Treatment of Severe Cardiogenic Pulmonary Edema with Continuous Positive Airway Pressure Delivered by Face Mask

The study design was approved by our institutional ethics committee. Because of the severity of cardiogenic pulmonary edema, no patient was able to give valid informed consent at entry into the study. Information was given to the patient and his or her next of kin and consent was requested in a two-stage procedure as soon as possible after study entry.

On the basis of calculations of statistical power, we chose a target sample size of 40 patients. This sample size would allow us to detect, with a 95 percent probability, a difference between a postulated 50 percent rate of intubation and mechanical ventilation in the oxygen group and a 10 percent rate in the oxygen-plus-positive-pressure group, with a power of 80 percent.

Selection of Patients

The aim of the recruitment process was to enroll patients with severe cardiogenic pulmonary edema and respiratory failure and randomly assign them to receive oxygen alone or oxygen plus continuous positive airway pressure. To ensure relatively uniform medical treatment before study entry, a consensus was achieved on a number of management guidelines for cardiogenic pulmonary edema. While a patient was receiving oxygen through a semirigid face mask (Hudson, Temecula, Calif.) at a flow rate of 8 liters per minute, the blood pressure, heart rate, and respiratory rate were to be recorded, intravenous access gained, and an arterial-blood sample obtained and stored on ice pending analysis. If the systolic blood pressure exceeded 90 mm Hg, nitroglycerin was administered both sublingually (600 μg) and topically (2.5 cm of 2 percent [wt/wt] nitroglycerin ointment; Fisons, Thornleigh, N.S.W., Australia). Either 40 mg of furosemide or twice the patient's normal daily dose, up to 500 mg, was administered intravenously. If the arterial carbon dioxide tension was less than 55 mm Hg, morphine could be given intravenously in 1-mg increments, up to 10 mg, as required for respiratory distress.

During the seven-month study period, all patients with cardiogenic pulmonary edema who had respiratory distress and either an arterial oxygen tension below 70 mm Hg or a carbon dioxide tension above 45 mm Hg while receiving oxygen at a rate of 8 liters per minute through a face mask were enrolled. Cardiogenic pulmonary edema was diagnosed when the patient had dyspnea of sudden onset, typical findings on a chest film, and widespread rales without a history suggesting pulmonary aspiration or infection. In most patients the jugular venous pressure was elevated and a third heart sound was heard. Patients were excluded if they had a diagnosis of myocardial infarction with shock; a systolic blood pressure below 90 mm Hg; severe stenotic valvular disease; or chronic airflow obstruction with known carbon dioxide retention before the current illness. No patient included in the study was later found to have carbon dioxide retention due to chronic airflow obstruction. The clinical course of all the patients was consistent with a diagnosis of cardiogenic pulmonary edema.

Study Protocol

Forty patients were randomly assigned, in four blocks of 10 patients each, to receive either oxygen alone or oxygen plus continuous positive airway pressure. All the patients received oxygen through a high-flow circuit and reservoir bag⁷ connected to a tight-fitting mask (Vital Signs, Totowa, N.J.). By means of the random selection of a colored cap, each patient was assigned to receive either oxygen alone or oxygen plus continuous positive airway pressure. Pressure was applied by connecting a 10-cm water valve (Vital Signs) to the mask and by weighting the reservoir bag to minimize changes in airway pressure.⁷ Although it would have been impossible to blind the investigators to the use of continuous positive airway pressure, we did use the same circuit and mask for both study groups. In the case of one patient who was randomly assigned to receive oxygen plus continuous positive airway pressure, a misreading of the colored cap resulted in her receiving oxygen alone instead. We regarded this as a randomization error and excluded this patient from the analysis. Consequently, 20 patients received oxygen alone and 19 patients received oxygen plus continuous positive airway pressure. Including the excluded patient in the analysis would not have altered the conclusions of this study. The minimal inspired oxygen concentration was 60 percent, as determined by an oxygen blender (Bird, Palm Springs, Calif). However, the fraction of inspired oxygen was increased up to 100 percent if pulse oximetry detected arterial oxygen saturation below 95 percent. Supplemental therapy, such as intravenous nitroglycerin, additional doses of a diuretic agent, or streptokinase, was unrestricted after study entry. Once their condition was stable, all patients were transferred from the emergency department or the ward to the intensive care unit.

The predetermined criteria for intubation and mechanical ventilation were clinical deterioration and either a fall in arterial oxygen tension to less than 70 mm Hg with the patient breathing 100 percent oxygen by mask or a rise in arterial carbon dioxide tension to more than 55 mm Hg.

Physiologic Measurements

Blood pressure, heart rate, and respiratory rate were measured at study entry and 30 minutes, 1 hour, 3 hours, and 24 hours later. At all five time points, arterial blood was obtained for blood gas analysis (IL-1312 Blood Gas Analyzer, Instrumentation Laboratory, Lexington, Mass.) and measurement of arterial lactate (Cobas Bio Analyzer, Hoffmann—LaRoche, Basel, Switzerland). Samples were stored on ice before analysis. Blood gas analysis was performed immediately after sampling, whereas plasma for arterial lactate measurements was stored frozen. At study entry and 24 hours later, blood was also sampled for measurement of electrolytes and cardiac enzymes (Hitachi-717 Analyzer, Boehringer–Mannheim, Mannheim, Germany). Because numerous samples were obtained, care was taken to minimize the volume of each sample, so that less than 70 ml of blood was removed in the first 24 hours. At study entry, an illness-severity score and predicted probability of mortality were determined for each patient with use of the APACHE (acute physiology and chronic health evaluation) II system.⁸

Transmural myocardial infarction was diagnosed when new Q waves at least 0.04 second in duration and 1 mm or more in depth developed. Nontransmural myocardial infarction was diagnosed when new ST-segment depression or T-wave inversion persisted for at least 72 hours and was associated with an increase in the serum creatine kinase level above the normal range (0 to 250 U per liter). Creatine kinase isoenzyme measurements were available for patients who had recently had surgery or an intramuscular injection. Myocardial ischemia was diagnosed when there was a history of typical chest pain in combination with transient ST-segment depression or T-wave inversion. Congestive cardiac failure was diagnosed if myocardial infarction and ischemia were absent and the patient was already receiving medication for congestive heart failure.

Statistical Analysis

Physiologic data obtained after intubation and mechanical ventilation were excluded from the analysis. To avoid bias resulting from the loss of these data, we restricted the statistical comparisons of physiologic measurements between the two groups to the data obtained at entry and at 30 minutes. Analysis of variance was used to compare the two groups both at study entry and at 30 minutes, when the entry value was used as a covariate. Fisher's exact test was used to compare the rate of intubation and the final in-hospital mortality rate in the two groups. All values are reported as means ±SD, and all P values are for two-tailed comparisons.

Table 1. Table 1. Patients' Characteristics at Study Entry.*

Table 2. Table 2. Physiologie Measurements at Study Entry and at 30 Minutes.*

Table 3. Table 3. Characteristics of the Nine Patients Who Received Mechanical Ventilation or Met the Blood Gas Criteria for Mechanical Ventilation.*

Table 4. Table 4. Patients' Outcomes and Lengths of Stay in the Intensive Care Unit (ICU).*

During the period from May 11, 1990, to December 13, 1990, 20 patients were randomly assigned to receive oxygen alone and 19 patients to receive oxygen plus continuous positive airway pressure. Thirty-seven patients were admitted through the emergency department, and two patients were already hospitalized. No significant differences were found between the two treatment groups at entry into the study (Tables 1 and 2). Seven patients met the blood gas criteria for intubation; however, in only five of these patients was clinical deterioration judged to be severe enough to warrant intubation and mechanical ventilation (Table 3). In two additional patients (Patients 10 and 32), clinical deterioration alone led to a decision to initiate intubation and mechanical ventilation (Tables 3 and 4). All nine patients had been randomly assigned to receive oxygen alone, and no patients in the group that received oxygen plus continuous positive airway pressure met the blood gas criteria or had clinical deterioration requiring intubation.

Continuous positive airway pressure was administered by face mask for a total of 9.3±4.9 hours. The stay in the intensive care unit was significantly shorter for the patients who received oxygen plus continuous positive airway pressure (P = 0.006); however, no difference in the length of stay in the intensive care unit was found when the seven patients who received mechanical ventilation were excluded. Four of the patients who required mechanical ventilation died in the intensive care unit; the two in-hospital deaths in the oxygen-plus-positive-pressure group occurred in the general medical ward.

Physiologic Measurements

Figure 1. Figure 1. Respiratory Indexes in Patients with Cardiogenic Pulmonary Edema Who Were Treated with Oxygen Alone (Open Circles) and Those Treated with Oxygen plus Continuous Positive Airway Pressure (CPAP) (Solid Triangles).

The values shown are means ±SD for patients randomly assigned to receive oxygen alone (n = 20) or oxygen plus CPAP (n = 19). Seven patients who received oxygen alone required intubation and mechanical ventilation within three hours after study entry; subsequent data on these patients have been excluded. The 30-minute values were compared by analysis of variance, with the value obtained at entry (0) as a covariate (the asterisk denotes P = 0.01, and the daggers P<0.01 for the comparison between the groups). PaC0₂ denotes arterial carbon dioxide tension, Pa0₂ arterial oxygen tension, and Fi0₂ fraction of inspired oxygen.

At study entry, all the patients had severe respiratory failure, the most common features of which were tachypnea, mixed respiratory and metabolic acidosis, and hypoxemia (Table 2). After 30 minutes, the patients receiving oxygen plus continuous positive airway pressure had significantly greater decreases in respiratory rate (P = 0.008) and arterial carbon dioxide tension (P<0.001) and a greater increase in arterial pH (P<0.001) and the ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen (P = 0.01) than the patients receiving oxygen alone (Table 2, Fig. 1). Improvement in acid–base status was attributable exclusively to the reduction in arterial carbon dioxide tension; the mean arterial bicarbonate concentration did not change. During the remainder of the study, all these indexes continued to improve in both groups (Fig. 1). Similarly, the systolic blood pressure, diastolic blood pressure, and heart rate decreased. Although the heart rate fell more rapidly in patients receiving oxygen plus continuous positive airway pressure (P = 0.037), no other difference in hemodynamic values was noted between the groups.

Table 5. Table 5. Blood Gas Values at Study Entry for Patients in the Oxygen Group Who Received Mechanical Ventilation and Those Who Improved Spontaneously.*

Although only seven patients in the study had an acute myocardial infarction, no difference was found in peak serum creatine kinase levels between the oxygen group (650 ±598 U per liter) and the group receiving oxygen plus continuous positive airway pressure (665±390 U per liter). We also found no difference in initial blood gas values between patients in the oxygen group who received mechanical ventilation and those who improved spontaneously (Table 5).

These results demonstrate that continuous positive airway pressure delivered through a face mask has several advantages over supplemental oxygen alone in the management of severe cardiogenic pulmonary edema. Continuous positive airway pressure resulted in more rapid improvement in respiratory rate, respiratory acidemia, and oxygenation, and fewer patients who received continuous positive airway pressure required mechanical ventilation. Although we presume that avoidance of mechanical ventilation is likely to be beneficial, no difference in mortality rate between the two study groups was found. This study was too small, however, to assess mortality adequately.

The primary end point in this study was the need for intubation and mechanical ventilation. Although respiratory failure may be defined by abnormalities in arterial-blood gases, clinicians base the decision to institute mechanical ventilation on both the trend of the arterial-blood gas values and the clinical status of the patient. We attempted to use predefined criteria for the institution of mechanical ventilation; in general, patients whose condition was clearly deteriorating had either a rise in arterial carbon dioxide tension to more than 55 mm Hg or a fall in arterial oxygen tension to less than 70 mm Hg during inspiration of 100 percent oxygen. However, two patients were clinically stable despite meeting these predefined criteria. Since the presenting episode of pulmonary edema was managed without intubation and mechanical ventilation, neither patient's results were considered a failure of treatment in the oxygen group. In contrast, two other patients in the oxygen group required intubation and ventilation solely on clinical grounds. Because this study was not blinded, the inclusion of these two patients could bias the results. Since the main question addressed by our study was whether continuous positive airway pressure would reduce the need for intubation and mechanical ventilation, however, we considered these patients to have had failure of oxygen therapy alone.

It is unlikely that differences in the study groups could explain our findings. The patients were prospectively randomized and well matched for relevant characteristics. Although the mean arterial-blood gas values were slightly worse at study entry in the oxygen group than the group that received oxygen plus continuous positive airway pressure, this difference was not statistically significant, and the entry data in the patients who received intubation were very similar to those in the patients who improved spontaneously.

In interpreting our data, it is important to recognize that we recruited patients who had a high likelihood of needing mechanical ventilation. Therefore, conclusions from this study may not apply to less severely ill patients. In an earlier study, however, Rasanen and coworkers found a physiologic benefit of continuous positive airway pressure in patients without respiratory acidosis.⁴ Although no complications could be attributed to continuous positive airway pressure in our study, possible side effects include nasal skin necrosis, gastric distention, pulmonary aspiration, barotrauma (if the valve of the mask becomes occluded), and asphyxia (if the gas supply fails). The additional cost of continuous positive airway pressure was about $30. Because the patients who received it had a shorter stay in the intensive care unit, we would expect the total cost of their care to be lower.

As continuous positive airway pressure delivered by mask is adjunctive therapy in cardiogenic pulmonary edema, we attempted to standardize drug therapy. Furosemide and morphine are time-honored treatments; recent data demonstrate clinical improvement⁹ and a reduction in left ventricular filling pressure with no change¹⁰ or an increase⁹ in cardiac output after the sublingual or intravenous administration of nitroglycerin. We chose to use sublingual and topical nitroglycerin in initial management because of its ease of administration; however, 11 patients (6 receiving oxygen alone and 5 oxygen plus continuous positive airway pressure) subsequently received intravenous nitroglycerin in the intensive care unit. Although furosemide is a potent diuretic and venodilator,¹¹ clinical improvement does not depend on the diuresis produced,¹² and furosemide may result in initial vasoconstriction and a decrease in cardiac output after its bolus intravenous administration.¹³ Since both groups received similar doses of furosemide, it is unlikely that these effects would have influenced the differences we observed.

Because the clinical circumstances of our study did not allow us to determine why continuous positive airway pressure delivered by mask was beneficial, we can only speculate about this question. Patients with acute heart failure have an increase in lung water, a reduction in lung volume and lung compliance, and an increase in airway resistance.^{14 , 15} Positive end-expiratory pressure may improve oxygenation by increasing the end-expiratory lung volume with recruitment of alveoli and redistribution of fluid,^{5 , 16} but not by decreasing lung water.¹⁶ The more rapid decrease in arterial carbon dioxide tension probably reflects a decrease in respiratory work due to an increase in lung compliance and a reduction in nonelastic power,⁵ and perhaps a reduction in threshold work (the work required to initiate a breath).¹⁷ Myocardial function may also be improved through a reduction in left ventricular afterload resulting from an increase in intrathoracic pressure.⁶ In contrast to mechanical ventilation, continuous positive airway pressure maintains respiratory effort, thus minimizing the consequent reduction in venous return.¹⁸

We conclude that continuous positive airway pressure delivered through a face mask may reduce the need for intubation and mechanical ventilation in patients with severe cardiogenic pulmonary edema. Further studies are required to define more precisely which patients are likely to benefit from this treatment and whether the use of continuous positive airway pressure results in any long-term improvement in patient outcome.