How does nitroglycerin (NTG) worsen outcomes in hemorrhagic stroke?

Mechanism of Nitroglycerin Worsening Hemorrhagic Stroke

Nitroglycerin (NTG) worsens outcomes in hemorrhagic stroke primarily through cerebral vasodilation, which increases cerebral blood flow and intracranial pressure, potentially leading to hematoma expansion and worse clinical outcomes.

Pathophysiological Mechanisms

Primary Mechanisms

1. Cerebral Vasodilation

   • NTG forms free radical nitric oxide (NO) which activates guanylate cyclase, increasing cyclic GMP in smooth muscle, leading to vasodilation 1
   • This vasodilation affects both arterial and venous beds, with venous effects predominating

2. Increased Cerebral Blood Flow

   • Cerebral vasodilation increases blood flow to the brain
   • In hemorrhagic stroke, this increased flow can worsen bleeding at the site of vessel rupture

3. Hematoma Expansion

   • Clinical evidence from the RIGHT-2 trial showed NTG was associated with larger hematoma and greater hematoma growth 2
   • Increased blood flow to damaged vessels promotes continued bleeding

4. Mass Effect and Midline Shift

   • NTG treatment was associated with increased mass effect and midline shift on neuroimaging 2
   • These structural changes correlate with worse clinical outcomes

Secondary Mechanisms

1. Blood Pressure Effects

   • While NTG lowers systemic blood pressure, the cerebral vasodilation may paradoxically increase local pressure at the bleeding site
   • Rapid BP lowering in hemorrhagic stroke may reduce cerebral perfusion pressure in areas surrounding the hematoma

2. Intracranial Pressure (ICP) Effects

   • In patients with normal intracranial compliance, NTG can cause significant elevation of ICP 3
   • This elevation of ICP can worsen secondary brain injury

Clinical Evidence

The RIGHT-2 trial provided strong evidence that prehospital treatment with transdermal GTN (nitroglycerin) worsened outcomes in patients with intracerebral hemorrhage 2:

• Modified Rankin Scale scores at 90 days were higher (worse) in the GTN group
• A global analysis of 5 clinical outcomes (dependency, disability, cognition, quality of life, and mood) showed worse outcomes with GTN
• Neuroimaging showed larger hematomas with more mass effect in the GTN group

Clinical Implications

Current guidelines for stroke management recognize the potential harm of NTG in hemorrhagic stroke:

• The American Heart Association/American Stroke Association guidelines do not recommend the routine use of nitrates in acute stroke management 4
• In contrast to acute coronary syndromes where NTG is recommended for symptom relief 4, 5, NTG should be avoided in suspected hemorrhagic stroke

Management Recommendations

1. Avoid NTG in suspected hemorrhagic stroke

   • NTG should not be administered to patients with suspected intracranial hemorrhage
   • Rapid neuroimaging is essential before considering vasodilator therapy in any stroke patient

2. Blood pressure management in hemorrhagic stroke

   • Unless the patient is hypotensive (systolic blood pressure <90 mm Hg), prehospital intervention for blood pressure is not recommended 4
   • If BP lowering is required, agents with less effect on cerebral vasodilation are preferred

3. Monitoring

   • If a patient with hemorrhagic stroke has inadvertently received NTG, close monitoring of neurological status and frequent neuroimaging may be warranted to detect worsening

Conclusion

The evidence strongly suggests that NTG worsens outcomes in hemorrhagic stroke through cerebral vasodilation, increased bleeding, hematoma expansion, and increased mass effect. This stands in contrast to its beneficial effects in cardiac conditions, highlighting the importance of early differentiation between ischemic and hemorrhagic stroke before administering vasodilatory medications.