Subarachnoid hemorrhage (SAH) by aneurysmal rupture accounts for 1% to 5% of all strokes [1,2]. One of the main complications conditioning SAH prognosis is cerebral arterial vasospasm, which occurs in 50% to 70% of cases [3]. Cerebral vasospasm is mostly asymptomatic, but may be complicated by secondary ischemic neurological deficit. Early management of asymptomatic forms of vasospasm can prevent ischemic complications and improve functional prognosis [4]. The first-line prophylactic treatment for cerebral vasospasm is nimodipine [5]. However, cerebral vasospasm can occur despite this prophylactic treatment, and several curative treatments have been proposed. Some of them, such as papaverine or milrinone, are administered directly in the vessel during cerebral arteriography [6,7]. Intravenously administered molecules are also proposed in this indication such as sildenafil, magnesium sulfate, or milrinone [8-12]. Milrinone appears to be a promising treatment to alleviate cerebral vasospasm [11]. It is a phosphodiesterase-3 inhibitor, with positive inotropic effect and systemic arterial vasodilator effect, whose main therapeutic indication is cardiogenic shock [13]. However, milrinone can induce cardiac arrhythmias by inhibiting the degradation of cyclic adenosine monophosphate, which leads to an increase in intracellular calcium.

In this paper, we raise new issues concerning milrinone and report an undescribed side effect of this treatment that we observed in two patients hospitalized in a neurosurgical intensive care unit (ICU) for SAH (with two different clinical presentations): dynamic left ventricular outflow tract obstruction (LVOTO). This is characterized by a pressure gradient between the left ventricle and the aorta. The narrowed left ventricular outflow tract is the site of substantial flow, which can lead to anterior translation of the mitral valve (systolic anterior motion [SAM]) and regurgitation of the valve. Fixed LVOTO is due to particular anatomical conditions that can be corrected by surgery. Dynamic LVOTO is favored by the addition of predisposing factors (decreased preload and afterload, increased inotropism). Clinically, LVOTO may induce hemodynamic failure up to shock, and neurosurgical intensivists should be aware of this complication of milrinone infusion.

To our knowledge, we describe here the two first cases of LVOTO induced by milrinone.

The dynamic LVOTO phenomenon is secondary to a decreased preload and a decreased postload with increased inotropism thus reducing the telediastolic and telesystolic volumes of the left ventricle [14-16]. These conditions often occur in common situations in the ICU, such as the use of positive inotropes in hypovolemic patients, or during septic shock [17]. They are also described in postoperative mitral or aortic valve replacement, in intraoperative noncardiac surgery, or in patients with hemorrhagic shock [16]. They result in a reduction of the size of the left ventricle in systole and in the development of an obstruction that may be medio-ventricular or caused by a SAM. Both types of obstruction, combined or not, are possible [17]. In case of SAM, the attraction of the large mitral valve toward the interventricular septum creates an opening of the valve that leads to functional mitral regurgitation, which can be important as in our first case. This mitral insufficiency disappears after SAM correction.

The difference must be made between fixed LVOTO, due to underlying anatomical factors (excessive mitral tissue, mitro-aortic angle less than 120°, septal hypertrophy) that are sometimes correctable by surgery. In patients with hypertrophic obstructive cardiomyopathy (HOCM), the onset or aggravation of the stenosis may be seen during hypovolemia, vasodilatation, physical exertion, or dobutamine stress ultrasound [16-18]. In patients who are HOCM free in the ICU, obstruction is found in the presence of a classic triad: hyperkinetic left ventricle, tachycardia, and hypovolemia [19]. Thus, logically, catecholamines are described as a potential inducer of LVOTO. This has mostly been described with inotropes such as dobutamine but also with dopamine and norepinephrine [20-25].

Diagnosis of LVOTO is difficult and can only be done with echocardiography. The diagnosis relies on the presence of an intraventricular pressure gradient (measured in continuous Doppler) with a velocity peak ≥1 m/s (or LVOTO pressure gradient at least 30 mmHg) or an anterior systolic movement of the large mitral valve, which is attracted into the left ventricle flushing chamber (SAM) [16,17]. A meso- or telesystolic exclusion of the middle part of the left ventricle may also be seen. This entity differs from fixed LVOTO because it occurs on a healthy heart, with a normal thickness of the interventricular septum.

The main differential diagnosis in this context of SAH is neurogenic myocardial stunning. This occurs in the acute phase of SAH. Unlike LVOTO, beta receptor overstimulation results in myocardial sideration. The common feature of the two conditions is the worsening with the use of catecholamines.

We did not find any study describing milrinone-induced dynamic LVOTO. When looking for studies dealing with hemodynamic effects of milrinone, several of them have described a decrease in systemic and pulmonary vascular resistance, an increase in cardiac index, an improvement in diastolic function, and a decrease in pulmonary capillary wedge pressure [26-29]. Other side effects frequently reported are headache, tachycardia, arterial hypotension, arrhythmias (especially atrial fibrillation), and ventricular extrasystoles [7,26-29]. These complications occur more frequently in patients with impaired left ventricular ejection fraction.

However, our cases showed the occurrence of LVOTO after milrinone infusion start in two patients without any cardiac disease before ICU admission. Indeed, in our first case, the only predisposing factor appeared to be a punctual bolus of milrinone, resulting in acute LVOTO with SAM, functional mitral insufficiency, and shock. Mitral regurgitation associated with LVOTO is most often eccentric and travels to the left pulmonary veins [30], resulting in unilateral acute pulmonary edema in this patient. In our second case, the hemodynamic effects of milrinone (afterload decrease and increased inotropism) were added to a relative decrease in preload induced by sepsis. The consequence was then a symptomatic subacute and less severe form of LVOTO clinically translated by the appearance of a new heart murmur and arterial hypotension requiring fluid therapy. The systolic murmur persisted after punctual use of crystalloids, and only disappeared when the milrinone infusion was stopped. These elements support, in our opinion, the hypothesis that the use of milrinone is the main and triggering mechanism in this case, sepsis being only an aggravating factor.

Given our observations and on the basis of LVOTO pathophysiology, we think that milrinone, by combining a positive inotropic effect with a systemic arterial vasodilator effect, could be a molecule that strongly promotes the occurrence of LVOTO.

Milrinone plays an important role in the treatment of cerebral vasospasm, and several neurosurgical ICU teams are using it for their patients with SAH. However, our reports and the analysis of the LVOTO pathophysiology suggest that in patients that are hypovolemic or septic, milrinone should probably be used with caution. The onset of LVOTO due to milrinone may be difficult to diagnose because of the lack of a specific clinical sign. However, its consequences are potentially serious since the occurrence of shock could worsen cerebral ischemia and neurological prognosis in patients already treated for arterial vasospasm. Echocardiography should probably be proposed early in patients with hemodynamic instability associated with milrinone. The use of echocardiography should probably be proposed in the presence of the aforementioned triggers or in case of hemodynamic instability in patients treated with milrinone. Prospective studies on a larger patient population are needed to determine the incidence of these disorders and their impact on the prognosis of patients treated for arterial vasospasm with milrinone.

In patients with septic shock, LVOTO appears to be an independent risk factor for mortality [17]. It therefore makes sense to try to reduce or even eliminate this complication among patients in the ICU. The treatment is mostly based on the management of the triggering factors such as the correction of a hypovolemia, the stop of inotropic treatments, and the treatment of a sepsis. The occurrence of tachycardia, which is frequent in neurosurgical ICU, should be carefully monitored, as it aggravates the dynamic LVOTO. In some cases, the use of α-agonists vasoconstrictors or the introduction of a beta-blocker to decrease the ventricular pressure gradient may be proposed [19].

LVOTO is probably an underestimated clinical situation in neurosurgical ICU. It may occur in patients without any previous cardiac diseases, and its diagnosis relies on echocardiography. There are numerous triggering factors that are frequent in patients in the ICU and that cumulatively promote its occurrence. Milrinone, because of its positive inotropic effect and systemic arterial vasodilator effect, appears to be a molecule that may provide LVOTO. Further studies are needed to evaluate the incidence of dynamic LVOTO and its impact on the prognosis of patients with cerebral vasospasm treated with milrinone.