Wanting again, I’m considerably shocked I by no means printed a First10 method to sympathetic crashing pulmonary edema. I assume it by no means felt obligatory, because it was the primary ever EMCrit submit, and due to this fact felt nicely coated within the FOAMed group. Nevertheless, a full 15 years after that first EMCrit podcast (congrats on the last decade and a half of FOAMed Scott), I nonetheless encounter many clinicians (nurses and docs alike) who’re uncomfortable with applicable doses of IV nitroglycerin. To be truthful, till now, the proof has principally been observational and retrospective. Nevertheless, we now have an RCT that reveals fairly exceptional enchancment with excessive dose intravenous nitroglycerin, so maybe observe will begin to change.
The Accompanying YouTube Video
The paper
Siddiqua N, Mathew R, Sahu AK, Jamshed N, Bhaskararayuni J, Aggarwal P, Kumar A, Khan MA. Excessive-dose versus low-dose intravenous nitroglycerine for sympathetic crashing acute pulmonary edema: a randomised managed trial. Emerg Med J. 2024 Jan 22;41(2):96-102. doi: 10.1136/emermed-2023-213285. PMID: 38050078
The Strategies
That is an open-label, single middle, pragmatic randomized managed trial from India.
Sufferers
Grownup sufferers with acute onset (lower than 6 hours of signs) dyspnea, hypertension, tachypnea, hypoxia, and bilateral crackles.
Particular standards have been systolic stress >159 and diastolic stress >100 (or MAP >120), RR >30, sats <90%.
Exclusions: acute MI, hypersensitivity to GTN, sildenafil inside 24 hours, tadalafil inside 48 hours, average to extreme aortic stenosis, hypertrophic cardiomyopathy, sufferers requiring instant intubation.
Intervention
Excessive dose intravenous nitroglycerine: 600–1000 mcg bolus adopted by an infusion beginning at 100 mcg/min and subsequently titrated by scientific response.
Comparability
Low dose intravenous nitroglycerine: no bolus and an infusion beginning at 20–40 mcg/min. Dose was titrated by the doctor, however was not allowed to exceed 250 mcg/min.
Widespread customary procedures
Each teams got BIPAP assist with an preliminary inspiratory constructive airway stress of 12 mm Hg and expiratory constructive airway stress of 6 mm Hg.
Consequence
They used ‘co-primary outcomes’ of decision of signs at 6 and 12 hours. (Subjective enchancment on a 7 level Likert scale, plus no less than 2 goal markers of enchancment: decision of tachypnea, decision of hypoxia, decision of hypertension.)
The Outcomes
They enrolled 52 sufferers out of 169 initially screened. The imply age was within the mid 40s with a few 50/50 male/feminine break up. This was a comparatively sick cohort, regardless of being so younger. 70% of the sufferers had persistent kidney illness and primarily all of them had baseline hypertension. Vitals indicators at presentation included a median respiratory price within the excessive 30s, oxygen saturation of 80-85%, and blood stress of about 200/125.
Excessive dose nitroglycerin was a lot better than low dose. At 6 hours, 65% of the excessive dose group had decision of their signs as in comparison with solely 12% of the low dose group (p<0.001). The distinction was nonetheless giant at 12 hours, with 89% decision as in comparison with 19% (p<0.001). (These numbers are all surprisingly low to me, as I get near 100% decision of SCAPE inside the first hour or two with excessive dose GTN and BiPAP.)
Principally all outcomes have been worse within the low dose group. Intubation was 19% vs 4% (though not statistically vital). (I’ve not intubated one among these sufferers in my profession, so this group appears means sicker, or completely different in another means, than what I’m seeing in Canada.) Admission charges, hospital size of keep, and MACE have been all larger with low dose nitroglycerin.
If you happen to care about monitor based mostly outcomes, the very important indicators additionally improved extra within the excessive dose group:
By way of hostile occasions, no sufferers developed hypotension in both group. 11 sufferers within the low dose group and three within the excessive dose group developed a headache.
My ideas
This is a vital research, however it’s clearly removed from an ideal research. It’s a small single middle research, with a inhabitants that appears very completely different from what I’m used to in North America. (Assets and administration methods may also be completely different, however I don’t know.) Opaque envelopes are usually not the perfect allocation concealment process. It’s dishonest to decide on co-primary outcomes, particularly when you’re simply utilizing completely different time frames that aren’t actually clinically completely different. The calculated pattern measurement is predicated on an anticipated 54% absolute distinction between the teams. Though I’m a fairly large supporter of excessive dose nitroglycerin, that appears ridiculously over-optimistic to me.
The most important particular person methodologic challenge with this research is that it was not blinded. Even when you’re measuring comparatively goal scientific outcomes, a scarcity of blinding introduces a excessive danger of bias. Vitals indicators needs to be goal, however we now have all rechecked vitals once they don’t match what we count on. Affected person reviews of enchancment might be influenced by the best way questions are requested. (“You’ve been on the best dose for a couple of hours now. You have to be feeling higher, proper?”) The variations on this trial appear too dramatic to be solely based mostly on bias, however we can’t have a excessive degree of certainty till we see prime quality, multi-center, blinded trials.
I do surprise about generalizability. These sufferers are youthful and sicker than my common affected person. That may clarify the outcomes, however I haven’t seen a SCAPE affected person that required intubation, or who wasn’t higher inside 6 hours, in my total profession. The truth that our sufferers are much less sick may be why so many individuals have gotten away with utilizing miniscule doses of nitroglycerin in North America.
Clearly, a single middle research of solely 52 sufferers is just not sufficient to essentially touch upon hostile occasions. Nevertheless, we already routinely give excessive doses of nitroglycerin on a regular basis (2 sprays of sublingual GTN is 800mcg as a bolus, about half of which is absorbed). Moreover, for those who rely all hostile occasions, together with hypoxia and intubation, and don’t simply give attention to hypotension, I’m not positive you even count on excessive dose remedy to be ‘riskier’.
There are a variety of different publications that counsel excessive dose nitroglycerin is comparatively secure (and possibly efficient). Wilson (2016) printed an observational cohort through which they used 2 mg IV (2,000 mcg) push doses of nitroglycerin, and it was related to much less ICU use. The incidence of hypotension was solely 2%. One other small research of 25 sufferers used bolus doses between 600 and 1000 mcg (common 872 mcg) relying on the presenting blood stress, with no issues. (Matthew 2021) Houseman et al (2023) describe a cohort of 67 sufferers who had nitroglycerin infusions >100mcg/min, with a hypotension price of 4%. (In fact, a variety of hypotension is brief lived and clinically irrelevant, being managed by merely stopping or lowering the infusion.)
I’m typically essential of observe change based mostly on small unblinded research. I believe it’s affordable to be cautious, and we positively want extra research on this space. Nevertheless, one other idea that I constantly emphasize is the necessary of pretest likelihood in proof based mostly drugs. We’re used to utilizing excessive dose nitroglycerin safely sublingually. There may be observational information suggesting that is the proper method. Thus, in comparison with the common small unblinded RCT, I believe the conlclusions of this trial usually tend to be right. The potential profit for sufferers seems giant, with minimal danger, so I believe this is sufficient to change observe whereas ready for larger research.
Backside line
I’ve been suggesting excessive dose nitroglycerin (mixed with BiPAP) for SCAPE for a few years. This RCT, though removed from good, demonstrates considerably improved outcomes with larger doses of nitroglycerin, and needs to be sufficient to vary observe for folks at the moment utilizing decrease doses.
Different FOAMed
Excessive dose nitroglycerin coated in Articles of the month Oct 2016,
The very first EMCrit Episode: Sympathetic Crashing Acute Pulmonary Edema (SCAPE)
Vital care infusion drug dosing cheat sheet
Proof based mostly drugs is straightforward
The EBM bibliography
Proof based mostly drugs assets
EBM deep dives
References
Houseman BS, Martinelli AN, Oliver WD, Devabhakthuni S, Mattu A. Excessive-dose nitroglycerin infusion description of security and efficacy in sympathetic crashing acute pulmonary edema: The HI-DOSE SCAPE research. Am J Emerg Med. 2023 Jan;63:74-78. doi: 10.1016/j.ajem.2022.10.018. Epub 2022 Oct 18. PMID: 36327753
Mathew R, Kumar A, Sahu A, Wali S, Aggarwal P. Excessive-Dose Nitroglycerin Bolus for Sympathetic Crashing Acute Pulmonary Edema: A Potential Observational Pilot Examine. J Emerg Med. 2021 Sep;61(3):271-277. doi: 10.1016/j.jemermed.2021.05.011. Epub 2021 Jun 30. PMID: 34215472
Siddiqua N, Mathew R, Sahu AK, Jamshed N, Bhaskararayuni J, Aggarwal P, Kumar A, Khan MA. Excessive-dose versus low-dose intravenous nitroglycerine for sympathetic crashing acute pulmonary edema: a randomised managed trial. Emerg Med J. 2024 Jan 22;41(2):96-102. doi: 10.1136/emermed-2023-213285. PMID: 38050078
Wilson SS, Kwiatkowski GM, Millis SR, Purakal JD, Mahajan AP, Levy PD. Use of Nitroglycerin by Bolus Prevents ICU Admission in Sufferers with Acute Hypertensive Coronary heart Failure. The American Journal of Emergency Drugs. 2016. article PMID: 27825693
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