Intra-arterial Milrinone Research Articles

Abstract 091: Intraventricular milrinone for management of vasospasm following aneurysmal subarachnoid hemorrhage

Introduction Aneurysmal subarachnoid hemorrhage (aSAH) accounts for about 10% of hemorrhagic strokes [1] and holds a high mortality and morbidity rate. [2, 3] Vasospasm is one of the more devastating complications of aSAH. Novel imaging modalities have drastically improved our ability in prompt detection of vasospasm in these patients. However, clinical management of this complication is still debated among experts. [4] Systemic cerebral vasodilators are widely used in aSAH patients, but guidelines for interventional and rescue procedures are not well developed. [5] Methods Here, we report a case of severe vasospasm following aSAH that was successfully treated with intraventricular injection of milrinone through external ventricular drain (EVD) in conjunction to standard therapy. Results A 70‐year‐old man with a history of diabetes, hypertension, and hyperlipidemia was brought to the emergency department after he was found down and unresponsive. He was intubated by EMS on route. Head CT on arrival showed a diffuse subarachnoid hemorrhage, more prominent in the posterior fossa, and grade IV on the modified Fisher scale. An initial DSA showed a ruptured aneurysm in the second segment of the right posterior inferior cerebellar artery, second segment. A right frontal EVD was placed on the second day. Hemodynamic augmentation was achieved with intravenous and intraventricular milrinone. Cerebral arterial patency was evaluated with daily transcranial doppler (TCD). The patient did not show any evidence of vasospasm until day 9 where TCD revealed severe vasospasm in the basilar and bilateral vertebral arteries, as well as mild vasospasm of anterior and middle cerebral arteries. Intraventricular milrinone was injected into the EVD in from day 9 to day 12. Using sterile technique, 4 mL of CSF was removed followed by the injection of 0.87mg (2mL) of milrinone into the EVD via a three way stop cock. EVD was then flushed with 2mL of preservative‐free saline and clamped for 1 hour. This procedure effectively improved vasospasm on serial TCDs and also DSAs (Figure1). The patient underwent several DSA’s on days 10, 14, 19, 20, and 21 with targeted intraarterial milrinone and verapamil injections. His final TCD showed only mild middle cerebral artery and moderate basilar artery vasospasm. At that point, no more intervention was deemed necessary. A ventriculoperitoneal shunt was also placed. CT scan before discharge showed mild improvement in ventricular size and stable SAH blood products. The course of hospitalization was complicated by hyponatremia, atrial fibrillation, and respiratory failure with inability to wean off ventilator, resulting in tracheostomy and gastrostomy tube placement. The patient was discharged in stable condition on day 30 to a rehabilitation center. Conclusion Intraventricular milrinone in addition to standard therapy can be an effective method in treatment of severe vasospasm in aSAH patients.

Management of refractory bacterial meningitis-associated cerebral vasospasm: illustrative case.

Cerebral vasospasm is an alarming complication of acute bacterial meningitis with potentially devastating consequences. It is essential for providers to recognize and treat it appropriately. Unfortunately, there is no well-established approach to the management of postinfectious vasospasm, which makes it especially challenging to treat these patients. More research is needed to address this gap in care. Here, the authors describe a patient with postmeningitis vasospasm that was refractory to induced hypertension, steroids, and verapamil. He eventually responded to a combination of intravenous (IV) and intra-arterial (IA) milrinone followed by angioplasty. To our knowledge, this is the first report of successfully using milrinone as vasodilator therapy in a patient with postbacterial meningitis-associated vasospasm. This case supports the use of this intervention. In future cases of vasospasm after bacterial meningitis, IV and IA milrinone should be trialed earlier with consideration of angioplasty.

Cerebral vasospasm as a consequence of pituitary apoplexy: illustrative case.

Cerebral vasospasm is a rare but devastating complication following pituitary apoplexy. Cerebral vasospasm is often associated with subarachnoid hemorrhage (SAH), and early detection is crucial for proper management. The authors present a case of cerebral vasospasm after endoscopic endonasal transsphenoid surgery (EETS) in a patient with pituitary apoplexy secondary to pituitary adenoma. They also present a literature review of all similar cases published to date. The patient is a 62-year-old male who presented with headache, nausea, vomiting, weakness, and fatigue. He was diagnosed with pituitary adenoma with hemorrhage, for which he underwent EETS. Pre- and postoperative scans showed SAH. On postoperative day 11, he presented with confusion, aphasia, arm weakness, and unsteady gait. Magnetic resonance imaging and computed tomography scans were consistent with cerebral vasospasm. The patient underwent endovascular treatment of acute intracranial vasospasm and was responsive to intra-arterial milrinone and verapamil infusion of the bilateral internal carotid arteries. There were no further complications. Cerebral vasospasm is a severe complication that can occur after pituitary apoplexy. It is essential to assess the risk factors linked to the cerebral vasospasm. In addition, a high index of suspicion will allow neurosurgeons to diagnose cerebral vasospasm after EETS early and take the necessary measures to manage it accordingly.

Hemodynamic response and clinical outcome following intravenous milrinone plus norepinephrine\u2013based hyperdynamic hypertensive therapy in patients suffering secondary cerebral ischemia after aneurysmal subarachnoid hemorrhage

PurposeIntravenous and intra-arterial milrinone as a rescue measure for delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) has been adopted by several groups, but so far, evidence for the clinical benefit is unclear and effect on brain perfusion is unknown. The aim of the actual analysis was to define cerebral hemodynamic effects and outcome of intravenous milrinone plus norepinephrine supplemented by intra-arterial nimodipine as a rescue strategy for DCI following aneurysmal SAH.MethodsOf 176 patients with aneurysmal SAH treated at our neurosurgical department between April 2016 and March 2021, 98 suffered from DCI and were submitted to rescue therapy. For the current analysis, characteristics of these patients and clinical response to rescue therapy were correlated with hemodynamic parameters, as assessed by CT angiography (CTA) and perfusion CT. Time to peak (TTP) delay in the ischemic focus and the volume with a TTP delay of more than 4 s (T4 volume) were used as hemodynamic parameters.ResultsThe median delay to neurological deterioration following SAH was 5 days. Perfusion CT at that time showed median T4 volumes of 40 cc and mean focal TTP delays of 2.5 ± 2.1 s in these patients. Following rescue therapy, median T4 volume decreased to 10 cc and mean focal TTP delay to 1.7 ± 1.9 s. Seventeen patients (17% of patients with DCI) underwent additional intra-arterial spasmolysis using nimodipine. Visible resolution of macroscopic vasospasm on CTA was observed in 43% patients with DCI and verified vasospasm on CTA, including those managed with additional intra-arterial spasmolysis. Initial WFNS grade, occurrence of secondary infarction, ischemic volumes and TTP delays at the time of decline, the time to clinical decline, and the necessity for additional intra-arterial spasmolysis were identified as the most important features determining neurological outcome at 6 months.ConclusionThe current analysis shows that cerebral perfusion in the setting of secondary cerebral ischemia following SAH is measurably improved by milrinone and norepinephrine–based hyperdynamic therapy. A long-term clinical benefit by the addition of milrinone appears likely. Separation of the direct effect of milrinone from the effect of induced hypertension is not possible based on the present dataset.

Vasospasm following low-velocity penetrating pediatric intracranial trauma

BackgroundBB guns or non-powder guns created in the modern era are able to reach exceedingly fast velocities as a result of advances in compressed-gas technology. While missile penetrating trauma has been well documented in neurosurgical literature, penetrating intracranial injury secondary to non-powder guns, along with their associated complications and treatments, is not well described, and even less so in the pediatric population.Case presentationHere, we describe an unusual case of a 6-year-old Indigenous child who was accidentally shot with a BB gun to the head. He subsequently developed delayed acute right-sided weakness due to symptomatic vasospasm. His symptoms resolved following hypertensive therapy, balloon angioplasty intervention, and intra-arterial milrinone therapy.ConclusionsThis case highlights the unique complication of delayed symptomatic vasospasm in a child following a non-missile intracranial penetrating injury. Intracranial vasospasm needs to be considered in the presence of delayed neurological deficit given its potential reversibility. This case also emphasizes the importance of gun safety and education when handling and storing these potential weapons around children.

Milrinone for refractory cerebral vasospasm with delayed cerebral ischemia.

Intravenous (IV) milrinone is a promising option for the treatment of cerebral vasospasm with delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). However, data remain limited on the efficacy of treating cases that are refractory to standard therapy with IV milrinone. The aim of this study was to determine predictors of refractory vasospasm/DCI despite treatment with IV milrinone, and to analyze the outcome of rescue therapy with intraarterial (IA) milrinone and/or mechanical angioplasty. The authors conducted a retrospective cohort study of all patients with aSAH admitted between 2010 and 2016 to the Montreal Neurological Institute and Hospital. Patients were stratified into 3 groups: no DCI, standard therapy, and rescue therapy. The primary outcome was frequency of DCI-related cerebral infarction identified on neuroimaging before hospital discharge. Secondary outcomes included functional outcome reported as modified Rankin Scale (mRS) score, and segment reversal of refractory vasospasm. The cohort included 322 patients: 212 in the no DCI group, 89 in the standard therapy group, and 21 in the rescue therapy group. Approximately half (52%, 168/322) were admitted with poor-grade aSAH at treatment decision (World Federation of Neurosurgical Societies grade III-V). Among patients with DCI and imaging assessing severity of vasospasm, 62% (68/109) had moderate/severe radiological vasospasm on DCI presentation. Nineteen percent (21/110) of patients had refractory vasospasm/DCI and were treated with rescue therapy. Targeted rescue therapy with IA milrinone reversed 32% (29/91) of the refractory vasospastic vessels, and 76% (16/21) of those patients experienced significant improvement in their neurological status within 24 hours of initiating therapy. Moderate/severe radiological vasospasm independently predicted the need for rescue therapy (OR 27, 95% CI 8.01-112). Of patients with neuroimaging before discharge, 40% (112/277) had developed new cerebral infarcts, and only 21% (23/112) of these were vasospasm-related. Overall, 65% (204/314) of patients had a favorable functional outcome (mRS score 0-2) assessed at a median of 4 months (interquartile range 2-8 months) after aSAH, and there was no difference in functional outcome between the 3 groups (p = 0.512). The aggressive use of milrinone was safe and effective based on this retrospective study cohort and is a promising therapy for the treatment of vasospasm/DCI after aSAH.

Which Protocol for Milrinone to Treat Cerebral Vasospasm Associated With Subarachnoid Hemorrhage?

Milrinone has emerged as an option to treat delayed cerebral ischemia after subarachnoid hemorrhage. However, substantial variation exists in the administration of this drug. We retrospectively assessed the effectiveness of 2 protocols in patients with angiographically proven cerebral vasospasm. During 2 successive periods, milrinone was administered using either a combination of intra-arterial milrinone infusion followed by intravenous administration until day 14 after initial bleeding (IA+IV protocol), or a continuous intravenous milrinone infusion for at least 7 days (IV protocol). The primary endpoint was the reversion rate of vasospastic arterial segments following the first IA infusion of milrinone (IA+IV protocol) compared with the reversion rate during the first week of IV infusion (IV protocol). There were 24 and 77 consecutive patients in IA+IV and IV protocols, respectively. The reversion rate was comparable between the 2 protocols: 71% (95% confidence interval [CI], 59%-83%) in the IA+IV protocol versus 64% (95% CI, 58%-71%) in the IV protocol (P=0.36). Rescue procedures for persistence or recurrence of vasospasm, that is, mechanical angioplasty and/or IA milrinone infusion, were similar between the 2 protocols. Patients with a good neurological outcome at 1 year, that is, modified Rankin Scale scores 0-2, were comparable between the 2 protocols. Side effects of milrinone were uncommon and equally distributed within the 2 protocols. These findings indicate that a continuous IV infusion of milrinone was as efficient as combined IA+IV infusion and suggest that this modality could be considered as a first easy-to-use option to treat patients with CVS.

Higher dose intra-arterial milrinone and intra-arterial combined milrinone-nimodipine infusion as a rescue therapy for refractory cerebral vasospasm.

Background Cerebral vasospasm (CV) is a major cause of delayed morbidity and mortality in patients with subarachnoid hemorrhage (SAH). Various cerebral protectants have been tested in patients with aneurysmal SAH. We aimed to research the success rate of treatment of CV via intra-arterial milrinone injection and aggressive pharmacological therapy for refractory CV. Methods A total of 25 consecutive patients who received intra-arterial milrinone and nimodipine treatment for CV following SAH between 2014 and 2017 were included in the study. Patients who underwent surgical clipping were excluded. Refractory vasospasm was defined as patients with CV refractory to therapies requiring ≥3 endovascular interventions. Overall, six patients had refractory CV. Long-term neurological outcome was assessed 6-18 months after SAH using a modified Rankin score and Barthel index. Results The median modified Rankin scores were 1 (min: 0, max: 3) and Barthel index scores were 85 (min: 70, max: 100) From each vasospastic territory maximal 10-16 mg milrinone was given to patients; a maximum of 24 mg milrinone was given to each patient in a session and a maximum of 42 mg milrinone was given to a patient in a day. Both milrinone and nimodipine were given to three patients. There was a large vessel diameter increase after milrinone and nimodipine injections. No patient died due to CV; only one patient had motor dysfunction on the right lower extremity. Conclusion Higher doses of milrinone can be used effectively to control refractory CV. For exceptional patients with refractory CV, high dose intra-arterial nimodipine and milrinone infusion can be used as a rescue therapy.

E.03 Use of intra-arterial milrinone rescue therapy in patients with refractory and super refractory vasospasm after aneurysmal subarachnoid hemorrhage

Background: Vasospasm causing delayed ischemic neurologic deficit (DIND) remains a leading cause of devastating outcome after aneurysmal subarachnoid hemorrhage (aSAH). Therapy using intravenous milrinone (IVM) and intra-arterial milrinone (IAM) has been described. We report our results using IAM in patients with refractory and super refractory vasospasm (RV and SRV respectively). Methods: Retrospective single center study of all adult patients treated with IAM between 2006 and 2016 inclusively. IAM was used as part of the Montreal Neurological Hospital Protocol when the patients’ symptoms failed to respond to initial and higher IVM doses. We report their clinical outcomes. Results: IAM was used in 19 patients. The median loading dose was 8 mg and average maintenance dose was 0.78 mcg/kg/min. Angiographic improvement was seen in 15 (79%) and clinical improvement - within the first 48 hours - was seen in all patients. The median mRS was 3 at time of discharge and 1 three months later. Five patients lost follow up. Conclusions: IAM appears to be safe and effective in this small retrospective series of RV and SRV complicating aSAH. Angiographic and clinical improvements were observed. Further prospective studies are warranted to confirm these findings.

Abstract TMP101: Safety and Outcome of High Doses IV Milirinone in Subarachnoid Hemorrhage With Refractory Vasospasm

Introduction: Vasospasm causing delayed cerebral ischemia (DCI) remains a leading cause of morbidity and mortality in aneurysmal subarachnoid hemorrhage (aSAH). Our previously reported series detailed the safety and efficacy of cardiac doses of milrinone in DCI. Since 2007, we have been treating refractory delayed cerebral ischemia (RDCI) with very large doses of IV milrinone. We report the safety and clinical effect of high-dose milrinone in aSAH with RDCI. Methods: Retrospective single center analysis of all patients treated between October 2014 and July 2015 for vasospasm refractory to the MNH protocol (RDCI). RDCI patients received a bolus and perfusion that were increased incrementally until resolution of signs. If 2 boluses and 2 increases in perfusion were unsuccessful, patients underwent angiogram for intra-arterial (IA) milrinone and possible angioplasty. Results: 40 patients were admitted for acute aSAH. Vasospasm was diagnosed clinically in 26 (65%). Initial milrinone therapy included a loading dose of 6 mg and an infusion of 0.75 mcg/kg/min. Of these patients, 18 had RDCI and received boluses of up to 8mg IV with perfusions of up to 2.75 mcg/kg/min. The maximum cumulative daily dose of milrinone was 230mg. There were no adverse cardiovascular events due to the drug. Neurologic improvement was seen in 8/18 with large IV bolus and perfusion of milrinone. Ten patients required angiography; all received IA milrinone, and angioplasty was performed in 3. Modified rankin scale (mRS) ≤ 2 on discharge was achieved in 6 of the 8 patients who improved with high-dose IV milrinone alone, 2 of 3 patients undergoing angioplasty and 4 of the 7 patients receiving IA milrinone without angioplasty. Conclusion: High doses of IV milrinone were effective in a large proportion of our patients with vasospasm and RDCI after aSAH, and it was extremely safe. This treatment could be considered prior to angioplasty.

E-008 Intra-arterial treatment of cerebral vasospasm

IntroductionAneurysmal subarachnoid hemorrhage (SAH) is associated with high morbidity and mortality primarily attributed to the delayed onset of cerebral vasospasm. Patient outcomes after aneurysmal SAH have considerably improved largely due...

Angiographic evaluation of the effect of intra-arterial milrinone therapy in patients with vasospasm from aneurysmal subarachnoid hemorrhage

Several methods have been used to treat cerebral vasospasm, which is a major cause of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (SAH). Here, we examined the effectiveness and safety of intra-arterial injection of milrinone for the treatment of vasospasm. Consecutive patients with angiographically confirmed vasospasm received intra-arterial milrinone between January 2006 and December 2007. The improvement in diameter of vessel (in millimeters) following treatment was assessed by paired t test for statistical significance. The angiographic improvement of supraclinoid internal carotid artery, M1 segment of middle cerebral artery, and A1 and A2 segment of anterior cerebral artery was compared with the modified Rankin score of the patients at discharge. A total of 15 milrinone treatments were performed in 14 patients (11 females and 3 males) with mean age of 52.7 years (31-68 years). There was significant angiographic improvement after milrinone therapy (p < 0.0001). Intra-arterial milrinone was a safe and effective treatment of cerebral vasospasm following aneurysmal SAH.

Intra‐Arterial Milrinone for Reversible Cerebral Vasoconstriction Syndrome

Reversible cerebral vasoconstriction syndrome (RCVS) usually presents with recurrent thunderclap headaches and is characterized by multifocal and reversible vasoconstriction of cerebral arteries that can sometimes evolve to severe cerebral ischemia and stroke. We describe the case of a patient who presented with a clinically typical RCVS and developed focal neurological symptoms and signs despite oral treatment with calcium channel blockers. Within hours of neurological deterioration, she was treated with intra-arterial milrinone, a phosphodiesterase inhibitor, which resulted in a rapid and sustained neurological improvement.

Milrinone for the Treatment of Cerebral Vasospasm After Aneurysmal Subarachnoid Hemorrhage

Attempts to reverse cerebral vasospasm (CVS) after aneurysmal subarachnoid hemorrhage (aSAH) rely on a limited number of treatments. Calcium channel blockers have proven a benefit but their vasodilating effect on spastic cerebral arteries is relatively modest. Milrinone, a phosphodiesterase inhibitor, combines vasodilating and inotropic properties, but limited data exist to support its use for the treatment of CVS. We assessed the efficacy and tolerance of milrinone in patients with CVS secondary to aSAH. Twenty-two consecutive patients with angiographically-proven CVS (arterial diameter reduction >40%) have been studied. Intraarterial milrinone was infused in the cerebral territory(ies) involved and followed by continuous intravenous infusion until Day 14 after initial bleeding. We evaluated angiographic reversal of CVS, hemodynamic tolerance, and neurological outcome 1 year after aSAH. Thirty-four selective intraarterial infusions of milrinone were required to treat 72 vasospastic territories. Intraarterial milrinone resulted in 53+/-37% increase in arterial diameter (P<.0001). Milrinone infusion resulted in moderately increased heart rate, but systemic arterial pressure remained unchanged. Five patients (23%) had angiographically-proven vasospasm recurrence within 48 hours after the procedure. Two of them were successfully reversed after another intraarterial infusion of milrinone. The remaining 3 underwent mechanical angioplasty. Two patients (9%) died in ICU, and 2 were lost to follow-up. All other patients had very good neurological outcome (modified Rankin scale: 0.8+/-1.0; Barthel index: 100 [95-100]). This study suggests that milrinone is effective and safe for reversal of CVS after aSAH and should be tested in a large randomized trial.

Milrinone as a Rescue Therapy for Symptomatic Refractory Cerebral Vasospasm in Aneurysmal Subarachnoid Hemorrhage

Delayed ischemic neurological deficit associated to cerebral vasospasm is the most common cause of sequelae and death that follows the rupture of an aneurysm. The objective of this study was to evaluate the safety and efficacy of intra-arterial Milrinone in patients with symptomatic refractory cerebral vasospasm. Eight patients diagnosed with aneurysmal subarachnoid hemorrhage who developed symptomatic cerebral vasospasm refractory to conventional medical therapy were enrolled. They received an intra-arterial infusion of Milrinone at a rate of 0.25 mg/min, with a total dose of 10-15 mg. Qualitative evaluation of angiographic response, neurological and systemic complications as well as functional outcome at 3 months were documented. All patients had a significant angiographic response. This was evidenced by a pre-treatment vessel stenosis greater than 70%, that improved to less than 50% after the intra-arterial Milrinone infusion. Three patients developed recurrent vasospasm that improved after a second intra-arterial Milrinone infusion. None of the patients developed neurologic or systemic complications attributed to the intervention. At 3 months follow-up all patients were alive and had a mean modified Rankin scale of 2 +/- 1 and a Barthel index of 83 +/- 10. Intra-arterial Milrinone infusion seems to be a safe and effective treatment for patients who develop refractory symptomatic cerebral vasospasm following aneurysmal subarachnoid hemorrhage.