Pre-hospital transdermal glyceryl trinitrate in patients with stroke mimics: data from the RIGHT-2 randomised-controlled ambulance trial

Background Prehospital stroke trials will inevitably recruit patients with non-stroke conditions, so called stroke mimics. We undertook a pre-specified analysis to determine outcomes in patients with mimics in the second Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial (RIGHT-2). Methods RIGHT-2 was a prospective, multicentre, paramedic-delivered, ambulance-based, sham-controlled, participant-and outcome-blinded, randomised-controlled trial of transdermal glyceryl trinitrate (GTN) in adults with ultra-acute presumed stroke in the UK. Final diagnosis (intracerebral haemorrhage, ischaemic stroke, transient ischaemic attack, mimic) was determined by the hospital investigator. This pre-specified subgroup analysis assessed the safety and efficacy of transdermal GTN (5 mg daily for 4 days) versus sham patch among stroke mimic patients. The primary outcome was the 7-level modified Rankin Scale (mRS) at 90 days. Results Among 1149 participants in RIGHT-2, 297 (26%) had a final diagnosis of mimic (GTN 134, sham 163). The mimic group were younger, mean age 67 (SD: 18) vs 75 (SD: 13) years, had a longer interval from symptom onset to randomisation, median 75 [95% CI: 47,126] vs 70 [95% CI:45,108] minutes, less atrial fibrillation and a lower systolic blood pressure and Face-Arm-Speech-Time tool score than the stroke group. The three most common mimic diagnoses were seizure (17%), migraine or primary headache disorder (17%) and functional disorders (14%). At 90 days, the GTN group had a better mRS score as compared to the sham group (adjusted common odds ratio 0.54; 95% confidence intervals 0.34, 0.85; p = 0.008), a difference that persisted at 365 days. There was no difference in the proportion of patients who died in hospital, were discharged to a residential care facility, or suffered a serious adverse event. Conclusions One-quarter of patients suspected by paramedics to have an ultra-acute stroke were subsequently diagnosed with a non-stroke condition. GTN was associated with unexplained improved functional outcome observed at 90 days and one year, a finding that may represent an undetected baseline imbalance, chance, or real efficacy. GTN was not associated with harm. Trial registration This trial is registered with International Standard Randomised Controlled Trials Number ISRCTN 26986053.

Myocardial Energy Response to Glyceryl Trinitrate: Physiology Revisited

Objective: Although intravenous nitrates are commonly used in clinical medicine, they have been shown to increase myocardial oxygen consumption and inhibit complex IV of the electron transport chain. As such we sought to measure whether myocardial energetics were impaired during glyceryl trinitrate (GTN) infusion.Methods: 10 healthy volunteers underwent cardiac magnetic resonance imaging to assess cardiac function and 31phosphorus magnetic resonance spectroscopy to measure Phosphocreatine/ATP (PCr/ATP) ratio and creatine kinase forward rate constant (CK kf) before and during an intravenous infusion of GTN.Results: During GTN infusion, mean arterial pressure (78 ± 7 vs. 65 ± 6 mmHg, p < 0.001), left ventricular (LV) stroke work (7,708 ± 2,782 vs. 6,071 ± 2,660 ml mmHg, p < 0.001), and rate pressure product (7,214 ± 1,051 vs. 6,929 ± 976 mmHg bpm, p = 0.06) all fell. LV ejection fraction increased (61 ± 3 vs. 66 ± 4%, p < 0.001), with cardiac output remaining constant (6.2 ± 1.5 vs. 6.5 ± 1.4 l/min, p = 0.37). Myocardial PCr/ATP fell during GTN infusion (2.17 ± 0.2 vs. 1.99 ± 0.22, p = 0.03) with an increase in both CK kf (0.16 ± 0.07 vs. 0.25 ± 0.1 s−1, p = 0.006) and CK flux (1.8 ± 0.8 vs. 2.6 ± 1.1 μmol/g/s, p = 0.03).Conclusion: During GTN infusion, despite reduced LV stroke work and maintained cardiac output, there was a 44% increase in myocardial ATP delivery through CK. As PCr/ATP fell, this increase in ATP demand coincided with GTN-induced impairment of mitochondrial oxidative phosphorylation. Overall, this suggests that while GTN reduces cardiac work, it does so at the expense of increasing ATP demand beyond the capacity to increase ATP production.

Comparison of Glyceryl Trinitrate Ointment versus Internal Lateral Sphincterotomy for Anal Fissure Pain Relief

Background: Anal fissure is a linear painful mucosal tearing in the distal part of anal canal. It extends from dentate to anal edge. Aim: To compare the glyceryltrinitrate ointment and internal lateral sphincterotomy for anal fissure pain relief in acute/chronic pts. Study Design: Prospective study Place and duration of study: Department of Surgery Unit-II, Fatima Memorial Hospital, Shadman Lahore from 1st October 2018 to 31stDecember 2020. Methodology: 40 pts with acute and chronic anal fissure were enrolled. Half of the patients undergo internal lateral sphincterotomy while other opted 0.2% use of glyceryl trinitrate ointment. Each patient was followed for pain, recovery, complications and recurrence until 12 months for internal lateral sphincterotomy and 18 months in glyceryl trinitrate ointment. Results: There were 24 males and 16 females with a mean age of patients as 30±3.2 years. Initial follow-up of patients showed 100% pain and fissure improvement in internal lateral sphincterotomy group as compared to 60% in glyceryl trinitrate ointment group respectively. Conclusion: Internal lateral sphincterotomy is most efficient and reliable procedure in relieving anal fissure pains. Keywords: Anal fissure, Internal lateral sphincterotomy, Glyceryl trinitrate

Glyceryl Trinitrate: History, Mystery, and Alcohol Intolerance

Glyceryl trinitrate (GTN) is one of the earliest known treatments for angina with a fascinating history that bridges three centuries. However, despite its central role in the nitric oxide (NO) story as a NO-donating compound, establishing the precise mechanism of how GTN exerts its medicinal benefit has proven to be far more difficult. This review brings together the explosive and vasodilatory nature of this three-carbon molecule while providing an update on the likely in vivo pathways through which GTN, and the rest of the organic nitrate family, release NO, nitrite, or a combination of both, while also trying to explain nitrate tolerance. Over the last 20 years the alcohol detoxification enzyme, aldehyde dehydrogenase (ALDH), has undoubtedly emerged as the front runner to explaining GTN’s bioactivation. This is best illustrated by reduced GTN efficacy in subjects carrying the single point mutation (Glu504Lys) in ALDH, which is also responsible for alcohol intolerance, as characterized by flushing. While these findings are significant for anyone following the GTN story, they appear particularly relevant for healthcare professionals, and especially so, if administering GTN to patients as an emergency treatment. In short, although the GTN puzzle has not been fully solved, clinical study data continue to cement the importance of ALDH, as uncovered in 2002, as a key GTN activator.

What is the optimum treatment of chronic anal fissure?

Aim: To compare the efficacy of topical Glyceryl trinitrate 0.2% (GTN) with Lateral internal spincterotomy (LIS) for treating chronic anal fissure (CAF). Methodology: A randomized control trial was carried out in the general surgery department, Lady reading hospital, LRH MTI, Peshawar (January 2018 to July 2018). All consecutive patients 18 to 60 year old presenting to OPD with a clinical diagnosis of chronic anal fissure were enrolled after informed consent. A total of 60 patients were enrolled. The patients were assigned two groups, including treatment group A (lateral internal spinterotomy) or treatment group B (use of Topical GTN ointment 0.2%). Results: Out of the 60 patients, 30 were enrolled into each group. The female had majority of 57% (group A) and 60% (group B). Mean duration regarding symptoms in group A was 1 year with SD ± 3.51 vs 1 year ± 2.98 in group B. Majority of patients in both groups were in the 20 to 40 years age group (74% in group A vs 83% in group B). Complete fissure healing and resolution of symptoms was observed in 27(91%) in group A vs 20(66%) in group B. Conclusion: In conclusion, we derive that lateral internal spincterotomy is more effectual than Topical Glyceryl trinitrate 0.2% for treating chronic anal fissure. Keywords: Chronic anal fissure, lateral internal spincterotomy, Glyceryltrinitrate

Paramacular Acute Middle Maculopathy Associated with Glyceryl Trinitrate

An unusual case of nitroglycerin-induced Paracentral Acute Middle Maculopathy (PAMM) is presented. A 50-year-old patient with sudden vision loss and scotoma was followed up with swept-source optical coherence tomography (SS-OCT), optical coherence tomography-angiography (OCT-A), and fluorescein angiography (FA). An anal fissure treated with glyceryl trinitrate (GTN) 0.2% ointment with headache and dizziness after application was reported. Fundoscopy OS revealed mild retinal venous dilatation and tortuosity with scattered blot hemorrhages and subtle, parafoveal, whitish lesions in the outer retina. SS-OCT revealed diffuse, hyperreflective lesions in the inner plexiform (IPL), inner nuclear (INL), and outer plexiform layers (OPL). OCT-A revealed focal dropout in the deep capillary plexus. FA showed masking due to blot hemorrhages and early punctuate leakage in the inner retina. This entity was identified as nitroglycerin-induced PAMM. Over the following 8 months, after discontinuation of the ointment application, the patient was symptom-free with stable visual acuity. OCT revealed INL/OPL thinning and confirmed complete lesion resolution. This first report of retinal vascular abnormalities due to nitrite ointment provides an insight into an unknown side effect of nitroglycerin ointment use. A dose-dependent correlation between GTN application and retinal vascular abnormalities remains to be confirmed.