Acute Pulmonary Edema - Nitro vs Lasix?

A 75yF presents to your ED acutely short of breath. Two hours prior to ED arrival, she became suddenly short of breath. Her family tried administering her salbutamol (Ventolin) to no avail. She was driven to the ED. Her PHx includes hypertension and asthma, the former poorly controlled recently despite amlodopine, HCTZ and ramipril. She denies chest pain, N/V or diaphoresis. She had a minor surgical procedure a few days prior.

At triage her vitals included a RR of 45, pulse 100 and O2 sat 70%. BP is unobtainable. She is rushed to your resuscitation area. Her exam reveals an alert and oriented woman in extemis who is able to speak 1-2 word sentences with a lot of accessory muscle use. On a NRB mask she manages an O2 sat of 94%. The lack of BP makes you worry about a large PE with hypotension. The nurses try again. Her JVP cannot be seen. There are diffuse crackles to the scapulae and wheezes bilaterally. Heart sounds are normal and regular without murmurs. There is no peripheral edema or leg swelling. The BP finally registers – 280/150!

 

Her EKG is below:

Sinus tachycardia with signs of LVH and strain (inverted T’s). Comparison to her recent pre-op EKG shows no significant new findings.

Her CXR is below. 

 

Consistent with pulmonary edema.

What is this patient? You could call her a hypertensive emergency with CHF. You could call her acute cardiogenic pulmonary edema. You could call her a SCAPE patient  (Sympathetic Crashing Acute Pulmonary Edema, trademark Scott Weingart – EMCrit podcast episode #1). As long as you label it something and identify how to treat it, then you’ve achieved goal #1. Not to be confused with the hypotensive patient of cardiogenic shock - that's a different discussion altogether.

So what is the best way to treat this patient? The approach must address the vicious cycle of catecholamines driving increased afterload, leading to pulmonary edema, leading to more fear/stress-induced catecholamine surge. Most would agree that NIPPV and nitrates are key. But what is the starting dose for nitroglycerine? How should it be administered: IV. SL, patch? What about loop diuretics like furosemide/Lasix?

An interesting Twitter conversation was started by Brian Hayes (@PharmERToxGuy) stating that although most drug refs suggest a starting dose of 10 mcg/min, the initial dose for IV Nitro in acute pulmonary edema should be 50 mcg/min. Zach Kiker (@zpkiker) and Haney Mallemat (@Criticalcarenow) also got in on the conversation. See excerpts below:

Drug references suggest starting nitro drips at 10mcg/min. For cardiogenic pulmonary edema, start at 50-100mcg/min and titrate up rapidly.
— Bryan D. Hayes (@PharmERToxGuy) February 22, 2013

@pharmertoxguy @criticalcarenow Head to head trial low v high dose NTG?Personally always had very good success with low dose NTG and Bipap
— Zach Kiker (@zpkiker) February 22, 2013

@zpkiker High dose nitrates have fared better than low. ncbi.nlm.nih.gov/pubmed?term=94… @criticalcarenow
— Bryan D. Hayes (@PharmERToxGuy) February 22, 2013

@zpkiker And, 80mcg/min isn't really all that high. It's similar to giving a 400mcg SL tab every 5 minutes. @criticalcarenow
— Bryan D. Hayes (@PharmERToxGuy) February 22, 2013

@zpkiker @pharmertoxguy @criticalcarenow in my ED nurses get nervous @ dose >20mcg/min. So instead 2 spray=800mcg more palatable +drip+bipap
— ElishaT (@ETtube) February 22, 2013

@ettube @zpkiker @pharmertoxguy Had nursing concerns at last place where I worked. Advise joint teaching session so nurses can learn safety
— Haney Mallemat (@CriticalCareNow) February 22, 2013

So there is variability out there. This much we know. What is best practice?

(This discussion will focus mainly on Nitrates and Furosemide. References for ACEi and NIPPV are below.)

High dose nitrates:

A 2007 Ann Emerg Med feasibility study by Levy et al demonstrated safety of a protocol using high dose nitrates (2 mg bolus q 3min prn). The protocol was “...associated with endotracheal intubation, BiPAP, and ICU admission less frequently than expected to occur without high-dose nitroglycerin, and adverse events were uncommon.”

This 1998 Lancet study showed that for in patients with acutely decompensated CHF in severe pulmonary edema, high-dose nitrates (3 mg bolus administered intravenously every 5 min) plus furosemide 40 mg IV was superior to low-dose nitrates isosorbide dinitrate 1 mg/h, increased every 10 min by 1 mg/h) and high-dose furosemide (80 mg q 15 min). Less mechanical ventilation and less myocardial infarctions.

What about furosemide?

Loop diuretics aim to reduce volume overload. In patients with chronic fluid overload and acute exacerbations of CHF, diuresis is still a mainstay. In acutely decompensated cardiogenic pulmonary edema, flush pulmonary edema or your SCAPE/hypertensive pulmonary edema, this patients may actually be volume deplete, in part due to the immense work of breathing required to overcome the acute shortness of breath.

According to this Emedicine article, loop diuretics may require up to 90 minutes to take effect, especially if there is intravascular depletion and reduced GFR.

This Ann Int Med 1985 study demonstrated that in severe CHF, furosemide activates the neurohormonal axis, leading to at least a short-lived surge of catecholamines.

This 1993 study in J Am Soc Neph in dogs suggests that furosemide in the acute phase of APE may lead to sodium retention.

Diuretics should perhaps be considered in the acutely decompensated pulmonary edema patient after an hour of treatment if there is evidence of overall volume overload.

NIPPV and Afterload reduction:

It is generally well accepted that positive pressure ventilation via CPAP or BiPAP is beneficial in acute cardiogenic pulmonary edema. There is variability between which modality is used. Both however reduce work of breathing and also reduce preload and may help avert intubation. A 1997 RCT in Crit Care Med showed that vitals and ventilation were improved more rapidly in BiPAP vs CPAP but that MI rate was higher in the BiPAP group. Subsequent meta-analyses in Ann Intern Med 2010 showed that BiPAP may trend towards lower mortality and that CPAP was associated with lower mortality.  

Often agents such as ACEi (captopril 25 mg po or enalapril 1.25 mg IV) can be considered for afterload reduction. Effect is often within 10 minutes. This, however, is not often my practice as I find patients often settle down very quickly with NIPPV and nitrates. The Crashing Patient website provides a small breakdown of doses and studies if you wish to read further.

What do some of the experts preach?

Scott Weingart’s legendary SCAPE podcast (Emcrit Episode #1) urges a protocol of 400 mcg/min for 2 min followed by 100 mcg/min and titration + NIPPV. “This first thing you do is get your lasix, and throw it in the trash!”

As you can also see from the above Twitter discussion, some well-respected physicians are proponents of high-dose Nitro while others stay more conservative. Clearly there is practice variation. It seems a lot of this may be influenced by personal experience, as the literature (at least by my search) doesn't have a plethora of exceptionally good studies.

Case Resolution:

The patient was given 2 sprays of SL Nitro 0.4mg/spray (for a load of 800 mcg over about ? 5-10 min – ½ life according to Epocrates is 1-3min) while the IV Nitro was being hung. She was also placed on BIPAP. The IV solution was started at 30 mcg/min and within 15 minutes her sats were 98% on an FIO2 of 40% and her breathing less laboured. BP came down steadily to 160/90 and pulse in the 80's. Repeat CXR less than one hour showed the following:

As you can see, substantially improved. She was admitted to the ward several hours later and did well.

What practice pattern do you follow? Do you agree with the discussion above? Comments encouraged and welcome! Either below or via Twitter.


References:

Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema. Cotter et al. Lancet. 1998 Feb 7;351(9100):389-93.

http://www.ncbi.nlm.nih.gov/pubmed?term=9482291

Treatment of severe decompensated heart failure with high-dose intravenous nitroglycerin: a feasibility and outcome analysis.

Levy et al. Ann Emerg Med. 2007 Aug;50(2):144-52. Epub 2007 May 23.

http://www.ncbi.nlm.nih.gov/pubmed/17509731

Meta-analysis: Noninvasive ventilation in acute cardiogenic pulmonary edema.

Weng et al. Ann Intern Med. 2010;152(9):590.

http://www.ncbi.nlm.nih.gov/pubmed?term=20439577

Randomized, prospective trial of bilevel versus continuous positive airway pressure in acute pulmonary edema.

Mehta S et al. Crit Care Med. 1997 Apr;25(4):620-8.

http://www.ncbi.nlm.nih.gov/pubmed/9142026

EMCrit Podcast 1-Sympathetic Crashing Acute Pulmonary Edema

http://emcrit.org/podcasts/scape/

Great Acute Pulmonary Edema summary at: The Crashing Patient

http://crashingpatient.com/medical-surgical/cardiology/heart-failure-acute-pulmonary-edema.htm/

Cardiogenic Pulmonary Edema (at Emedicine)

http://emedicine.medscape.com/article/157452

Acute Vasoconstrictor Response to Intravenous Furosemide in Patients with Chronic Congestive Heart Failure: Activation of the Neurohumoral Axis.

Francis G et al. Ann Intern Med. 1 July 1985;103(1):1-6 http://annals.org/article.aspx?articleid=699765

Low-Dose Atrial Natriuretic Factor and Furosemide in Experimental Acute Congestive Heart Failure.

Felt D et al. J. Am Soc. Nephrol. 1993; 4:162-167) http://jasn.asnjournals.org/content/4/2/162.long

Some additional articles not referenced above:

Dr Smith’s ECG blog – case of hypertensive pulmonary edema that was actually a STEMI. Always consider this. http://hqmeded-ecg.blogspot.ca/search/label/hypertension

Bolus i.v. nitroglycerin treatment of ischemic chest pain in the ED.

Nashed et al. Am J Emerg Med. 1994 May;12(3):288-91.

Intravenous nitroglycerin boluses in treating patients with cardiogenic pulmonary edema.

Nashed et al. Am J Emerg Med. 1995 Sep;13(5):612-3.

Intravenous nitrates in the prehospital management of acute pulmonary edema.

Bertini et al. Ann Emerg Med. 1997 Oct;30(4):493-9.

A Protocol of Bolus-Dose Nitroglycerin and Non-Invasive Ventilation to Avert Intubation in Emergency Department Acute Pulmonary Edema

Mallick et al. Prepublication abstract.

Available at EMCrit website http://emcrit.org/podcasts/scape/