Article, Cardiology

Continuous positive airway pressure for cardiogenic pulmonary edema: a randomized study

Original Contribution

continuous positive airway pressure for cardiogenic pulmonary edema: a randomized study?,??

Philippe Frontin MD, Vincent Bounes MD?, Charles Henri Houze-Cerfon MD, Sandrine Charpentier MD, Vanessa Houze-Cerfon, Jean Louis Ducasse MD

SAMU 31, Pole de medecine d’urgences, Hopitaux Universitaires, 31059 Toulouse cedex 9, France

Received 8 December 2009; revised 7 March 2010; accepted 8 March 2010

Abstract

Study Objective: The purpose of this randomized controlled trial was to determine the immediate and delayed effects of noninvasive ventilation for patients in acute cardiogenic pulmonary edema (ACPE) in addition to aggressive usual care in a medical prehospital setting.

Methods: Out-of-hospital patients in severe ACPE were eligible for the study. Patients were randomized to receive either usual care, including conventional Optimal treatment with furosemide, oxygen, and high-dose boluses of isosorbide dinitrate plus oxygen, or conventional medications plus out-of-hospital Continuous positive airway pressure . The primary outcome was the treatment success defined as all of respiratory rate less than 25 breaths per minute and oxygen saturation of greater than 90% at the end of 1-hour study. Secondary end points included death during 30 days after inclusion. Lengths of intensive care unit and hospital stays were also recorded.

Results: In total, 124 patients were enrolled into the study. The 2 groups had similar baseline characteristics. For the primary outcome analysis, 22 (35.5%) of 62 patients were considered as experiencing a treatment success in the usual care group vs 19 (31.7%) of 60 in the CPAP group (P = .65). Seven patients died within 30 days in the usual care group vs 6 in the CPAP group (P = .52). There were no statistically significant differences between the treatment groups for length of stay either in hospital or in the intensive care unit.

Conclusion: In the prehospital setting, in spite of its potential advantages for patients in ACPE, CPAP may not be preferred to a strict optimal Intravenous treatment.

(C) 2011

Introduction

? Work attributed to: SAMU 31. CHU Purpan. Toulouse, France.

?? Support: The authors have no commercial associations or sources of support that might pose a conflict of interest. Support was provided solely by institutional sources; this work was sponsored by the University Hospital of Toulouse for regulatory and ethic submission.

* Corresponding author.

E-mail address: [email protected] (V. Bounes).

Acute cardiogenic pulmonary edema is a frequent presenting disease for acute out-of-hospital prac- tice. Acute left ventricular failure may occur from a variety of processes that rapidly deteriorates to this generalized cardiopulmonary disorder. The classical treatment of out-of- hospital ACPE includes supplemental oxygen, vasodilators, and Loop diuretics. If not effective or because of the associated respiratory depression, tracheal intubation and

0735-6757/$ – see front matter (C) 2011 doi:10.1016/j.ajem.2010.03.007

mechanical ventilation are often needed, which, by themselves are associated with a worse prognosis [1]. Bilevel positive airway pressure (BiPAP) and continuous positive airway pressure (CPAP) has been proposed to avoid mechanical ventilation in severe ACPE [2-6]. The overall effect of CPAP in the acute management of ACPE is to improve cardioRespiratory function and sustained Tissue oxygenation. This technique not only decreases intrapul- monary shunt [6] and Work of breathing [7] but also reduces left ventricular afterload and both right and left ventricular preload [8]. Collectively, the available data suggest that CPAP is effective in reduction in Intubation rate and that there is a trend toward reduced mortality in emergency departments [9]. Some randomized Prospective trials [10-12] have demonstrated significant improvements in vital signs and Gas exchange as well as drastic reductions in intubation rates attributable to the use of CPAP. In patients with ACPE, with no effect on short-term mortality. However, the evidence for CPAP in the out-of-hospital setting is limited only to several case series, nonrandomized studies, and few randomized studies [13-21]. One random- ized study focused on severe respiratory distress with paramedic-staffed ambulances [20], and another study focused on immediate effects on early vs late CPAP in a prehospital setting with physician-staffed ambulances [21]. To our knowledge, no study focused on ACPE in a prehospital setting compared CPAP to a placebo treatment, and no study was focused on delayed effects of CPAP vs usual care for ACPE (eg, later than in-hospital death). The purpose of this study was then to determine whether out-of- hospital treatment with CPAP improves significantly respiratory distress for patients in ACPE.

Patients and methods

Study design

This prospective, randomized, controlled, nonblinded trial was registered with ClinicalTrials.gov (identifier NCT00439075). Enrollment began in September 2006 and finished when the desired number of patients was reached in March 2008. The regional ethics committee (Toulouse II, France) approved this study, with exception to preliminary written informed consent. Patients meeting eligibility criteria were read a standard statement that briefly explained the nature of the study, and if they (or any family members present) did not refuse participation, they were enrolled. Full informed consent was obtained from patients or their surrogates as soon as was practically possible.

Setting

In France, management of out-of-hospital Medical emergencies is the responsibility of the “Service d’Aide Medicale Urgente” (SAMU). mobile intensive care units

(ICUs) are staffed by an attending physician (who is usually an experienced emergency physician or anesthesiologist), a nurse, and an emergency medical technician. Mobile ICUs are distributed throughout France, providing a comprehen- sive coverage of Prehospital advanced life support services. The decision to provide ACPE treatment including nonin- vasive ventilation is the responsibility of physicians, according to protocols based on furosemide, morphine, and nitrates. The prehospital emergency service of the University Hospital of Purpan (Toulouse, France) located in an urban area participated in this study. Before study, physicians underwent a comprehensive education program concerning the ethical conduct of research and the study protocols, including on the treatment of ACPE. Then, shorter refresher sessions were incorporated into the physicians’ usual ongoing training throughout the study period.

Patient selection

Patients were eligible for inclusion if they were 18 years or older with clinical symptoms of ACPE such as orthopnea, diffuse crackles without evidence of pulmonary aspiration or infection, pulse oximetry (SpO2) less than 90% and a respiratory rate greater than 25 breaths per minute. Patients were excluded if they had Cardiovascular collapse or an impaired level of consciousness, acute myocardial infarc- tion, or if they had an immediate need for intubation. Patient with a history of gastric surgery (b8 days) and patients vomiting were also excluded. A table of random numbers determined the randomization sequence, using a restricted randomization scheme equilibrated by blocks of 4 to ensure roughly equal numbers in each group. When physicians enrolled a patient into the study, they contacted the SAMU dispatcher by telephone with a request for randomization. Group assignments were sealed in opaque envelopes and opened sequentially by the SAMU dispatcher who then randomly assigned the patient to 1 of 2 treatment groups: usual care or CPAP.

Intervention

Patients in both groups otherwise received standard protocol-driven therapy for severe ACPE. In the field, this included furosemide, 1 mg/kg; 15 L/min of oxygen delivered by face mask; and continuous infusion of isosorbide dinitrate at an initial rate of 2 mg/h. If systolic blood pressure was above 180 mm Hg, 2 mg of intravenous isosorbide dinitrate was administered. Further doses of nitrate were unrestricted according to Clinical response. Patients assigned to the usual care group received only those treatments, whereas patients assigned to the CPAP group received 10 cm H2O CPAP through a facemask fitted with a CPAP valve and controlled with a portable flow generator (CPAP Boussignac, Vygon, Belgium). The use of CPAP outside the study protocol was forbidden and strictly controlled. Patients in both group were intubated in the out-of-hospital phase if they met any of the

following criteria: progressively worsening pulse oximetry despite effective treatment, loss of airway protective reflexes (cough, swallow), decreased level of consciousness, hemo- dynamic instability, intolerance/poor fit of facemask for the CPAP group, medical clinical impression of deterioration, or patient request.

Patients were monitored with pulse oximetry, noninvasive blood pressure recordings, and electrocardiography. Respi- ratory rate was measured by observation over 1-minute period. A 10-cm, unmarked, visual analog scale of breathlessness (ranging from “not at all breathless” to “the worst breathlessness imaginable to me”) was used to assess the patients’ perception of dyspnea at the start of the study and at 30-minute intervals over the 1-hour period. Arterial blood samples were drawn at baseline (after Oxygen administration but before randomization) and at discharge at the hospital and analyzed for pO2, and pCO2. Twelve-lead electrocardiographs were recorded at baseline, 1 hour, and 2 hours to monitor for the development of acute myocardial infarction. After protocol completion, patients were trans- ported to an ICU in the nearest hospital. Once in the ICU, all patients were treated at the discretion of the attending admitting physician, including the continuation of CPAP therapy if indicated. The decision to intubate after arrival in the ICU was left to the judgment of the treating physician. The follow-up was then performed by Research staff (phone calls to the patient and/or the general practitioner and analysis of patients’ files) during 30 days. At the end of the study, 2 physicians experts in the field independently reviewed the medical data including the electrocardiogram, chest radiography, Brain natriuretic peptide measure- ments, cardiac echo studies (when available), and cardiolo- gist’s diagnostic assessment (when available), the outcome, and assigned a final diagnosis. Those physicians were blinded to the results of the study, and the final diagnosis was based on the agreement of the 2 reviewers.

End points

The primary end point was the effect of early CPAP administration with a treatment success defined, a priori, as all of respiratory rate less than 25 breaths per minute and oxygen saturation of greater than 90% at the end of the 1- hour study. According to our protocol, the minimum time spent with the patient was 1 hour, even if the time needed to go to the nearest hospital was shorter. Secondary end points were the impact of early CPAP on the frequency of failure of the care strategy, defined as a need for tracheal intubation during the ICU stay and death during 30 days after inclusion. Noninvasive blood pressure recordings, pulse rate, PaO2, and PaCO2 at T60 were also analyzed as secondary end points. Lengths of ICU and hospital stays were also recorded. As patients with acute heart failure associated with hypertension frequently respond quickly to aggressive control of blood pressure with vasodilators, we categorized patients with hypertension (eg, systolic blood

pressure N140 mm Hg) or normotension and performed subgroups analysis. The main hypothesis and primary outcome measures were hidden from those making the measurements (respiratory rate and saturation).

Statistical analysis

The determination of sample size was based on a preliminary pilot experiment (40 patients, unpublished) that found that 15% of patients in the usual care group would reach treatment success as defined previously vs 40% in the CPAP group. A sample size of 62 per treatment group was calculated a priori as sufficient to detect this difference with 85% power with an ? level of .05. Data were analyzed on an intention-to-treat basis. Statistics are reported as means with SDs and medians with interquartile ranges. Differences between means are reported with 95% confidence intervals. Variables were defined as continuous on the basis of Skewness-Kurtosis test. Means were compared using a t test for normally distributed data or the nonparametric 2- sample Mann-Whitney rank sum test for data not fitting the assumptions of parametric testing. Qualitative data were analyzed using ?2 tests. When ?2 validity criteria were not present, we used a Fisher exact test. Odds ratios with their 95% confidence intervals were also computed. The duration of ICU and hospital stay was also shown graphically with the use of Kaplan-Meier survival estimates. All tests were 2- sided, at the .05 significance level. Data analysis was performed using Stata/SE (version 9.0; StataCorp LP, College Station, Tex).

Results

One hundred ninety consecutive ACPE were screened between September 2006 and March 2008. One hundred twenty-four patients were enrolled in the study (Fig. 1). Sixty-two patients were randomly assigned to usual care and 62 to CPAP. No patient was enrolled in the study twice. The 2 groups had similar baseline characteristics (see Table 1), with a nonsignificant trend toward a difference in the rate of previous ACPE between the 2 groups (45% in the usual care group vs 30% in the CPAP group; P = .12). As expected, patients were initially in significant respiratory distress, with high respiratory rates and low oxygen saturations. There were 8 out-of-hospital misdiagnoses (5 in the CPAP group and 3 in the usual care group); all these patients were labeled as having acute pulmonary edema but were diagnosed as having pulmonary disease in the ICU. Two patients had a discontinued intervention in the CPAP group, one on physician decision and the other on patient request; those 2 patients received then 15 L/min oxygen delivered by face mask. All these patients were included in the analysis. Two patients (in the CPAP group) refused the ongoing use of their data once their condition stabilized and were not analyzed. The remaining 122 patients were observed during 30 days

Fig. 1 Flow diagram of patients.

after inclusion. All patients received intravenous furosemide,

1 mg/kg; the median number of intravenous isosorbide dinitrate injections was 4 (range, 3-5) in both groups (P =

.76). Intravenous morphine use was not forbidden in this study, but no patient received morphine during the prehospital phase of the treatment.

For the primary outcome analysis on an intention-to-treat basis, 22 (35.5%) of 62 patients were considered as experiencing a treatment success in the usual care group vs 19 (31.7%) of 60 in the CPAP group (P = .65). At baseline and at 60 minutes, there were no significant differences in heart rate, mean blood pressure, oxygen saturation by pulse oximetry, arterial oxygen pressure, and arterial carbon dioxide pressure (Table 2). At 60 minutes, the respiratory rate was lower in the usual care group (26.9 vs 30.1 breaths per minute; P b .05), and PaO2 in CPAP group was higher even if not statistically different than in usual care group (117.9 mm Hg vs 97.3 mm Hg; P = .08). Only one patient was intubated during the out-of-hospital study period (in the usual care group). Globally, 5 patients of the 122 needed a tracheal intubation during the 1-month study period (3 in the usual care group vs 2 in the CPAP group; P = .52). Two patients in the usual care group died on scene by unexpected

sudden cardiac arrest. Seven patients died within 30 days in the usual care group vs 6 in the CPAP group (P = .52). There were no statistically significant differences between the treatment groups for length of stay either in hospital (6 days median for the usual treatment group vs 6 in the CPAP group; P = .5) or in the ICU (8.2 hours median for the usual treatment group vs 8 in the CPAP group; P = .27) as showed in Fig. 2. There were no differences in outcomes when we categorized patients by blood pressure groups (eg, normo- tensive vs hypertensive group). Only 2 patients experienced emesis in the CPAP group and 3 in the Standard care group. No other adverse CPAP events such as mask intolerance, barotrauma, or gastric distension were related.

Limitations

Inferences that can be drawn from these data are limited in several respects. Our study was conducted in a prehospital setting with a white European population and with physician-staffed ambulances. So, the results may not be generalizable to other prehospital settings, such as paramed- ic-staffed ambulances. Even if inclusion criteria were typical clinical symptoms of acute pulmonary edema such as

addition, the sample size calculation was based on measure- ments of pulse oximetry and respiratory rate. However, analyses also are performed on the Death rate, number of days in the hospital and ICU, and other patient-centered variables. As designed, this study may not be powered to detect a difference in these variables. This limits our ability to arrive at definitive conclusions.

a The patients reported their degree of dyspnea on a visual analog scale ranging from 0 (no breathlessness) to 10 (maximal breathlessness).

7.9 +- 2.2

7.5 +- 2.2

77.1 +- 10.9

77 +- 12.6

168.6 +- 40.3

97.3 +- 23.1

35 +- 7

165.5 +- 35

94.7 +- 22.5

35.4 +- 8.4

Systolic Diastolic

Respiratory rate, mean +- SD (breaths/min)

Peripheral oxygen saturation, mean +- SD (%)

Dyspnea score, a mean +- SD

Blood pressure, mean +- SD (mm Hg)

108.7 +- 21.4

109 +- 27.9

37

1

7

33

4

8

0

14

2

16

4

1

9

1

13

18

Nonspecific congestive heart disease

Ischemic heart disease Valvular heart disease

Risk factors for heart failure Peripheral vascular disease Symptoms of myocardial infarction

Hypertension Cerebrovascular disease Atrial fibrillation

Physiologic measurements Pulse rate, mean +- SD (beats/min)

Table 1 Baseline characteristics of the patients

Usual care CPAP group, group, n = 62 n = 60

Age, mean +- SD (y) 79.3 +- 10.5 79.4 +- 10.7

Male sex, n (%) 29 (46.8) 23 (38.3)

History (n of patients) 28 18

Previous acute cardiogenic pulmonary edema

Discussion

Our study was designed to ascertain that the known mechanisms by which CPAP works in ACPE would result in an improved outcome in addition to usual care in a medical prehospital setting. In the present study, when adding CPAP in one group, patients did not exhibit significantly less symptoms of respiratory fatigue. Moreover, intubation rate, overall mortality, and hospital length of stay were equally distributed in the 2 treatment groups. There are still controversial studies in the literature; some authors report a reduction in the work of breathing, an increase in pulmonary compliance, and a decrease in airway resistances [2,3,7]. Lin et al. [4] concluded that there is no significant difference in short-term mortality and hospital stay between CPAP therapy and face mask oxygen therapy. In the prehospital

orthopnea, diffuse crackles without evidence of pulmonary aspiration, or infection, other clinical presentation distinct from pulmonary edema such as exacerbation of chronic obstructive pulmonary disease or pneumonia may fulfill these criteria. As mentioned, the study data were analyzed on an intention-to-treat basis, and we rely on the field diagnosis of the emergency physician. Diagnosis of pulmonary edema for patients included in this study is not different from “real- life” prehospital diagnosis, so the results may be more useful to out-of-hospital settings. Another major limitation of this study was that it was unblinded. As a consequence, a bias related to nonblinded investigators cannot be ruled out, although the treatments during the study period were standard. As in similar studies done previously, we did not include a placebo treatment, to do so was thought to be technically and operationally unfeasible. According to the Study objectives, another approach for the study design would be a noninferiority or equivalence design with CPAP plus standard of care as the new treatment and the usual standard of care as the active comparator. With a predefined noninferiority or equivalence margin, this type of design nearly always requires larger samples. Thus, CPAP did not significantly improve treatment success may be, in part, because it is underpowered for such a study design. In

a The patients reported their degree of dyspnea on a visual analog scale ranging from 0 (no breathlessness) to 10 (maximal breathlessness).

Fig. 2 Kaplan-Meier survival curves. Panel A estimates the proportion of patients remaining in the hospital (including ICU). Panel B estimates the proportion of patients remaining in the ICU.

Usual care, n = 62

CPAP, n = 60

Odds ratio (95% confidence interval)

P

Success, a n (%)

22 (35.5)

19 (31.7)

1.19 (0.56 to 2.53)

.65

Intubation, n (%)

3 (4.8)

2 (3.3)

1.47 (0.23 to 9.23)

.52

Death within 5 d, n (%)

3 (4.8)

2 (3.3)

1.47 (0.23 to 9.23)

.52

Death within 30 d, n (%)

7 (11.3)

6 (10)

1.14 (0.36 to 3.65)

.52

Difference between means b

(95% confidence interval)

Length in ICU, median (IQR) (h)

8.2 (5.3-14.5)

8 (5.2-12.5)

4.1 (-3.2 to 11.4)

.27

Length of hospital stay, median (IQR) (d)

6 (2-9)

6 (3-8)

0.9 (-1.8 to 3.7)

.5

Physiology at 1 h

Respiratory rate, mean (breaths/min)

26.9

30.1

3.1 (0.5 to 5.7)

.02

Peripheral oxygen saturation, mean (%)

93.7

95.3

1.66 (-0.35 to 3.67)

.1

Pulse rate, mean (beats/min)

95.9

97.5

1.6 (-7.1 to 10.3)

.71

Blood pressure, mean (mm Hg)

Systolic

165.5

168.6

3.1 (-10 to 16.8)

.65

Diastolic

77.9

81.1

3.15 (-3.54 to 10.17)

.37

PaO2, mean (mm Hg)

97.3

117.9

20.6 (-2.3 to 43.5)

.08

PaCO2 (mm Hg)

46.4

47.7

1.36 (-6.61 to 9.32)

.74

Dyspnea score, c median

4.8

5.3

0.51 (-9.92 to 1.95)

.47

a The success of the treatment is defined by a respiratory rate of less than 25 breaths per minute and an SpO2 of greater than 90% at 1 hour.

b The difference between means is the difference between the means for CPAP therapy and usual care.

c The patients reported their degree of dyspnea on a visual analog scale ranging from 0 (no breathlessness) to 10 (maximal breathlessness).

setting, one study compared early vs delayed CPAP for the management of ACPE [20]. It proved that ACPE treatment can be effectively initiated by the immediate application of CPAP alone but did not compare CPAP and oxygen in the context of optimal pharmaceutical treatment. Another study included patients in severe respiratory distress from all causes and showed a significant benefit for patients treated with CPAP with respect to need for subsequent intubation [21]. However, the best therapy for treating an episode of acute respiratory failure due to cardiogenic pulmonary edema is still a controversial matter [22,23]. Nevertheless, concerning ACPE, all these data suggest that the right treatment needs to be applied as soon as possible and delaying even 15 minutes may be less efficient. Continuous positive airway pressure alone appears to initiate cardiore- spiratory recovery, as supported by other studies. However, during the study period, the out-of-hospital pulmonary edema management literature [22-25] and therefore our physicians’ treatment, evolved toward less emphasis on ventilation as the main treatment and more emphasis on nitrate boluses, which may have resulted in physicians performing fewer intubations overall due to rapid clinical amelioration. Moreover, patients included in our study did not differ from those included in other clinical trials and were initially in significant respiratory distress, with high respiratory rates and Low Oxygen Saturations, but overall mortality was low. We can add to this argument the lower- than-expected difference in treatment success rate between groups (35.5% actual in the usual care group vs 15% expected). In a systematic review of in-hospital studies, Peter et al [9] conclude that the use of CPAP in patients with cardiogenic pulmonary edema decrease the need for

Table 2 Primary and secondary end points

endotracheal intubation with a reduction in hospital mortality. However, they also conclude that heterogeneity of treatment effects was not evident for mortality or mechanical ventilation across patients’ groups. In another study, patients in severe pulmonary edema were randomized to receive BiPAP and usual care or high-dose isosorbide dinitrate [25]. The results of this study indicate that BiPAP ventilation combined with usual care is significantly inferior to high-dose nitrates. This was manifested by increased rate of mechanical ventilation and myocardial infarction and combined primary end point as well as decreased control of pulmonary edema as demonstrated by slower improvement in pulse and respiration rate and oxygen saturation. In our study, the rapid clinical amelioration of patients, the low tracheal intubation rate compared to that of other studies, and our primary and secondary end points may be explained by the early beginning of aggressive intravenous treatment as soon as the diagnostic was established.

Conclusion

In the prehospital setting, in spite of its potential advantages for patients in ACPE, CPAP may not be preferred to a strict optimal treatment including low-dose morphine, furosemide, oxygen, and high-dose boluses of isosorbide dinitrate unrestricted according to clinical response.

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