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European Journal of Heart Failure (2010) 12, 1193–1202 doi:10.1093/eurjhf/hfq138

Acute pulmonary oedema: clinical characteristics, prognostic factors, and in-hospital management John T. Parissis 1*, Maria Nikolaou 1, Alexandre Mebazaa 2, Ignatios Ikonomidis 1, Juan Delgado 3, Fabio Vilas-Boas 4, Ioannis Paraskevaidis 1, Antony Mc Lean 5, Dimitrios Kremastinos 1, and Ferenc Follath 6 1 Heart Failure Clinic and Second Cardiology Department, Attikon University Hospital, University of Athens, Athens, Greece; 2Department of Anesthesiology and Critical Care Medicine, Hospital Lariboisie`re, APHP, Universite´ Paris Diderot Paris 7, U942 Inserm, Paris, France; 3Heart Failure and Transplant Unit, Cardiology Department, Hospital Doce de Octubre, Madrid, Spain; 4Cardiology Division and Heart Failure and Transplantation Program, Hospital Espanhol, Salvador, Bahia, Brazil; 5Department of Intensive Care Medicine, Nepean Hospital, University of Sydney, Penrith, New South Wales, Australia; and 6Department of Internal Medicine, University Hospital Zurich, Zurich, Switzerland

Received 27 February 2010; revised 10 May 2010; accepted 14 May 2010; online publish-ahead-of-print 13 September 2010

Aims

Acute pulmonary oedema (APE) is the second, after acutely decompensated chronic heart failure (ADHF), most frequent form of acute heart failure (AHF). This subanalysis examines the clinical profile, prognostic factors, and management of APE patients (n ¼ 1820, 36.7%) included in the Acute Heart Failure Global Survey of Standard Treatment (ALARM-HF). ..................................................................................................................................................................................... Methods ALARM-HF included a total of 4953 patients hospitalized for AHF in Europe, Latin America, and Australia. The final and results diagnosis was made at discharge, and patients were classified according to European Society of Cardiology guidelines. Patients with APE had higher in-hospital mortality (7.4 vs. 6.0%, P ¼ 0.057) compared with ADHF patients (n ¼ 1911, 38.5%), and APE patients exhibited higher systolic blood pressures (P , 0.001) at admission and higher left ventricular ejection fraction (LVEF, P , 0.01) than those with ADHF. These patients also had a higher prevalence of diabetes (P , 0.01), arterial hypertension (P , 0.001), peripheral vascular disease (P , 0.001), and chronic renal disease (P , 0.05). They were also more likely to receive intravenous (i.v.) diuretics (P , 0.001), i.v. nitrates (P , 0.01), dopamine (P , 0.05), and non-invasive ventilation (P , 0.001). Low systolic blood pressure (P , 0.001), low LVEF (,0.05), serum creatinine ≥1.4 mg/dL (P , 0.001), history of cardiomyopathy (P , 0.05), and previous cardiovascular event (P , 0.001) were independently associated with increased in-hospital mortality in the APE population. ..................................................................................................................................................................................... Conclusion APE differs in clinical profile, in-hospital management, and mortality compared with ADHF. Admission characteristics (systolic blood pressure and LVEF), renal function, and history may identify high-risk APE patients.

----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords

Acute heart failure † Acute pulmonary oedema † Medical management † Prognosis

Introduction Acute heart failure (AHF) is a heterogeneous syndrome associated with increased morbidity and mortality worldwide. Recent AHF registries in the USA, Europe, and Japan have grouped various clinical situations and provided important information about patients’ clinical characteristics and prognosis.1 – 6 However, these registries have shown a wide range of in-hospital mortality underlining the

variety of AHF syndromes and the lack of a universally accepted definition of AHF. The international Acute Heart Failure Global Survey of Standard Treatment (ALARM-HF) was planned to assess the utility of the European Society of Cardiology (ESC) guidelines7 for describing and comparing the clinical presentation, management, and outcome of AHF under ‘real life’ conditions in different countries and regions of the world. AHF can present as acute de novo

* Corresponding author. Tel: +30 210 6123720, Fax: +30 210 5832195, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2010. For permissions please email: [email protected].

1194 (new onset heart failure) or worsening of chronic heart failure (CHF) and can be classified into several distinct clinical conditions such as (i) acutely decompensated chronic heart failure (ADHF) defined as signs and symptoms of AHF that do not fulfil the criteria for cardiogenic shock, pulmonary oedema, or hypertensive crisis, (ii) hypertensive AHF defined as signs and symptoms of heart failure accompanying high blood pressure, relatively preserved ejection fraction, and chest X-ray compatible with acute pulmonary oedema (APE), (iii) APE defined as alveolar or interstitial oedema verified by chest X-ray and/or with O2 saturation ,90% on room air prior to treatment accompanied by severe respiratory distress, with crackles over the lungs and orthopnoea, (iv) cardiogenic shock defined as tissue hypoperfusion induced by heart failure after correction of pre-load, accompanied by systolic blood pressure ,90 mmHg, low urine output ,0.5 mL/kg/h with a pulse rate .60 b.p.m., (v) high output heart failure, and (vi) right heart failure characterized by low output, hypotension, increased jugular venous pressure, and liver enlargement. One of the main problems in managing patients with AHF syndromes is the fact that each patient represents a different entity, a different clinical scenario, derived from a different pathophysiological mechanism with a different outcome. As a result, grouping patients for educational purposes may only partly reflect reality. The clinical classification was suggested by the ESC as a simple, easy, and rapidly applied classification that provides useful information since the patients’ admission, although overlapping cannot be avoided. This classification was only slightly modified in the most recent ESC guidelines published in 2008, by omitting the entity of high output heart failure and inserting the acute coronary syndrome entity.8 Undoubtedly, APE represents the most dramatic condition, following cardiogenic shock, although it is poorly described in the majority of registries. Our study therefore has three main objectives: first to evaluate the clinical characteristics of APE and compare them with ADHF, because these two AHF phenotypes are the most frequent, involving about 76% of the overall patient population in the ALARM-HF survey; secondly, to assess the prognostic markers of APE; and thirdly, to describe the management of APE patients registered in ALARM-HF.

Methods The ALARM-HF survey was an in-hospital observational survey that included patients hospitalized for AHF in Europe, Latin America, and Australia. Anonymized data were collected for 4953 patients. This database contains detailed patient characteristics from initial presentation in the hospital or emergency department until discharge, transfer, or in-hospital death. The ALARM-HF survey included patients hospitalized with AHF in community, tertiary, and academic centres. The database includes information on demography, medical history, baseline clinical characteristics, initial evaluation, treatment received, procedures performed, and hospital course. Standardized definitions are used for all patient-related variables, clinical diagnoses, and hospital outcomes. Institutional Review Board approval was required for all participating centres; however, informed consent of individuals was not required for survey entry. Diagnosis was made at discharge, and patients were classified according to the definition and classification of the ESC guidelines 2005.7

J.T. Parissis et al.

Survey description The hospital sample was recruited to be representative according to geographical region, hospital size (by number of beds), sector (public vs. private), and type (university vs. non-teaching status). Paper-based data collection was conducted over the period from October 2006 to March 2007. Patient case report forms were completed for five to eight consecutive patients at or close to discharge, based on medical records. Diagnoses at discharge were classified according to ESC categories by the responsible cardiologists and/or intensive care unit (ICU) physicians. Where two or more categories were indicated by a respondent, the final appropriate classification was adjudicated according to the additional clinical data supplied. The retrospective methodology also enabled the assessment of both primary (present on admission) and secondary (occurring in hospital) causes of AHF. Clinical history, co-morbidities, precipitating factors, signs and symptoms, and medication (admission as well as discharge) were recorded. Details of intravenous (i.v.) drugs including timing and location of initiation as well as dosage and duration were also registered. Where available, echocardiography data were collected at diagnosis and/or prior to discharge. Finally, there were no exclusion criteria in this survey.

Discrimination of acute pulmonary oedema and acute decompensated heart failure ESC definitions were used to classify APE and ADHF.7 APE is a diagnosis based on patient’s history (abrupt onset), clinical examination (orthopnoea and rales), chest X-ray (alveolar oedema), oxygen desaturation, and treatment response. Unfortunately, there is no definite measurement that can distinguish the level of alveolar congestion, since this is related not only to the pressures in the microcirculation, but also to the membrane properties. Right catheterization was available in only 12% and natriuretic peptides in 6.2% of the patient population and therefore did not help in the differential diagnosis of the two conditions by the treating physicians. The distinction between APE and ADHF is not always clear, as these two clinical entities represent a continuous range of the same pathophysiology, with no clear cut-offs. As a result, the discrimination is based primarily on the severity and often on the rapidity of symptom evolution, as judged by the clinician, and secondarily by the X-ray findings that may or may not support the diagnosis (e.g. flash pulmonary oedema).

Statistics Statistical analysis was performed using the SPSS 13.0 statistical software package (SPSS Inc., Chicago, IL, USA). Categorical variables are presented as counts and percentages and quantitative variables as mean and standard deviation. Subgroups of patients were compared using x2 tests for categorical variables and t-test or analysis of variance Wilcoxon rank-sum tests for quantitative variables. Age categories were compared using the x2 test for trend. Receiver operating characteristic (ROC) analysis was used to identify the best cut-off value for the continuous variable of serum creatinine. Univariate and multivariable logistic regression analysis was used to identify prognostic predictors. All variables with P , 0.1 at univariate analysis were included in the multivariable model. Both backward and forward stepwise analyses were used to determine the independent predictors of outcome. All interactions between covariates were assessed. The odds ratio and corresponding 95% confidence intervals are given for each covariate. Kaplan– Meier in-hospital survival curves were constructed by dividing patients into subgroups according to the quartiles of systolic blood pressure or to the cut-off value of serum creatinine. The survival rates between the various subgroups were compared using the log

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rank test. All tests were two-sided, and P-values less than 0.05 were considered as indicating significant differences.

Results The ALARM-HF survey included a total of 4953 patients (France n ¼ 588, Germany n ¼ 617, Italy n ¼ 679, Spain n ¼ 700, UK n ¼ 623, Greece n¼255, Turkey n ¼ 628, Mexico n ¼ 601, and Australia n ¼ 262), admitted to 666 hospitals of different sizes and types and managed by either cardiologists (n ¼ 655) or ICU physicians (n ¼ 287). The clinical characteristics of the whole cohort of AHF patients have already been presented.9 Thirty-five per cent of the patients needed ICU/Coronary Care Unit (CCU) management. APE and ADHF were the most common presentations, affecting 37 and 39% of the total patient population, respectively. Moreover, cardiogenic shock presented with a frequency of 12%, hypertensive heart failure 7%, right ventricular failure 4%, and high output heart failure 1%. The percentage of APE and ADHF patients in the different countries is shown in Figure 1. Table 1 summarizes the differences in the clinical profile and laboratory findings between the two conditions. No differences in gender or age were observed. Concerning the transfer to hospital, APE patients were more often already hospitalized compared with ADHF patients (14.6 vs. 9.3%) or admitted at the emergency room by ambulance (48.6 vs. 41.3%), whereas ADHF patients were more frequently admitted independently (16.4 vs. 11.0%) or from referral centres (27.0 vs. 19.7% P , 0.001 for all comparisons). A higher percentage of APE patients had de novo heart failure (39.2 vs. 28.1% for ADHF, P , 0.001), and APE patients were more frequently diagnosed later during the hospitalization (24.9 vs. 17.7% of patients had a secondary diagnosis of APE and ADHF, respectively, P , 0.001). The onset of symptoms was more abrupt in APE patients (,6 h in 42.9% of APE vs. 34.0% of ADHF, 6 h to 5 days in 10.4% of APE vs. 26.5% of ADHF, P , 0.001) and the clinical status more dramatic [39.0% of APE vs. 30.1% of ADHF patients were classified as New York Heart Association (NYHA) IV, whereas 31.6 vs. 42.8% were classified

as NYHA III, respectively]. Differences in symptoms and clinical signs between these two conditions are also described in Table 1. APE patients exhibited higher systolic blood pressure (P , 0.001), higher heart rate (P , 0.001), and lower levels of oxygen saturation (P , 0.001) at admission. These patients also had a slightly (but statistically significant) higher left ventricular ejection fraction (LVEF) (P , 0.01) (Table 2). About 14% of the APE patients vs. 39% of the ADHF patients had no evidence of congestion (interstitial or alveolar oedema) on chest radiography. In these cases, the APE diagnosis was based on severe respiratory distress accompanying low arterial saturation oxygen (,90%) and signs implying congestion as described previously.7 Cardiovascular and non-cardiovascular co-morbidities are also summarized in Table 1. Acute coronary syndrome, new onset of arrhythmia, and post-surgery clinical worsening were aetiologies of exacerbation favouring APE, whereas poor compliance with treatment and dietary habits as well as infection favoured ADHF. Consequently, APE patients more frequently had positive markers of myocardial injury. Differences in pre-admission medications are described in Table 3. Although medication was optimized during hospitalization in both groups, the differences persisted at discharge. In-hospital treatment modalities also differed between the two conditions, as shown in Table 4.

In-hospital outcome APE patients experienced worse in-hospital outcomes compared with ADHF patients, with increased in-hospital mortality (7.4 vs. 6%, P ¼ 0.057), increased ICU discharge (P , 0.05), and increased transfer to rehabilitation centres (P , 0.05) (Table 5). Furthermore, 80.8% of the APE vs. 65.2% (P , 0.001) of the ADHF patients required ICU/CCU during hospitalization. Univariate analysis of prognosis for patients with APE is demonstrated in Table 6. The multivariate model including those parameters univariately associated with survival revealed that low systolic blood pressure (P ¼ 0.019), low LVEF (P , 0.05), serum creatinine ≥1.4 mg/dL (P , 0.001), history of cardiomyopathy (P , 0.05) or previous cardiovascular event (P , 0.001),

Figure 1 Percentages of acute pulmonary oedema (APE) vs. acutely decompensated chronic heart failure (ADHF) patients in countries of ALARM-HF.

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Table 1 Differences in clinical presentation between patients with acutely decompensated heart failure (ADHF) and acute pulmonary oedema (APE) ADHF (n 5 1911)

APE (n 5 1820)

P-value

Table 1 Continued ADHF (n 5 1911)

APE (n 5 1820)

P-value

................................................................................ CRT (%)

3.2

1.2

0.001

................................................................................

ICD (%)

5.3

3.2

0.001

Age ,50 years (%)

18.4 37.9

25.5 35.9

0.001 NS

65.2

80.8

0.001

9.2

8.1

NS

Smoker (%) Ex-smoker (%)

46.8

47.3

NS

ICU hospitalization (%)

.75 years (%) 44.0 Cardiovascular co-morbidities

47.7

NS

50–75 years (%)

Atrial fibrillation/ flutter (%)

27.9

24.7

Cardiomyopathy (%)

14.9

11.7

0.002

6.5

9.9

,0.001

30.4 40.5

31.8 35.2

NS ,0.001

Peripheral vascular disease (%) CAD (%) CHF (%)

0.015

Obesity (%)

25.1

26.1

NS

Diabetes mellitus (%) Dyslipidaemia (%)

44.1 38.3

48.4 44.8

0.005 ,0.001

Arterial hypertension (%)

66.3

72.7

,0.001

Non-cardiovascular co-morbidities Anaemia (%) Benign tumour (%)

13.9 0.6

15.9 0.6

Malignancy (%)

3.5

2.7

NS

Depression (%) Dementia (%)

8.3 3.9

8.0 5.3

NS 0.039

Hyponatraemia (%)

6.4

5.6

NS

Chronic obstructive pulmonary disease (%)

25.3

25.4

NS

Chronic renal disease (%)

20.4

24.3

3.7

3.4

18.8

26.0

,0.001

74.9

75.3

NS

Liver disease (%) Symptoms and signs Cool extremities (%) Dyspnoea (at rest and/ or exertional) (%)

0.054 NS

ADHF

APE

P-value

130.9 + 32.8

138.5 + 37.1

,0.001

104.7 + 28.8

109.5 + 25.2

,0.001

89.1 + 17.1

87.3 + 7.6

,0.001 ,0.01

................................................................................ Vital signs Systolic blood pressure (mmHg) Heart rate (b.p.m.) Oxygen saturation (%) Echocardiography LVEF (%) Preserved EF (.45%) (%)

37.2 + 14.1

38.8 + 13.2

22.3

25.3

61

86

0.07

Interstitial or alveolar oedema (%)

,0.001

NS

Fatigue (%)

49.1

42.3

,0.001

51.3 49.8

65.6 38.6

,0.001 ,0.001

Jugular venous distension (%)

40.1

39.6

NS

Rales (%)

55.4

72.0

,0.001

28.5

23.7

,0.001

Troponin T (%)

23.9

33.6

0.001

CKMB (%) Precipitating factors

17.5

24.1

0.001

ACS (%)

35.0

37.3

0.07

Arrhythmia (%) Non-compliance (%)

26.6 14.5

29.9 12.0

0.012 0.013

Infection (%)

17.9

15.3

0.02

2.4

4.1

0.003

Post-surgery (%)

Table 2 Vital signs, left ventricular ejection fraction (LVEF), and chest radiographic findings in acutely decompensated heart failure (ADHF) and acute pulmonary oedema (APE) patients

Chest X-ray 0.003

Orthopnoea (%) Peripheral oedema (%)

Weight gain (%) Positive cardiac markers

CAD, coronary artery disease; CHF, chronic heart failure; CKMB, cardiac isoenzyme of creatinine phosphokinase; ACS, acute coronary syndrome; CRT, cardiac resynchronization therapy; ICD, implantable cardioverter defibrillator; ICU, intensive care unit.

Continued

secondary diagnosis of APE (P , 0.001), and treatment with diuretics (P , 0.01) were independently associated with in-hospital outcome (Table 7). Table 8 summarizes the clinical characteristics, in-hospital management, and outcomes of patients with APE according to systolic blood pressure quartiles. For the stronger predictors of survival such as systolic blood pressure (relevant quartiles) and serum creatinine, Kaplan–Meier plots are constructed and depicted in Figures 2 and 3, respectively.

Discussion APE is a common manifestation of AHF syndromes and is associated with dramatic clinical presentation and worse in-hospital outcome.10 – 12 The principal pathophysiological mechanism is the abrupt increase in the pulmonary capillary wedge pressure that leads to pulmonary interstitial and alveolar oedema. Unlike ADHF, which is characterized by milder and more slowly worsening symptoms due to chronic cardiac dysfunction per se, APE has been attributed to both cardiac and vascular failure, with low

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Table 3 Differences in admission (pre-existing) and discharge oral medications between acutely decompensated chronic heart failure (ADHF) and acute pulmonary oedema (APE) patients Admission

............................................................. ADHF

APE

P-value

Discharge

.............................................................

ADHF

APE

P-value

............................................................................................................................................................................... Diuretics

38.0

29.8

,0.001

68.7

63.7

,0.001

ACE-I/ARBs

47.5

53.2

,0.5

63.1

70.1

,0.01

BB Nitrates

26.8 9.8

21.6 9.1

,0.001 NS

39.1 20.9

33.8 22.3

0.001 NS

CCB Digoxin ASA Clopidogrel AVKs

0.1

0.2

14.3 30.7

10.2 36.9

0.3

0.5

,0.001 ,0.001

4.8 13.7

NS

25.0 48.5

20.8 56.7

NS

5.5

NS

13.3

16.8

0.003

9.3

,0.001

23.3

18.1

,0.001

0.002 ,0.001

ACE-I, angiotensin-converting enzyme-inhibitor; ARB, angiotensin II receptor I blockers; BB, beta-blockers; CCB, calcium channel blockers; ASA, aspirin; AVK, vitamin K antagonist.

Table 4 Therapeutic modalities given during hospitalization in acutely decompensated heart failure (ADHF) vs. acute pulmonary oedema (APE) patients ADHF (%)

APE (%)

P-value

Table 5 Differences in in-hospital outcome between acutely decompensated heart failure (ADHF) and acute pulmonary oedema (APE) patients ADHF (%)

APE (%)

P-value

6.0 8.5

7.4 13.5

0.057 ,0.05

Discharged rehabilitation centres or required healthcare facilities

10.7

12.0

,0.05

Discharged home

70.1

61.9

,0.05

................................................................................ Diuretics

95.1

97.9

,0.001

Diuretics per os

73.9

71.4

0.04

Diuretics i.v. ACE-I/ARBs

87.5 74.5

94.9 82.6

,0.001 ,0.01

BB

50.0

48.1

NS

Nitrates per os/TTS Nitrates i.v.

25.7 37.9

29.9 50.3

0.002 ,0.001

CCB

0.7

1.6

0.004

Other vasodilators Analgesics i.v.

1.6 23.8

2.6 33.2

0.021 ,0.001

Digoxin

34.2

29.9

0.003

ASA Clopidogrel

52.7 15.4

61.5 20.8

,0.001 ,0.001

AVKs

25.6

21.0

,0.001

CPAP MV

6.6 9.3

10.8 15.8

,0.001 ,0.001

PCI

8.8

14.5

,0.001

CABG Valve surgery

2.4 2.9

3.4 4.0

0.04 0.05

1.6

3.8

,0.001

19.3 9.8

18.2 12.0

NS 0.018

Noradrenaline

2.2

3.1

0.05

Levosimendan

7.3

5.8

0.03

IABP Dobutamine Dopamine

ACE-I, angiotensin-converting enzyme-inhibitor; ARBs, angiotensin receptor blockers; BB, beta-blockers; CCB, calcium channel blockers; ASA, aspirin; AVKs, vitamin K antagonist; MV, venturi mask; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft surgery; IABP, intra-aortic balloon pump.

................................................................................ Death Discharged intensive care unit

cardiac contractility reserve, low tissue perfusion, and fluid accumulation, along with increased arterial stiffness, neurohormonal activation, and fluid redistribution, resulting in pulmonary congestion.13,14

Epidemiology Although APE is common, few data are available about this clinical entity. Registries such as ADHERE and OPTIMIZE-HF recruited few critically ill patients and therefore had low overall in-hospital mortality rates (about 4%).1,2 Thus, the percentages of APE and cardiogenic shock were lower in these registries compared with ALARM-HF, which recruited more severe AHF patients with an overall in-hospital death rate of 12%.9 The most recent EHFS II reported that 16% of the AHF patients present with APE, which is lower than in ALARM-HF. This variation can probably be explained by differences in the assessment of pulmonary congestion in chest X-rays. As some degree of interstitial congestion is seen in most patients with acute decompensation, categorization will depend on the individual judgement of the clinicians. This assumption is in agreement with the finding that the overall incidence of

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Table 6 Univariate analysis for in-hospital outcome in acute pulmonary oedema patients

Table 6 Continued P-value

P-value

EXP (B)

EXP (B)

95.0% CI for EXP (B)

.....................

Lower bound

.....................

Lower bound

Upper bound

95.0% CI for EXP (B)

Upper bound

................................................................................

................................................................................

ARB

0.002

0.481

0.304

0.763

Demographic characteristics

Nitrate

0.180

0.605

0.291

1.26

Sex (male) Age

0.105 0.348

0.755 1.034

0.537 0.964

1.060 1.109

Digoxin CCB

0.052 0.999

1.645 0.000

0.996 0.000

2.719 9.99

BMI

0.467

1.015

0.976

1.056

ASA

0.190

0.776

0.531

1.134

CPAP MV

0.030 0.000

1.707 6.434

1.053 4.457

2.767 9.287 1.111 2.416

First evaluation Heart rate

0.015

1.009

1.002

1.016

LVEF

0.000

0.957

0.939

0.976

SBP Oxygen saturation

0.000 0.835

0.957 0.997

0.939 0.973

0.976 1.022

PCI CABG

0.107 0.780

0.617 0.864

0.343 0.309

Treatment at hospitalization

Sodium

0.438

1.010

0.985

1.035

Valve surgery

0.890

0.937

0.371

2.365

Cr ≥ 1.4 mg/dL Troponin negative

0.013 0.000

1.613 0.430

1.108 0.293

2.410 0.632

Adrenaline Dobutamine

0.000 0.000

6.362 3.371

3.213 2.339

12.598 4.859

CKMB negative

0.000

0.487

0.333

0.712

Noradrenaline

0.000

5.057

2.721

9.401

Levosimendan Dopamine

0.626 0.000

1.192 2.398

0.588 1.561

2.419 3.684

Co-morbidities Atrial fibrillation

0.664

1.081

0.760

1.537

Atrial flutter

0.778

0.943

0.629

1.415

Cardiomyopathy PVD

0.016 0.008

1.773 1.925

1.111 1.184

2.830 3.131

Heart valve disease

0.75

1.081

0.66

1.757

CAD CHF

0.844 0.073

1.039 1.389

0.712 0.969

1.516 1.990

Obesity

0.034

0.611

0.387

0.963

Diabetes Arterial hypertension

0.211 0.686

0.796 0.922

0.557 0.623

1.138 1.365

Dyslipidaemia

0.018

0.639

0.441

0.926

Smoking Anaemia

0.698 0.367

0.920 1.238

0.605 0.778

1.399 1.970

Depression

0.160

0.548

0.237

1.268

Dementia CRD

0.000 0.003

2.922 1.778

1.646 1.214

5.188 2.603

Chronic obstructive pulmonary disease

0.072

0.657

0.416

1.039

No co-morbidities

0.034

0.659

0.449

0.968

Previous CV event Precipitating factors

0.000

3.016

1.811

5.023

Primary/secondary

0.001

1.889

1.308

2.728

ACS Arrhythmia

0.064 0.825

1.98 0.957

0.980 0.650

1.992 1.410

Compliance

0.098

0.573

0.296

1.109

Post-surgery Valvular heart disease

0.001 0.32

2.862 0.761

1.530 0.44

5.355 1.304

ICU stay

0.047

1.754

1.008

3.053

0.001

1.002

1.001

1.003

Diuretics

0.005

0.529

0.338

0.828

BB ACE-I

0.018 0.002

0.541 0.509

0.325 0.330

0.900 0.787

Length of ICU stay Treatment at admission

Continued

BMI, body mass index; LVEF, left ventricular ejection fraction; SBP, systolic blood pressure; CKMB, cardiac isoenzyme of creatinine phosphokinase; PVD, peripheral vascular disease; CAD, coronary artery disease; CHF, chronic heart failure; ACS, acute coronary syndrome; CRT, cardiac resynchronization therapy; ICD, implantable cardioverter defibrillator; ICU, intensive care unit; ACE-I, angiotensin-converting enzyme-inhibitor; ARB, angiotensin receptor blockers; CCB, calcium channel blockers; ASA, aspirin; MV, venturi mask; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft surgery.

ADHF and APE was almost identical in both studies (76% in ALARM-HF and 81% in EHFS II). In addition, the ALARM-HF data were based on the final discharge diagnosis and consequently included events occurring in hospital. Twenty-four per cent of the patients in ALARM-HF were categorized as ‘secondary’ AHF, and the majority of these deteriorations were due to APE or cardiogenic shock in patients hospitalized for acute coronary syndrome. Thus, a considerable proportion of patients would not have been included if only the admission diagnosis had been considered. Furthermore, the relatively high proportion of ICU/CCU hospitalizations (83%) shifts the present study between EHFS II and the EFICA study which included only ICU/CCU admissions, and presented very high percentages of APE (82%) and cardiogenic shock (29%). Additionally, the Italian nationwide survey also reported a high percentage of APE patients (49.6%). Finally, although chest radiography is the cornerstone of diagnosis, approximately one in every five patients with AHF have no signs of congestion on radiography. Alveolar oedema appears to be a very specific (99%) but poorly sensitive (6%) marker of heart failure, and clinicians should consider the prevalence of negative radiography, when evaluating dyspnoeic patients.15

Clinical presentation APE presents with an abrupt onset of symptoms (,6 h in about 50% of individuals), dramatic clinical status, requiring direct admission by ambulance to the emergency room in half of the cases, whereas a

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Table 7 Multivariate analysis of in-hospital outcome in acute pulmonary oedema patients p-value

EXP (B)

95.0% CI for EXP (B)

.....................

Lower bound

Upper bound

................................................................................ Demographic characteristics Sex (male) Age

0.149 0.302

0.640 1.061

0.349 0.948

1.174 1.189

Heart rate LVEF

0.595 0.017

1.003 0.972

0.992 0.949

1.014 0.995

SBP

0.019

0.986

0.974

0.998

Creatinine ≥1.4 mg/dL

0.000

3.064

1.690

5.556

0.396

1.347

0.677

2.680

Cardiomyopathy

0.033

2.192

1.063

4.520

PVD CHF

0.422 0.918

1.438 0.965

0.593 0.489

3.484 1.905

Obesity

0.214

0.618

0.289

1.321

Dyslipidaemia Chronic obstructive pulmonary disease Dementia

0.315 0.124

0.726 0.559

0.388 0.266

1.357 1.174

0.008

4.020

1.428

11.316

Previous CV event

0.000

4.966

2.270

10.864

Reason for hospitalization ACS 0.945

First evaluation

Troponin Co-morbidities

0.971

0.420

2.245

Compliance

0.186

0.327

0.062

1.717

Post-surgery Primary/secondary

0.574 0.000

1.443 3.320

0.401 1.797

5.188 6.134

Diuretics BB

0.006 0.125

0.369 0.509

0.183 0.215

0.747 1.207

ACE-I

0.404

0.725

0.340

1.544

ARB Digoxin

0.635 0.060

1.184 2.293

0.590 0.965

2.376 5.446

Treatment

BMI, body mass index; LVEF, left ventricular ejection fraction; SBP, systolic blood pressure; CKMB, cardiac isoenzyme of creatinine phosphokinase; PVD, peripheral vascular disease; CAD, coronary artery disease; CHF, chronic heart failure; ACS, acute coronary syndrome; CRT, cardiac resynchronization therapy; ICD, implantable cardioverter defibrillator; ICU, intensive care unit; ACE-I, angiotensin-converting-enzyme-inhibitor; ARB, angiotensin receptor blockers; BB, beta-blockers; CCB, calcium channel blockers; ASA, aspirin; MV, venturi mask; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft surgery.

quarter of APE cases occur during hospitalization for another reason. Dyspnoea was observed in a similar percentage of patients in both groups. Although this may seem an unexpected finding, one should bear in mind that the mechanism of dyspnoea differs between these two groups. CHF patients presenting with decompensation have a restrictive pattern of pulmonary disease due to chronic interstitial oedema and increased cardiothoracic ratio, pulmonary muscle myopathy, and remodelling of the pulmonary vascular bed. As a result, the symptom of dyspnoea is as common as it is in APE patients, in which

the rapidity of symptoms results more often in orthopnoea. Concerning the clinical examination, APE patients present with higher systolic blood pressure along with cold extremities, underlining the mechanism of vasoconstriction, increased peripheral resistance, and ventricular–vascular mismatch, leading to alveolar oedema, clinically evidenced by orthopnoea, rales, and low oxygen saturation, despite an almost preserved LVEF. In conjunction with the EHFS II findings, ALARM-HF confirmed the role of cardiovascular co-morbid conditions in APE and showed that the most common precipitating factors were acute coronary syndrome, new onset of arrhythmia, and post-surgery aetiology. Concerning the chest radiography findings, one in five APE patients had no signs of alveolar or interstitial oedema, and this cannot be attributed to the abrupt evolution of the syndrome. The proportion is consistent with recently published findings from the ADHERE registry, in which almost 20% of the patients deemed to have heart failure during their inpatient stay had negative chest radiography for signs of congestion in the emergency room.15 Furthermore, two out of five ADHF patients had no signs of congestion on chest radiography, possibly due to the chronic elevation of LV filling pressures, leading to interstitial fibrosis and prevention of fluid extravasation.

Treatment As expected, the first-line treatment of APE patients was i.v. diuretics and vasodilators, compatible with the pathophysiology and treatment guidelines of this condition.7,16 – 18 Almost all (97.9%) APE patients in ALARM-HF received i.v. diuretics and half (50.3%) received i.v. nitrates; respective percentages in EHFS II were 94 and 70.6%.3 The high percentage of i.v. nitrates in EHFS II is surprising, considering that almost 40% of the population required i.v. inotropes. In ALARM-HF, one-fifth of the patients required dobutamine, whereas almost 12, 6, and 3% required dopamine, levosimendan, or nor adrenaline, respectively. Severe respiratory distress was underlined by the relatively high percentage of patients requiring a venturi mask (15.8%) or noninvasive ventilation (10.8%). It has already been elucidated that non-invasive ventilation relieves symptomatology and reduces the need for intubation, but its impact on mortality is still under debate.19 – 22 APE patients were also treated more frequently with interventional procedures and were more likely to receive an intra-aortic balloon pump due to the higher incidence of an acute coronary syndrome in this condition. Another important finding from ALARM-HF is that hospitalization results in an almost doubling of treatment at discharge compared with treatment at admission, despite the relative low usage of beta-blockers at discharge (33% for APE and 39% for ADHF).

Prognosis Our data illustrate the clinical profile of an APE patient who is a middle-aged male, smoker, hypertensive, diabetic, transferred by the paramedics in a sitting position with a venturi mask, without a previous history of hospitalization, who was well until the previous day, and who usually ‘forgets’ to mention his chest discomfort. This patient is an individual from the general population with a 7.4% risk of death during his hospitalization, despite optimization of AHF management. This study has identified that history

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J.T. Parissis et al.

Table 8 Characteristics and in-hospital outcomes of acute pulmonary oedema patients according to systolic blood pressure (SBP) quartiles SBP < 100 mmHg, n (%)

SBP 5 100–120 mmHg, n (%)

SBP 5 120–160 mmHg, n (%)

3.5 11.4

2.4 10.6

2.2 17.1

1.1 7.6

,0.001 ,0.001

8.5

8.2

18.5

9.0

,0.001

19.8

22.7

24.9

31.8

,0.005

71.1 44.5

80.5 55.4

84.2 48.0

86.3 47.0

,0.0001 ,0.05

SBP > 160 mmHg, n (%)

P-value

............................................................................................................................................................................... Age (years) ,50 51–70 .71 Echocardiography LVEF . 45% In-hospital treatment ACE-I/ARBs Beta-blockers i.v. nitrates

20.5

26.3

33.8

34.9

,0.001

i.v. diuretics Dobutamine

96.8 34.7

98.8 20.8

98.7 14.2

97.2 13.3

NS ,0.001

Dopamine

24.0

14.7

6.5

7.7

,0.001

5.3 6.4

3.4 3.7

1.0 2.3

0.8 1.2

,0.001 ,0.001

14.1

8.0

5.4

3.4

,0.001

Adrenaline Noradrenaline In-hospital outcome Death

LVEF, left ventricular ejection fraction; ACE-I, angiotensin-converting enzyme-inhibitor; ARBs, angiotensin receptor blockers.

Figure 2 Kaplan– Meier survival curves for systolic blood pressure quartiles in acute pulmonary oedema patients. Patients with a systolic blood pressure ≤100 mmHg had higher in-hospital mortality (survival rate 79%) compared with those with systolic blood pressure from 101 to 119 mmHg (survival rate 86%), systolic blood pressure from 120 to 159 mmHg (survival rate 90%), or systolic blood pressure ≥160 mmHg (survival rate 99.8%; log rank ¼ 37.8, P , 0.001).

of previous cardiovascular event, cardiomyopathy, LVEF, systolic blood pressure, serum creatinine at presentation, and treatment with diuretics are independent prognostic factors associated with outcome in APE patients.

Few data are available concerning the mortality risk of patients with APE.23 – 31 The ALARM-HF survey supports the strong prognostic significance of LVEF and systolic blood pressure at admission, which has previously been proposed by small retrospective trials.25 – 29

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APE management

Figure 3 Kaplan– Meier survival curves for creatinine levels in acute pulmonary oedema patients (receiver operating characteristic derived best cut-off level 1.4 mg/dL). Patients with a serum creatinine ≥1.4 mg/dL had an increased mortality (survival rate 85%) compared with those with serum creatinine ,1.4 mg/dL (survival rate 92%; log rank ¼ 4.3, P ¼ 0.03). The present survey also demonstrates the linear relationship between these parameters. Additionally, impaired renal function as estimated by a serum creatinine ≥1.4 mg/dL is another parameter associated with higher in-hospital mortality. Concerning patient history, a previous cardiovascular event is associated with a five-fold risk of in-hospital death, known cardiomyopathy with a two-fold risk, whereas a secondary diagnosis of APE is associated with a four-fold risk. The ALARM-HF survey also showed that treatment with a diuretic on admission reduces the risk of in-hospital death, although a trend for increased risk was observed for chronic digoxin use in APE patients, possibly due to pro-arrhythmic actions.

Limitations Data collection in the participating centres of ALARM-HF was limited to five to eight consecutive admissions with a clinical diagnosis of AHF, so the cases included may not be representative of the overall AHF population in all countries. Additionally, the differential diagnosis between AHF syndromes was made retrospectively at discharge. The final diagnosis of AHF, although made at discharge and consequently a ‘true positive’, was not confirmed centrally. The overlapping of different AHF syndromes may also provoke extra difficulties, underlining the need for a more clear classification. Finally, as ALARM-HF was designed to collect anonymized data, the lack of long-term outcome data is inevitable.

Conclusion Our data suggest that a patient with APE can be stratified very early in his clinical course, even from the time of diagnosis and subjected to intense monitoring according to the presence of the prognostic factors mentioned earlier.

Table 9 Differences and similarities of acute pulmonary oedema (APE) and acutely decompensated chronic heart failure (ADHF) APE

ADHF

................................................................................ Onset of symptoms

Rapid

Over weeks

Pathophysiological mechanism

Acute event in usually euvolaemic patients

Volume overload

Left ventricular filling pressures

Increased

Increased

Left ventricular ejection fraction

Preserved

Reduced

Treatment

Vasodilators non-invasive ventilation

Vasodilators or inotropes diuretics

Based on epidemiological data from the main AHF registries as well as the ALARM-HF survey, Table 9 summarizes the differences and similarities in the clinical profile and the management of these two clinical entities, which may help clinicians to diagnose and treat each condition more effectively in routine clinical practice.

Conflict of interest: J.T.P., A.M., J.D., F.V.-B., and F.F. report being consultants for and receiving honoraria from Abbott USA.

Funding Abbott USA funded the ALARM-HF survey and data were acquired by IMS, UK.

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