Wanting again, I’m considerably shocked I by no means printed a First10 strategy to sympathetic crashing pulmonary edema. I assume it by no means felt mandatory, because it was the primary ever EMCrit publish, and due to this fact felt effectively lined 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 medical doctors alike) who’re uncomfortable with acceptable doses of IV nitroglycerin. To be honest, till now, the proof has principally been observational and retrospective. Nevertheless, we now have an RCT that exhibits fairly outstanding enchancment with excessive dose intravenous nitroglycerin, so maybe apply 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 had been systolic strain >159 and diastolic strain >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 rapid intubation.
Intervention
Excessive dose intravenous nitroglycerine: 600–1000 mcg bolus adopted by an infusion beginning at 100 mcg/min and subsequently titrated by medical 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 normal procedures
Each teams got BIPAP help with an preliminary inspiratory constructive airway strain of 12 mm Hg and expiratory constructive airway strain of 6 mm Hg.
Final result
They used ‘co-primary outcomes’ of decision of signs at 6 and 12 hours. (Subjective enchancment on a 7 level Likert scale, plus at the least 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 cut up. This was a comparatively sick cohort, regardless of being so younger. 70% of the sufferers had continual kidney illness and basically all of them had baseline hypertension. Vitals indicators at presentation included a median respiratory charge within the excessive 30s, oxygen saturation of 80-85%, and blood strain 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 throughout the first hour or two with excessive dose GTN and BiPAP.)
Mainly all outcomes had been worse within the low dose group. Intubation was 19% vs 4% (though not statistically important). (I’ve not intubated certainly one of these sufferers in my profession, so this group appears approach sicker, or totally different in another approach, than what I’m seeing in Canada.) Admission charges, hospital size of keep, and MACE had been all increased with low dose nitroglycerin.
Should you care about monitor based mostly outcomes, the important indicators additionally improved extra within the excessive dose group:
When it comes to opposed 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 crucial research, however it’s clearly removed from an ideal research. It’s a small single middle research, with a inhabitants that appears very totally different from what I’m used to in North America. (Assets and administration methods may additionally be totally different, however I don’t know.) Opaque envelopes usually are not the most effective allocation concealment process. It’s dishonest to decide on co-primary outcomes, particularly if you find yourself simply utilizing totally different time frames that aren’t actually clinically totally different. The calculated pattern dimension relies on an anticipated 54% absolute distinction between the teams. Regardless that I’m a fairly large supporter of excessive dose nitroglycerin, that appears ridiculously over-optimistic to me.
The largest particular person methodologic challenge with this research is that it was not blinded. Even if you find yourself measuring comparatively goal medical outcomes, an absence of blinding introduces a excessive danger of bias. Vitals indicators ought to be goal, however now we have all rechecked vitals once they don’t match what we anticipate. Affected person studies of enchancment could be influenced by the best way questions are requested. (“You could have been on the very best dose for a couple of hours now. You should be feeling higher, proper?”) The variations on this trial appear too dramatic to be fully based mostly on bias, however we can not have a excessive degree of certainty till we see top quality, multi-center, blinded trials.
I do marvel 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 whole profession. The truth that our sufferers are much less sick could 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 will not be sufficient to essentially touch upon opposed 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, in case you rely all opposed occasions, together with hypoxia and intubation, and don’t simply deal with hypotension, I’m not certain you even anticipate excessive dose remedy to be ‘riskier’.
There are a selection of different publications that recommend excessive dose nitroglycerin is comparatively protected (and doubtless efficient). Wilson (2016) printed an observational cohort during 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 strain, with no issues. (Matthew 2021) Houseman et al (2023) describe a cohort of 67 sufferers who had nitroglycerin infusions >100mcg/min, with a hypotension charge of 4%. (After all, a whole lot of hypotension is brief lived and clinically irrelevant, being managed by merely stopping or reducing the infusion.)
I’m usually vital of apply change based mostly on small unblinded research. I feel it’s cheap to be cautious, and we undoubtedly want extra research on this space. Nevertheless, one other idea that I constantly emphasize is the vital 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 correct strategy. Thus, in comparison with the typical small unblinded RCT, I feel the conlclusions of this trial usually tend to be right. The potential profit for sufferers seems giant, with minimal danger, so I feel this is sufficient to change apply 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 excellent, demonstrates considerably improved outcomes with increased doses of nitroglycerin, and ought to be sufficient to vary apply for folks at present utilizing decrease doses.
Different FOAMed
Excessive dose nitroglycerin lined in Articles of the month Oct 2016,
The very first EMCrit Episode: Sympathetic Crashing Acute Pulmonary Edema (SCAPE)
Essential care infusion drug dosing cheat sheet
Proof based mostly drugs is simple
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 Research. 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 Medication. 2016. article PMID: 27825693