESSURE AFFECTS PULSATILE The normal value for a measured on in vitro mounted PULMONARY ARTERIAL PRESSURE pulmonary resistive vessels is 2% change in diameter per mmHg change in pressure, and is remarkably constant in a wide The above considerations do not take into account the natural spectrum of animal species [10]. It is interesting that the same pulsatility of the pulmonary circulation. Pulmonary flow reaches distensibility a-value of 2% per mmHg has been recovered by a maximum during , and is inappreciable at the end of the application of the distensibility model equation to either . Accordingly, in a normal pulmonary circulation, invasive [10] or noninvasive [11–13] measurements of pulmon- diastolic Ppa is approximately equal to Pla [14]. It has been ary vascular pressures and flows. The distensibility factor a is assumed, after taking into account errors for measurements of ¡ higher in young healthy females when compared with males 1–2 mmHg, 5 mmHg would be a reasonable upper limit for [12], and decreases with aging [12] or with chronic hypoxic normal diastolic Ppa/Ppcw gradient.Thisisindeedwhatwas exposure [13]. established on the basis of invasive hemodynamic measurements in 44 healthy volunteers aged 17–83 yrs, at rest and at various The distensibility equation allows for the modelling of the levels of exercise in either recumbent and sitting positions effects of increased Q or Pla on mean Ppa at various levels of associated with Ppcw values up to 34 mmHg and cardiac outputs -1 vascular distensibility and PVR. The results are shown in of up to 25–30 L?min [14]. Systolic Ppa and mean Ppa,atany figures 2 and 3. It is apparent that an increase in a decreases given diastolic Ppa, increase in a fixed proportion depending on mean Ppa or TPG at any given level of flow (figs 2 and 3) and stroke volume (SV) and pulmonary arterial compliance (Cpa), also decreases the TPG along with an increase in Ppcw (fig. 3) In which decreases along with increased Pla. Therefore systolic Ppa other words, an increase in Q and/or Pla may falsely decrease and mean Ppa can be predicted from diastolic Ppa using the the TPG that would ordinarily be increased because of the following equations [14]: pulmonary vasoconstriction or remodelling. systolic Ppa 5 1.41 + 1.61 diastolic Ppa + 0.09 SV (2) Distensible models provide a satisfactory explanation for all mean Ppa 5 -1.33 + 1.34 diastolic Ppa + 0.05 SV (3) possible normal or pathological pulmonary vascular pressure– flow relationships in fully recruited lungs. Pulmonary vascular Predicted mean Ppa and systolic Ppa as a function of Ppcw at various SVs are illustrated in figures 4–6. 45 Ppcw=10 mmHg It now appears that the TPG may remain unchanged if diastolic 40 PVR=3 Ppa increases less than Ppcw, but increases if diastolic Ppa increases by an equal amount or more than Ppcw.Alternatively, 35 the diastolic Ppa/Ppcw gradient (DPG) decreases or remains unchanged as long as the upstream transmission of Ppcw remains α 30 =1% equal or less than the unity, which is expected in the absence of 25 α=2% pulmonary vasoconstriction or remodelling.

mmHg The tight correlation between systolic, mean, and diastolic Ppa PVR=1 pa 20

P α=1% was recently rediscovered, with similar prediction equations 15 α=2% that interestingly remained valid in pulmonary hypertension of various severities and aetiologies [15–17]. This is explained by 10 the monotonous response of the pulmonary circulation to insults, leading to proportional inverse changes in Cpa and PVR 5 with an unaltered time constant Cpa 6 PVR 0.6–0.7 s [18, 19]. 0 There may be one noticeable exception: pulmonary hyperten- 0 5 10 15 sion on passive upstream transmission of increased Pla in left Q L·min-1 heart conditions. In these patients Cpa decreases proportionally more than the increase in PVR, because increased Pla is a cause FIGURE 2. Mean pulmonary arterial pressure (Ppa) as a function of cardiac of both pulmonary arterial stiffening and decreased PVR. output (Q) at two different levels of pulmonary vascular resistance (PVR). Increasing Accordingly, the time constant in pulmonary hypertension on distensibility (a) decreases Ppa at any given level of Q. Thus pulmonary vascular left heart conditions is shorter than in other types of pulmonary distensibility results in a Ppa that is less than the one predicted by a linear model, hypertension [20]. This spuriously increases the TPG, but does c which is the PVR equation. not affect DPG.

EUROPEAN RESPIRATORY JOURNAL VOLUME 41 NUMBER 1 219 SERIES: PHYSIOLOGY IN RESPIRATORY MEDICINE R. NAEIJE ET AL.

a) 35 Ppcw=10 mmHg b) 18 Q=5 L·min-1

16 30 PVR=3 PVR=3 14 25 12

20 α=1% 10 α=1%

α=2% 8 15 α=2% TPG mmHg TPG mmHg 6 10 PVR=1 PVR=1 4 α=1% α=1% 5 α=2% 2 α=2%

0 0 0 5 10 15 5101520 Q L·min-1 Ppcw mmHg

FIGURE 3. In the linear model, the transpulmonary pressure gradient (TPG) is only a function of flow rate (Q) as shown in a), and is not affected by pulmonary capillary wedge pressure (Ppcw), as shown in b), whatever the pulmonary vascular resistance. An increase in pulmonary vascular distensibility decreases the TPG as a function of Q as well as of Ppcw.

It must be reminded that Cpa should not be confused with the preferable because this gradient is less sensitive to changes in distensibility coefficient a. Cpa is a global calculation, influ- Cpa, SV, and absolute values of Pla. enced by proximal pulmonary arterial elasticity, while dis- tensibility coefficient a strictly corresponds to the distensibility THE DPG FOR THE DIFFERENTIAL DIAGNOSIS OF of small peripheral pulmonary resistive vessels. PULMONARY HYPERTENSION

Thus the disproportionate decrease in Cpa in the presence of The DPG used to be implemented in the assessment of cardiac increased Pla may be a cause of increased TPG without any versus pulmonary causes of acute respiratory failure in coexistent pulmonary vasoconstriction or remodelling. How critically ill patients [21]. Here we propose an adaptation of this may cancel out the decrease in TPG, related to pulmonary this DPG-derived decision tree to make it more generally vascular recruitment and distension, is unpredictable. applicable (fig. 7). The previous decision tree rested on a cut- off value for Ppcw of 10 mmHg. A Ppcw of 12 mmHg, or a Clinicians, understandably, like to have cut-off values for direct measure of left ventricular end-diastolic pressure of decision making purposes that are based on haemodynamic 15 mmHg, would seem a more reasonable cut-off value as measurements. We regret to have to tell them that a TPG of extreme upper limits of normal; as used in diagnostic 12 mmHg cannot be used for that purpose. The DPG may be algorithms of diastolic heart failure [22]. The next step is a a) 100 b) 30

25 80 SV mL 120 20 80 60 40 sPpa 120 80 15 40 mPpa TPG 40 SV mL Pressure mmHg Pressure mmHg 10

Δ 120 80 20 dPpa=0.75×Ppcw+3 5 40

DPG 0 0 01020304050 01020304050 Ppcw mmHg Ppcw mmHg

FIGURE 4. Effects of pulmonary capillary wedge pressure (Ppcw) and stroke volume (SV) on systolic (s), diastolic (d) and mean (m) pulmonary arterial pressures (Ppa). If only a fraction of Ppcw is transmitted to diastolic Ppa, the transpulmonary pressure gradient (TPG) is not a function of Ppcw but increases proportionally with SV. The diastolic Ppa/Ppcw gradient (DPG) decreases with increased Ppcw, independently of SV. The equations from [14] were used to model the response of the vasculature.

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a) 100 b) 30

SV mL 120 25 SV mL 80 80 40 120 P s pa 80 120 20 60 80 40 40 TPG mPpa 15

40 Pressure mmHg Pressure mmHg dPpa=Ppcw+3 10 Δ

20 5 DPG

0 0 01020304050 01020304050 Ppcw mmHg Ppcw mmHg

FIGURE 5. Effects of pulmonary capillary wedge pressure (Ppcw) and stroke volume (SV) on systolic (s), diastolic (d) and mean (m) pulmonary arterial pressures (Ppa). If Ppcw is directly transmitted to diastolic Ppa, there is a disproportional increase in systolic Ppa and mean Ppa depending on SV. The transpulmonary pressure gradient (TPG) increases, but the diastolic Ppa/Ppcw gradient (DPG) is independent of both Ppcw and SV. The equations from [14] were used to model the response of the vasculature.

DPG below or above 5 mmHg, to discern passive upstream proposed because of insufficient evidence and the desire to transmission of Pla from increased PVR due to pulmonary propose a decision tree with sufficient flexibility to assist, rather vasoconstriction and/or pulmonary vascular structural changes. than impose, clinical decisions. The last step is cardiac output, being normal or decreased in heart failure, or normal or increased in hypervolaemia and/or CONCLUSION AND PERSPECTIVE increased venous return on low systemic vascular resistance in In 1971, HARVEY et al. [14] stated: ‘‘The pulmonary circulation anaemia, systemic shunts, or sepsis. The arteriovenous oxygen has been under intensive study by innumerable investigators for content difference (Dav,O2) can be used as a surrogate of cardiac almost 30 years. From the vast amounts of carefully accumulated output, as the Fick equation predicts that both variables are data, certain conclusions can be drawn’’. More than 40 yrs later, inversely correlated at any given value of oxygen uptake [21]. there has been progress, but also some persisting misconcep- The Dav,O2 is a useful internal control to integrate in haemody- tions. A typical example is the reliance of the TPG for the namic measurements at right heart catheterisation, as errors on a differential diagnosis of pulmonary vascular disease. The present measurement of cardiac output are always possible. Low discussion shows how the TPG may over-diagnose or under- systemic blood pressure argues in favour of a septic complica- diagnose pulmonary vascular disease in left heart conditions tion. Cut-off values for cardiac output or blood pressure are not associated with an increased pulmonary venous pressure, and a) 100 b) 30 SV mL SV mL 120 120 80 80 40 25 80 40 sPpa TPG 120 80 20 40 60 mPpa 15

40 dPpa=1.1×Ppcw+3 Pressure mmHg

Pressure mmHg 10 Δ DPG 20 5

0 0 01020304050 01020304050 Ppcw mmHg Ppcw mmHg

FIGURE 6. Effects of pulmonary capillary wedge pressure (Ppcw) and stroke volume (SV) on systolic (s), diastolic (d) and mean (m) pulmonary arterial pressures (Ppa). If diastolic Ppa increases more than Ppcw, there is an out of proportion increase in systolic Ppa and mean Ppa that is a function of SV. The transpulmonary pressure gradient (TPG) increases. The diastolic Ppa/Ppcw gradient (DPG) increases linearly, but only slightly, with Ppcw and is independent of SV. The equations from [14] were used to model c the response of the vasculature.

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Ppcw

≥12 mmHg <12 mmHg

Evidence of cardiac dysfunction No evidence of cardiac dysfunction

Normotension

DPG DPG DPG

≤5 mmHg >5 mmHg >5 mmHg ≤5 mmHg

Cardiac output Cardiac output

Decreased Normal Decreased Normal

Pulmonary vascular disease LV failure Hypervolaemia Hypovolaemia Hypervolaemia Pump failure

FIGURE 7. Pulmonary capillary wedge (Ppcw)-derived algorithm for the diagnosis of heart failure (low or high output) versus intrinsic pulmonary vascular disease. A cut- off value of 12 mmHg is selected as a true upper limit for normal Ppcw measured at right heart catheterisation. If the cardiac catheterisation is left, Ppcw is replaced by left ventricular (LV) end-diastolic pressure, with a cut-off value of 15 mmHg. Systemic hypotension is considered to make the decision tree applicable to . DPG: diastolic pulmonary arterial pressure/Ppcw gradient. that this is, to a large extent, avoided by the use of a DPG. The measurements and they should be cross-checked with clinical DPG combined with clinical probability assessment, absolute probability assessments and alternative imaging techniques values of Ppcw or Pla, cardiac output or DavO2 and blood pressure should be pursued, whenever possible. measurements appear to be more useful for the diagnosis of ‘‘out of proportion’’ pulmonary hypertension secondary to left heart STATEMENT OF INTEREST conditions, and may help in the management of critically ill A statement of interest for R. Naeije can be found at www.erj. patients with sepsis or acute lung injury. ersjournals.com/site/misc/statements.xhtml It is of course understood that the presently proposed diagnostic tree requires prospective validation. This could be undertaken REFERENCES along with TPG-based algorithms as all these measurements are 1 Galie` N, Hoeper M, Humbert M, et al. Guidelines for the diagnosis currently performed during diagnostic catheterisations. and treatment of pulmonary hypertension. The Task Force for As a final word of caution, one should never forget that decision the Diagnosis and Treatment of Pulmonary Hypertension of trees based on single measurement cut-off values are vulner- the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of able. This was recently illustrated by a poor agreement between Heart and Lung Transplantation (ISHLT). Eur Respir J 2009; 34: right and left heart catheterisation measurements of Ppcw and 1219–1263. Pla in a large patient population [23], and persistant discussion 2 McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 on how optimally measure Ppcw [24]. The measurement of expert consensus document on pulmonary hypertension: a report diastolic Ppa is more exposed than mean Ppa to motion artefacts of the American College of Cardiology Foundation Task Force and inadequate dynamic responses due to over damping or on Expert Consensus Documents and the American Heart under damping (insufficient or excessive flushing of the Association developed in collaboration with the American manometer fluid-filled catheter system). This may explain College of Chest Physicians, American Thoracic Society, Inc., why Ppcw higher than diastolic Ppa are sometimes observed and the Pulmonary Hypertension Association. Circulation 2009; [14], although this is physically impossible. Furthermore, 119: 2250–2294. 3 diagnostic cut-off values do not necessarily coincide with upper Naeije R, Lipski A, Abramowicz M, et al. Nature of pulmonary hypertension in congestive heart failure. Effects of cardiac limits of normal [1, 2], and some uncertainty also remains with transplantation. Am J Respir Crit Care Med 1994; 147: 881–887. the limits of normal of pulmonary haemodynamics in respect of 4 Naeije R. Pulmonary vascular resistance: a meaningless variable? aging, as the number of reported studies in old but healthy Intensive Care Med 2003; 29: 526–529. subjects remains limited [10–12, 14]. Thus the upper limit of 5 Permutt S, Bromberger-Barnea B, Bane HN. Alveolar pressure, normal for the DPG may have to be increased in elderly, healthy pulmonary venous pressure and the vascular waterfall. Med subjects. Great care must be applied in the quality control of Thorac 1962; 19: 239–260.

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