No More Nitro

The truth is sometimes I enjoy a good medication shortage.  It forces us to come off of autopilot and think through the goals of therapy and how we can achieve them now that a commonly-used medication is unavailable.  Think about how much fun you all had using ketamine when we had a benzo shortage!  Shortages force us to get comfortable with unfamiliar medications, and look at you all now!  I’d be surprised to hear that one of you hasn’t used ketamine in some fashion.  Groovy stuff!

Shortages also create the opportunity to revisit the evidence behind certain therapies in order to reserve the medication for the most appropriate patients.  Who knows, you might uncover something that changes your practice.  Let’s take a look at what some smart people have to say about IV nitroglycerin use in acute decompensated heart failure:

Heart Failure Society of America 2010 Guidelines

Intravenous vasodilators (nitroprusside, nitroglycerin, or nesiritide) may be considered in patients with ADHF who have persistent severe HF despite aggressive treatment with diuretics and standard oral therapies.  

Nitroprusside (Strength of Evidence = B)  

Nitroglycerin, Nesiritide (Strength of Evidence = C) 

Intravenous vasodilators (nitroglycerin or nitroprusside) and diuretics are recommended for rapid symptom relief in patients with acute pulmonary edema or severe hypertension. (Strength of Evidence = C)    

European Heart Failure 2012 Guidelines

An i.v. infusion of a nitrate should be considered in patients with pulmonary congestion/edema and a systolic blood pressure >110 mmHg, who do not have severe mitral or aortic stenosis, to reduce pulmonary capillary wedge pressure and systemic vascular resistance. Nitrates may also relieve dyspnea and congestion (Class IIb, Level of Evidence B).   

ACCF/AHA Heart Failure 2013 Guidelines

Intravenous nitroglycerin, nitroprusside, or nesiritide may be considered an adjuvant to diuretic therapy for stable patients with HF (Class IIb, Level of Evidence A).    

I’m seeing a lot of nesiritide and nitroprusside talk along with this nitroglycerin (and shocked to see an A rating on evidence from ACCF/AHA).  When we look at the references cited for grouping nitroglycerin in with the other two medications, we find that there is VERY sparse data for nitro.  It’s all nesiritide and nitroprusside data. For nitro, there’s one nonrandomized, open-label, feasibility study of high-dose bolus nitro in 29 patients, and a 1998 Israeli study of 104 patients that is riddled with protocol violations.  There is one other trial comparing nesitiride vs. nitro called the VMAC study.  Spoiler alert: nesiritide outcompeted nitroglycerin.

If you are scared of the potential adverse events of nesiritide (elevated serum creatinine, questionable trend towards mortality in a meta analysis) or nitroprusside (thiocyanate toxicity…SUPER rare), know that nitroglycerin has potential harm as well.  In fact, in that VMAC study, more patients in the nitro group experienced adverse effects than with nesiritide.  Also, 7-day and 6-month mortalities were similar in the nitro and nesiritide group for VMAC.  Thirty-day readmission was similar with both as well.

Nitro tolerance and resistance are also big problems not seen with the other two.  Initially a benefit may be seen but over the course of hours, there may be no further improvement with subsequent increases in dose.

Additionally, keep in mind that many of these studies occurred before BiPAP became more popular for managing heart failure patients (we thought it led to a higher mortality, then it seemed to reduce mortality, now it may seem as though it leads to a higher mortality again…that’s for you all to determine).  I only point this out to show there has been a change in management for these patients since most of this data was published.

To further bash nitro, in a relatively recent review article on nitroglycerin for acute decompensated heart failure, the authors flatly conclude that there is currently not enough evidence to recommend nitro as a standard treatment.     

My bottom line for judicious nitro administration:

Nitro has NEVER been shown to have a mortality benefit in ADHF, weight risk vs benefit     

Patients presenting with concomitant ischemia take precedence  

Couple it with a good dose of diuretic

Reserve it for patients requiring BiPAP or intubation  

Reserve it for patients with an SBP of at least 120    

Start at a LOW dose and titrate up every 5-10 minutes to max of 200 mcg/min      

Avoid hypotension! Hypotensive events = mortality in these patients. BiPAP will drop their pressure. Give them a minute to have those million molecules of oxygen bombard their lungs. Their work of breathing will decrease, their endogenous catecholamine surge will subside, their pressure will go down.

Give the nurse clear instructions for titrations and explain the goals of therapy  


Titrate the drip with the nurse for a while to see how the patient is responding to therapy

Get weird with it and request some nitroprusside or nesiritide!  Increase your drug repertoire, increase your knowledge, increase your comfort level  


Feel free to approach me with any questions or concerns about the medication management of heart failure patients.  I can also get you my references if you want your mind blown.    

Forget what ya’ heard.  Nitro may not be the saving grace you may think it is.

CK here- you may be thinking, What? Nesiritide kills people and NTG is awesome, everyone knows that. just look at

Or at least nesiritide doesn't work [see or read the ASCEND-HF trial in NEJM 2011].

Neal, however, has a well reasoned reply:

NTG:  We do not use it as they do in these studies.  I’ve never seen high-dose boluses of NTG in our ER.  I’m not sure how that blog crashingpatient gets away with using strong wording like “very effective” when referencing a trial of 9 patients.  I have been noticing a regurgitation of Scott Weingart anecdotes that are only based on a couple of his patients and his expert opinion…the same level of evidence he jokingly calls “GOBSAT (Good ole boys sitting around a table).”  
These studies have incredibly low numbers, most are non-randomized, convenience sampling, open-label, violate their pre-specified protocols, and don’t reflect current practice (i.e. non-invasive ventilation).
How is no one bringing any of this up?  There is clear bias towards utilizing NTG.  My argument in the post is that this bias is at least partially due to unfamiliarity with other medications.
Nesiritide:  I didn’t mean for it to seem that nesiritide is a clear winner over NTG.  I agree the data is not great.
Nitroprusside: Where are the criticisms for this medication in the setting of ADHF?  I personally believe that more people are silent on this because there is some data advocating the use but got overshadowed by ease of NTG, thus falling to the wayside.  This is a great candidate to replace NTG if there was no more NTG.
The whole point of this is to have critical responses.  The culture is to give NTG.  The levels of recommendation were put in there to show that evidence is sparse and most are in context of diuretic administration (people love to bash diuretics, but fail to admit there is just as big a void of data for nitrates).  I personally don’t care how much NTG gets used when we have it, whether the patient is a good candidate or not (just as long as they don’t get symptomatically hypotensive).  What I advocate is the responsible use of a dwindling product.