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!

Source

 
"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!