Midodrine to liberate ICU patients from intravenous vasopressors: another negative fixed-dose trial

Dear Editor,

We read with interest the two-center, open-label, feasibility randomized-controlled trial of fixed-dose midodrine administration to hasten weaning from low-dose vasopressor infusions by Costa-Pinto and colleagues [1]. Their cohort of 62 mostly post-operative and septic subjects was enrolled over 22 months, but the study was terminated early due to the COVID-19 pandemic. The investigators concluded midodrine administration (10 mg every 8 hours) was not associated with a shorter time to cessation of vasopressor infusions compared to usual care (16.5 vs. 19 hours; p=0.32). We thank them for this pragmatic trial, but had several concerns regarding their intervention.

We are aware of seven published reports, including 1,572 subjects, in which midodrine was administered to facilitate weaning of vasopressor infusions in critically ill patients (Table 1) [1–7]. All four studies incorporating dose titration of midodrine concluded it was effective, while three studies employing a fixed-dose strategy, including the trial by Costa-Pinto, concluded midodrine was ineffective. Three of the four dose titration studies were retrospective, compared to one of the three fixed-dose studies, limiting the strength of those conclusions.

Table 1:

Studies describing midodrine administration to wean vasopressors in ICU patients arranged by dosing strategy

Author, Year	Design	Setting, Sample Size	Midodrine Dose, Duration	Multiple Vasopressorsa	% with Bradycardia, Definition	Results
Titration Studies
Levine 20132	Prospective, observational Paired before-after analysis	SICU n=20	5-20 mg TID 4 (3-7) days	Not reported	None Reported	Greater decline in vasopressor weaning rate. (−0.62 vs. −2.2 mcg/min/hr; p=0.012)
Whitson 20163	Retrospective, observational, controlled	MICU n=135	10-40 mg q8h 6.2 days	Not reported	0.7% Not defined	Shorter duration of vasopressors (3.8 vs. 2.9 days; p<0.001)
Poveromo 20174	Retrospective, observational controlled	CICU, SICU, MICU, NICU n=94	2.5-10 mg 2-6x daily 4.4 (3-8) days	59.6%	12.8% Not Defined	Vasopressors discontinued in 1.2 (0.5-2.8) days. Pressor rate decreased 97.3% at 24 hours
Rizvi 20185	Retrospective, observational, uncontrolled	CTICU, SICU, MICU, NICU n=1,119	5-30 mg q8h 11.8 (21) daysb	Not reported	15% HR <50 BPM	48% weaned off vasopressors at 24 hours (p<0.001)
Fixed-dose Studies
Santer 20207	Randomized, placebo controlled	MICU, SICU n=68	20 mg q8h 1.8 (1.0-3.0) days	0%	7.6% HR <40 BPM or 20% decrease	No difference in time to vasopressor discontinuation (23.5 vs. 22.5 hours; p=0.62)
Tremblay 20206	Retrospective, observational, Propensity matched	CTICU n=74	10 mg TID 1.7 (1.0-3.0) days	15%	NR	No difference in duration of vasopressors (63 vs. 44 hours; p=0.052)
Costa-Pinto 20221	Randomized, open-label, controlled	MICU, SICU n=62	10 mg q8h	Not reported	31.2% HR ≤50 BPM	No difference in duration of vasopressors (16.5 vs. 19 hours; p=0.32)

^a– percentage of patients treated with two or more vasopressors at time of midodrine initiation

^b– duration data taken from a follow-up report from this same study [8]

BPM = beats per minute; CICU = cardiac intensive care unit; CTICU = cardiothoracic intensive care unit; HR = heart rate; MICU = medical intensive care unit; NE-E = norepinephrine equivalents; NICU = neurological intensive care unit; RCT = randomized-controlled trial; SICU = surgical intensive care unit

The dose-response of midodrine for increasing blood pressure was confirmed in a double-blind, placebo-controlled, crossover trial conducted by Wright and colleagues in 25 subjects with neurogenic orthostatic hypotension [8]. It is possible the fixed-dose strategy employed by Costa-Pinto and colleagues limited the therapeutic benefit of midodrine akin to administering norepinephrine at a low, fixed-dose, rather than titrating to a clinical endpoint. Additionally, because their trial was stopped early, it is probable they were underpowered to identify significant differences in their outcomes.

Midodrine is a prodrug that is metabolized to its active moiety desglymidodrine which has a half-life of three to four hours [9]. Although the dosing frequency for midodrine is often every eight hours, the prescribing information describes daytime dosing every three to four hours [9]. A recent retrospective study administered midodrine every six hours, with doses ranging from 5-20 mg; this approach reduced norepinephrine-equivalent doses by 50% within 24 hours [10]. The every eight hour interval used by Costa-Pinto and colleagues may also have contributed to their negative results.