They were fine yesterday, now they’re drowning!
“Flash” (acute) pulmonary edema is a common critical condition in the emergency department, and it can have multiple precipitating factors and etiologies. After evaluating for acute myocardial infarction, tachydysrhythmias, and valvular pathologies based on physical exam and ECG, the treatment for these patients hinges upon positive pressure non-invasive ventilation, acute preload/afterload reduction, and other adjuncts such as IV ACE inhibitors and furosemide. Acute pulmonary edema, in the setting of diastolic heart failure can be a quickly reversible condition, and typically does not require definitive airway management given the rapid improvement that is seen with aggressive treatment. After reading this post, hopefully you’ll have a better understanding of acute cardiogenic pulmonary edema with a preserved ejection fracture and be more familiar with various diagnostic and treatment modalities in these patients. Here we go…
First, the case:
A 53 year-old female with unknown history (limited by her condition) was brought in by EMS as a “STEMI notification” with AMS and dyspnea. Initially in the field, the patient demonstrated agonal breathing, crackles diffusely, bilateral LE edema, and ST-elevations in aVR and diffuse ST-depressions. The patient was intubated in the field with etomidate and brought to YOUR emergency department.
What are your first steps?
- ET tube confirmed by laryngoscopy and/or waveform capnography
- Tachypnea, diffuse crackles, bilateral breath sounds
- Tachycardia + decreased peripheral pulses
- Arousable, purposeful movements
IV: Nitroglycerin 400 mcg bolus x 2, propofol for sedation.
O2: Lung-protective mechanical ventilation: TV 400 RR 16 PEEP 12 O2: 70%
Monitor: HR 124, RR 24, BP 159/87, O2 Sat 89% (initially on BVM)
In the ED, the remainder of the exam is unchanged.
ECG showed sinus tachycardia with PACs, minimal ST-elevation aVR and diffuse ST-depressions (presumed due to hypoxemia); LV enlargement.
A bedside ultrasound showed diffuse B lines throughout all lung fields and a normal ejection fraction. CXR showed bilateral congestion with no consolidation or effusions.
Additional history was obtained from family: The patient has a history of HTN, DM, asthma, and an “enlarged heart.” She is non-adherent to her medication regiment. Today she was in the car, in her usual state of health and suddenly became short of breath and then became altered. The previous day, she was complaining of some mild chest pain and “gas pain” in her upper abdomen.
Let’s start from the beginning and then narrow the discussion to our focus. This patient had pulmonary edema, which is generally classified into cardiogenic versus non-cardiogenic; the respective etiologies and treatments vary widely. We discussed non-cardiogenic pulmonary edema a few weeks ago, which mostly involves lung-protective ventilation strategies and some adjuvant therapies (see here). Now let’s discuss the diagnosis of cardiogenic pulmonary edema, which is dependent on history, exam, and a few diagnostic modalities including ultrasonography, BNP measurements, and the chest x-ray (CXR).
Multiple meta-analyses have shown the utility of bedside ultrasonography in diagnosing cardiogenic pulmonary edema. It has become common knowledge in today’s EM world that B-lines on ultrasound, especially in the apices, are highly predictive of pulmonary edema; when combined with a bedside echocardiogram showing a decreased ejection fraction (EF), this can strongly suggest a cardiac etiology of the pulmonary edema (sensitivity 94%, specificity 92%,, +LR 7.4 for B lines and 4.1 for reduced EF,). However, one very interesting study of patients with APE related to hypertension (onset<6hrs, SBP>160, CXR findings of pulmonary edema) showed that half of the patients with acute pulmonary edema (APE) had a normal EF, and more importantly, that this normal EF was unchanged between an echocardiogram done DURING their acute episode and after its resolution. This suggests that up to 50% of acute pulmonary edema patients will have isolated diastolic dysfunction, perhaps making the diagnosis of cardiogenic pulmonary edema more difficult. In attempting to differentiate cardiogenic APE from ARDS in this setting, an excellent study found these lung findings present ONLY in ARDS: Spared areas, absent lung sliding, and consolidations, with pleural line abnormalities being present in 100% of ARDS patients but only 25% of APE patients.
Interjection – Heart Failure with Preserved Ejection Fraction (HFpEF)
This subset of patients with APE have a preserved ejection fraction, also known as HFpEF. While this may be a portion of APE patients, even in patients with a reduced EF, the ejection fraction measured during and after resolution of the episode of APE were similar, suggesting that diastolic dysfunction may play a large role in APE even in the setting of reduced EF.  This is further supported in a paper by Zile et al which showed that elevated diastolic pulmonary artery pressures were a significant factor in acute exacerbations regardless of baseline EF.
Recent data on BNP has shown that it is useful as a “rule-in” only at very high levels and more useful as a rule-out test for acute decompensated heart failure when it is low. In the large meta-analysis by Martindale et al, the negative LR of a BNP<100 was 0.11 and the +LR of a BNP>1000 was 7.2.3 The negative LR of a NT-proBNP<300 was 0.09 and the +LR of NT-proBNP>1550 was only 3.1. However, these data can become more complicated when the pulmonary edema and cardiac dysfunction associated with APE happen rapidly, presumably what occurs in exacerbations of HFpEF. This would result in less ventricular wall dilatation, at least initially, and therefore lead to lower BNP/NT-proBNP levels. This is suggested by one study which reported that BNP was more elevated in patients with HFrEF than patients with HFpEF (average 1320 vs. 535).6
Chest x-rays have poor test characteristics for APE. While the usual cardiogenic pulmonary edema pattern is bilateral vascular congestion, there is a subset of cardiogenic pulmonary edema which can present with unilateral edema (~2%). In one study of these patients, the edema was almost all right-sided and the etiology in all cases was severe mitral regurgitation. These patients had a significantly increased mortality (39% compared to 8% for bilateral edema), likely due to their delay in diagnosis.
Hypertensive acute cardiogenic pulmonary edema
A brief aside into pathophysiology
Now we’ve narrowed the discussion to cardiogenic from non-cardiogenic pulmonary edema, and more specifically, cardiogenic edema caused by a hypertensive crisis (and not ischemia/valvular insufficiency/dysrhythmia/renal artery stenosis). This is a sudden rise in left-sided pressures leading to increased pulmonary capillary pressure. This consequently causes filtration of protein-poor liquid across the pulmonary endothelium into the pulmonary interstitium and alveolar spaces, leading to decreased diffusing capacity, hypoxia, and shortness of breath. Compensatory increased sympathetic tone and activation of the renin-angiotensin-aldosterone system cause tachycardia, increased SVR, and fluid retention, leading to worsening pulmonary edema due to decreased diastolic filling times and increased afterload.
A concept known as Ventricular-Vascular coupling is nicely summarized in a paper by Viau et al. Essentially, chronic HTN causes vascular stiffening as well as ventricular stiffening (in HFpEF) and ultimately ventricular dilatation (in HFrEF). During an acute rise in systolic blood pressure, an increase in afterload (Vascular) would normally prompt a coupled increase in stroke volume (Ventricular). However in HFpEF, this ventricular response is inadequate due to a reduction in pre-load (as we know, the heart is a supply-driven pump, but when it is stiff as in heart failure, all the supply in the world can’t fill the stiffened LV to increase stroke volume). This uncouples the ventricular-vascular matching, leading to a marked increase in end-systolic pressures. The increased end-systolic pressure is further increased by the stiff large arterial vessels more quickly transmitting back-pressure from the smaller arterioles during systole (smaller arterioles account for most of the dynamic constriction in acute hypertensive episodes). Those pressures are then passed on to the pulmonary vasculature leading to pulmonary edema. (Figure 1 from Viau et al, 2015)
Resolution of the case:
The patient was treated with IV nitroglycerine (400mcg bolus x2 followed by an infusion at 200mcg/min) with significant improvement in her oxygenation and mental status. Labs showed a very mildly elevated BNP (133), a negative troponin (0.05), leukocytosis (15.2), hyperglycemia (300), and an ABG with respiratory acidosis (pH 7.28). The patient was initially started on propofol but then changed to a fentanyl infusion (remember, analgesia first for intubated patient). IV enalaprilat 1.25mg and IV furosemide 120mg were administered. The patient became more arousable and was able to follow commands and cough sufficiently, so the decision was made to extubate. Vital signs were good for 60-90 minutes. The patient was extubated successfully to BiPAP (12/6 at 50%) and was admitted to the cardiac care unit. As an inpatient, the patient had an official echo which showed grade 1 diastolic dysfunction and preserved EF of 65%.
Positive pressure ventilation
A Cochrane review from 2013 (n=32 studies) concluded that non-invasive positive pressure ventilation (CPAP or BiPAP) can significantly reduce mortality (RR 0.66), the need for endotracheal intubation rate (RR 0.52), and the number of days spent in the ICU (0.89 days) without increasing the risk of MI during or after treatment. Clearly this therapy is a beneficial and has become one of the first tools we reach for in treating a large range of pathologies related to acute dyspnea. It can be also be an excellent initial treatment in the undifferentiated dyspneic patient as it involves minimal risk. And, in the event that intubation may be needed, non-invasive ventilation can provide excellent pre-oxygenation as well.,
Furosemide & Nitrates
Many arguments have been made for and against the use of IV furosemide in an acute exacerbation. The major argument FOR the use of diuretics is data showing weight gain in the majority of decompensated heart failure patients (mostly over the previous week) – this suggests that this is a more chronic decompensation. Arguments against its use are mostly physiologic, including an old study of IV furosemide (1985) in CHF patients which showed that within 20 minutes of administration, IV furosemide caused decreased stroke volume and increased heart rate, systemic vascular resistance, and neuro-hormones such as norepinephrine, renin, and vasopressin. However, there is suggestion that when afterload and preload reduction is reduced before IV furosemide treatment, that these deleterious effects can be avoided.
Clinically, there are few good studies. In one randomized placebo controlled trial of IV furosemide in hypertensive APE, patients had no difference in their perceived dyspnea at 1 hour (although, arguably, this is a les-than-relevant outcome to study). Another pre-hospital study compared various combinations of furosemide, nitrates, and morphine showing that nitrates with furosemide trended towards better outcomes, but 25% of their 57 patients didn’t have cardiogenic pulmonary edema, largely invalidating their study. An older RCT using high-dose isosorbide dinitrate (3mg IV boluses x 5) after furosemide administration showed decreased intubation rates (13% vs 40%) compared to giving additional furosemide and lower-dose isosorbide dinitrate (1mg/hr IV), suggesting that maybe nitrates are a more important treatment than diuretics.
Treatment with nitrates has a sound physiologic basis. They reduce both preload (knowing that elevated diastolic pressures contribute to APE) and afterload, as well as inhibit the neuroendocrine response. A Cochrane review from 2013 of nitrates in acute heart failure syndromes showed no significant difference between nitrates and other alternative interventions with respect to hemodynamic parameters and only a trend towards decreased adverse events at 3 hours with nitrates compared to placebo. The review highlighted a lack of high-quality evidence, and these outcomes were only based largely on one study.
There has been a lot of discussion of high-dose nitroglycerine administration for these patients. A non-controlled trial in 2007 of 2mg boluses of IV nitroglycerine every 3 minutes up to 10 times showed that this therapy was relatively safe; hypotension developed in only 3.5% of patients. Compared to historical controls (again, not an ideal study design), high-dose nitroglycerine was associated with less need for intubation (13% vs 26%) and decreased ICU admission (38% vs 80%). However, this study also sparingly used CPAP or NIPPV (7-20%) demonstrating the difference in usual care at the time of the trial.
The use of IV angiotensin converting enzyme (ACE) inhibitors has been suggested as an adjunct treatment given their effects of reducing afterload and down-regulating the neurohormonal activation (renin-angiotensin-aldosterone system). A prospective RCT compared captopril to placebo after treatment with IV furosemide, nitrates, and morphine. Patients who received captopril sublingually had a significantly greater improvement in their symptoms at 30 minutes (43% improvement vs 25%), and a non-significant reduction in need for mechanical ventilation (9% vs 20%). Albeit, this study was limited by the lack of a validated outcome measure (the improvement was measured by an non-validated score). Sublingual captopril use has been associated with decreased ICU admissions (OR 0.29) and intubation (0.16). Physiologically, there are data suggesting that when combined, nitrates and captopril have beneficial, synergistic hemodynamic effects. In one study where the two treatments were combined, there was a larger reduction in systemic and pulmonary vascular resistance as well as a larger increase in stroke volume.
Morphine: No, no!
Outcomes from the large ADHERE registry suggest that giving morphine for acute, decompensated heart failure was an independent predictor of increased hospital mortality with an odds ratio of 4.8. More recent studies suggest a strong association between increased mortality and morbidity (e.g. intensive care unit admissions or intubation rates), although causality is difficult to establish due to research methodologies. The current evidence does not support the routine use of morphine in the treatment of APE.
- Cardiogenic APE can be differentiated from non-cardiogenic APE using a combination of history, physical exam, ultrasonography, BNP
- Bedside ultrasonography is the most accurate, readily available test for pulmonary edema.
- HFpEF is responsible for a large portion of cardiogenic APE.
- Even when volume overload is not present, increased diastolic pressures and sympathetic activation play large roles in APE.
- Treatment with non-invasive ventilation can improved mortality and is an excellent idea given its safety and broad treatment of many pathologies in the dyspneic patient.
- IV nitrates (even high doses up to 2mg) and IV ACE inhibitors are generally supported by current evidence to be both safe and effective, although high-quality evidence is lacking.
- IV furosemide, if given to the fluid-overloaded patient, should be given AFTER treatment with nitrates and ACE inhibitors to avoid unintended increased vascular tone.
- Avoid the use of morphine in these patients.
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