View metadata, citation and similar papers at core.ac.uk brought to you by CORE Journal of the American College of Cardiology providedVol. by Elsevier 42, No. - 4,Publisher 2003 Connector © 2003 by the American College of Cardiology Foundation ISSN 0735-1097/03/$30.00 Published by Elsevier Inc. doi:10.1016/S0735-1097(03)00758-7 Hypoalbuminemia in Elderly Patients With Acute Diastolic Heart Failure Ste´phane Arque`s, MD,* Pierre Ambrosi, MD, PHD,† Richard Ge´lisse, MD,* Roger Luccioni, MD, FACC,† Gilbert Habib, MD, FACC† Aubagne and Marseille, France

OBJECTIVES This study evaluated the relative contribution of serum colloid osmotic pressure (COP) lowering and pulmonary artery wedge pressure (PAWP) elevation in the pathogenesis of pulmonary edema in patients with systolic or isolated diastolic heart failure (DHF). BACKGROUND The role of hypoalbuminemia and the resulting low COP have been shown in some patients with acute systolic heart failure (SHF). METHODS Colloid osmotic pressure and PAWP were determined in 100 patients with acute heart failure (HF) (56 with DHF and 44 with SHF; mean age, 78 Ϯ 12 years), in 35 patients with acute dyspnea from pulmonary origin, and in 15 normal controls. Pulmonary artery wedge pressure was estimated using transthoracic Doppler echocardiography. RESULTS Colloid osmotic pressure was significantly lower in the DHF group (20.5 Ϯ 5 mm Hg) than in the SHF group (24.2 Ϯ 3.7 mm Hg, p Ͻ 0.001), pulmonary disease group (25.1 Ϯ 4.2 mm Hg, p Ͻ 0.001), or normal control group (24.7 Ϯ 3 mm Hg). Low COP resulted from hypoalbuminemia due to age, malnutrition, and sepsis. Pulmonary artery wedge pressure was significantly higher in patients with SHF (26 Ϯ 6.3 mm Hg) than in the patients with DHF (20.3 Ϯ 7 mm Hg, p Ͻ 0.001) and was significantly higher in the patients with DHF than in the patients with pulmonary disease (13 Ϯ 4.2 mm Hg, p Ͻ 0.001). The COP–PAWP gradient was similar in patients with SHF (Ϫ1.6 Ϯ 7.1 mm Hg) and patients with DHF (0.7 Ϯ 6 mm Hg). CONCLUSIONS Frequent hypoalbuminemia resulting in low COP facilitates the onset of pulmonary edema in patients with DHF who usually have lower PAWP than patients with SHF. (J Am Coll Cardiol 2003;42:712–6) © 2003 by the American College of Cardiology Foundation

According to Starling’s hypothesis, the main cause of (5,6). More recently, Doppler echocardiography has been pulmonary edema is a decrease in the serum colloid osmotic validated for the estimation of PAWP, using new combined pressure–pulmonary artery wedge pressure (COP–PAWP) indexes that can be used in the emergency care unit (7,8). gradient (1). Critical decrease in the COP-PAWP gradient The aim of this study was, therefore, to assess the relative is usually related to a major increase in PAWP due to left importance of COP and PAWP in acute DHF compared ventricular (LV) failure. In 1978, Weil et al. (2), then in with acute systolic heart failure (SHF), using serum protein 1982, Rakow et al. (3) demonstrated that in some cases a concentration and Doppler echocardiography to estimate substantial decline in COP can be an additional cause for the imbalance of Starling forces.

See page 717 METHODS the decrease of this gradient and favors acute exacerbation of Study population. PATIENTS WITH ACUTE HF. We in- chronic heart failure (HF) (2,3). In these early works, cluded 100 consecutive patients admitted for acute dyspnea diastolic heart failure (DHF) was not clearly identified as a with the final diagnosis of acute congestive left-HF, in the cause of frequent pulmonary edema, and the relative con- absence of severe mitral valve disease, rest angina, or acute tributions of COP and PAWP abnormalities in the patho- myocardial infarction (9). genesis of acute DHF have not been evaluated. Despite the difficulties in affirming the diagnosis of DHF, there is now The diagnosis of acute congestive HF was based on much evidence that in nearly half of the patients presenting Framingham criteria, the absence of patent primary pulmo- with pulmonary edema, HF is due to isolated diastolic nary disease, the response to diuretics, and the result of dysfunction (4). further cardiac imaging (9). All the patients had congestive According to experimental and clinical studies, COP may signs at auscultation and pulmonary edema on chest X-ray. be accurately estimated from albuminemia and protidemia In all the patients, transthoracic Doppler echocardiography was performed within 30 min after the initiation of loop diuretics. The diagnoses of DHF and SHF were based on From the *Department of Cardiology, Aubagne Hospital, Aubagne, and the the presence at echocardiography of LV ejection fractions †Department of Cardiology, la Timone Hospital, Marseille, France. Ͼ Ͻ Manuscript received November 9, 2002; revised manuscript received January 11, 50% and 50%, respectively. The presence of malnutri- 2003, accepted February 20, 2003. tion was assessed according a subjective method (10). Sepsis JACC Vol. 42, No. 4, 2003 Arque`s et al. 713 August 20, 2003:712–6 Hypoalbuminemia and DHF

valve plane to 4 cm distally into the LV cavity (7,8). The Abbreviations and Acronyms slope of the transition from no color to color was assumed A ϭ serum albumin to be Vp when peak velocity (E) was lower than aliasing COP ϭ serum colloid osmotic pressure velocity. Results of three to five consecutive beats were ϭ DHF diastolic heart failure averaged. Pulmonary artery wedge pressure (mm Hg) was G ϭ serum globulin concentration ϭ estimated using the equation proposed by Gonzalez-Vilchez HF heart failure ϭ ϫ ϫ ϩ Ϫ ht ϭ hematocrit et al. (8): PAWP 4.5 1,000/(2 IRT Vp) 9. IRT ϭ isovolumic relaxation time Mitral inflow patterns were defined as: normal pattern by LV ϭ left ventricular E/A Ͼ1 and E/V p Ͻ 2; abnormal relaxation pattern by ϭ P serum protein E/A Ͻ1; normalized pattern by 1 Ͻ E/A Ͻ 2 and E/Vp Ͼ PAWP ϭ pulmonary artery wedge pressure Ͼ SHF ϭ systolic heart failure 2; and restrictive pattern by E/A 2. Diastolic dysfunction Vp ϭ velocity of color M-mode Doppler mitral flow was defined by abnormal relaxation, normalized, or restric- propagation tive patterns at Doppler mitral inflow examination (11). Doppler echocardiography recordings were read indepen- dently by two echocardiographers. Intra- and inter-observer was defined by the association of fever, C-reactive protein variability of PAWP was calculated in 15 consecutive Ͼ100 mg/l, and a diagnosis of infection at discharge. patients. Statistical analysis. All descriptive data are given as mean PATIENTS IN THE PULMONARY DISEASE GROUP. Pulmonary Ϯ SD. Inter-group comparison for clinical, biological, and artery wedge pressure was measured in 35 patients who hemodynamic data used one-way analysis of variance. Inter- suffered from acute dyspnea from various pulmonary causes. group comparison for the percentages of hypoalbuminemia NORMAL CONTROL GROUP. Pulmonary artery wedge pres- and main mechanism of pulmonary edema used a chi-square sure was also measured in 15 elderly subjects (8 women, 7 test. Linear regression analysis was used to assess the men) without overt cardiovascular or pulmonary disease. relationship between albuminemia and age, C-reactive pro- Biochemistry. Total serum protein (P) and serum albumin tein, or creatinine clearance. A p value Ͻ0.05 was consid- (A) concentrations were obtained from venous blood sam- ered statistically significant. pled at the admission in all the patients. Serum protein was measured using the Biuret method (Vitros; normal value RESULTS between 6 and 8 g/dl), and A was measured using the immunoturbidimetry method (Behring turbidimeter; nor- There were 56 patients in the DHF group (mean age ϭ 79 mal value between 3.5 and 5.0 g/dl). Serum globulin Ϯ 12 years), 44 in the SHF group (mean age ϭ 76 Ϯ 12 concentration (G) was calculated as P Ϫ A. We used the years), 35 in the pulmonary disease group (mean age ϭ 78 Landis-Pappenheimer formula to estimate COP: (mm Hg) Ϯ 11 years), and 15 in the normal control group (75 Ϯ 8 ϭ A/P ϫ (2.8 ϫ P ϩ 0.18 ϫ P2 ϩ 0.012 ϫ P3) ϩ G/P ϫ years) (Table 1). (1.6 ϫ P ϩ 0.15 ϫ P2 ϩ 0.006 ϫ P3), with A, G, and P in Doppler estimate of PAWP and diastolic function. The g/dl. A previously reported normal value of COP was 25.4 feasibility of PAWP measurement was 91% (Table 2). Ϯ 2.3 mm Hg (5). Creatinine clearance was determined Correlation coefficients were 0.98 for intra-observer and using the Cockcroft formula. Early variation of hematocrit 0.96 for inter-observer comparison of PAWP. (ht) was measured between the admission and 72 h (or 48 h The PAWP was significantly higher in SHF (26 Ϯ 6.3 when ht at 72 h was not available). mm Hg) than in DHF (20.3 Ϯ 7 mm Hg, p Ͻ 0.001); Doppler echocardiography. All Doppler echocardiogra- PAWP was significantly higher in the DHF group than in phy examinations were performed by the same operator the pulmonary disease group (13 Ϯ 4.2 mm Hg, p Ͻ 0.001); (S.A.) using either ESAOTE Challenge (ESAOTE Bio- and PAWP was slightly higher in the pulmonary group than medica, Italy) or ALOKA SSD5500 PHD (Aloka Co. Ltd., in the normal control group (10.7 Ϯ 2.1 mm Hg, p ϭ Tokyo, Japan) ultrasound systems with 2.5 MHz and 3.5 0.044). A generally accepted cut-off value of PAWP for the MHz transducers. Two-dimensional and Doppler record- diagnosis of cardiogenic pulmonary edema in patients pre- ings were acquired in apical views. Left ventricular ejection senting with acute dyspnea is Ն18 mm Hg. A PAWP Ն18 fraction was determined with the Simpson biplane method mm Hg was found in 98% of the SHF, 60% of the DHF, from two-dimensional images. The isovolumic relaxation 12% of the pulmonary disease, and none of the normal time (IRT) (ms) was measured from the end of aortic flow control patients (Fig. 1). to the onset of mitral flow. The velocity of color M-mode Mitral inflow pattern was not obtained in 42 patients, Doppler mitral flow propagation (Vp) (cm/s) was recorded because of atrial fibrillation, cardiac pacing, or E/A fusion in an apical four-chamber view, positioning the M-mode (Table 2). Among the 93 other patients, the mitral inflow cursor through the longest column of color flow from the pattern suggested diastolic dysfunction in 100% of the mitral annulus to the apex; Vp was measured as the slope of patients with SHF, 95% of the patients with DHF, and 85% the first aliasing velocity during early filling, from the mitral of the patients with pulmonary disease (Table 2). Pseudo- 714 Arque`s et al. JACC Vol. 42, No. 4, 2003 Hypoalbuminemia and DHF August 20, 2003:712–6

Table 1. Characteristics of the Patients DHF SHF Pulmonary Disease †p Value (35 ؍ p Value* (n (44 ؍ n) (56 ؍ n) Age (yrs) 79 Ϯ 12 76 Ϯ 12 0.2 78 Ϯ 11 0.55 Heart rate (beats/min) 86 Ϯ 14 93 Ϯ 16 0.012 88 Ϯ 13 0.3 Sinus rhythm (no. of patients) 38 31 27 History of heart failure (no. of patients) 35 37 0 Main cardiac disease (no. of patients) Ischemic 20 31 6 Dilated cardiomyopathy 0 10 0 Aortic valvular disease 4 3 0 Hypertensive heart 18 0 22 Other 14 0 7 Systolic blood pressure (mm Hg) 140 Ϯ 19 119 Ϯ 19 Ͻ 0.001 135 Ϯ 21 0.2 Medications at the time of admission On diuretics (no. of patients) 28 35 — On ACE inhibitors (no. of patients) 9 25 — On beta-blockers (no. of patients) 15 5 — Left ventricular ejection fraction (%) 63 Ϯ 832Ϯ 9 Ͻ 0.001 66 Ϯ 9 0.09 Creatinine clearance (ml/min) 44 Ϯ 28 44 Ϯ 25 0.92 42 Ϯ 24 0.65

*p values are for the comparison between DHF and SHF groups; †p values are for the comparison between diastolic and pulmonary disease groups. ACE ϭ angiotensin-converting enzyme; DHF ϭ diastolic heart failure; SHF ϭ systolic heart failure. normal and restrictive patterns were significantly more and 6% of pulmonary disease patients, compared with 34% frequent in the SHF and DHF groups than in the pulmo- of the patients with DHF (p Ͻ 0.001 vs. SHF and nary disease group (p Ͻ 0.001). pulmonary disease patients) (Fig. 1). Hematocrit did not Biochemistry data. Albuminemia was significantly lower show significant variations between admission (ht0) and in the DHF group (2.58 Ϯ 0.7 g/dl) than in either the SHF 72 h (ht72) (SHF: ht0 ϭ 38.9 Ϯ 5.8%, ht72 ϭ 38.5 Ϯ group (3.2 Ϯ 0.54 g/dl), pulmonary disease group (3.18 Ϯ 5.8%; DHF: ht0 ϭ 36.2 Ϯ 5.4%, ht72 ϭ 34 Ϯ 9.2%; 0.65 g/dl), or normal control group (3.44 Ϯ 0.43 g/dl) (p Ͻ pulmonary disease: ht0 ϭ 41.1 Ϯ 5.8%, ht72 ϭ 39.6 Ϯ 0.001), with no significant difference between the SHF and 5.7%). pulmonary disease groups (Table 3). Albuminemia Ͻ3 g/dl Colloid osmotic–hydrostatic pressure gradient. The was present in 38 of the 56 patients with DHF (68%), 14 of COP–PAWP gradient was significantly lower in the DHF 44 patients with SHF (32%, p Ͻ 0.001 vs. DHF), and 11 of and SHF than in the pulmonary disease or normal control 35 patients with pulmonary disease (31%, p Ͻ 0.001 vs. groups (Table 3). In the previous invasive studies, a value of DHF). Main causes of hypoalbuminemia Ͻ3 g/dl in the COP–PAWP gradient Յ6 mm Hg was shown to be DHF group were malnutrition in 77% and/or sepsis in 41% associated with pulmonary edema with a high sensitivity of the patients. Albuminemia was significantly inversely and specificity (2,3). A COP–PAWP gradient Յ6mmHg correlated to age (r ϭϪ0.24, p Ͻ 0.005) and to plasma was present in 48 patients (86%) with DHF, 40 patients C-reactive protein concentration (r ϭϪ0.37, p Ͻ 0.001). (90%) with SHF, one patient with pulmonary disease, and There was no significant correlation between albuminemia one control, respectively. and creatinine clearance (p ϭ 0.52); COP was significantly lower in DHF (20.5 Ϯ 5 mm Hg) than in SHF (24.2 Ϯ 3.7 DISCUSSION mm Hg, p Ͻ 0.001) or pulmonary disease patients (25.1 Ϯ In the present work, we used Doppler echocardiography to 4.2 mm Hg, p Ͻ 0.001), with no significant difference measure PAWP in 100 patients at the acute phase of between SHF and pulmonary disease patients (p ϭ 0.29). pulmonary edema. This method appeared to be feasible in Previously, a COP Յ18 mm Hg has been shown to most of the patients (91%) in this setting. The reliability of facilitate pulmonary edema in critically ill patients (12). A Doppler echocardiography for the measurement of PAWP COP Յ18 mm Hg was present in 7% of patients with SHF has been assessed by previous studies, by comparison with

Table 2. Mitral Inflow Pattern at Doppler Echocardiography in the Three Groups of Patients DHF SHF Pulmonary Disease (35 ؍ n) (44 ؍ n) (56 ؍ n) Non-feasible (no. of patients) 21 13 8 Normal (no. of patients) 2 0 4 Relaxation abnormality (no. of patients) 9 0 18 Pseudo-normal (no. of patients) 18 7 5 Restrictive (no. of patients) 6 24 0

DHF ϭ diastolic heart failure; SHF ϭ systolic heart failure. JACC Vol. 42, No. 4, 2003 Arque`s et al. 715 August 20, 2003:712–6 Hypoalbuminemia and DHF

Figure 1. Starling’s imbalance forces in patients with acute dyspnea and either acute heart failure or pulmonary disease. Relationship between pulmonary artery wedge pressure (PAWP) (mm Hg) and serum colloid osmotic pressure (COP) (mm Hg) according to the group. Open circles ϭ diastolic heart failure; open triangles ϭ systolic heart failure; solid diamonds ϭ pulmonary disease. invasive measurements (7,8,11). For this measurement, we systolic) with pulmonary edema. Thus, this gradient was lower used a validated index derived from Weiss’ formula (8,13). than 6 mm Hg, an accepted threshold value for the setting of The elevation of PAWP correlated well in our study with pulmonary edema, in most of the patients with DHF (2,3). the abnormality of E/A ratio. In most cases, hypoalbuminemia was related to malnu- Our first important finding is that PAWP is usually lower trition or sepsis and was not the consequence of hemodilu- in patients with pulmonary edema due to isolated diastolic tion, because diuretic therapy did not increase ht. Consis- dysfunction than in patients with pulmonary edema and tently, albuminemia was inversely correlated with C-reactive systolic dysfunction. Moreover, PAWP was higher in pa- protein and age. tients with DHF than in patients with acute dyspnea of The study population was an unselected sample of pa- pulmonary origin or in normal controls. tients presenting for acute dyspnea with a mean age very Our study strongly suggests that a major additional similar to the age of patients hospitalized for acute HF in mechanism for pulmonary edema in DHF is low oncotic France or the U.S. (14,15). Thus, our results suggest that pressure. First, we demonstrated that hypoalbuminemia hypoalbuminemia is a frequent and major cause of exacer- resulting in low oncotic pressure is significantly more bation of DHF, besides acute elevation of blood pressure, common in patients with acute DHF than in patients with renal failure, tachycardia, ischemia, or high sodium intake. SHF or patients with pulmonary disease. Albuminemia Ͻ3.0 This mechanism may, at least partly, explain why serum g/dl was present in about one-third of the patients with SHF albumin concentration is a strong predictor of high mortal- or pulmonary disease and two-thirds of the patients with ity in HF (16,17). Through a similar mechanism, hypoalbu- DHF. Second, as a result of the low oncotic pressure, the minemia has been recently proposed as facilitating acute gradient of Starling’s imbalance forces (oncotic pressure– respiratory distress syndrome (18). To confirm the role of PAWP) was similarly lowered in the two groups (diastolic and hypoalbuminemia in the exacerbation of DHF, we need

Table 3. Proteinemia, Albuminemia, COP, and PAWP in the Three Groups of Patients and in the Normal Control Group DHF SHF p Pulmonary Disease p Normal Control p †Value (15 ؍ Value† (n (35 ؍ Value* (n (44 ؍ n) (56 ؍ n) Protidemia (g/dl) 5.97 Ϯ 0.94 6.57 Ϯ 0.7 Ͻ 0.001 6.76 Ϯ 0.7 Ͻ 0.001 6.6 Ϯ 0.5 Ͻ 0.001 Albuminemia (g/dl) 2.58 Ϯ 0.7 3.21 Ϯ 0.54 Ͻ 0.001 3.18 Ϯ 0.65 Ͻ 0.001 3.44 Ϯ 0.43 Ͻ 0.001 COP (mm Hg) 20.5 Ϯ 5 24.2 Ϯ 3.7 Ͻ 0.001 25.1 Ϯ 4.2 Ͻ 0.001 24.7 Ϯ 3 Ͻ 0.001 PAWP (mm Hg) 20.3 Ϯ 726Ϯ 6.3 Ͻ 0.001 13 Ϯ 4.2 Ͻ 0.001 10.7 Ϯ 2.1 Ͻ 0.001 COP-PAWP (mm Hg) 0.7 Ϯ 6 Ϫ1.6 Ϯ 7.1 0.03 12.3 Ϯ 5.4 Ͻ 0.001 13.1 Ϯ 4.2 Ͻ 0.001

*p values are for the comparison between DHF and SHF groups; †p values are for the comparison between DHF and pulmonary disease or normal control groups. COP ϭ colloid osmotic pressure; DHF ϭ diastolic heart failure; PAWP ϭ pulmonary artery wedge pressure; SHF ϭ systolic heart failure. 716 Arque`s et al. JACC Vol. 42, No. 4, 2003 Hypoalbuminemia and DHF August 20, 2003:712–6 further interventional studies evaluating the effects of albu- 8. Gonzalez-Vilchez F, Ares M, Ayuela J, Alonso L. Combined use of min infusions or of improved nutrition in patients with pulsed and color M-Mode Doppler echocardiography for the estima- tion of pulmonary capillary wedge pressure: an empirical approach DHF and severe hypoalbuminemia. based on an analytical relation. J Am Coll Cardiol 1999;34:515–23. 9. Remme WJ, Swedberg K. Guidelines for the diagnosis and treatment of chronic heart failure: Task Force for the Diagnosis and Treatment of Chronic Heart Failure, European Society of Cardiology. Eur Reprint requests and correspondence: Dr. Pierre Ambrosi, De- Heart J 2001;22:1527–60. partment of Cardiology, La Timone Hospital, Boulevard Jean 10. Detsky AS, Baker JP, Mendelson RA, Wolman SL, Wesson DE, Moulin, 13385 Marseille, France. E-mail: [email protected]. Jeejeebhoy KN. Evaluating the accuracy of nutritional assessment techniques applied to hospitalised patients: methodology and compar- REFERENCES isons. J Parenter Enteral Nutr 1984;8:153–9. 11. Garcia MJ, Thomas JD, Klein AL. New Doppler echocardiographic applications for the study of diastolic function. J Am Coll Cardiol 1. Guyton AC, Lindsey AW. Effect of elevated left atrial pressure and 1998;32:865–75. decreased plasma protein concentration on the development of pul- 12. Van der Linden P. Clinical practice interpretation of oncotic pressure, monary edema. Circ Res 1959;7:649–56. serum albumin, and protein determination and their ability for guiding 2. Weil MH, Henning RJ, Morissette M, Michaels S. Relationship therapeutics in cases of disturbances of capillary exchanges. Ann Fr between colloid osmotic pressure and pulmonary artery wedge pressure Anesth Reanim 1996;15:456–63. in patients with acute cardiorespiratory failure. Am J Med 1978;64: 643–50. 13. Gonzalez Vilchez F, Ayuela J, Ares M, Mata NS, Gonzalez AG, Dur 3. Rakow EC, Fein IA, Siegel J. The relationship of the colloid RM. Comparison of Doppler echocardiography, color M-mode osmotic-pulmonary artery wedge pressure gradient to pulmonary Doppler and tissue Doppler imaging for the estimation of pulmonary edema and mortality in critically ill patients. Chest 1982;82:433–7. capillary wedge pressure. J Am Soc Echocardiogr 2002;15:1245–50. 4. Banerjee P, Banerjee T, Khand A, Clark AL, Cleland JG. Diastolic 14. Cohen Solal A, Bouhour JB, The´baut JF. The management of patients failure: neglected or misdiagnosed? J Am Coll Cardiol 2002;39:138– with heart failure in France. Eur J Heart Fail 2000;2:223–6. 41. 15. Senni M, Tribouilloy CM, Rodeheffer RJ, et al. Congestive heart 5. Morissette MP. Colloid osmotic pressure: its measurement and clinical failure in the community: a study of all incident cases in Olmsted value. Can Med Assoc J 1977;116:897–900. County, Minnesota, in 1991. Circulation 1998;98:2282–9. 6. Mullins RE, Pappas AA, Gadsden RH, Vence-Pastor DE. Correla- 16. Anker SD, Ponikowski P, Varney S, et al. Wasting as independent risk tion of standardized serum protein determination with calculated and factor for mortality in chronic heart failure. Lancet 1997;349:1050–3. measured colloid osmotic pressure. Am J Clin Pathol 1983;80:170–5. 17. Cederholm T, Jagren C, Hellstrom K. Outcome of protein-energy 7. Garcia MJ, Ares MA, Asher C, Rodriguez L, Vandervoort P, Thomas malnutrition in elderly medical patients. Am J Med 1995;98:67–74. JD. An index of early left ventricular filling that combined with pulsed 18. Arif SK, Verheij J, Groeneveld AB, Raijmakers PG. Hypoproteinemia Doppler peak E velocity may estimate capillary wedge pressure. J Am as a marker of acute respiratory distress syndrome in critically ill Coll Cardiol 1997;29:448–54. patients with pulmonary edema. Intensive Care Med 2002;28:310–7.