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Saturday, March 23, 2013

Nitroglycerin - Old and New: Pt 3

I really wasn't planning on doing a part 3, since I had thought there was only so much you could say! A recent discussion on Facebook, however, revealed a surprising amount of enthusiasm for a seemingly boring question:

"SL Nitro tabs or spray?"
It probably matters somewhat whether the NTG is being used to treat ACS or CHF, but that didn't come up in the discussion. Other concerns and opinions, as well as some questions, came up, and I thought it would interesting to see what research was out there to back up some statements or answer questions. 

First off, some straight-forward information of UpToDate about the kinetics of the various forms of nitroglycerin. This shouldn't be viewed as the final answer, but it probably isn't far from it.

I'll be using quotations out of the comments from the FB post, since this probably represents the thinking of a good number of people (or at least the thinking of people who like to talk about tab versus spray on a Friday night!

Or a Friday night! (Source)
 Onto the questions!
"I heard it works faster? Not sure if its true."
 "I have always wondered with the sprays just how much nitro they are getting. I know its supposed to be the same as a tab but I guess I just wonder."
Does the spray work faster, or the tablet? Which formulation gives a higher dose? Three studies, all from the 90s, suggest that if there is a difference, it's a small one!

Danish researchers compared 2 sprays of 0.4 mg each versus one 0.5 mg tablet, and checked the blood levels. Not surprisingly, the higher-dose sprays reached a higher dose than the tablets, and faster as well. However, after they corrected for the higher dose, they calculated the time-to-onset and blood levels to be equivalent.

Researchers from Montreal took a different tack. Instead of looking at blood levels, they looked at how quickly nitro spray or tablets could cause arterial vasodilation. Both the tablet and the spray were 0.4 mg. The graph shows the response: note that both the spray and the tablet had each reached their max effect at the 3 minute mark. However, the spray both acted more quickly, and had a more prolonged effect, and also had a higher maximum response.

A third group took yet another approach. Instead of looking at brachial artery dilation, or plasma levels, they gave nitro during cardiac catheterizations to directly evaluate cardiac effects. After giving 0.4 mg of the spray or tablet, they found a mixed picture. For example, the spray reduced the LV end-diastolic pressure 30 seconds faster than the tablet, but was 30 seconds slower at lowering the LV end-systolic picture. Basically a wash.

"The tabs have the added problem of the non-english speaking patients not understanding the directions and just swallowing them."  
I would add that it is often difficult to get a English-speaking patient to lift up their tongue. In their defense, how often in your life are you asked to do that? It can seem like an odd, "Simon-says" request. 

Therefore, it's an advantage, I think, that you can just shoot the spray at the tongue, under or over. According to the manufacturer of one brand of nitro spray, it can be sprayed on either area, which ought to make conversations simpler in the back of the rig at 2 AM!

"Our pt have dry mouth from being anxious. Tabs don't dissolve in a dry area."
Perhaps the best place to store NTG isn't in a little brown bottle - perhaps it should be kept under the tongues of CHF patients who are struggling to breath. It certainly seems to be the best place to keep a pile of NTG tabs from dissolving!

For example, back in 1986, one doctor found that:
"The addition of 1 ml of saline under the tongue of a patient with visibly dry sublingual tissue will moisten the tissue in preparation for dissolving the nitroglycerin. This simple action has frequently resulted in prompt relief of pain when previous doses of nitroglycerin administered by the patient, and later by hospital staff, had failed."
There also appears to be some science to back up this impression. A group from Japan took an innovative route; instead of looking at critical patients, they had subjects with stable angina ride an exercise bicycle until they felt critical! Well, not critical, but until they felt chest pain. The researchers then did two things. First, they checked how wet or dry the subjects' mouths were. Second, they gave them either nitro tabs SL, or a nitro spray.

It turns out that, for those subjects who had wet mouths, it didn't matter which med they got. But the subjects with dry mouths had their chest pain relieved much more quickly with the spray!

Taking it a step further, another team of researchers looked at giving a teaspoon of water at the same time as giving the SL NTG or the spray NTG. The patients were getting a cardiac cath at the same time (but did not have their mouths checked for wetness!). They found that the patients who got the teaspoon of water with the SL tab had a much greater drop in BP than those who got the SL tab without water. With the spray, however,they got the same drop in BP either with or without the water.

So if you don't have the spray, probably the best idea would be to squirt in some saline or H20 right before you pop in the tabs!

Ask FD to help! (source)
"Is paste an option?" ... "Having the paste which allows for slower absorption and removal value where after a spray, there is no taking it back."
Many paramedics have a high regard for the topical ointment preparation of NTG. I'm not sure why, since topical drugs are not very useful in EMS - they absorb slowly, wear off slowly, and have uncertain absorbation, especially when patients are cold, vasoconstricted, or poorly perfusing. The table at the start of the post really illustrates this - it can take 30 minutes to start working, and 7 hours to wear off!

I only found one study that compared intravenous, pill, and paste NTG delivery. They took patients with unstable angina, and split them into 2 groups - IV NTG, or a combination of pills & paste. They adjusted the doses in both groups so that everyone dropped their BP by about the same amount. They found two things.

First, both seemed to relieve the symptoms of angina at the same rate. That's good, because that's the only time I use the paste - when I have a hemodynamically stable patient complaining of mild-moderate chest pain.

Second, they found, unsurprisingly, that IV NTG can achieve a higher blood level than the paste. On the IV stuff, levels of NTG were, on average, around 18 ng/ml, whereas the levels 2 hours after paste application only got up to 1.3 ng/ml.

This issue about the "slow & low" blood levels doesn't matter so much for angina, or even a STEMI. NTG likely doesn't save lives in ACS, and we have other agents that can treat pain. But when EMS is treating a hypertensive CHF patient, they need therapy that works fast, works hard, and that can be "turned off" fast as well. The paste doesn't seem to do any of that.

The Bottom Line
IV nitroglycerin is the ideal EMS drug. 

It works almost instantly, it gets to peak effect almost instantly, it's very good at treating severe hypertensive CHF, and it can be titrated very precisely. Also, we don't need to take the CPAP mask off every 5 minutes to give tablets and water. (You know, they call it continuous positive airway pressure for a reason!)

But until your service can work out the training and supply issues for the IV pumps, and until the cost of the spray comes down a smidge, we may be stuck with the tablets for a while longer. Just understand the differences!


  1. Not to mention paste will not be effective with any degree of diaphoresis present. 3x NTG SL + 2" NTG paste for most patients just means you have to wipe crap off their chest and they still have C/P (or worse, pulmonary edema).

    The only downside to the spray is the inevitable, "ehh, did that actually spray?" And you might get Goose Egg or 1.2 mg, depending on your strategy for solving the dilemma :)

    1. Ah, the misfire. Does everyone perform a "priming spray," aimed at the floor, before spraying the patient?

      On the downside, I read a story (can't find it now), where a medic accidentally sprayed a cat while priming the spray. It recovered...

  2. There was a very small in hospital study out of Pittsburgh where they gave patients a NTG bolus of 2mg IV. It worked well and had no deleterious side effects. By small I mean something like 11 patients.

    I think that would be a good study for EMS, but just try getting that by the IRB.

    I generally do a priming spray, it just seems to work better.

    My subjective observation is that the spray works faster. Then again maybe it's because I always tell the patient it does. The placebo effect on the paramedic, not the patient.

    I do have one NTG paste story. Not mine, but told to me by an ED attending.

    I'll give you the short story.

    A teen age couple in love was trying to consummate their passion. The girl was a bit, uh, dry.

    Looking in the medicine cabinet for a suitable unguent they found a tube of what turned out to be Granny's NTG paste.

    Mucusa is Mucusa...

    I don't know if the story is true, but it sure is funny.

    1. Another apocryphal story, supposedly about "the new nurse graduate." When the doctor's order read "NTG past 1"," she attempted to cover the entire patient in paste 1" deep.

      I don't believe a word of it though - how many packets would it take to cover an arm?

      As for the Pittsburgh study, I'll look around some more (Maybe on EMCRIT...). A dose of 2 mg is just 5 tablets, so that sounds about right!

    2. Well, I found a study using 2 mg IV boluses, but was in the ED, not EMS.

  3. I think that's the study, but if so I got a few details wrong. It's even better if it's a different study since it duplicates what I read.

    It's an area that needs more study, especially in EMS.

    Like so many other things, we under treat CHF in the field.

    1. Yeah, and if we have EMS start using more aggressive measures, the patients will come into the ED looking "too good!" You'll have to take pictures on-scene (like at an MVA) to get the ED to appreciate the initial presentation.

      BTW - follow local guidelines on the use of photography, etc., while working!

  4. You laugh, but we hear that sort of thing from doctors and nurses all the time. Not in the they don't believe us sort of way, but in the we've done all of the hard work and all they have to do is write the admission orders.

    I love CPAP and it does a great job. I'd love CPAP even more if we could give IV NTG along with it.

  5. So my question here is somewhat off the topic of Ntg/CHF because I believe it work in that setting. Is there any evidence of ntg decreasing m&m in the setting of ACS or STEMI? I can't find a study but finding studies is not my greatest strength. Thanks.

    1. There is some mild evidence out there, using animal models, etc., that NTG reduces infarct size. However, the clinical human data is far less convincing, and the AHA simply states:
      "The treatment benefits of nitroglycerin are limited, however, and no conclusive evidence has been shown to support the routine use of IV, oral, or topical nitrate therapy in patients with AMI."