Double-blinded, placebo-controlled crossover trial to determine the effects of midodrine on blood pressure during cognitive testing in persons with SCI

Jill M Wecht, Joseph P Weir, Caitlyn G Katzelnick, Nancy D Chiaravalloti, Steven C Kirshblum, Trevor A Dyson-Hudson, Erica Weber, William A Bauman, Jill M Wecht, Joseph P Weir, Caitlyn G Katzelnick, Nancy D Chiaravalloti, Steven C Kirshblum, Trevor A Dyson-Hudson, Erica Weber, William A Bauman

Abstract

Study design: Clinical trial.

Objectives: Individuals with spinal cord injury (SCI) above T6 experience impaired descending cortical control of the autonomic nervous system, which predisposes them to hypotension. However, treatment of hypotension is uncommon in the SCI population because there are few safe and effective pharmacological options available. The primary aim of this investigation was to test the efficacy of a single dose of midodrine (10 mg), compared with placebo, to increase and normalize systolic blood pressure (SBP) between 110 and 120 mmHg during cognitive testing in hypotensive individuals with SCI. Secondary aims were to determine the effects of midodrine on cerebral blood flow velocity (CBFv) and global cognitive function.

Setting: United States clinical research laboratory.

Methods: Forty-one healthy hypotensive individuals with chronic (≥1-year post injury) SCI participated in this 2-day study. Seated SBP, CBFv, and cognitive performance were monitored before and after administration of identical encapsulated tablets, containing either midodrine or placebo.

Results: Compared with placebo, midodrine increased SBP (4 ± 13 vs. 18 ± 24 mmHg, respectively; p < 0.05); however, responses varied widely with midodrine (-15.7 to +68.6 mmHg). Further, the proportion of SBP recordings within the normotensive range did not improve during cognitive testing with midodrine compared with placebo. Although higher SBP was associated with higher CBFv (p = 0.02), global cognitive function was not improved with midodrine.

Conclusions: The findings indicate that midodrine increases SBP and may be beneficial in some hypotensive patients with SCI; however, large heterogeneity of responses to midodrine suggests careful monitoring of patients following administration.

Clinical trials registration: NCT02307565.

Conflict of interest statement

Conflict of Interest Statement: The authors report no financial conflict of interest in association with conducting the current clinical trial.

Figures

Figure 1:
Figure 1:
Results of the repeated measures ANOVA models for heart rate [a], systolic blood pressure [b], diastolic blood pressure [c], systolic flow velocity [d], mean flow velocity [e] and diastolic flow velocity [f] pre to post placebo (closed circles) and midodrine (open squares). *** p<0.001; ** p<0.01; * p<0.05 for the drug by time interaction effect.
Figure 2:
Figure 2:
The relationship between change in systolic blood pressure (SBP) and mean cerebral blood flow velocity (FV) following administration of placebo [a] and midodrine [b].
Figure 3:
Figure 3:
Average [a] and the change [b] in 5-minute seated resting systolic blood pressure (mmHg) following administration of placebo and midodrine for each participant. The dashed lines represent the upper and lower limits of the normotensive range [a] and the no change [b].
Figure 4:
Figure 4:
Systolic blood pressures Pre (closed circles) and Post (open squares) midodrine administration in 3 individual participants (top) and the AUC curves which were generated from these data (bottom). Left panel: the participant is hypotensive Pre and Post midodrine [a] and the AUC indicates a modest improvement in normalizing systolic blood pressure Post midodrine [b]. Middle panel: the participant is hypotensive Pre midodrine and normotensive Post midodrine [c] and the AUC reflects an increased proportion of normal blood pressure Post midodrine [d]. Right panel: the participant is hypotensive Pre midodrine and hypertensive Post midodrine [e] and the AUC reflects a reduced proportion of normal blood pressure Post midodrine [f].

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