Oral blood pressure augmenting agents for intravenous vasopressor weaning

Table 1 Pharmacology and overview of oral blood pressure augmenting agents

Agent	Onset	Half-life	Metabolism	Special considerations
Midodrine, desglymidodrine	1 hour	0.5 hour, 3-4 hours	Rapid deglycination to desglymidodrine	Avoid during bradycardia. Dose reductions necessary in renal dysfunction
Droxidopa	1 hour	2-3 hours	Metabolized to norepinephrine via the catecholamine pathway	Recent data suggests that capsule may be opened and administered via feeding tube
Pseudoephedrine	0.5 hour	3-16 hours1	Not substantially metabolized	Dose reductions should be considered in renal dysfunction
Atomoxetine	1 hour	5-24 hours2	Hepatic, cytochrome P4502D6 (major) and cytochrome P450 family 2 subfamily C member 19 (minor)	Avoid during agitated delirium. Dose reductions necessary in hepatic dysfunction

¹Half-life prolonged with elevated urine potentiel d'hydrogène.

²Half-life prolonged in cytochrome P4502D6 poor metabolizers.

Table 2 Summary of evidence for use of oral blood pressure augmenting agents in vasopressor weaning

Drug	Ref.	Study type	Population	Drug dosing	Duration of IVV	ICU LOS	Adverse reactions	Outcomes
Midodrine	Sharma et al[33], 2008	Case series	Coronary artery stenting (n = 55), midodrine (n = 4), dopamine (n = 11)	10 mg Q8H x 3 doses	15 hours in dopamine group and 0 hour in midodrine group	2 days vs 0 day	None	Midodrine was well tolerated. Cost of hospitalization was higher in the dopamine group because of the need for ICU admission
	Levine et al[34], 2013	Prospective	Surgical ICU (n = 20)	5-20 mg Q8H	Median 17 hours after midodrine initiation	NR	NR	The change in IVV rate decreased from -0.62 to –2.20 mcg/minutes/hour of phenylephrine equivalents following the initiation midodrine, P = 0.01
	Poveromo et al[35], 2016	Retrospective	Mixed ICU (n = 188)	10 mg Q8H	Median 1.2 days (0.5–2.8 days) after midodrine initiation (not compared to control group)	No difference	Bradycardia in 12.8% midodrine group vs 0% in control group	Discharge from the ICU occurred sooner after IVV discontinuation in the midodrine group compared to the control group (0.8 days vs 1.5 days, P = 0.01). There was no difference in ICU LOS; and hospital LOS was longer in the midodrine group
	Whitson et al[45], 2016	Retrospective	MICU, septic shock (n = 275), IVV only (n = 140), IVV plus midodrine (n = 135)	10 mg Q8H	Mean duration 3.8 vs 2.9 days, P < 0.001	9.4 vs 7.5 days, P = 0.02	Bradycardia requiring midodrine discontinuation in 1 patient	Midodrine decreased duration of IVV use and ICU LOS
	Rizvi et al[48], 2019	Observational	ICU patients that received midodrine and survived to discharge (n = 1119)	5-30 mg Q8H	NA	NA	NA	The study assessed continuation of midodrine during transition of care and 34% of patients were continued on midodrine at hospital discharge
	Tremblay et al[47], 2020	Retrospective	Cardiac surgery patients (n = 148), IVV only (n = 74), IVV plus midodrine (n = 74)	10 mg Q8H	Median duration 44 hours (26-66 hours) vs 63 hours (40-86.5 hours), P = 0.05	68 hours (48-99 hours) vs 99 hours (68-146 hours), P < 0.01	No significant difference in acute kidney injury	Negative results with midodrine use association with an increased ICU LOS
	Santer et al[36], 2020	RCT	ICU patients (n = 132), midodrine (n = 66), placebo (n = 66)	20 mg Q8H	Median duration 23.5 hours (10.0–54.0 hours) vs 22.5 hours (10.4–40.0 hours), P = 0.62	6.0 days (5.0–8.0 days) vs 6.0 days (4.0–8.0 days), P = 0.46	Bradycardia 5 (7.6%) vs 0 (0%), P = 0.02	No difference in IVV use duration or ICU LOS
	Macielak et al[46], 2021	Observational	ICU and floor patients, (n = 44), received IVV (n = 23)	5-20 mg Q6H	NR	12 days (5–27 days)	The 1 case of mesenteric ischemia	NEE requirements decreased from 0.1 to 0.05 norepinephrine equivalents at 24 hours after midodrine was ordered for Q6H
	Lal et al[49], 2021	RCT	MICU (n = 32), midodine (n = 17), placebo (n = 15)	10 mg Q8H	Median duration 14.5 hours ± 8.1 hours vs 18.8 hours ± 7.1 hours, P = 0.19	2.29 days vs 2.45 days, P = 0.36	No major adverse events	Study not powered to detect statistically significant results
	Adly et al[37], 2022	RCT	Septic shock (n = 60)	10mg Q8H	Median duration NE 4 days with midodrine vs 6 days control, P < 0.01	NR	NR	Use of midodrine resulted in reduced IVV duration and improved mortality rates
Droxidopa	Zundel et al[38], 2016	Case report	53F with vasoplegic shock post cardiac transplant	Titrated to 600 mg 4× daily.	Not weaned off despite 10 days of droxidopa	NR	No apparent adverse effects	Droxidopa temporarily increased MAP and reduction in vasoactive requirements after midodrine was not effective. Patient died on post-op day 60 with multiorgan failure
	Hong et al[40], 2022	Retrospective	The 64M with SS and midodrine-induced bradycardia. The 73M with SS and midodrine-induced bradycardia	100 mg TID, 100 mg BID titrated up to 600 mg TID	The 1 day after droxidopa initiation and MAP goal reduction. The 9 days after starting droxidopa and 5 days after restarting midodrine	NR	NR	Droxidopa was weaned off prior to patient discharge. Droxidopa in combination with midodrine led to avoidance of pacemaker placement. Patient was discharged to rehabilitation on droxidopa and midodrine
	Noble et al[39], 2023	Case report	The 57F with persistent hypotension despite midodrine	100 mg TID titrated to 500 mg TID	3 days after droxidopa initiation	NR	NR	After initiation of droxidopa the patient was weaned off IVV and continuous renal replacement therapy and ultimately discharged home on droxidopa
	Webb et al[25], 2024	Retrospective	n = 21 (80.5% cardiac ICU) with persistent hypotension despite midodrine	Most frequent starting dose 100 mg TID. Max dose: 600 mg TID	Median time to discontinuation 87 hours (interquartile range 34-175)	NR	Similar rates of tachycardia pre- and post-initiation	NEE requirements were lower after initiation of droxidopa in patients that were trial on alternative oral vasoactive agents prior to droxidopa. About half of the patients died in the hospital. The number of patients discharged on droxidopa was not reported
Pseudoephedrine	Patterson et al[41], 2008	Case report	The 77F with idiopathic autonomic dysfunction	60 mg Q8H and tapered to 60 mg Q6H	NR	NR	NR	Norepinephrine was weaned off temporarily within 14 hours of PSE initiation, but frequency was increased to Q6H to permanently liberate patient from IVV
	Curran et al[42], 2023	Case report	Male in 40s with autonomic dysfunction and refractory bradycardia and hypotension on midodrine at home	60 mg Q6H that was weaned off within 7 days	< 24 hours	NR	NR	Addition of PSE facilitated IVV weaning in a patient with bradycardia and hypotension refractory to midodrine
	Wood et al[43], 2014	Case series	n = 38 SS	Daily PSE dose varied widely (30–720 mg)	The mean time to discontinuation of vasopressors and/or atropine was 8 days	Mean: 39 days	No adverse events directly attributed to PSE therapy were documented	‘Success’: Vasopressor discontinuation or decreased use of atropine was achieved in 82% of patients
Atomoxetine	Lessing et al[44], 2024	Retrospective	Congenital tracheal stenosis patients with midodrine-refractory hypotension (n = 45), atomoxetine (n = 18), droxidopa (n = 17), both (n = 10)	Starting daily dose: Atomoxetine 10-20 mg; droxidopa 300 mg. Maximum daily dose: Atomoxetine 40 mg; droxidopa 1800 mg	Median time to discontinuation 21.9 days vs 8 days vs 13.9 days, P = 0.26	Median: 30 days vs 18 days vs 35 days	Hypertension requiring treatment in 2 patients receiving atomoxetine and in 2 patients receiving both. Ischemic bowel complication in 1 patient receiving atomoxetine and 1 patient receiving both. New onset arrhythmia in 3 patients receiving atomoxetine and 2 patients receiving droxidopa and 1 patient receiving both	There was no difference in IVV duration or LOS. A higher percentage of patients who survived to hospital discharge received both study medications or droxidopa alone (90% vs 76.5%) compared to atomoxetine alone (44.4%, P = 0.03)
Desmopressin	Ahmed et al[21], 2022	RCT	SS, control (n = 30), midodrine (n = 30), minirin (n = 30)	Midodrine 10 mg Q8H. Minirin 60 mcg Q8H	Control 6.93 days, midodine3.3 days, minirin 4.8 days, P <0.01	9.03 days, 5.13 days, 5.5 days, P < 0.01	NR	Midodrine and minirin use significantly reduced duration of pressors and ICU LOS. Duration of pressors was shorter in midodrine group compared to midodrine, but ICU LOS was similar between these two groups

ICU: Intensive care unit; IVV: Intravenous vasopressor; LOS: Length of stay; MAP: Mean arterial pressure; MICU: Medical intensive care unit; NA: Not available; NEE: Norepinephrine equivalents; NR: Not reported; PSE: Pseudoephedrine; RCT: Randomized control trial; SS: Spinal shock.