Cerebral Vasospasm After Subarachnoid Hemorrhage: Respective Short-Term Effects of Induced Arterial Hypertension and its Combination With IV Milrinone: A Proof-of-Concept Study Using Transcranial Doppler Ultrasound

Abstract

Objectives: It is unclear whether IV milrinone relaxes spasmed cerebral arteries and therefore reduces cerebral blood mean velocity (V_mean). In patients treated for cerebral vasospasm, we aimed to assess and delineate the respective impacts of induced hypertension and its combination with IV milrinone on cerebral hemodynamics as assessed with transcranial Doppler.

Design: Observational proof-of-concept prospective study.

Setting: ICU in a French tertiary care center.

Patients: Patients with aneurysmal subarachnoid hemorrhage who received induced hypertension (mean arterial blood pressure [MBP] of 100-120 mm Hg) and IV milrinone (0.5 µg/kg/min) for moderate-to-severe cerebral vasospasm. We excluded patients who underwent invasive angioplasty or milrinone discontinuation within 12 hours after the diagnosis of vasospasm.

Interventions: None.

Measurements and main results: V_mean was measured at vasospasm diagnosis (T_DIAGNOSIS), after the induction of hypertension (T_HTN), and 1 (T_{HTN+MILRINONE_H1}) and 12 hours after the adjunction of IV milrinone (T_{HTN+MILRINONE_H12}). Thirteen patients were included. Median V_mean was significantly lower (p < 0.01) at T_{HTN+MILRINONE_H1} (99 [interquartile range (IQR) 89; 134] cm.s^-1) and T_{HTN+MILRINONE_H12} (85 [IQR 73-127] cm/s) than at T_DIAGNOSIS (136 [IQR 115-164] cm/s) and T_HTN (148 [IQR 115-183] cm/s), whereas T_DIAGNOSIS and T_HTN did not significantly differ. In all patients but one, V_mean at T_{HTN+MILRINONE_H1} was lower than its value at T_DIAGNOSIS (p = 0.0005). V_mean-to-MBP and V_mean-to-cardiac output (CO) ratios (an assessment of V_mean regardless of the level of MBP [n = 13] or CO [n = 7], respectively) were, respectively, similar at T_DIAGNOSIS and T_HTN but were significantly lower after the adjunction of milrinone (p < 0.01).

Conclusions: The induction of arterial hypertension was not associated with a significant decrease in V_mean, whereas the adjunction of IV milrinone was, regardless of the level of MBP or CO. This suggests that IV milrinone may succeed in relaxing spasmed arteries.

Keywords: Doppler; cerebrovascular circulation/drug effects; delayed ischemia; intracranial; milrinone; subarachnoid hemorrhage; transcranial; ultrasonography; vasospasm.

Figure 1.

The main message of this figure is that the induction of arterial hypertension did not significantly affect blood mean velocity measured in the middle cerebral artery with trans-temporal Doppler (V_mean), whereas the adjunction of IV milrinone was associated with a significant decrease in V_mean. This finding was independent of the level of mean BP (n = 13) or CO (n = 7) as illustrated by the indexation of V_mean to these parameters. Respective effects of induced arterial hypertension and its combination with IV milrinone. The interquartile range (IQR) is calculated: IQR = third – first quartile. The upper inner fence box‑and‑whisker plots were constructed as follows: a box is drawn from the first to third quartile, and a horizontal line is drawn at the median, an imaginary line, is drawn at the third quartile + 1.5 × IQR. The horizontal line above the box is the highest measurement just below the upper inner fence. Similar lines are drawn at the lower side of the plot. A bracket indicates a significant difference (p < 0.01) between two timepoints. BP = arterial blood pressure, T_DIAGNOSIS = at vasospasm diagnosis, T_HTN = 1 hr after the induction of hypertension, T_{HTN+MILRINONE_H1} = 1 hr after the adjunction of IV milrinone, T_{HTN+MILRINONE_H12} = 12 hr after the adjunction of IV milrinone.