By Thomas D. Bernier, PharmD; and Michael Schontz, PharmD, BCPS, BCCCP
Aneurysmal subarachnoid hemorrhage (aSAH) accounts for 5% of all strokes, and due to a multitude of complications, patients are at exceptional risk of mortality and morbidity.1 The incidence of aSAH is geographically diverse varying between 2 and 16.5 per 100,000 hospitalized adults globally.2 Patients are at risk of multifactorial mortality and morbidity in aSAH, as patients can experience rebleeding, hydrocephalus, seizures, infections and notably delayed cerebral ischemia (DCI).3 DCI occurs in approximately one-third of patients following aneurysmal rupture, typically presenting as acute changes in patients’ neurological status four to 14 days after the initial hemorrhage event.2,3 Often thought to be secondary to cerebral vasospasms (CVS), the prevalence of DCI in aSAH is now attributed to a multifactorial process due to both vascular and neural changes.4 The lack of effective and well-vetted treatment options for DCI in aSAH establishes the need for continued research into potential treatments.
Milrinone, an antagonist of the phosphodiesterase III enzyme (PDE III), represents a potentially promising agent for the treatment of DCI. Through the inhibition of PDE III, milrinone increases systemic levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) increasing positive inotropy and vasodilation. Additionally, increases in cAMP may result in anti-inflammatory effects through the reduction of cytokine production.8-10 The multiple potentially beneficial mechanisms may differentiate milrinone from previous pharmacologic agents that primarily focused on vasodilatory effects.5,11
Clinical experience of using milrinone has primarily focused on its use through two different routes, intraarterial (IA) and intravenous (IV). The studies evaluating IA administration of milrinone would initiate therapy upon the development of symptoms consistent with DCI. Following the IA milrinone bolus(es), continuous IV milrinone therapy was initiated.12-14 The use of IA followed by IV milrinone demonstrated the ability to reverse CVS and appeared to improve neurologic status with minimal adverse events. This success resulted in an evaluation of IV monotherapy for patients experiencing DCI, avoiding the invasive procedure associated with IA therapy.15 The results were overall positive with 66 of 88 patients (75%) achieving a positive neurological outcome, defined as modified Rankin Score <2. Adverse events from milrinone therapy were low. An additional trial was conducted to evaluate milrinone IA followed by IV versus IV alone in a more severely affected patient population than previously studied.16 The study found no significant difference between the two arms in revision rate of suspected causative CVS or clinical outcome. A high portion of patients, 17% vs. 18%, required rescue therapy due to recurrent or unresponsive symptoms.
The high rate of rescue therapy prompted the initial questioning of whether more aggressive use of milrinone would be beneficial in preventing the need of rescue therapy and improving clinical outcomes. The Montreal Neurological Institute and Hospital recently published their experience over six years of using an aggressive standard and rescue milrinone treatment strategies.17 Their protocol consisted of using infusion rates up to a maximum of 2.5 mcg/kg/min and aggressive boluses of IV milrinone ranging from 50-100 mcg/kg. Patients would receive rescue IA milrinone if there was acute worsening of mental status despite therapy or incomplete response after 3-4 hours of IV therapy. After IA therapy, patients were reinitiated on IV milrinone and aggressively titrated with boluses. Enrollment consisted of 322 patients: 212 had no DCI symptoms, 89 received standard milrinone therapy and 21 received rescue therapy. Patients were found to be more likely to require rescue therapy if they had moderate or severe CVS on radiological images. Higher World Federation of Neurosurgical Societies score and mild, moderate or severe CVS on radiological images were associated with requiring standard therapy. Significantly different ceiling doses of milrinone therapy were required based on the severity of CVS, with the highest ceiling doses being seen in those patients with severe CVS. Clinical outcomes did not significantly differ across the three groups of patients with 65% of patients having favorable functional outcomes. Notable adverse events included two patients developing transient myocardial ischemia attributed to the receipt of milrinone and 15% of patient developing hypotension defined as a decrease in blood pressure by 25% within one day after starting milrinone therapy and requiring vasopressor therapy > one day. Mortality due to cerebral infarcts occurred in eight patients in the standard therapy arm, while mortality due to cerebral infarcts occurred in zero patients in the rescue therapy arm. This may further support the use of aggressive initial therapy for the treatment of DCI.
The available evidence supports the premise of milrinone being a potentially efficacious and safe agent for the treatment of DCI in aSAH. However, there also are limitations preventing the widespread adoption of milrinone therapy. First, all the evidence is derived from either small case series or single-center cohorts. This makes it difficult to extrapolate the findings to different treatment centers with different patient populations and practices. Second, the cited literature also spans a large amount of time and treatment strategies making it difficult to determine a cohesive strategy to implement at new centers. Finally, none of the available data has incorporated a control group of patients with DCI, so while results appear positive, conclusions on true treatment effect with milrinone cannot be determined. These limitations establish the need for further evaluation of milrinone and specifically calls for a randomized clinical trial focusing on whether aggressive milrinone therapy benefits patients who develop DCI.
In the design of the randomized clinical trial, specific questions should be addressed to provide further insight into the effectiveness and safety of milrinone therapy: Should all patients with CVS or symptomatic DCI be empirically started on milrinone? Can severity of vasospastic regions on angiography play a role in guiding dosing of IV therapy? Is IA therapy or the more aggressive dosing of IV therapy following intervention the key to preventing cerebral infarcts? Would increasing bolus frequency or scheduling boluses of milrinone have a positive impact on outcomes? What specific patient characteristics lead to an increased risk of adverse events? What type of monitoring and how frequent should assessments be performed to ensure safety? What precautions should be taken in those patients with pre-existing cardiovascular disease, particularly heart failure, coronary artery disease or renal dysfunction? What would be implications on safety if more patients with these conditions were included?
- Nieuwkamp DJ, Setz LE, Algra A et al. Changes in case fatality of aneurysmal subarachnoid haemorrhage over time, according to age, sex, and region: a meta-analysis. Lancet Neurol. 2009;8(7):635-642
- Conolly ES, Rabinstein AA, Carhuapoma JR, et al. Guidelines for management of aneurysmal subarachnoid hemorrhage: A guideline for healthcare professionals from the American heart association/American stroke association. 2012;43:1711-1737
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- Macdonald R, Higashida R, Keller E, et al. Clazosentan and endothelin receptor antagonist, in patients with aneurysmal subarachnoid hemorrhage undergoing surgical clipping: a randomized, double-blind placebo controlled phase 3 trial. (CONSCIOUS-2). Lancet Neurol. 2011;10(7):618-625
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- Gathier CS, van den Bergh WM, van der Jagt M, et al. Induced hypertension for delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage: a randomized clinical trial. 2018;49:76-83
- Mollhoff T, Loick HM, Van Aken H, et al. Milrinone modulates endotoxemia, systemic inflammation, and subsequent acute phase response after cardiopulmonary bypass (CPB). Anesthesiology. 1999;90(1):72–80.
- Yamaura K, Okamoto H, Akiyoshi K, et al. Effect of low-dose milrinone on gastric intramucosal pH and systemic inflammation after hypothermic cardiopulmonary bypass. J Cardiothorac Vasc Anesth. 2001;15(2):197–203.
- Chanani NK, Cowan DB, Takeuchi K, et al. Differential effects of amrinone and milrinone upon myocardial inflammatory signaling. 2002;106(12 Suppl 1):I284–9.
- Rosensburg N, Lazzaro MA, Lopes DK, Prabhakaran S. High-dose intra-arterial nicardipine results in hypotension following vasospasm treatment in subarachnoid hemorrhage. Neurocrit Care. 2011;15(3):400-414
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