July 9, 2021, by sbzaj1
50 at 50: Transforming healthcare: High explosive treatment for treatment of stroke
I have been in Nottingham since 1998 having previously been a Clinical Lecturer then Senior Lecturer in South-West then South-East London. My research and clinical interest in nitric oxide, a gas comprising a molecule of just one oxygen and nitrogen atom, started when working for my MD postgraduate research degree at the “University of Beckenham”, properly then called the Wellcome Foundation, a drug company that developed anti-HIV drugs and was then taken over by Glaxo (now GSK). The late 1980s were heady days in Beckenham with Salvador Moncada and colleagues demonstrating that nitric oxide explained the activity of endothelium-derived relaxing factor, is a key controller of blood flow and blood cell function, and is made from L-arginine, a semi-essential amino acid. Salvador was inspiring but sadly did not get the 1998 Nobel prize when others did for elucidating the importance and physiology of nitric oxide. Since then, the fundamental role of nitric oxide has become increasingly clear; it is a control and defence molecule that may have been used by early organisms three billion years to protect themselves from the toxic environment back then. In mammalian physiology, it has additional neurotransmitter, anti-infection and reproductive effects.
High blood pressure is common in acute stroke and causes poor outcome, increased death and early stroke recurrence. Although the clinical management of high blood pressure has been debated since 1985, it still remains unclear exactly when and how we should lower blood pressure although we do commonly do so before giving clot-busting drugs and to patients with a brain bleed. The question is what drug to use, when and to what sort of stroke, and much of my research over 28 years has focussed on this question.
Nitric oxide levels are low in acute ischaemic stroke, and even more so in brain bleeds. In view of the multiple potentially beneficial actions of NO, supplementation might then be beneficial. Laboratory-based studies in experimental stroke found that NO donors reduced stroke size, but only if administered early after stroke induction; NO also improved blood supply in permanent models of ischaemia. Clinically, NO can be administered as L-arginine or nitrate (both make NO), as NO gas, as a NO donating drug (e.g. isosorbide), as a drug that stimulates NO synthesis in blood vessels (e.g. statins), or as a drug that inhibits an enzyme that breaks down the effects of NO (phosphodiesterase-5, e.g. sildenafil). Of these interventions, the most relevant for human study includes organic nitrates such as glyceryl trinitrate (GTN).
GTN is the medical name for nitroglycerin (NTG), a high explosive found in dynamite. Alfred Nobel made his fortune in the late 1800s when he learnt to stabilise NTG (it regularly exploded and killed factory workers, including his brother) and make its routine use feasible and safe; this fortune supports the prizes that are given his name. Ironically, Nobel developed angina and used NTG for pain prevention. Even more ironic, he died of a brain bleed so, if the GTN-stroke story is correct, he might have been able to treat himself with his own invention!
We did three pilot trials of transdermal GTN in patients with acute and sub-acute stroke and found that it rapidly reduced blood pressure but did not alter platelet function or reduce brain blood flow. On the basis of these data, the safety and effect
of GTN was tested in 4011 patients with acute stroke within 48 hours of onset across 5 continents, 23 countries and 173 hospital sites in the Efficacy of Nitric Oxide in Stroke (ENOS) trial. Unfortunately, GTN did not improve outcome except in people treated within 6 hours of stroke onset, a pre-planned subgroup. Separately, GTN improved outcome in the small ambulance-based Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial (RIGHT) with paramedics performing screening, recruitment, consent and treatment. Data from all five GTN trials (4197 patients) were aggregated in an individual patient data metaanalysis and these supported the hypothesis that GTN might improve outcome if given within 6 hours of stroke.
To give GTN really early and get a definitive answer as to whether it does improve outcome required that we do a large trial delivered by paramedics although this had only ever been done once before (in the US). The Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2 (RIGHT-2) recruited 1149 patients with ultra-acute stroke within 4 hours of onset across 8 of the UK ambulance services and involving 516 paramedics; the average time to recruitment was 71 minutes. Unfortunately, the trial did not support the metaanalysis and was neutral; indeed, GTN appeared to worsen outcome in the subgroup of patients with a brain bleed, probably by preventing blood vessels from constricting. More strangely, GTN improved outcome in the subgroup of people with a stroke mimic, i.e. conditions such as migraine, seizures and functional disturbance but presenting as a stroke; we do not understand this finding although it may just reflect chance.
So where do we go from here? We have just started a small trial to see if it is feasible to give GTN between 3 and 5 hours in hospital, the time when the metaanalysis suggests most effect. And we are taking part in other blood pressure lowering trials around the world. The reality is that we know little more about how to manage blood pressure than we did 37 years ago, except perhaps that high explosive therapy should not be given within the first two hours after stroke.
Philip M Bath, Stroke Association Professor of Stroke Medicine
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