Without evidence of benefit, an intervention should not be presumed to be beneficial or safe.

- Rogue Medic

Safety and Effectiveness of Field Nitroglycerin in Patients with Suspected ST Elevation Myocardial Infarction

 

Is prehospital use of NTG (NiTroGlycerin; GTN GlycerylTriNitrate in Commonwealth countries) safe for treating prehospital suspected STEMI (ST segment Elevation Myocardial Infarction) patients?

The evidence is limited, but does not suggest that prehospital NTG produces enough harm to discourage use in suspected STEMI. These researchers looked at the emergency department assessments of patients following prehospital NTG for suspected STEMI.  

Despite the theoretical risk, the limited retrospective studies of NTG in the prehospital setting for multiple indications suggest that the medication is safe.(10-13) However, with regard to NTG use for STEMI, the AHA International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care concluded that there was not enough evidence to determine the benefit or harm of out-of-hospital use of NTG.(14) Given the high false positive rates for STEMI identified in the field, an additional concern is that many patients treated with NTG for presumed STEMI will ultimately have an alternate etiology for their pain.(15, 16) Therefore, it is not clear that the benefits outweigh the risks of administering NTG to all patients with suspected STEMI in the field.[1]
 

This paper helps to show the safety of prehospital NTG for suspected STEMI, providing evidence that blood pressure changes were similar in suspected STEMI patients with an SBP (Systolic Blood Pressure) of 100, or higher, regardless of whether they were treated with NTG. The study is a retrospective chart review, so we do not know why some of the patients were not treated with NTG.

One reason mentioned, but not discussed, is that only 22% (96 of 440) suspected STEMI patients not treated with NTG are documented to have had pain, but there is no information on the type of pain or other cardiac symptoms of the patients. Were the paramedics avoiding treating atypical chest pain, such as pressure, heaviness, gastric discomfort, difficulty breathing, et cetera? We do not know. Was only chest pain being documented, rather than shoulder, or arm, or jaw, pain? We do not know. Did the pain resolve prior to EMS arrival? We do not know. Were the paramedics correctly recognizing when the machine interpretation of the ECGs (ElectroCardioGrams) were wrong? We do not know.

The median Initial Pain Score is documented as 8, with an IQR (Inter-Quartile Range) of 5-9 for those treated with NTG. For those not treated with NTG the Initial Pain Score is documented as 0, with an IQR of 0-0. We do not know the Initial Pain Score of those who did have pain, but were not treated with NTG. All of these patients were in an IQR that was not documented in the paper. The good news is that the suspected STEMI patients not treated with NTG act as a control group, although possibly with important differences that are not discussed in the paper.

Click on the image of the LA County protocol to make it larger.[2]

What about the 17% of suspected STEMI patients with SPB <100 mmHg who were treated with NTG?

Was medical command (California has certified MICNs [Mobile Intensive Care Nurses] providing medical command on the radio, with physicians available, as well) contacted for authorization to deviate from the protocol? If so, that is something that should be documented in the charts, which were reviewed for this paper. That information is not included in this paper. Those patients are much more interesting to me.

I do not object to using NTG to treat suspected STEMI with an SBP below 100 mmHg, but the authors seem to think that EMS should not even consider it. Do the outcomes of those patients support the approach of the authors? We do not know.

I suspect that the fears of bottoming out the blood pressure are very exaggerated, but it would be nice to have some evidence either way.

An important secondary end point was the differences between those with inferior/right ventricular STEMI, but treated with NTG.  

By vasodilating all blood vessels, and the venous system in particular, it causes a drop in blood pressure and preload. Thus, there is concern for precipitating hypotension in ACS involving the right ventricle.(1-3) Contraindications to the use of NTG, as outlined by the American Heart Association (AHA) Guidelines on the treatment of ACS, include right ventricular infarction.(4) This raises concern for use in inferior ST-segment elevation myocardial infarction (STEMI) in the prehospital setting, since many inferior STEMI result from proximal right coronary artery (RCA) occlusion and 50% involve the right ventricle.(3) Traditional 12-lead ECG is focused mainly on the left side of the heart and typically EMS protocols do not include acquisition of right-sided ECG leads. Further, in many systems, Basic Life Support (BLS) protocols allow for administration of NTG without differentiating the location of STEMI. There is also risk of other adverse events including bradycardia and cardiac arrest.(5-9)[1]
 

I have aggressively promoted the use of NTG for even hypotensive CHF/ADHF (Congestive Heart Failure/Acute Decompensated Heart Failure). Many physicians are not comfortable with that, even though the available evidence shows that aggressive IV NTG doubled the survival rate for these hypotensive patients. More research is needed on the use of NTG, especially in hypotensive patients.  

Further, we did not find an increased risk of hypotension among patients with proximal or mid RCA occlusions confirmed on coronary angiography. There are several possible reasons for our findings. First, while right ventricular involvement in inferior STEMI is common, hemodynamic instability is actually rare due to the right ventricle’s more favorable oxygen supply-demand ratio compared to the left heart and more extensive collateral flow.(3, 22) In addition, left heart occlusions may also involve the right ventricle and result in a preload dependent condition.(23-25) While limited by sample size, our results suggests that specifically avoiding NTG use in inferior STEMI, which is common in EMS systems, may be misguided. One quarter of the local EMS agencies in the state of California, for example, currently prohibit the use of NTG in inferior STEMI.(26) This analysis would benefit from additional study with a larger sample size and specific information about the infarct territory. Further studies are needed to determine which patients, in particular, are at increased risk for hypotension when treated with NTG.[1]
 

Perhaps NTG is also safe for treating patients with inferior ischemia and even right ventricular ischemia.

Footnotes:

[1] Safety and Effectiveness of Field Nitroglycerin in Patients with Suspected ST Elevation Myocardial Infarction.

Bosson N, Isakson B, Morgan JA, Kaji AH, Uner A, Hurley K, Henry TD, Niemann JT.

Prehosp Emerg Care. 2018 Dec 17:1-9. doi: 10.1080/10903127.2018.1558318. [Epub ahead of print]

PMID: 30556765

[2] Treatment Protocol: Chest Pain */ Acute MI

Reference No. 1244

LA County Paramedic Protocols

Los Angeles County Department of Health Services – Emergency Medical Services

Protocol

.

ILCOR wants the appearance of public comments with less than half the substance

 

The International Liaison Committee on Resuscitation (ILCOR) shows its priorities in the way it handles its problem with public comments.
 

Last week ILCOR posted the two new draft CoSTRs listed below for public comment. It became apparent that the commenting link was broken and those who visited the site could not comment. We apologize for the inconvenience. The commenting link is now fixed and we invite you to comment at ilcor.org/costr.

  • Advanced Airway Management During Adult Cardiac Arrest
  • Vasopressors in Adult Cardiac Arrest
  • As a reminder, the public comment period will close on 4 April 2019.[1]

     

    ILCOR made a mistake that prevented public comments from being submitted for most of the public comment period.

    ILCOR is so interested in your public comments that they have decided to send out an email to let people know that they have the same drop dead date for the comments as before, but this time they might actually be able to get the comments to work. Maybe.

    The lack of evidence of benefit of epinephrine (adrenaline in Commonwealth countries) has lasted over half a century, so what is the rush to get these new guidelines out?

    There is only one outcome that matters – survival without severe brain damage.
     


     

    ILCOR evaluates 23 outcomes.

    ILCOR considers 15 of these outcomes critical, but they are really just 5 outcomes, with some of them repeated over different rhythms. These are (in increasing order of importance to the only one that matters):

    1. For the critical outcome of survival to hospital discharge, 2. For the critical outcome of survival at 3 months, 3. For the critical outcome of favorable neurologic outcome at hospital discharge, 4. For the critical outcome of survival with unfavorable neurologic outcome at 3 months, 5. For the critical outcome of favorable neurologic outcome at 3 months,

    Many of them are repeated for each cardiac arrest rhythm or for each vasopressor, or vasopressor cocktail:

    1. Epinephrine plus vasopressin compared to epinephrine only – Any rhythm 2. Initial vasopressin compared to initial epinephrine – Any rhythm 3. Epinephrine compared to placebo – Non-shockable rhythms 4. Epinephrine compared to placebo – Shockable rhythms 5. Epinephrine compared to placebo – Any initial rhythm

    There is only one outcome that matters – survival without severe brain damage.

    There is only one study that was large enough to answer this:
     

    CONCLUSIONS
    In adults with out-of-hospital cardiac arrest, the use of epinephrine resulted in a significantly higher rate of 30-day survival than the use of placebo, but there was no significant between-group difference in the rate of a favorable neurologic outcome because more survivors had severe neurologic impairment in the epinephrine group.[2]

     

    If the people at ILCOR really think that epinephrine is beneficial in cardiac arrest, they should encourage a much larger study.

    There were 4,000 patients in each group – 4,000 placebo and 4,000 epinephrine.

    Maybe with 8,000 patients in each group, the ever decreasing “trend toward better outcome” will reach significance. Maybe it will be shown to be just another insignificant appearance of a “trend” that is the result of having so few survivors to compare.

    There were only 161 survivors without severe brain damage out of 8,000 cardiac arrest patients – 74 placebo and 87 epinephrine.

    Those resuscitated before receiving epinephrine/placebo were excluded from the study, so this is not a case of EMS that only has a 2% resuscitation rate. The focus on epinephrine is a focus on the patients least likely to be resuscitated and a focus on counterproductive outcomes.

    Almost all of our good outcomes (without severe brain damage) will be without epinephrine, because these resuscitations happen before epinephrine can be give by even the most aggressive epi enthusiast.

    What we are doing is making excuses for memorizing ineffective interventions and requiring their application is a specific way, in order to determine the quality of care. We are promoting fantasy.

    We learned that distracting from the quality of chest compressions is the most deadly thing we can do in resuscitation.

    CPR = only chest compressions – the exception is when the arrest is believed to be due to a respiratory event, such as when the Smurf sign or a respiratory/choking history is present. Chest compressions provide all of the pulmonary resuscitation that a human needs for a non-respiratory event and the respiratory events are not easily missed.

    Why require a whole bunch of skills be applied for such a tiny portion of good outcomes among cardiac arrest patients?

    Why not give up on requiring these skills when the evidence makes it clear that there is no benefit?

    All we are doing is adding cognitive load to make us feel like we are doing something special.

    We could learn something that actually benefits patients, such as how to assess patients when giving high-dose NTG (NiTroGlycerin or GTN GlycerylTriNitrate in Commonwealth countries) for even hypotensive CHF/ADHF (Congestive Heart Failure/Acute Decompensated Heart Failure), where we can make much more of a difference and prevent cardiac arrest, but we don’t.[3],[4],[5]
     


     

    Cognitive load is not just a problem for paramedics and nurses, or med/surg doctors, but also for emergency physicians:

    Cognitive Load and the Emergency Physician
    April 12, 2016
    James O’Shea
    emDocs
    Article

    Why are we distracting everyone from things that do improve the only outcome that matters, in order to promote things that do not improve any outcome that matters?

    Here is what I wrote –
     

    The primary source for the recommendation to keep things the same is a brand new study – PARAMEDIC2.

    This showed no statistically significant improvement in the only outcome that matter – survival without severe brain damage.

    A larger study might show that there is a real improvement – or it may put the epi hypothesis out of its misery.

    I will eventually have a cardiac arrest. If I am resuscitated, whom will ILCOR send to change my diaper, and attend to the other things I can no longer attend to?

    We need evidence of a significant benefit in order to justify distracting everyone from interventions that actually do improve survival without severe brain damage.

    .

     

    The commenting link is now fixed and we invite you to comment at ilcor.org/costr

    Maybe they will pay attention. Dr. Rory Spiegel of EM Nerd has a detailed comment that is also critical of ILCOR’s proposed “strong recommendation” of epinephrine.

    Footnotes:

    [1] Vasopressors in Adult Cardiac Arrest
    Time left for commenting: 11 days 15:49:49
    ILCOR staff
    Created: March 21, 2019 · Updated: March 21, 2019
    Draft for public comment
    Consensus on Science with Treatment Recommendations (CoSTR)
    Vasopressors in Adult Cardiac Arrest page for comments until April 04, 2019 at 06:00 Eastern Time

    [2] A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest.
    Perkins GD, Ji C, Deakin CD, Quinn T, Nolan JP, Scomparin C, Regan S, Long J, Slowther A, Pocock H, Black JJM, Moore F, Fothergill RT, Rees N, O’Shea L, Docherty M, Gunson I, Han K, Charlton K, Finn J, Petrou S, Stallard N, Gates S, Lall R; PARAMEDIC2 Collaborators.
    N Engl J Med. 2018 Aug 23;379(8):711-721. doi: 10.1056/NEJMoa1806842. Epub 2018 Jul 18.
    PMID: 30021076

    Free Full Text from N Engl J Med.
     

    In a Bayesian analysis that used an assumption of no benefit from adrenaline, the posterior probability that the absolute rate of survival was at least 1 percentage point higher in the epinephrine group than in the placebo group was 37% (Fig. S3 in the Supplementary Appendix). The probability that the absolute survival rate was at least 2 percentage points higher was 0.2%. With respect to the rate of survival with a favorable neurologic outcome at hospital discharge, the probabilities that the rate was at least 1 or 2 percentage points higher with epinephrine were 1.9% and 0%, respectively (Fig. S4 in the Supplementary Appendix).

     

    The probability of a good outcome (no severe brain damage) is not improved with epinephrine.

    If we want to improve outcomes, we need to look elsewhere, because there is nothing to be gained with epi.

    [3] Intravenous nitrates in the prehospital management of acute pulmonary edema.
    Bertini G, Giglioli C, Biggeri A, Margheri M, Simonetti I, Sica ML, Russo L, Gensini G.
    Ann Emerg Med. 1997 Oct;30(4):493-9.
    PMID: 9326864 [PubMed – indexed for MEDLINE]

    [4] Unreasonable Fear of Hypotension and High-Dose NTG – Part I
    Thu, 29 Aug 2013
    Rogue Medic
    Article

    [5] Unreasonable Fear of Hypotension and High-Dose NTG – Part II
    Wed, 04 Sep 2013
    Rogue Medic
    Article

    .

    $16M on EMS Stroke Trial? Dr. Rick Bukata Wants His Money Back!


     

    FAST-MAG[1] actually has good methodology, so why is Dr. Rick Bukata so upset? Is this just USC vs. UCLA off the field/court?

    Should the hypothesis being tested have received the Queen for a Decade treatment?

    He wants his money back? Roughly 160 million tax payers in the US, so $0.10 per tax payer, but he makes more than the average schlub, so maybe as much as 50 cents for him. He can’t even buy enough caffeine to raise his blood pressure with that.
     

    In a commentary regarding the IMAGES trial by Larry Goldstein of the Duke Center for Cerebrovascular Disease in the same issue of the Lancet in which the study was published, he noted that of more than 40 clinical trials of “neuroprotectants” involving over 11,000 patients, none has shown any evidence of benefit. Ten years later, the same is true.[2]

     

    But look at the animal studies!

    But look at the time being saved!

    The authors actually like to repeat the term Golden Hour – as if that is new or valid.
     

    So, if you are still a believer in the potential of magnesium, why not try and give magnesium in a pilot clinical study involving stroke patients in the ED? It would have been a relatively simple study to do. It could have been performed in selected EDs throughout the country and the answer would have been established in a fraction of eight years and at a very small fraction of $16 million.

    Instead, the Fast-Mag investigators decide that giving magnesium in the field (probably about 10-20 minutes faster than could be given in the ED) would be a reasonable study.[2]

     

    Gosh, when he brings reason into the argument, it just seems that the other side has none.

    What could the money have been spent on?

    Epinephrine vs. placebo in cardiac arrest? The number of lives affected is large and we are currently treating based on philosophy, not science.

    IV (IntraVenous) bolus NTG (NiTroGlycerin – GTN GlycerylTriNitrate in Commonwealth countries) vs. SL (SubLingual) NTG for acute CHF (Congestive Heart Failure)? This affects even more patients than cardiac arrest and there is good evidence that IV bolus NTG dramatically improves outcomes, while SL NTG is not based on evidence.

    Excited delirium treatment with various IM (IntraMuscular) medications to see what is safest and most effective and at what dose. A large trial would be necessary.

    With no good reason to be optimistic about outcomes, why take this multimillion dollar long shot?

    Maybe it has to do with tPA (tissue Plasminogen Activator) and the failure to get emergency physicians to accept the poor research on tPA – tPA showed harm, or no benefit, in 9 out of 11 studies.[3]

    Ironically, if those studies used methodology similar to this study, that could be showed harm, or no benefit, in 11 out of 11 studies.

    Dr. Jeffrey L. Saver, one of the authors, has a presentation on FAST-MAG that spends a lot of time on tPA, even prehospital tPA.

    What does Dr. Sarver consider to be positive about FAST-MAG? Here are some of his slides.[4]
     


     

    FAST-MAG means more tPA use.
     


     

    FAST-MAG means doing a lot of things that have not been done before and expecting the outcome to be good.

    This is the kind of person who starts turning all of the dials on a ventilator and then looks at the patient to see what the result is.

    A reasonable approach to research is to limit variables, not brag about how much prudence has been abandoned.
     


     

    FAST-MAG means time will be saved, but . . . .
     

    Walter Koroshetz, MD, neurologist and deputy director of the National Institutes of Health’s (NIH’s) National Institute of Neurological Disorders and Stroke, sponsor of the FAST-MAG study, says that lessons can be learned from the trial.[5]

     

    “The NIH have a new network to do more prehospital trials, but we need phase 2 studies first that demonstrate some biological effect before going into a large costly phase 3 trials.”[5]

     

    This is a $16 million bet that time is the only factor that matters.

    I hope these doctors do not drive the way they gamble.

    What were the results?

    The results were the same as all of the previous studies of magnesium – no improvement.

    There is no Magnesium Golden Hour.
     

    And, please, no – don’t even consider the idea of giving tPA in the field.[2]

     

    Well, . . . .
     

    Dr. Saver explained that tPA cannot be given at present in a prehospital setting because hemorrhagic stroke has to be ruled out with computed tomography (CT). The use of ambulances with a CT scanner on board has been studied in Germany and is now starting to be tested in the United States.[5]

     

    Be very afraid.

    On the other hand, the authors did not rush this treatment into EMS protocols, as we recently have in EMS in so many places with therapeutic hypothermia, based entirely on research done in the ED (Emergency Department). It works in the ED, but not in the ambulance. 😳

    FAST-MAG was approved in 1999, several years after the EMS nifedipine (Procardia) for hypertensive crisis crisis. There was no study in the EMS setting of a treatment for the EMS setting. This involved treatment of the surrogate endpoint of blood pressure numbers, which makes for an easy win, such as a systolic drop of 250 -> 90 in ten minutes. 😳

    We need a balance between rushing to add the new cool treatment (and the predictable removal of the treatment decades later) and the inappropriate rush to a large scale trial of something that has repeatedly failed smaller studies.
     

    Go read Dr. Bukata’s full article.

    Footnotes:

    [1] Methodology of the Field Administration of Stroke Therapy – Magnesium (FAST-MAG) phase 3 trial: Part 2 – prehospital study methods.
    Saver JL, Starkman S, Eckstein M, Stratton S, Pratt F, Hamilton S, Conwit R, Liebeskind DS, Sung G, Sanossian N; FAST-MAG Investigators and Coordinators.
    Int J Stroke. 2014 Feb;9(2):220-5. doi: 10.1111/ijs.12242.
    PMID: 24444117 [PubMed – in process]

    Methodology of the Field Administration of Stroke Therapy – Magnesium (FAST-MAG) phase 3 trial: Part 1 – rationale and general methods.
    Saver JL, Starkman S, Eckstein M, Stratton S, Pratt F, Hamilton S, Conwit R, Liebeskind DS, Sung G, Sanossian N; FAST-MAG Investigators and Coordinators.
    Int J Stroke. 2014 Feb;9(2):215-9. doi: 10.1111/ijs.12243. Epub 2014 Jan 13.
    PMID: 24444116 [PubMed – in process]

    [2] $16M on EMS Stroke Trial? I Want My Money Back!
    by Rick Bukata, MD
    March 24, 2014
    Emergency Physicians monthly
    Article

    [3] The Guideline, The Science, and The Gap
    Wednesday, April 17, 2013
    Dr. David Newman browngorilla540
    Smart EM
    Article

    [4] Treat Stroke in the Field:
    Lessons from the NIH FAST-MAG Trial

    Jeffrey L. Saver, MD, Professor of Neurology
    UCLA Stroke Center
    2012
    Presentation Slides in PDF Downoad format.

    [5] FAST-MAG: No Benefit of Prehospital Magnesium in Stroke
    Sue Hughes
    February 14, 2014
    Medscape
    Article

    .

    Is 50 NTG Too Much for One Patient?


    Image credit. Three different forms of nitroglycerin, intravenous, sublingual spray, and the nitroglycerin patch.
     

    In the comments to Unreasonable Fear of Hypotension and High-Dose NTG – Part I is the following from Kasey Marshall on the patient I treated with over 50 NTG (NiTroGlycerin – GTN GlycerylTriNitrate in Commonwealth countries) for CHF/ADHF (Congestive Heart Failure/Acute Decompensated Heart Failure).
     

    My question is how long did the study go on that one patient received over 50 NTG tablets and is still functioning.

     

    That patient was not in the study.

    That was a patient I was treating with over 50 NTG.

    The patient’s systolic blood pressure (the top number) never dropped below 200 mmHg.

    Where is the problem?
     

    I didn’t think that an individual was supposed to receive more than 3 NTG tablets in 5 minutes intervals before professional medical assistance.

     

    As used in this case, NTG is an off-label use of NTG, but there is good evidence that high-dose NTG is safe and effective for CHF/ADHF. There is better evidence for high-dose NTG to improve outcomes for CHF/ADHF patients than there is evidence that standard-dose NTG improves outcomes for patients with chest pain/heart attacks/ischemia.
     

    INDICATIONS AND USAGE
    Nitroglycerin is indicated for the acute relief of an attack or prophylaxis of angina pectoris due to coronary artery disease.
    [1]

     

    I am a paramedic.

    I am professional medical assistance.

    One reason for the maximum of 3 NTG is to encourage the patient to go to the hospital and not stay home taking NTG, which wears off quickly. Once at the hospital, the patient will often be receiving IV (IntraVenous) NTG.
     

    Patients with ischemic discomfort should receive up to 3 doses of sublingual or aerosol nitroglycerin at 3- to 5-minute intervals until pain is relieved or low blood pressure limits its use (Class I, LOE B).[2]

     

    By ischemic discomfort, they mean heart attack symptoms, not CHF patients, but they do not provide any evidence. They suggest that there is evidence by writing (Class I, LOE B), but there is not a single reference listed to support this.

    There is no reference to doses for CHF treatment. Doses for CHF should be much higher than doses for heart attack.
     

    I know the earlier NTG is administered, the better but I think that there should be a limit on how much can be can be administered to one patient in a 48 hour period before more serious medical attention should be sought.

     

    I have not yet had a transport that came close to 48 hours, so I do not worry about that kind of time period.

    Serious medical attention? Rein in my pathetic attempts at humor? 😳

    We should give NTG to CHF patients until it is coming out of the patient’s ears, until the patient’s systolic blood pressure drops by 30%, or until the patient improves.

    We should be giving IV boluses of 1 mg or 2 mg every three minutes with CPAP (Continuous Positive Airway Pressure), rather than interrupting CPAP to give SL (SubLingual) NTG or using NTG by an ineffective route (paste that is not absorbed through the skin, because circulation is shunted away from the skin).
     

    Conclusion: In this single-center, retrospective, unadjusted analysis of primarily African-American patients with acute hypertensive heart failure, nitroglycerin administered by higher dose bolus without concurrent intravenous infusion was associated with a significant decrease in ICU admissions and hospital length of stay. Based on our findings, bolus higher dose nitroglycerin appears to be a viable option for the management of such patients.[3]

     

    The IV bolus NTG was better than the IV drip NTG.
     

    I know when my mom had a prescription for NTG she was only told to take two, NTG tablets and if a third was needed to call paramedics. And that it was needed two days in a row that she needed to stay in the hospital for observation.

     

    I expect that the reason for staying in the hospital was the heart condition that resulted in her taking the NTG.

    Two doses of NTG will wear off quickly and are not a reason for hospitalization.

    EMS will probably be giving multiple-dose NTG every 3-5 minutes, often 10, 20, or 30 NTG to one patient for CHF/ADHF.
     

    Administration of high-dose nitroglycerin is an effective treatment that has been shown to improve the respiratory symptoms associated with ADHF, and decrease the incidence of death due to myocardial infarction and mechanical ventilation, particularly when initiated early.4 – 6 [4]

     

    MSN (Multiple Simultaneous Nitroglycerin) is safe and effective for CHF/ADHF.
     

    CONCLUSION:
    Hypotension was rare and self-limited in prehospital patients receiving MSN.
    [4]

     

    The scary side effect of high-dose NTG almost never happened, but when hypotension did occur, it went away without any need for treatment.

    Footnotes:

    [1] INDICATIONS AND USAGE
    NITROGLYCERIN tablet
    [Glenmark Generics Inc., USA]
    DailyMed
    FDA Label

    [2] Nitroglycerin (or Glyceryl Trinitrate)
    2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science
    Part 10: Acute Coronary Syndromes
    Initial General Therapy for ACS
    Free Full Text from Circulation.

    [3] Nitroglycerin for Treatment of Acute, Hypertensive Heart Failure: Bolus, Drip or Both?
    Kwiatkowski GM, Saely S, Purakal J, Mahajan A, Levy PD/Detroit Receiving Hospital, Detroit, MI; Wayne State University School of Medicine, Detroit, MI
    Annals of Emergency Medicine, Volume 60, issue 4 (October, 2012), p. S9.
    ISSN: 0196-0644 DOI: 10.1016/j.annemergmed.2012.06.049
    Abstract 22 Indexed with OhioLINK Journal Article Locator

    [4] Prehospital High-dose Sublingual Nitroglycerin Rarely Causes Hypotension.
    Clemency BM, Thompson JJ, Tundo GN, Lindstrom HA.
    Prehosp Disaster Med. 2013 Aug 21:1-4. [Epub ahead of print]
    PMID: 23962769 [PubMed – as supplied by publisher]

    .

    Unreasonable Fear of Hypotension and High-Dose NTG – Part II

    ResearchBlogging.org
     

    Continuing from Part I to look at the results of the study of high-dose SL (SubLingual) NTG (NiTroGlycerin – GTN GlycerylTriNitrate in Commonwealth countries) by EMS for CHF (Congestive Heart Failure) that Peter Canning wrote about.[1]
     

    For CHF, more NTG does not produce more of a drop in blood pressure.
     

    If you disagree, provide evidence.

    I tend to get anecdotes, with excuses, rather than any kind of evidence.

    Anecdotes are often indications that the person telling the anecdote does not understand and is trying to make up for that lack of understanding with bravado.
     


     

    Therefore, we will continue to look at the evidence.
     


    Click on images to make them larger.
     

    You can see that some patients did have large drops in systolic blood pressure with only a double dose of NTG. To clarify, I highlighted the large drops in red below.
     


     

    Only six large drops in systolic blood pressure.

    Three systolic blood pressures dropped below 100 mmHg.

    The expected happened with these dramatic drops in blood pressure and cases of hypotension –

    Nobody had any bad outcomes.

    The patients recovered without any intervention, such as fluid bolus, epinephrine, or whatever other placebo might be suggested.

    Placebo?

    A treatment that does not do anything more than doing nothing (benign neglect) is a placebo.

    All these patients needed was a paramedic smart enough to use benign neglect.

    Anecdotalists give a lot of treatments, because they mistakenly feel that that their intervention improve outcomes. Where is their evidence? In their overactive imaginations.

    Those drops with double doses of NTG are scary. How bad was the outcome with triple doses of NTG?
     


     

    Again, I highlighted the single big drop – only one – only dropped to about 130 mmHg systolic – in red below.

    I added green to highlight the increases in systolic blood pressure after triple dose NTG. There were plenty of increases in systolic blood pressures after double dose NTG, but there were so many increases that it would have made the graph more difficult to read.
     


     

    Multiple dose NTG every 5 minutes was clearly safe in this study.

    Multiple dose anecdotes about Oh, no! What if . . . ? – continue to be wrong.

    Forget the anecdotes.

    There is plenty of evidence of safety.

    Footnotes:

    [1] Safety of High Dose Nitro in CHF
    StreetWatch: Notes of a Paramedic
    August 29, 2013
    Peter Canning
    Article

    [2] Prehospital High-dose Sublingual Nitroglycerin Rarely Causes Hypotension.
    Clemency BM, Thompson JJ, Tundo GN, Lindstrom HA.
    Prehosp Disaster Med. 2013 Aug 21:1-4. [Epub ahead of print]
    PMID: 23962769 [PubMed – as supplied by publisher]

    Clemency BM, Thompson JJ, Tundo GN, & Lindstrom HA (2013). Prehospital High-dose Sublingual Nitroglycerin Rarely Causes Hypotension. Prehospital and disaster medicine, 1-4 PMID: 23962769

    .

    Comments on High-Dose NTG for CHF

     

    There are a couple of important comments to Unreasonable Fear of Hypotension and High-Dose NTG – Part I. In one, Brooks Walsh writes –
     

    50 NTG tabs for 1 patient? Holy cow, that sounds labor intensive!

     

    This would have been labor intensive.
     


     

    There are 52 NTG tabs in that picture. The study protocol mentioned tabs, but I was using NTG spray.

    If I had been using tabs, the patient might have ended up being treated for thrush, or for a seizure, due to the white paste in his mouth, rather than CHF.

    Even with all of the not expired, still potent, NTG spray, his systolic blood pressure never dropped below 200 mm/Hg.
     

    Did you have to have another ALS unit intercept to re-supply you with more little brown bottles?

     

    Medium-size red spray bottles.
     


     

    The spray level did descent like a low MPG fuel gauge.
     

    In the other comment, JJ Greulich writes –
     

    We were just talking about this today in Medic class.

     

    This is a topic that seems to require a lot more time than most others, but after seeing large doses dramatically improve outcomes without any significant side effects, the concept seems to be easier to grasp.
     

    I was curious as to why it is alright to give NTG or another Nitrate every 3-5 minutes without worrying about the BP tanking, but didn’t have time to ask. Can you elaborate on this a little for me?

     

    I do not worry about why. Failed treatments are often supported by claims that the mechanism is _________. Those are the failed treatments.

    Similarly, misplaced endotracheal tubes are often accompanied by the words – I saw it go through the cords.

    We have known since the 1970s that most CHF patients are not fluid overloaded, but people continue to claim that we need to remove the imaginary fluid overload with furosemide (Lasix). That’s a reasonable explanation, but it’s lousy medicine.

    Expect explanations to be wrong.

    High-dose NTG works. The improvement in outcomes is repeatable, predictable, and results in many fewer deaths and many fewer intubations.

    Pathophysiology can be years behind research, because pathophysiology is derived from research, the conclusions of which may be extrapolated well beyond what is reasonable. Pathophysiology tends to lead us to believe that we know more than we do.

    This can lead to excessive caution, which is dangerous, or to recklessness, which can be just as dangerous as excessive caution being too safe.

    Based on research, we could probably save half of the patients who will die due to acute CHF, if we would only stop trying to be safe.

    We are killing our patients with caution and congratulating ourselves on how careful we are.

    CHF/ADHF (Congestive Heart Failure/Acute Decompensated Heart Failure) patients seem to be resistant to nitrates.

    This may be similar to giving morphine to someone who has been taking regular doses of an opioid. To treat the patient’s pain, we need to give a much larger dose than would be needed for pain management for an opioid naive patient (no recent opioid use) with similar pain. The same is true for addicted patients, since tolerance is one part of what changes with addiction.

    In-hospital treatment with nitrates can include nitrate holidays – temporary removal (holiday) of the nitrate to allow the tolerance to decrease.

    The pathophysiology appears to be that high-dose NTG – especially when given as an IV Bolus – has much more of an effect on afterload (the resistance that the heart is pushing against and part of what is causing the failing heart to fail), than on anything else.

    Large IV bolus doses of NTG to reduce afterload, even for hypotensive patients, may be the most beneficial drug treatment for acute CHF.
     

    Go listen to the very first EMCrit podcast.
     

    In under 10 minutes Dr. Weingart explains how to save the lives of crashing CHF patients.

    .

    Unreasonable Fear of Hypotension and High-Dose NTG – Part I

    ResearchBlogging.org
     

    Peter Canning writes about a study of high-dose SL (SubLingual) NTG (NiTroGlycerin – GTN GlycerylTriNitrate in Commonwealth countries) by EMS for CHF (Congestive Heart Failure).[1]

    I have some problems with the study.
     


    Click on images to make them larger.
     

    This is just moderate-dose, not high-dose.

    I have had protocols that allow for more aggressive dosing (every 3-5 minutes) going back to 2008.[2]
     


     

    I have probably given more triple-dose NTG than was given to the entire intervention group. I have given over 50 SL NTG to just one patient, while they only managed to give a total of 87 tablets in 29 triple doses in the entire study.
     


     

    It is good to provide more evidence that multiple dose NTG is safe, but we have had good evidence that prehospital high-dose IV NTG dramatically improves outcomes since the 1990s.

    We need more prehospital aggressive IV (IntraVenous) NTG research.
     

    Administration of high-dose nitroglycerin is an effective treatment that has been shown to improve the respiratory symptoms associated with ADHF, and decrease the incidence of death due to myocardial infarction and mechanical ventilation, particularly when initiated early.4 – 6 [3]

     

    I agree with that.

    However, EMS is the best earliest place to start IV NTG.
     

    From 1984 through 1991, new guidelines for the use of intravenous nitrates, based on differential treatment according to blood pressure, were in use.

    RESULTS:
    Overall prehospital mortality rate for APE in all patients was 7.8% (50 of of 640 patients). Mortality after 1984 was significantly lower than before (5.3% versus 13%, P < .01). Nitrates were effective in reducing mortality, even in hypotensive patients. Multivariate analysis showed that outcome was significantly affected by two clinical features (dyspnea and low blood pressure), treatment with nitrates, and calendar period effects (before/after 1984).
    [4]

     

    Not just hypertensive patients, but also hypotensive patients benefited from EMS IV NTG!

    Nitrates were effective in reducing mortality, even in hypotensive patients.

    The CHF death rate dropped from 13% all the way down to 5.3%
     


     

    Am I complaining that the current study is useless?

    Not at all.

    There is some excellent information that debunks much of the dogma against multiple-dose NTG.
     


    Look at the cases of hypotension – systolic blood pressure less than 100 mm/Hg.

    3 cases, but only in the double dose group.

    All of the hypotension went away without any treatment.

    Zero cases in the triple dose group and the quadruple dose patient did not become hypotensive.
     

    For CHF, more NTG does not produce more of a drop in blood pressure.
     

    Disagree?

    Provide evidence, not anecdotes.

    Part II will look at the evidence of safety from this study more closely.

    Also see –

    Nitroglycerin for Treatment of Acute, Hypertensive Heart Failure – Bolus, Drip or Both?
    Wed, 17 Oct 2012

    Is a half a bottle of nitro too much for a single dose?
    Sun, 18 Nov 2012

    NTG and the Hero Medic
    Street Watch
    November 7, 2012

    Footnotes:

    [1] Safety of High Dose Nitro in CHF
    StreetWatch: Notes of a Paramedic
    August 29, 2013
    Peter Canning
    Article

    [2] Congestive Heart Failure
    5002– ALS – Adult/Peds
    2008, 2011, and 2013 Statewide ALS Protocol
    Pennsylvania
    Page with link to Full Text Download of Full Protocols in PDF format.

    [3] Prehospital High-dose Sublingual Nitroglycerin Rarely Causes Hypotension.
    Clemency BM, Thompson JJ, Tundo GN, Lindstrom HA.
    Prehosp Disaster Med. 2013 Aug 21:1-4. [Epub ahead of print]
    PMID: 23962769 [PubMed – as supplied by publisher]

    [4] Intravenous nitrates in the prehospital management of acute pulmonary edema.
    Bertini G, Giglioli C, Biggeri A, Margheri M, Simonetti I, Sica ML, Russo L, Gensini G.
    Ann Emerg Med. 1997 Oct;30(4):493-9.
    PMID: 9326864 [PubMed – indexed for MEDLINE]

    Clemency BM, Thompson JJ, Tundo GN, & Lindstrom HA (2013). Prehospital High-dose Sublingual Nitroglycerin Rarely Causes Hypotension. Prehospital and disaster medicine, 1-4 PMID: 23962769

    Bertini G, Giglioli C, Biggeri A, Margheri M, Simonetti I, Sica ML, Russo L, & Gensini G (1997). Intravenous nitrates in the prehospital management of acute pulmonary edema. Annals of emergency medicine, 30 (4), 493-9 PMID: 9326864

    .

    Dr. Nicholas DeRobertis, Improved Care for the Patients, Not for the Good Old Boys Club, Sudden Death at 60

     

    One of my first medical directors was Dr. Nicholas DeRobertis. He tried to change the common practice of the local paramedics of dumping intoxicated, or otherwise undesirable patients, at Yonkers General Hospital regardless of which hospital was closest.

    Sadly, this puerile EMS favoritism is still common in many places. He also tried to change other practices that are bad for patients and bad for EMS.
     


     

    He was at St. Joseph’s on Sunday helping to implement a new electronic medical records system when he began to feel ill. He entered the emergency room he directed for many years – this time as a patient.

    Friends said he suffered a heart attack. DeRobertis was later transferred to Montefiore Medical Center in the Bronx, where he died late Monday.
    Dr. DeRobertis, and other attending physicians, would offer continuing education classes for free for EMS, but too often I was the only one attending. He had a lot of work to do to change EMS from the good old dangerous boys club to something that is focused on excellent patient care.
    [1]

     

    We had to call medical command for almost everything back then. I had one patient who was combative due to CHF (Congestive Heart Failure) and called for orders for aggressive NTG (NiTroGlycerin – GTN GlycerylTriNitrate in Commonwealth countries). The command doctor refused orders for NTG, with the excuse that “Prehospital nitro doesn’t work.” Even two decades ago, there was evidence that nitrates are the best medicine for CHF.

    I talked with Dr. DeRobertis and he said that he would make sure that did not happen again. After talking with Dr. DeRobertis, I never encountered that problem again.

    With Dr. DeRobertis it was clear that good patient care came first, not the doctors, not the nurses, not the most senior medics (often those who have been harming patients the longest), not even the protocol.

    Back in the 1970s there was good evidence that furosemide (Lasix [frusemide in Commonwealth countries]) does not improve outcomes for CHF patients, but many of us still give furosemide to CHF patients.[2]

    Back in the 1980s there was good evidence that aggressive treatment with nitrates (NTG, ISMN [IsoSorbide MonoNitrate], ISDN [IsoSorbide DiNitrate], . . . ) does improve outcomes for CHF patients, but many of us still only give small doses of nitrates to CHF patients.[3],[4],[5]

    Dr. DeRobertis was making EMS evidence-based when even in-hospital emergency medical practice was still mostly traditional.

    His death is is a great loss for his family, his patients, and all of the patients he affected through his recognition of the benefits treatment based on evidence, rather than tradition.

    Footnotes:

    [1] Dr. Nicholas DeRobertis, Westchester emergency medicine leader, dies
    Jul. 2, 2013 11:01 AM
    lohud.com
    Jane Lerner
    Article

    [2] Blood volume prior to and following treatment of acute cardiogenic pulmonary edema.
    Figueras J, Weil MH.
    Circulation. 1978 Feb;57(2):349-55.
    PMID: 618625 [PubMed – indexed for MEDLINE]

    Free Full Text Download from Circulation in PDF format
     

    The concept that acute heeart failure with pulmonary edema is associated with an increase in intravascular volume is therefore not supported. To the contrary, there is a reduction of blood volume during acute pulmonary edema.

    This is just one of the studies from the 1970s showing the problems with furosemide.

    [3] Comparison of nitroglycerin, morphine and furosemide in treatment of presumed pre-hospital pulmonary edema.
    Hoffman JR, Reynolds S.
    Chest. 1987 Oct;92(4):586-93.
    PMID: 3115687 [PubMed – indexed for MEDLINE]

    Free Full Text from Chest.

    Group A patients were the only patients not to receive morphine sulfate, group B patients the only ones not to receive nitroglycerin, and group D patients the only ones not to receive furosemide. Group

    Group A patients (No morphine [received NTG and furosemide]) had the best outcome. No intubations when eliminating morphine.

    Group B patients (No NTG [received morphine and furosemide]) had the worst outcome. 31% intubated when eliminating NTG.

    [4] [The use of injectable nitroglycerin (a bolus of 3 mg) in the treatment of cardiogenic pulmonary edema].
    Bosc E, Bertinchant JP, Hertault J.
    Ann Cardiol Angeiol (Paris). 1982 Oct-Nov;31(6):477-80. French. No abstract available.
    PMID: 6818888 [PubMed – indexed for MEDLINE]
     
    This is in French, but PMID: 7662071 (1995) describes the results –

    Bosc et al4 administered one 3-mg intravenous trinitroglycerin bolus to patients with CPE. There was improvement in 71% of the 35 patients studied. Five patients (13%) became hypotensive to an SBP <90; however, each recovered after a few minutes.

    [5] Emergency treatment of severe cardiogenic pulmonary edema with intravenous isosorbide-5-mononitrate.
    Harf C, Welter R.
    Am J Cardiol. 1988 Mar 25;61(9):22E-27E.
    PMID: 3348137 [PubMed – indexed for MEDLINE]
     

    These data indicate that i.v. IS-5-MN is effective and safe for the management of severe acute cardiogenic pulmonary edema.

    .