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!

Nitroglycerin - Old and New: Pt 1

The modern medic gets to use a lot of fancy technology. She interprets capnographic waveforms, reads 12-lead (and 13- and 15-lead) ECGs, places ET tubes, LMAs , and CPAP masks, uses portable lactate analyzers, and even knows how to spell "sphygmomanometer."

Let's face it - compared with all that, nitroglycerin is not a "sexy" EMS tool. 

Unlike this little beauty. You know, I think I've seen this before...

Nitro has been used for angina since 1879, and was also used for "spasms," headaches, and even toothaches. After 133 years of clinical experience, it seems we would have nothing new to say. For example, we take for granted 2 things about NTG:

• The dose is one tab (or spray), every 5 minutes, to a maximum of 3 doses; and
• You should to do an ECG to check for an inferior MI before giving it.

I'll talk about using "high-dose" nitro tablets for CHF in Part 1 today, and discuss the evidence-based concerns about using NTG during an inferior or right-sided MI in Part 2.

Increasing the dose - 1, 2, or 3 tabs sublingual
In case you haven't heard, Lasix is old-fashioned, at least for EMS. It's not a good drug for acute hypertensive congestive heart failure, for any number of reasons, and the modern EMS system uses CPAP and nitro instead.

So how do I usually give NTG for CHF? Once the patient gets to the hospital, I'll use a starting dose of IV NTG at 200 - 400 µg/minute.For the first 20 minutes I'll be adjusting the dose up & down pretty frequently, until the patient's breathing gets better, and the BP has come down.

However, the sublingal NTG dosing used by EMS for CHF is usually the same small dose used for angina pectoris, 0.4 mg every 5 minutes. That's about 80 µg/minute, if you assume that it's absorbed over that 5 minutes. 

Let me point out some basic math:

80 µg < 400 µg

As an emergency doctor, I can get around this problem easily: if I don't have IV NTG available, I give several NTG tabs at once. While the nurses are scrambling to get a second IV and program the IV pump, and the respiratory tech is setting up the CPAP, I'm practically dumping the bottle of NTG under their tongue. The higher their blood pressure is, the more I can give. And I don't stop at 3 doses either; I keep giving it every 5 minutes until the IV juice is flowing.

So, this strategy makes sense pharmacokinetically, and some paramedics having been doing this for years, albeit "off-protocol". For one example, read Peter Canning's excellent blog post NTG and The Hero Medic, about a medic who, evidently, felt comfortable with pretty aggressive NTG doses.

So it's good to read about an EMS system that decided to act rationally, and then study it. In an abstract in the most recent Prehospital Emergency Care, EMS researchers in Buffalo discuss their experience with changing the EMS protocol to allow multiple simultaneous doses of nitro for CHF with hypertension, depending on the BP. I copied the entire article below, but the protocol was simply:

• SBP < 160 mmHg --> 1 tab (0.4 mg)
• SBP > 160 mmHg --> 2 tabs
• SBP > 200 mmHg --> 3 tabs
• Repeat as needed, no maximum # doses

So were patients dropping like flies from this crazy dosing? 

Not so much. Out of 95 patients who got the high-dose NTG, only 3 patients dropped their BP. Which could have been concerning, except that the breathing of those patients was better (which is the whole point), while the hypotension was transient, resolving on the next BP measurement. 

The Bottom Line
Nitroglycerin is an old drug, but we are still learning about how to best use it. Our old habit of "1 q 5', to a max of 3" is perhaps just that, an old habit!

The SHCGB Guidelines, on the other hand, do not set a limit on the maximum number of doses that can be given, and allow the medic to aggressively treat CHF. If the blood pressure is severely elevated during an episode of likely CHF, you can give up to 4 tablets at a time.

Unfortunately, some paramedics may have ingrained patterns of behavior, and there may be doctors who haven't heard about developments in nitro use since 1880. Time to drag them into the 21st century, with all our fancy "new" medications and medical devices!

As for the "sexy" airway tool that looked so familiar above...

Found it!

PREHOSPITAL ADMINISTRATION OF MULTIPLE SIMULTANEOUS NITROGLYCERINE SUBLINGUAL TABS RARELY CAUSES HYPOTENSION
Brian Clemency, Gina Tundo, Jeffrey Thompson, Heather Lindstrom, University at Buffalo, State University of New York
  Background. High-dose intravenous nitroglycerin is a common in-hospital treatment for respiratory distress due to congestive heart failure (CHF) with hypertension. Intravenous nitroglycerin administration is impractical in the prehospital setting. In 2011, a new regional emergency medical services (EMS) protocol was introduced allowing advanced providers to treat CHF with oral nitroglycerin. Patients were treated with two sublingual tabs (0.8 mg) when systolic blood pressure (SBP) was >160 mmHg or three sublingual tabs (1.2 mg) when SBP was >200 mmHg every 5 minutes as needed. To assess the protocol’s safety, we studied the incidence of hypotension following prehospital administration of multiple simultaneous nitroglycerin (MSN) tabs by EMS providers. 
Methods. A retrospective case review of records from a single commercial EMS agency over a six-month period (January–June 2012). Cases with at least one administration of MSN were reviewed. For each administration, the first documented vital signs before and after administration were compared. Administrations were excluded if they were missing pre- or post-administration vital signs. Blood pressure was measured in mmHg.  
 Results. One hundred cases had at least one MSN administration by an advanced provider during the study period. Twenty-five cases were excluded because of incomplete vital signs. Seventy-five cases with 95 individual MSN administrations were included for analysis. There were 65 administrations of two tabs, 29 administrations of three tabs, and one administration of four tabs. The mean change in SBP following MSN was –14.7 (standard deviation 30.7; range +59 to –132). Three administrations had documented systolic hypotension in the post-administration vital signs (97/71, 78/50, and 66/47 mmHg). All three patients were over 65 years old, were administered two tabs, had documented improved respiratory status, and had repeat SBP of at least 100 mmHg. The incidence of hypotension following MSN administration was 3.2%.  
 Conclusion. Hypotension was rare and self-limited in this sample of prehospital patients receiving MSN. 
 

 

Morphine for MI - Benefit and risk

Should we be using morphine to treat chest pain? It seems like an odd question - we're supposed to treat pain, right? - but there some interesting wrinkles to this issue when it comes to heart problems; i.e. acute coronary syndrome (ACS).

At the outset, let me emphasize that the Sponsor Hospital Council guidelines suggest that morphine be used, up to 0.1 mg/kg IV, if chest pain of suspected cardiac origin is not relieved with 3 tabs/sprays of nitroglycerin. That hasn't changed!

The benefit of morphine in ACS
Angina and infarction hurt, and morphine can treat that. There are other supposed benefits (reducing ischemia, reducing "stress," blood pressure reduction), but these are mostly theoretical, and often can be accomplished with other agents.

For example!  (Source)

Okay, perhaps not bourbon, but there are others.

The risk of morphine in ACS
Of course, morphine causes (infrequently) respiratory depression, hypotension, or depressed mental status. These are true for any patient, not just those with ACS, and are generally avoidable with careful administration.

The patient with ACS may face specific risks with morphine though, leading to worse outcomes with their ischemia. This is a controversial area, and there is little good evidence. Nonetheless, breathless headlines like this came out after publication of a study in 2005 (PDF link).

"News" link

This study did not prove a cause & effect relationship with morphine - the study design could only show an association - but people have proposed 3 ways that morphine could potentially harm cardiac patients; 1) direct harm to the myocardum, 2) the side effects of orphine harm the myocardium, and 3) the "masking" of ischemic pain, such that it delays definitive therapy, such as angiography/angioplasty.

1. Does morphine directly harm the myocardium in ACS?
Some people are concerned that morphine, during an episode of ACS, may directly harm the ischemic heart. The authors of the "morphine increases death risk" study remark on the discussion section that "in animal studies, morphine has been demonstrated quite conclusively to actually increase myocardial infarction size." 

They cite, as "quite conclusive," a study from 1982, where rats where given a subcutaneous dose of morphine at 3 mg/kg. (That would be 210 mg for an adult human!) They then performed open-heart surgery, and tied-off a coronary artery - just blocked it off. When they looked at the hearts 2 days later, the rats who had morphine had MIs that involved 10% more myocardium than the morphine-free rats.

Rat open-heart surgery, w/ ligation of LAD. source

On the other hand, North Carolina researchers studied rats who underwent a limited period of coronary occlusion, and found that the morphine pre-treated rats had smaller infarct extent.

So it's an open question whether any of these animal studies represent great (or even mediocre) evidence that can guide our clinical management. It's not conclusive, that much is clear.

2. Do the adverse effects of morphine (hypotension, hypoxia) cause harm in ACS?
Perhaps morphine doesn't have a direct toxic effect on the myocardium, but the known adverse effects can certainly cause problems. Generally, though, these are not common if morphine is administered cautiously, and in practice hypotension or hypoxia are rare.

One study that has been cited as demonstrating the potential for hypotension in MI patients was conducted 1969. In The effect of morphine on blood pressure and cardiac output in patients with AMI the authors gave 15 mg morphine, intramuscularly, to 10 patients with an MI. They found a "slight tendency to development of orthostatic hypotension."

So if you give 15 mg IM of morphine, you might want to be ready to give them some fluids, or just not have them stand, but this doesn't seem persuasive as a severe adverse effect.

 3. Does morphine "mask" the ischemic pain, rather than treat it?
 This is really the most interesting question - should we avoid using opiod medications that could "mask" recurrent or continuing ischemic pain, so that we can make better decisions about further interventions?  I.e., does morphine delay angiography?

Spoiler alert: We have no idea. There is no evidence here, only opinion. 



Chest pain today = abdominal pain 50 years ago?
An analogy with abdominal pain is appealing. In the past physicians relied on the severity and evolution of abdominal pain to aid them in the decision to pursue surgery. If a patient's pain was "masked," the physicians had few means to understand the evolution of the disease. Nowadays, given the accuracy of blood tests and CT scans, most clinicians feel they may safely treat the abdominal pain prior to full evaluation of the patient.

A number of people would argue that we are still at the "pre-CT scan" point now for ACS. The argument is that, absent angiography, we have few means to establish the need for invasive treatment. Like the surgeons of ye olden days, we may be led to a "false sense of security" after morphine reduces the pain.

This is an important question since, in the UA/ACS patient, we use "recurrent ischemic pain" as one factor determining how urgently the patient is taken to angiography. Dr. Stephan Smith, of Dr. Smiths ECG Blog points out one case, for example, where he believes that the heavy-handed use of opiods contributed to a delay in angiography. 
  
But how much do we depend on the character or presence of recurrent/refractory pain, as opposed to other factors? We have the ability to check troponins, perform sequential (or even continuous) ECGs, and we can look "directly" at the myocardium with a bedside echo. We are not dependent on the unimpaired report of symptoms - technology has provided a few tools!

Two patients
Let's consider two extremes, two different patient presentations.

First, how should we consider a patient who adamantly denies any chest pain/pressure (or back pain, shoulder aches, or jaw discomfort...), but has an ECG that looks like this:
 

True story. Yeah, it was an RCA.

This patient was in serious denial, but after intensive interviewing (the Geneva conventions were observed!) he admitted to "chest congestion" that improved with NTG, and consented to cath.

Second, how should we proceed with a patient who describes "crushing" chest pain, with left arm radiation, an sensation of doom, etc., and looks like this...

... but whose ECG looks like this?

Stop looking, it's normal.

Yes, pain means something, but so do the troponins, the echo, and of course the ECG. 

In the end, it's worth pointing out that Dr Smith's "missed MI"  had an initial ECG that actually showed a STEMI, albeit an uncommon (but not rare) pattern. 


Bottom line: Still a recommended therapy!
This post contains more opinion than I usually like to write. There just isn't the level of evidence to help us. I think my observations are pretty mainstream, however. Talking with my colleagues, most of them tend to agree with the use of morphine in this situation. One emergency physician remarked "That's what morphine is for - to mask pain."

Despite the hypothesis-generating evidence provide by the CRUSADE trial, there is little other evidence that suggests that morphine is harmful, or that analgesia must be deferred while patients are in pain. Despite the inflammatory press coverage of the CRUSADE results, the AHA continues to recommend the use of morphine in ACS.


But hold the bourbon!