The effects of transdermal glyceryl trinitrate, a nitric oxide donor, on blood pressure, cerebral and cardiac hemodynamics, and plasma nitric oxide levels in acute stroke

https://doi.org/10.1016/S1052-3057(03)00037-5Get rights and content

Abstract

High blood pressure in acute stroke is common and appears to be associated with a poor outcome. Lowering blood pressure might therefore improve outcome, provided that cerebral perfusion is not compromised. We assessed the effects of glyceryl trinitrate (GTN) on cerebral and systemic hemodynamic measures in acute stroke. Ninety patients with acute ischemic or hemorrhagic stroke were randomized within 72 hours of ictus to transdermal GTN given daily for 10 days (either 5 mg, 5 mg for 4 days then 10 mg, or 10 mg) or control. Twenty-four hour blood pressure monitoring, middle cerebral artery blood velocity, cardiac output, augmentation index, and plasma nitric oxide levels were each measured at baseline and then on days 1, 4, 5, and 10. The primary outcome was blood pressure on day 1. We found that GTN lowered mean peripheral arterial blood pressure on day 1 by 5.3% to 6.7% in a dose dependent manner as compared with control (mean, SD): control, 108.8 (15.1) mmHg; 5 mg, 102.5 (13.9) mmHg; 5/10 mg, 103.4 (14.9) mmHg; 10 mg, 101.5 (12.6) mmHg; (P = .005). Increasing the dose from 5 to 10 mg on day 5 resulted in an overall reduction in blood pressure of 11.4% as compared with leaving the dose at 5 mg (P = .006). GTN reduced peripheral pulse pressure, central aortic blood pressure, pulse pressure, and augmentation index on day 1. Middle cerebral artery blood velocity and pulsatility index in the affected hemisphere, cardiac output, systemic peripheral resistance, and plasma nitric oxide levels were not altered by GTN. Treatment with GTN was associated with headache: control 0 (0%), GTN 9 (15%) (P = .027); no negative effect on end-of-treatment death or deterioration, or 3 month death or dependency was discernable. GTN reduced peripheral blood pressure in a dose-dependent fashion in patients with acute stroke at day 1 and also reduced central blood pressure and augmentation index. In contrast, GTN did not alter middle cerebral artery blood velocity or pulsatility index in the affected hemispheres, suggesting that cerebral blood flow did not change. A trial assessing the effect of lowering blood pressure with GTN on safety and functional outcome in patients with acute stroke is now warranted.

Section snippets

Design

A prospective single-center dose-comparison, open-label blinded-endpoint randomized controlled trial was performed. The primary outcome measure was 24 hour mean arterial blood pressure (MAP) on day 1 (ie, reflecting the first 24 hours of treatment); day 1 was also the main timing of interest for other hemodynamic measures to avoid the potentially confounding effects of tolerance. A sample size of 21 patients per group was calculated assuming the following: difference in blood pressure, 10 mmHg17

Results

Consent or assent was given by 93 patients, 3 of whom withdrew from the study prior to randomisation (Fig 1). The patients in the control and GTN groups were well matched for age, gender, history of hypertension, and stroke severity and type (Table 1); a non-significant trend to less total anterior circulation syndrome was present in patients randomized to GTN (Table 1). The average time from stroke onset to randomization was 50 hours.

Conclusions

This trial confirms the finding of our previous study17 that GTN lowers systolic, diastolic, and mean arterial blood pressure in patients with acute stroke. Importantly, the study extends this information in three ways. First, GTN lowered blood pressure in a dose-dependent manner: as compared with control, GTN at doses of 5 mg and 10 mg reduced blood pressure by 7.0% and 7.8% respectively. Second, we studied approaches which might delay the appearance of tolerance, a known pharmacological

Acknowledgements

We thank the patients for taking part in this trial and Mrs. Bev Whysall for performing some of the 3 month follow-up assessments. No pharmaceutical company was involved in the conception, design, execution, analysis, interpretation, or funding of this trial. P.B. is the Stroke Association Professor of Stroke Medicine; the Division of Stroke Medicine receives core funding from The Stroke Association. This work was presented in part at the American Stroke Association meeting, San Antonio, TX,

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      Five randomised trials7–11 of an NO donor, transdermal glyceryl trinitrate (GTN; also known as nitroglycerin), in acute stroke showed that GTN lowered peripheral and central blood pressure, 24 h blood pressure, pulse pressure, and augmentation index. Conversely, GTN had no effect on middle cerebral artery blood flow velocity, cerebral blood flow, intracranial pressure, or platelet function.7–9 Although four of the trials7–9,11 were neutral for functional outcome, GTN improved functional outcome in the phase 2 Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial (RIGHT),10 with randomisation by paramedics within 4 h of stroke, and in a prespecified subgroup analysis of the phase 3 hospital-based Efficacy of Nitric Oxide in Stroke trial (ENOS),11,12 with randomisation within 6 h of stroke.

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