Inhaled Nitric Oxide Treatment for Aneurysmal SAH Patients With Delayed Cerebral Ischemia

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Inhaled Nitric Oxide Treatment for Aneurysmal SAH Patients With Delayed Cerebral Ischemia

Christian Fung^1*†, Werner J. Z'Graggen^2†, Stephan M. Jakob³, Jan Gralla⁴, Matthias Haenggi³, Hans-Ulrich Rothen³, Pasquale Mordasini⁴, Michael Lensch³, Nicole Söll², Nicole Terpolilli^5,6, Sergej Feiler², Markus F. Oertel⁷, Andreas Raabe², Nikolaus Plesnila⁵, Jukka Takala³ and Jürgen Beck¹

• ¹Department of Neurosurgery, Medical Center, University of Freiburg, Freiburg, Germany
• ²Department of Neurosurgery, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
• ³Department of Intensive Care Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
• ⁴Department of Diagnostic and Interventional Neuroradiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
• ⁵Institute for Stroke and Dementia Research (ISD), Munich University Hospital, Munich, Germany
• ⁶Department of Neurosurgery, Munich University Hospital, Munich, Germany
• ⁷Department of Neurosurgery, University Hospital Zurich, Zurich, Switzerland

Background: We demonstrated experimentally that inhaled nitric oxide (iNO) dilates hypoperfused arterioles, increases tissue perfusion, and improves neurological outcome following subarachnoid hemorrhage (SAH) in mice. We performed a prospective pilot study to evaluate iNO in patients with delayed cerebral ischemia after SAH.

Methods: SAH patients with delayed cerebral ischemia and hypoperfusion despite conservative treatment were included. iNO was administered at a maximum dose of 40 ppm. The response to iNO was considered positive if: cerebral artery diameter increased by 10% in digital subtraction angiography (DSA), or tissue oxygen partial pressure (PtiO₂) increased by > 5 mmHg, or transcranial doppler (TCD) values decreased more than 30 cm/sec, or mean transit time (MTT) decreased below 6.5 secs in CT perfusion (CTP). Patient outcome was assessed at 6 months with the modified Rankin Scale (mRS).

Results: Seven patients were enrolled between February 2013 and September 2016. Median duration of iNO administration was 23 h. The primary endpoint was reached in all patients (five out of 17 DSA examinations, 19 out of 29 PtiO₂ time points, nine out of 26 TCD examinations, three out of five CTP examinations). No adverse events necessitating the cessation of iNO were observed. At 6 months, three patients presented with a mRS score of 0, one patient each with an mRS score of 2 and 3, and two patients had died.

Conclusion: Administration of iNO in SAH patients is safe. These results call for a larger prospective evaluation.

Introduction

Despite advances in emergency medicine, neurocritical care, and aneurysm occlusion techniques, aneurysmal subarachnoid hemorrhage (aSAH) remains a rare but severe subtype of stroke with high mortality and poor outcome (1, 2). Delayed cerebral ischaemia (DCI) is thought to be the major reason for poor outcome in survivors of aSAH (2). Up to this day and despite decades of experimental and clinical research, causes and pathomechanisms of DCI are still not completely clear and most probably multifaceted (3). Cerebrovascular spasm (CVS), a narrowing of cerebral arteries thought to be caused by blood breakdown products, usually peaks between day 5 and 14 after hemorrhage and can be observed in up to 88% of patients with severe aSAH (4). While it is still not completely understood whether angiographic CVS is an epiphenomenon or symptom of other mechanisms or a pathomechanism directly causing DCI, it is thought to relevantly contribute to DCI. Despite advances in its detection and treatment, 20–40% of CVS patients experience cerebral ischaemia, which is associated with an adverse outcome (5). So far, there is no established therapy to improve cerebral perfusion and thus avoid tissue ischaemia and infarct formation. In patients with critical cerebral hypoperfusion without established cerebral infarction, rescue therapies such as induced hypertension, intra-arterial application of vasodilators, or angioplasty are used to improve cerebral perfusion. The efficacy of such interventions is not proven, their effects are temporary at best, and adverse effects are possible, including exposure to radiation (6–8).

As early as the 1980ies, depletion of nitric oxide (NO), a potent endogenous vasodilator and mediator, was recognized to be heavily involved in the pathogenesis of delayed cerebral ischemia after SAH (9–11). Up to now there are, however, no established clinical tools to replenish NO to the cerebral circulation. In series of translational experimental studies using animal models for ischaemic stroke, traumatic brain injury, and SAH we demonstrated that inhaled nitric oxide (iNO) selectively dilates cerebral arteries and arterioles in hypoperfused brain tissue (12–15). After SAH in mice, iNO significantly reduced the number and severity of SAH-induced microvasospasm, thereby improving cerebral perfusion, survival, and functional outcome. Systemic blood pressure was not affected by iNO, which is a major advantage over other vasodilating treatment strategies (15, 16). In contrast to many other therapeutics evaluated in experimental studies, iNO already has regulatory approval for human use from the United States Food and Drug Administration and the European Medicines Agency in the treatment of several pulmonary pathologies (e.g., respiratory distress syndrome, pulmonary hypertension) in infants (17–20) and in adults (21, 22) and has a good safety record of use in humans since the 1990s. The efficacy of iNO was thought to be limited to the lungs but, given the promising results of the experimental studies and its safety record, we hypothesized that iNO may improve cerebral perfusion in patients with aSAH. We therefore performed a prospective pilot study evaluating the effects of iNO on cerebral perfusion in patients with delayed cerebral ischemia after aSAH.

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