Randomized Trial of Bilevel versus Continuous Positive Airway Pressure for Acute Pulmonary Edema

The Journal of Emergency Medicine, Vol. -, No. -, pp. 1–11, 2013 Copyright Ó 2013 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/$ - see front matter

http://dx.doi.org/10.1016/j.jemermed.2013.08.015

Brief Reports RANDOMIZED TRIAL OF BILEVEL VERSUS CONTINUOUS POSITIVE AIRWAY PRESSURE FOR ACUTE PULMONARY EDEMA Timothy Liesching, MD,* David L. Nelson, RRT,† Karen L. Cormier, RRT,† Andrew Sucov, MD,‡ Kathy Short, RN, RRT,§ Rod Warburton, BA,jj and Nicholas S. Hill, MDjj *Division of Pulmonary, Critical Care and Sleep Medicine, Lahey Clinic, Burlington, Massachusetts, †Department of Respiratory Care, ‡Division of Emergency Medicine, Rhode Island Hospital, Providence, Rhode Island, §Department of Respiratory Care, University of North Carolina, Chapel Hill, North Carolina, and jjDivision of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center, Boston, Massachusetts Reprint Address: Nicholas S. Hill, MD, Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center, 800 Washington St #257, Boston, MA 02111

, Abstract—Background: Studies have shown different clinical outcomes of noninvasive positive pressure ventilation (NPPV) from those of continuous positive airway pressure (CPAP). Objective: We evaluated whether bilevel positive airway pressure (BPAP) more rapidly improves dyspnea, ventilation, and acidemia without increasing the myocardial infarction (MI) rate compared to continuous positive pressure ventilation (CPAP) in patients with acute cardiogenic pulmonary edema (APE). Methods: Patients with APE were randomized to either BPAP or CPAP. Vital signs and dyspnea scores were recorded at baseline, 30 min, 1 h, and 3 h. Blood gases were obtained at baseline, 30 min, and 1 h. Patients were monitored for MI, endotracheal intubation (ETI), lengths of stay (LOS), and hospital mortality. Results: Fourteen patients received CPAP and 13 received BPAP. The two groups were similar at baseline (ejection fraction, dyspnea, vital signs, acidemia/oxygenation) and received similar medical treatment. At 30 min, PaO2:FIO2 was improved in the BPAP group compared to baseline (283 vs. 132, p < 0.05) and the CPAP group (283 vs. 189, p < 0.05). Thirty-minute dyspnea scores were lower in the BPAP group compared to the CPAP group (p = 0.05). Fewer BPAP patients required intensive care unit (ICU) admission (38% vs. 92%, p < 0.05). There were no differences between groups in MI or ETI rate, LOS, or mortality. Conclusions: Compared to CPAP to treat APE, BPAP more rapidly improves oxygenation and

dyspnea scores, and reduces the need for ICU admission. Further, BPAP does not increase MI rate compared to CPAP. Ó 2013 Elsevier Inc. , Keywords—acute pulonary edema; myocardial infarction; noninvasive ventilation

INTRODUCTIONS Multiple randomized controlled studies and metaanalyses have demonstrated the efficacy of either continuous positive airway pressure (CPAP) or noninvasive positive pressure ventilation (NPPV) (i.e., the combination of positive end expiratory pressure and pressure support administered via a face mask) to treat acute cardiogenic pulmonary edema (APE) (1–18). When compared with standard oxygen and medical therapy, these modalities more rapidly improve dyspnea and gas exchange abnormalities, greatly reduce the need for intubation and, at least in the case of CPAP, mortality rates (1–4,6,8,10–15,18). Randomized studies and meta-analyses comparing NPPV and CPAP have shown no differences with regard to intubation or mortality rates, but some have shown more rapid improvements in dyspnea and gas exchange with NPPV (8,13,15,16,19–28).

RECEIVED: 13 September 2012; FINAL SUBMISSION RECEIVED: 23 May 2013; ACCEPTED: 7 August 2013 1

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In a previous randomized trial comparing bilevel positive airway pressure (BPAP, a form of NPPV administered by bilevel airway pressure devices) to CPAP, our group found that BPAP improves ventilation and vital signs more rapidly than CPAP, but the study was prematurely terminated due to the unexpected occurrence of a higher rate of myocardial infarction (MI) associated with BPAP compared to CPAP use (71% vs. 31%, p = 0.05) (19). The authors speculated that the different MI rates might be related to randomization problems (there were more patients presenting with chest pain in the BPAP group) or to the tendency of the BiPAP S/T ventilator used in the study to apply sustained inspiratory pressure in the face of air leaks (up to 3 s) that might have raised intrathoracic pressure higher than with CPAP alone (19). However, because the trial lacked statistical power, the authors were cautious in drawing conclusions and highlighted the need for more investigations to further explore the possible association between BPAP use and MI rate. Subsequently, several trials and meta-analyses found no significant difference in MI rate between NPPV and CPAP used to treat APE, but not all of these studies used BPAP devices, and MI rate was not the primary outcome in others (7,11,14,21,23,26). In the current study, we used a BPAP device (VisionÔ, Phillips/Respironics, Inc., Murrysville, PA) that is designed to minimize the prolongation of inspiration encountered in the face of air leaks. We also used a lower inspiratory pressure (12 cm H2O) than used in the previous study (15 cm H2O). We hypothesized that NPPV delivered in this fashion would improve gas exchange and dyspnea more rapidly than CPAP alone, as it did in the previous study, but without a higher MI rate (19). METHODS The study was approved by Rhode Island Hospital’s institutional review board. Written informed consent was obtained from either the patient or the proxy prior to study enrollment and randomization. Patients Inclusion criteria. Patients $18 years of age were recruited from those presenting to the Rhode Island Hospital Emergency Department (ED) or inpatient units with a clinical diagnosis of APE. The diagnosis was made by the emergency or primary physician in patients with acute respiratory distress, as evidenced by moderate-to-severe dyspnea, breathing frequency >30 breaths/min, and use of accessory respiratory muscles or paradoxical abdominal motion in combination with tachycardia (heart rate >100 beats/min), cardiac gallops, and bilateral rales. Chest radiographs showed typical findings of congestion. The biomarker B-type natriuretic peptide was not used

because it was not routinely obtained in the ED for the evaluation of acute dyspnea when the study received institutional review board approval. Blood gas criteria for entry included a pH <7.35 and a PaO2 <60 mm Hg or O2 saturation <94% on room air. Arterial blood gases were routinely obtained prior to initiation of BPAP or CPAP, but initiation was not delayed awaiting results to avoid possible further deterioration of the patient’s condition. Exclusion criteria. Criteria for exclusions were based on generally accepted NPPV patient selection guidelines (28). Exclusions were cardiac or respiratory arrest, initial blood pH <7.1, unstable cardiac rhythm, or systolic blood pressure (BP) of <90 mm Hg at presentation because these conditions may result in higher NPPV failure rates (29–31). Likewise, patients with unresponsiveness, agitation, uncooperativeness, or any condition that precluded application of a facemask (e.g., facial trauma, upper airway obstruction, witnessed aspiration) were also excluded (28–31). The diagnosis of acute MI (defined in the primary outcomes section) or STsegment depression $2 mm in two contiguous leads were also exclusions from the study to ascertain that patients with evidence of evolving MIs at the time of study entry would not be included in the primary end-point analysis. Patients initially enrolled but subsequently found to have conditions besides APE, such as pneumonia, aspiration, or pneumothoraces that were thought to be responsible for their clinical presentation, were excluded from data analysis. Randomization. Upon study enrollment, patients were randomized to receive CPAP 10 cm H2O or BPAP 12 cm H2O inspiratory and 4 cm H2O expiratory pressures. Randomization was achieved using sealed envelopes, with distribution assigned using a computer-generated randomization scheme that assured equal numbers in each group. Study protocol. Upon study entry, patients were promptly fitted with a standard oronasal mask (small, medium, large) (Respironics, Inc.) and were connected to a BPAP device that had previously been set to deliver either BPAP (inspiratory positive airway pressure of 12 cm H2O and expiratory positive airway pressure of 4 cm H2O) or CPAP (10 cm H2O). Further upward or downward 1–2 cm H2O adjustments could be made every 3–5 min to optimize patient comfort. Inspiratory and expiratory pressures were not allowed to exceed 20 and 8 cm H2O, respectively. The oronasal mask could be changed to a nasal mask for mask intolerance. Supplemental oxygen was supplied to patients in both groups

Bilevel vs. Continuous Positive Airway Pressure for Pulmonary Edema

and FiO2 was adjusted to maintain oxygen saturation $90%. Humidification was used routinely. All patients received standardized medical therapy and were weaned and discontinued from CPAP or BPAP according to guidelines provided to primary physicians, as per our previous report (19). The control panel on the device was covered, so physicians, nurses, and patients were blinded to the ventilator mode. Respiratory therapists were unblinded to make ventilator adjustments. Ventilator. The study used a pressure-limited bilevel ventilator (Vision, Phillips/Respironics, Inc.) to deliver BPAP or CPAP. Unlike the earlier generation BiPAP S/ T device used in our previous study, the Vision ventilator has an oxygen blender that delivers FiO2s ranging from room air to nearly 100% and estimates tidal volumes. In addition, it has a proprietary software algorithm (AutoTrakÔ) that tracks inspiratory flow and uses a moving signal to lower the inspiratory flow threshold for cycling to expiration as inspiration continues, thus avoiding the excessive cycling delays that occur with the BiPAP S/T in the face of air leaks (Respironics website). Physiologic outcome variables. BP, heart rate, breathing frequency, oxygen saturation, and arterial blood gases were recorded at study entry prior to BPAP or CPAP and at the 30-min and 1-h time points. Arterial blood gases were repeated at 3 h or at the time of intubation, if required. Chest radiograph, electrolytes, blood urea nitrogen, creatinine, electrocardiogram (ECG), and cardiac enzymes (creatine kinase, troponin I) were obtained at study entry. ECG and cardiac enzymes were repeated every 8 h for 24 h. Serum lactate was measured at study entry, 1 h, and 8 h. Patients rated their dyspnea and mask comfort using a visual analog scale based on a simple vertically aligned scale from 1 to 10 (1 as the least and 10 as the most dyspnea or mask discomfort) that has been validated by others (32). Ratings were recorded at study entry and then again at 30 min, 1 h, and 3 h after study entry. Outcome variables. The primary outcome was the rate of spontaneous acute MI, defined according to the joint European Society of Cardiology and American College of Cardiology consensus guidelines (33). This consisted of a typical rise and fall of troponin I accompanied by typical clinical or electrocardiographic features. In patients with a creatinine of >1.5 mg/dL, creatine kinase/CK-MB fraction was used as the biochemical marker. Secondary outcome measures included changes in vital signs and gas exchange during the first 90 min of the study, intubation rate, length of time using the BPAP or CPAP device, requirement for intensive care

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unit (ICU) admission, length of ICU and hospital stays, and hospital mortality. Groups were monitored for complications, including nasal ulceration, conjunctivitis, gastric insufflation, pneumothorax, hypotension, and aspiration. Criteria for intubation.Patients were endotracheally intubated at the discretion of the ED or ICU physicians, without input from study personnel, based on clinical or arterial blood gas criteria, as previously described (19). Criteria for ICU admission.ICU admission was at the discretion of the Emergency Medicine and ICU medical staff based on whether the patient had adequately stabilized. Study personnel were not involved in this decision and caregivers were blinded to study group. If patients remained moderately or severely dyspneic, tachypneic (breathing frequency >24 breaths/min), tachycardic (heart rate >100 beats/min), or severely hypoxemic (requiring FIO2 >40 % to maintain O2 saturation >90%), or had hemodynamic instability (systolic BP <90 mm Hg or need for vasopressors), the patient was sent to the ICU. Statistical Analysis Physiologic measurements between the BPAP and CPAP groups were compared using unpaired t-tests. Withingroup comparisons were done using paired t-tests. Where pairing of data resulted in very small numbers, unpaired data were included and analyzed using unpaired tests. The t-test formula for unequal variances was applied where appropriate. For comparisons of baseline laboratory and physiologic measurements between the CPAP and BPAP groups, t-tests were performed for normally distributed parametric samples and the Mann-Whitney U test was performed for nonparametric samples. Continuity-adjusted chi-squared test for small sample size was employed when appropriate for comparisons among controls, the BPAP group, and CPAP group. When testing the difference in proportions, the chisquared test was utilized. A power analysis was performed using the difference in MI rate as the primary outcome variable, and anticipating a between-group difference of 10%. The MI rate of 31% noted in the Mehta et al. study for the CPAP group was used as the baseline rate and was based on historical controls, and is similar to the MI rate reported by another large randomized controlled trial (11,19). For an alpha of 0.05 and a beta of 0.80, the power analysis indicated that a total of 44 enrollees was necessary. However, the study was terminated prior to reaching the enrollment target due to slow recruitment and the low likelihood of finding significant differences in the major outcome variable.

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Values are mean 6 SD and a p < 0.05 was considered statistically significant.

Table 1. Baseline Demographic Characteristics and Past Medical History Demographic Characteristics

RESULTS From a total of 150 screened patients with a presumed diagnosis of APE, 36 were enrolled. Nineteen patients were randomized to CPAP and 17 patients were randomized to BPAP. Of the remaining 114 patients, 42 patients had a diagnosis other than APE (chronic obstructive pulmonary disease exacerbation [n = 25], pneumonia [n = 7], asthma exacerbation [n = 7], pulmonary embolism [n = 1], idiopathic pulmonary fibrosis [n = 1], and obstructive sleep apnea [n = 1]); 26 had a respiratory rate #24; 15 presented to the ED after hours when study personnel were not onsite to enroll the subject; 13 experienced a respiratory arrest requiring immediate intubation prior to study enrollment; NPPV was started prior to enrollment screening could be completed in 11; 4 patients refused/declined study enrollment; 2 patients were hypotensive; and one patient had an unstable cardiac rhythm. Of the 36 patients enrolled in the study, postenrollment review led to nine additional exclusions. Five patients were excluded from the CPAP group due to a documented MI prior to enrollment (3 patients), a post hoc diagnosis other than APE (1 patient with pneumonia), and lack of cooperation (1 patient). Four patients were excluded from the BPAP group due to a documented MI prior to enrollment (3 patients), and a post hoc diagnosis other than APE (1 patient with pulmonary embolism). Baseline characteristics revealed an elderly population (mean age mid 70s) and no significant differences between the groups in age, gender distribution, or past medical history, including the presence of known coronary artery disease, left ventricular hypertrophy, or reduced left ventricular ejection fraction (Table 1). At the time of study entry, none of the patients in either group had a ‘‘do not resuscitate’’ or ‘‘do not intubate’’ order. Patients from both the CPAP and BPAP groups had comparable degrees of respiratory distress, as evidenced by similar presenting baseline symptoms, vital signs, and laboratory values such as arterial blood gases and lactic acid (Table 2). Respiratory rate, heart rate, and mean arterial pressure were also similar between the groups. All patients in both groups had radiograph findings and at least one physical finding consistent with the diagnosis of APE (Table 2). Baseline ECGs in both groups were similar, as were the baseline cardiac enzyme values (Table 3). Patients in both groups also received similar standard medical treatments (Table 4). The time required for mask placement and total time using noninvasive ventilation was similar between the groups (Table 4). Mean airway

Demographic characteristics Age (mean)* Male: Female† Smoking history† Past medical history Prior MI† Coronary artery disease† Coronary artery bypass graft† LVEF [%] (median)‡ Heart valve disease† Left ventricular hypertrophy† Hypertension† Diabetes mellitus† Prior endotracheal intubation† Renal insufficiency† Dialysis dependant† Chronic obstructive pulmonary disease† Obstructive sleep apnea†

CPAP

BPAP

74.1 6 2.3 75.8 6 2.3 7:7 7:6 43% 67%

p Value 0.5788 0.592 0.277

64% 71%

53% 62%

0.850 0.931

21%

27%

0.975

55.0% 64% 33%

57.5% 46% 46%

0.678 0.182 0.859

79% 64% 7%

68% 50% 18%

0.833 0.205 0.999

43% 21% 36%

54% 29% 25%

0.877 0.904 0.205

14%

9%

0.154

CPAP = continuous positive airway pressure; BPAP = Bilevel positive airway pressure ventilation; MI = myocardial infarction; LVEF = left ventricular ejection fraction. * t-test. † Chi-squared test. ‡ Mann-Whitney.

pressure was 10.0 cm H2O for the CPAP group, and mean inspiratory and expiratory pressures for the BPAP group were 12.0 and 4.4 cm H2O, respectively. MI after enrollment, the primary outcome variable, occurred in only 1 patient in the BPAP and none in the CPAP group (p = 0.97). The 8% (1/13) MI rate in BPAP was not significantly higher than the 0% MI rate in the CPAP group. Despite the limited enrollment, the probability that we missed a significant difference in the rate of MI was only 3%. Mean creatine kinase and CK-MB values did not significantly differ between the two groups (Figure 1, panels A and B). The presenting ECG for the 1 BPAP patient who had the MI showed normal sinus rhythm with left bundle branch block (LBBB) and with 1-mm ST-segment depressions in leads V5 and V6 that increased to 2 mm at hour 16, corresponding to a peak troponin value of 2.29 ng/mL. Whereas the ECG changes described do not meet the strict Sgarbossa criteria for an acute MI in the setting of LBBB, the patient’s biomarker elevation and new ST-segment changes fulfilled our study’s criteria for MI and was therefore considered to have met the primary end point (34). The patient received BPAP for only 3.0 h, never complained of chest pain or required ICU admission, and was discharged alive after 7 days. Only 1 patient in the CPAP group and none in the BPAP group required intubation during the intervention,

Bilevel vs. Continuous Positive Airway Pressure for Pulmonary Edema

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Table 2. Symptoms, Physical Findings, and Laboratory Values at Study Entry

Symptoms Chest pain* Shortness of breath* Vital signs Respiratory rate/min† Heart rate/min† Mean arterial pressure (mm Hg)† Oxygen saturation on room air‡ Physical findings Jugular venous distention* Crackles* S3 or S4* Peripheral edema* Laboratory values pH† PaCO2† PaO2† PaO2:FiO2† Lactate‡ Creatinine‡

CPAP

BPAP

p Value

38% 100%

38% 100%

ns ns

35.8 6 6.0 106.6 6 21.03 106.0 6 17.66 85.9% 6 0.065

35.6 6 4.2 97.1 6 21.4 107.9 6 21.07 85.1% 6 0.07

0.928 0.158 0.820 0.707

54% 100% 31% 71%

55% 100% 27% 91%

ns ns ns 0.230

7.31 6 0.02 51.36 6 4.5 128.4 6 14.1 162.2 6 22.6 1.0 median 2.4

7.32 6 0.02 47.35 6 4.0 108.5 6 29.2 134.9 6 15.4 1.2 median 3.9

0.606 0.446 0.494 0.323 0.961 0.535

CPAP = continuous positive airway pressure; BPAP = bilevel positive airway pressure ventilation; ns = nonsignificant. * Fisher’s exact test. † t-test. ‡ Mann-Whitney.

and 2 patients in the CPAP group and 1 in the BPAP died during the hospitalization. The CPAP patient was intubated 30 min after randomization due to worsening hypoxemia and persistent severe dyspnea, and later died after developing acute renal failure and declining further interventions. The other CPAP patient and the BPAP patient died from recurrent APE on hospital days 6 and 15, respectively, after requesting comfort measures only. Fewer patients in the BPAP group (38%) than in the CPAP group (92%) were deemed to require transfer to an ICU from the ED (p < 0.05). Among those requiring ICU transfer, BPAP patients tended to have shorter ICU lengths of stay than CPAP patients, and hospital lengths of stay were similar between the groups (Table 5). Table 3. Electrocardiogram Findings and Mean Cardiac Enzymes at Study Entry CPAP Electrocardiogram* Left bundle branch block Right bundle branch block ST elevation ST depression Nonspecific ST-T abnormalities No acute changes Cardiac enzymes (mean)† Creatine kinase (IU/L) Troponin I

Among other secondary outcomes, serial dyspnea scores and PaO2:FiO2 ratios improved more rapidly in the BPAP than the CPAP group, as evidenced by significantly better indices at 0.5 h (Figure 2, panels A and B, both p < 0.05). No other secondary outcome variables revealed serial differences between the BPAP and CPAP groups, including pH and PaCO2 (Figure 3, panels A and B) and vital signs (heart and respiratory rates and mean systolic BP) (Figure 4, panels A, B and C, all p > 0.05), although all of these improved significantly over baseline. Both CPAP and BPAP were well tolerated by patients. None in either group experienced any complications from the application of the ventilator or mask, and mask comfort was similar in both groups for all time periods evaluated (data not shown). DISCUSSION

BPAP

1 2 0 5 2 7

2 1 0 5 1 7

111.1 <0.15

108.2 <0.15

CPAP = continuous positive airway pressure; BPAP = bilevel positive airway pressure ventilation. * Fisher’s exact test. † Mann-Whitney.

Our findings indicate that, contrary to our previous study, patients with APE treated with BPAP do not have higher MI rates than those treated with CPAP (19). Furthermore, BPAP more rapidly improves oxygenation and dyspnea scores in these patients, compared to CPAP therapy. Perhaps related to these more rapid improvements, fewer BPAP than CPAP patients required ICU admission. Although both CPAP and BPAP have demonstrated improved outcomes in APE patients when compared to oxygen therapy alone, the two modalities are not identical in their actions; BPAP actively assists inspiration by providing a pressure ’’boost’’ during inspiration and may

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Table 4. Medical and Ventilator Management CPAP Medical management Nitroglycerin* Furosemide* Furosemide dose (mg)† Enalapril* Enalapril dose (mg)† Morphine* Emergent dialysis* Ventilator management Time to ventilator (minutes)‡ Pressure (cm H2O)‡ Hours ventilated‡

71% 79% 85 mg 46% 1.15 21% 29% 20.2 10 2.13

BPAP 85% 73% 89 mg 36% 1.46 10% 31% 19.1 12/4.4 2.65

p Value 0.73 0.98 0.74 0.89 0.44 0.23 0.58 0.79 0.34

CPAP = continuous positive airway pressure; BPAP = bilevel positive airway pressure ventilation. * Fisher’s exact test. † Mann-Whitney. ‡ t-test.

reduce work of breathing and dyspnea more rapidly than CPAP (1–3,5,7,9,20,27,35). In our previous study, we hypothesized that these potential advantages of BPAP vs. CPAP would lead to more rapid improvements in dyspnea, vital signs, and gas exchange, and these would be associated with lower intubation rates than in patients with APE treated with CPAP (19). Although we observed a number of the hypothesized physiologic benefits, we also observed, to our surprise, a strong trend toward a higher MI rate, leading to the premature discontinuation of the trial. We hypothesized that the higher MI rate in the previous study might be related to unequal distribution of MIs in the two groups despite randomization, due to the small numbers. In support of this idea, the previous study had a higher number of patients presenting with chest pain in the BPAP group (71.4%) compared to the CPAP group (30.1%)

(7,19). Alternatively, we speculated that the pattern of gas delivery by the BiPAP S/T device used in the previous study might have predisposed to MIs. In the face of air leaks, the BiPAP S/T may fail to sense the decrease in inspiratory flow that signals the onset of patient expiration, and delivers inspiratory pressure for up to 3 s prior to cycling. With persistent leak, this can create a situation in which inspiratory pressure is delivered for most of the respiratory cycle, which has physiologically been shown to lead to elevated mean airway pressures (36). In the Mehta et al. study, the BiPAP S/T device used could have resulted in such a phenomenon, leading to higher mean inspiratory and intrathoracic pressures in the BPAP over the CPAP group, reducing venous return and cardiac output more in the BPAP group and predisposing to cardiac ischemia in marginally perfused areas (19). The observation in the Mehta et al. study that the BPAP group experienced a more rapid drop in systolic blood pressure compared to the CPAP group further supports such an explanation (7,19). The current trial attempted to address these possibilities by more rigorously excluding patients with evidence of MI prior to enrollment by using strict electrographic criteria and a more sensitive biomarker, troponin I (37– 39). We were, therefore, less apt to enroll patients with evolving MIs when they began mask ventilation. We also used a more sophisticated BPAP ventilator (BiPAP Vision) that has a software algorithm designed to enhance cycling from inspiration to expiration in the face of air leaks. Finally, we used lower inspiratory (12 vs. 15 cm H2O) and expiratory (4 vs. 5 cm H2O) pressures to reduce the chance that intrathoracic pressure could have deleterious effects. The most likely explanation for our observation that excess MIs were not seen in the BPAP group of the

Figure 1. Mean total creatine kinase (CK) (left panel) and % MB-CK (right panel) for both CPAP and BPAP groups at baseline, 8 and 16 h after randomization. CPAP = continuous positive airway pressure; BPAP = bilevel positive airway pressure ventilation; *p < 0.05.

Bilevel vs. Continuous Positive Airway Pressure for Pulmonary Edema Table 5. ICU Admission Rate, Length of Stay, and Mortality for Patients with Acute Pulmonary Edema Treated with CPAP vs. BPAP

ICU admission ICU length of stay Hospital length of stay Hospital mortality

CPAP

BPAP

p Value or z Value

91.67% 4.63 6.64 14.28%

38.46% 3.43 6.50 7.69%

0.008* 0.143 0.623 0.084

ICU = intensive care unit; CPAP = continuous positive airway pressure; BPAP = bilevel positive airway pressure ventilation. * p < 0.05.

current study is that we had better randomization of risk factors for ischemic events in our groups. The two groups were more evenly matched compared to those in the prior study, especially with regard to the distribution of patients presenting with chest pain (19). We were also able to detect and exclude MIs that were already evolving upon ED presentation. Three patients from each group were detected on admission and excluded from the study. In contrast, the prior study was less likely to detect evolving MIs prior to study enrollment (19). As with our previous study, BPAP manifested some advantages over CPAP with regard to resolution of APE. The previous Mehta study observed more rapid amelioration of dyspnea and hypercapnia in the BPAP than CPAP group, and the current study observed more rapid improvements in dyspnea and PaO2:FIO2 ratios in the BPAP group within 30 min (19). Others have observed more rapid improvements in respiratory rate when comparing NPPV to CPAP, but ours is the first to observe a more rapid improvement in oxygenation (8).

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As with multiple previous studies and meta-analyses, though, these did not translate into lower intubation or mortality rates (13,15,16,23–26). The finding that fewer BPAP patients required ICU transfer is of interest due to the potential to more efficiently use ICU beds. The decision to admit patients to the ICU was based on the clinical judgment of emergency physicians and intensivists using standard guidelines, as described in the Methods section. Other factors like availability of ICU beds were also considered, but these should have been similar between the experimental groups. To minimize possible bias, investigators were not involved in the transfer decision and clinical decision-makers were blinded to treatment group. Thus, the more rapid improvements in dyspnea and oxygenation would seem to best explain the lower transfer rate of BPAP than CPAP patients to the ICU. This could have resulted in greater cost savings for BPAP patients by reducing the need for ICU beds, but overall hospital lengths of stay were similar between the groups. Limitations The lack of enrollment in our study is unquestionably a serious limitation. Nonetheless, we decided to terminate the study due to slow enrollment and the low likelihood (3%) that a significant difference in the rate of MI would be found, even if we had continued enrolling. Furthermore, the only MI that occurred (albeit in the BPAP group) was not clinically significant and was associated with no other clinical sequelae. In addition, troponin and CPK levels were nearly identical in the two groups in the current study, whereas the CPK level was higher in the BPAP than CPAP group in the Mehta study (19).

Figure 2. Dyspnea score (left panel) and PaO2: FiO2 ratio (right panel) for patients in both groups at baseline, 30 min and 1 h after randomization. Dyspnea based on visual analog scale where zero (‘‘0’’) represents no dyspnea and ten (‘‘10’’) represents maximum dyspnea. CPAP = continuous positive airway pressure; BPAP = bilevel positive airway pressure ventilation; *p < 0.05 for CPAP vs. noninvasive positive pressure ventilation (NPPV).

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Figure 3. Mean PaCO2 (left panel) and pH (right panel) for both CPAP and BPAP groups at, 30 min, and 1 h after randomization. CPAP = continuous positive airway pressure; NPPV = noninvasive positive pressure ventilation; *p < 0.05.

Another potential limitation is lack of generalizability given the strict inclusion and exclusion criteria compared to our previous study. However, selection criteria of most studies have generally become stricter, partly as a consequence of our earlier study, with patients routinely excluded if they meet electrographic criteria for ST elevation MIs or are likely to undergo invasive intervention. Thus, the criteria used for enrollment in our study are typical of those currently advocated for initiation of either CPAP or BPAP in patients with APE.

Another limitation is the lack of a control group treated with standard medical therapy alone. Lacking such a control, we cannot be certain that either BPAP or CPAP were effective in improving outcomes compared to oxygen therapy alone. On the other hand, the evidence from multiple randomized controlled trials is quite strong that both modalities lower intubation rate and probably mortality, and including such a control group would have raised ethical concerns (2–4,6,8,10,13–15,17).

Figure 4. Heart rate (upper left panel), respiratory rate (upper right panel), and mean arterial pressure (lower panel) for CPAP and BPAP patients at baseline and at 30 min, 1 and 2 h after randomization. CPAP = continuous positive pressure ventilation; BPAP = bilevel positive airway pressure ventilation; bpm = beats or breaths per minute; MAP = mean arterial blood pressure; mm Hg = millimeters mercury; *p < 0.05.

Bilevel vs. Continuous Positive Airway Pressure for Pulmonary Edema

CONCLUSIONS In this follow-up study to the Mehta study on APE that found a strong trend for increased MI rate in a BPAP compared to a CPAP group, we found no indication that MI rate was increased in either group (19). This contrary finding is most likely related to better randomization, improved methods to detect and exclude patients with MIs upon ED presentation, and advances in BPAP device technology. BPAP manifested early advantages over CPAP with regard to resolution of dyspnea and better oxygenation, but these differences were transient and not related to differences in major outcomes such as intubation or mortality. On the other hand, BPAP may permit less utilization of scarce ICU beds. Further studies will be necessary to determine whether BPAP can improve the efficiency and lower the cost of care. Acknowledgments—The authors are very grateful for the assistance of the Department of Respiratory Care at Rhode Island Hospital, who were very helpful in identifying possible candidates for the study and collecting data. Oronasal masks connected to BPAP were donated by Respironics, Inc. Nicholas S. Hill, MD, received a research grant from Breathe Technologies.

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Bilevel vs. Continuous Positive Airway Pressure for Pulmonary Edema

ARTICLE SUMMARY 1. Why is this topic important? The submission is important because our group previously published the article by Mehta et al (Crit Care Med 1997:25(4):620–626) that raised concerns about the association of bi-level positive airway pressure (BPAP) with myocardial infarction when treating acute cardiogenic pulmonary edema (APE). This follow-up study finds no such association and also makes the interesting observation that the ICU admission were less frequent in the BPAP group. 2. What does this study attempt to show? Compared to continuous positive airway pressure(CPAP) to treat acute cardiogenic pulmonary adema, bilevel positive airway pressure (BPAP) was associated with a more rapidimprovement in oxygenation and dyspnea scores while reducing the need for ICU admission without increasing myocardial infarction (MI) rate. 3. What are the key findings? (1) More rapid improvement in oxygenation when APE patients are treated with BPAP vs CPAP. (2) More rapid improvement in dyspnea scores when APE patients are treated with BPAP vs CPAP. (3) There is similar low rate of MI in patients with APE treated with either BPAP or CPAP. 4. How is patient care impacted? Patients presenting with APE may more respond to standard therapy plus BPAP therapy compared to the addition of CPAP and this more rapid improvement may decrease the need for ICU admission.

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