Midodrine initiation criteria, dose titration, and adverse effects when administered to treat shock: A systematic review and semi-quantitative analysis
Categoría del artículo: Review
Publicado en línea: 31 ene 2025
Páginas: 5 - 22
Recibido: 15 may 2024
Aceptado: 16 ene 2025
DOI: https://doi.org/10.2478/jccm-2025-0007
Palabras clave
© 2025 Madeleine M. Puissant et al., published by Sciendo
This work is licensed under the Creative Commons Attribution 4.0 International License.
Fig. 1.
Patient characteristics and outcomes of included studies
|
TICU n=30 MID n=30 Control |
NR | Spinal |
MID first day SCr 0.72 ± 0.39 Control first day SCr 1.02 ± 0.59 p=0.005 MID last day SCr 1.04 ± 0.62 Control last day SCr 1.39 ± 1.27 p=0.276 |
ICU |
ICU MID 5.13 ± 1.83 Control 9.03 ± 3.74 p<0.001 Hospital—NR |
NR | |
|
MICU n=32 MID n=30 Control |
APACHE III MID 49.5 (41, 56.25) Control 48.5 (38.25, 58) p=0.76 |
Septic; post-op |
MID SCr 0.82 (0.66, 1.17) Control SCr 0.83 (0.64, 1.00) p=0.53 |
ICU |
ICU MID 2.08 (1.06, 3.08) Control 2.46 (1.6, 3.89) p=0.14 Hospital MID 9 (5.75, 25.25) Control 7.5 (6, 14.5) p=0.92 |
ICU MID 1 (3.1%) Control 0 (0%) p>0.99 Hospital MID 3 (9.4%) Control 2 (6.7%) p>0.99 |
|
|
General ICU n=15 MID n=13 Control |
APACHE II MID 17.06 ± 3.15 Control 16.15 ± 4.01 p=0.10 SOFA MID 7.5 ± 2.17 Control 8.3 ± 2.25 p=0.99 |
Septic |
MID SCr 1.2 (0.9,1.7) Control SCr 1.3 (0.85, 1.95) p=0.95 |
ICU |
ICU MID 8 (4, 15) Control 12 (4.5, 20) p=0.55 Hospital—NR |
ICU—NR Hospital (28-d) MID 8 (55.4%) Control 9 (69.2%) p=0.32 |
|
|
General ICU n=30 MID n=30 Control |
APACHE II MID 24 (13–39) Control 21.5 (7–39) SOFA MID 11.5 (13–39) Control 9 (3–20) |
Septic | NR | ICU |
ICU Control 11.9 ± 7 MID 11.5 ± 6.8 p=0.876 Hospital—NR |
ICU Control 22 (73.3%) MID 13 (43.4%) p=0.018 Hospital—NR |
|
|
ICU to Floor n=19 MID n=132 Control |
NR | NR | NR | Floor (post-ICU) |
ICU MID 4.1 ± 3.8 Hospital MID 13.3 ± 12.2 |
ICU—NR Hospital Association between MID and mortality: OR 7.5 (1.3–44.5); p=0.03 |
|
|
MICU n=17 MID n=15 Placebo |
SOFA MID 6.8 ± 3.3 Placebo 6.3 ± 2.6 p=0.64 |
Septic |
MID SCr 2.0 ± 0.9 Placebo SCr 1.4 ± 0.6 p=0.03 |
ICU |
ICU MID 2.29 (1.5, 3.9) Placebo 2.45 (1.6, 3.2) p=0.36 Hospital MID 7 (3.5, 10.5) Placebo 7 (4, 12) p=0.41 |
NR | |
|
SICU n=20 MID |
APACHE II MID 18 ± 6 |
Post-op | MID SCr 0.74 ± 0.28 | ICU |
ICU time from MID initiation to discharge 4 (3, 6) Hospital time from MID initiation to discharge 8.5 (5, 16) |
ICU 1 (5%) Hospital 1 (5%) |
|
|
General ICU n=33 MID Floor n=11 MID |
NR | NR | MID SCr 1.56 (0.85, 2.33) | Any |
ICU 12 (5, 27) Hospital—NR |
ICU—NR Hospital 13 (29.5%) |
|
|
MICU, SICU, CVICU, NICU, TICU n=94 MID n= 94 Control |
APACHE IV MID 59 (44, 83) Control 82 (66, 93) p=0.02 |
Cardiogenic; Spinal; Post-op; Septic | NR | ICU |
ICU MID 5.5 (3, 14.8) Control 5 (3, 10) p=0.29 Hospital MID 12 (8, 21.8) Control 9.5 (5, 16) p<0.01 |
ICU—NR Hospital MID 8 (8.5%) Control 21 (22.3%) P=0.01 |
|
|
MICU, SICU, CTICU, TICU, NICU, CICU n=1119 MID n=456 no IVP n=663 yes IVP |
APACHE III MID (no IVP) 76 (62, 93) MID (yes IVP) 78 (62, 96) |
Cardiogenic; Spinal; Septic |
SCr before MID: 1.96 SCr 24 h after MID: 1.94 p=0.3 |
ICU |
ICU MID (no IVP) 4 (2, 9) MID (yes IVP) 6 (3, 14) Hospital MID (no IVP) 15 (8, 31) MID (yes IVP) 18 (8, 37) |
ICU MID (no IVP) 35 (8%) MID (yes IVP) 74 (11%) Hospital MID (no IVP) 77 (17%) MID (yes IVP) 129 (19%) |
|
|
MICU, SICU, CTICU, TICU, NICU, CICU n=1010 MID |
APACHE III MID 78 ± 25.6 |
Cardiogenic; Septic | NR | ICU |
ICU MID continued at ICU discharge 8.5d ± 10.7 MID stopped at ICU discharge 10.6 ± 13.4 Hospital—NR |
ICU—NR Hospital MID continued at ICU discharge HR 0.45 (0.30–0.68), p<0.001 1-year MID continued at ICU discharge HR 1.56 (1.23–1.99) p<0.001 |
|
|
SICU, MICU n=66 MID n=66 Placebo |
APACHE II MID 14.7 ± 5.5 Placebo 14.8 ± 5.9 |
Septic; Post-op; Other |
MID SCr 0.8 (0.6, 1.0) Placebo SCr 0.9 (0.6, 1.3) |
ICU |
ICU MID 6 (5, 8) Placebo 6 (4, 8) p=0.46 Hospital MID 11 (9, 21) Placebo 14 (9, 22) p=0.45 |
NR | |
|
CTICU n=74 MID n=74 Control |
Euroscore II MID 1.94 (1, 2.91) Control 2.08 (1.31, 4) p=0.088 |
Vasoplegia after cardiac surgery |
Acute kidney injury: MID 11 (14.9%) Control 10 (13.5%) p=0.462 |
ICU |
ICU MID 4.13 (2.83, 6.08) Control 2.83 (2, 4.13) p=0.001 Hospital—NR |
ICU—NR Hospital MID 10 (13.5%) Control 1 (1.4%) p=0.036 |
|
|
MICU n=135 MID n=140 Control |
APACHE IV MID 82.6 ± 26.4 Control 84.3 ± 26.8 p=0.55 |
Septic |
Change in SCr: MID 0.5 ± 1.3 Control 0.8 ± 1.6 p=0.048 |
ICU |
ICU MID 7.5 ± 5.9 Control 9.4 ± 6.7 p=0.017 Hospital MID 21.9 ± 14.4 Control 24.2 ± 14.3 p=0.3 |
ICU MID 15 (11.1%) Control 26 (18.6%) p=0.08 Hospital MID 31 (23%) Control 32 (25.7%) p=0.6 |
|
| Wood 2022 |
SICU, MICU n=19 MID n=42 Control |
APACHE II MID 15 (12, 17) Control 18.5 (17, 25) |
Septic, Post-op, Other | NR | ICU or step down unit |
ICU MID 7 (6, 13) Control 6 (5, 6) p=0.0058 Hospital MID 26 (14, 51) Control 14 (10, 17) p=0.022 |
NR |
Design of included studies
| RCT; blinding unclear; single center | Egypt | Spinal shock in the ICU; age ≥18 years; hemodynamically stable on low-dose NE (<8 mcg/min) monotherapy | Anuric or oliguric; CKD; allergy | Total duration of IVP | |
| Pilot RCT; open-label; multicenter | Australia and New Zealand | Admitted to the ICU; age ≥18 years; clinically stable with hypotension for >24 hours requiring low-dose IVP (≤10 mcg/min of NE or ≤100 mcg/min of metaraminol) monotherapy | Lactate >4 mmol/L; renal failure; hemorrhagic, obstructive, or cardiogenic shock; liver failure; severe heart disease; acute brain pathology; pregnancy; thyrotoxicosis; bradycardia (HR <50 bpm), NPO or fed via jejunal tube; allergy | Time from randomization to discontinuation of IVP | |
| Pilot RCT; open-label, single-center | Iran | Septic shock (MAP <65 mmHg and lactate ≥2 mg/dL despite fluid resuscitation) in the ICU; age ≥18 years; requiring IVP | ≥24 hours since septic shock onset; CKD (GFR <30 mL/min); neurogenic bladder and urination disorders; PAD; scleroderma, bradycardia (HR <60 bpm); MID PTA | Lactate clearance at 4, 24 and 48 hours | |
| RCT; open label; single-center | Egypt | Septic shock in the ICU; age 18–80 years; hypotension (SBP <90 mmHg and MAP <65 mmHg) for >24 hours requiring IVP | Hypovolemic shock; HF (EF <30%); CKD (SCr >2 mg/dL); thyrotoxicosis; pheochromocytoma; CMO; DDI (MAOIs, alpha-1 blockers, TCAs); orthostatic hypotension; bradycardia (HR <50 bpm); MID PTA; NPO; allergy | Total duration of IVP; duration of IVP wean; cumulative dose of IVP | |
| Retrospective cohort study; single center | USA | Patients admitted to ICU from ED then transferred to floor | ICU mortality; admitted to ICU due to diabetic ketoacidosis or tissue plasminogen activator administration | ICU readmission; rapid response team activation; hospital LOS; in-hospital mortality; 30 day hospital readmission | |
| Pilot RCT; double-blinded; multicenter | USA; United Arab Emirates | Septic shock (MAP <70 mmHg and SBP <130 mmHg despite antibiotics and fluids 30 mL/kg) in the ICU; age ≥18 years | ACS or EF <30%; GIB; obstructive or cardiogenic shock; lactate > 4 mmol/L; acute intraabdominal process; transferred from outside facility; cardiac arrest; child-bearing age; thyrotoxicosis; pheochromocytoma; PAD or ischemic bowel; CMO; DDI (MAOIs); bradycardia (HR <40 bpm); MID PTA; NPO; allergy | Duration of IVP in the first 24 hours | |
| Prospective cohort study; single-center | USA | Admitted to the SICU; age ≥18 years; clinically stable (otherwise discharge ready) with hypotension for >24 hours requiring low-dose IVP (phenylephrine <150 mcg/min or NE <8 mcg/min) | Hypovolemic shock; adrenal insufficiency; <3 doses of MID; orthostatic hypotension; MID PTA | Time from MID initiation to discontinuation of IVP; Change in IVP rate before/after MID initiation | |
| Retrospective cohort study; single center | USA | Age ≥18 years; receiving MID dosed “four times daily” or “every six hours” | Incarcerated; pregnancy | Characterization of patients receiving MID “four times daily” or “every six hours” | |
| Retrospective cohort study; single-center | USA | Admitted to the ICU with diagnosis related to cardiovascular, trauma, or sepsis; age ≥18 years; requiring ≥1 IVP | ICU mortality within 24 hours; duration of IVP <2 hours; <3 doses of MID; MID for indication other than IVP weaning | Time from MID initiation to discontinuation of IVP | |
| Retrospective case series; single-center | USA | Admitted to the ICU; age ≥18 years; initiated on MID | MID PTA | Cumulative dose of IVP at MID initiation and 24 hours; MAP at MID initiation and 24 hours | |
| Retrospective case series; single-center | USA | Admitted to the ICU; age ≥18 years; initiated on MID | ICU mortality; MID PTA | Incidence of MID continuation after ICU discharge | |
| RCT; double-blinded; multicenter | USA, Australia | Admitted to the ICU or step-down unit; age ≥18 years; clinically stable with hypotension for >24 hours requiring low-dose (<100 mcg/min phenylephrine, <8 mcg/min of NE, or <60 mcg/min of metaraminol) IVP monotherapy | Clinical evidence of inadequate tissue oxygenation; adrenal insufficiency; liver failure; CKD (SCr >2 mg/dL); HF (EF <30%); acute urinary retention; pheochromocytoma; thyrotoxicosis; pregnancy; bradycardia (HR <50 bpm); MID PTA; NPO; allergy | Time from randomization to discontinuation of IVP | |
| Retrospective propensity matched cohort study; single center | Canada | Admitted to the ICU following cardiac surgery requiring CPB; age ≥18 years; hypotension requiring IVP for >12 hours post-surgery | MID before surgery; mechanical circulatory support before surgery; emergency surgery; transplantation; cirrhosis | Number of days alive and free from ICU at 30 days | |
| Retrospective cohort study; single-center | USA | Septic shock in the ICU; clinically stable with hypotension for >24 hours requiring IVP | NR | Total duration of IVP; ICU LOS | |
| Wood 2022 | Retrospective case-control; single center | Australia | Admitted to ICU or step-down unit; age ≥18; clinically stable with hypotension for >24 hours requiring low-dose (<8 mcg/min of NE or <60 mcg/min of metaraminol) IVP monotherapy | Clinical evidence of inadequate tissue oxygenation; adrenal insufficiency; liver failure; CKD (SCr >2 mg/dL); HF (EF <30%); acute urinary retention; pheochromocytoma; thyrotoxicosis; pregnancy; bradycardia (HR <50 bpm); NPO; allergy | Time from intervention to discontinuation of IVP |
Midodrine Use
| Yes | 4 doses of MID, then IVP weaning initiated | 10 mg every 8 h | 10 mg every 8 h | Fixed | After | NR | PO | No | No | |
| Yes |
MID administered until off IVP for at least 24 h Wean: 7.5 mg every 8 h for 24 h, then 5 mg every 8 h for 24 h, then DC |
10 mg every 8 h | 10 mg every 8 h | Fixed | After | NR | NR | Yes | NR | |
| Yes | Randomly assigned to adjunctive MID to facilitate IVP wean | 10 mg TID | 10 mg TID | Fixed | With | Up to 5 d | If conscious, PO; if not, via NGT | NR | NR | |
| Yes | Randomly assigned to adjunctive midodrine to facilitate IVP wean | 10 mg TID | 10 mg TID | Fixed | After | NR | PO tablet or crushed (via Ryle) | NR | NR | |
| No | No protocol | NR | NR | NR | NR | NR | NR | 19 (12.6) | NR | |
| Yes | If septic shock without response to antibiotics and fluids, randomized to MID or placebo | 10 mg every 8 h | 10 mg every 8 h | Fixed | After or monotherapy | 3 doses | PO | No | No | |
| No | No protocol | NR | 20 mg TID | Titration; no details | After | 4 (3–7) | PO | NR | NR | |
| No | No protocol | NR | 20 mg every 6 h | Titration |
After n=23 (52.3%) Continued from home n=18 (40.9%) Monotherapy n=3 (6.8%) |
NR | NR | Yes | Yes | |
| No | No protocol | NR | 10 mg every 4 h | Titration | After | 4.4 (3.2, 7.8) | NR | NR | NR | |
| No | No protocol | NR | 30 mg every 8 h | Titration |
After (59%); Before (41%) |
NR | PO | NR | NR | |
| No | No protocol | NR | 40 mg every 8 h | Titration |
After: 58% Before or monotherapy: 42% |
11.8 ± 20.9 | PO | 672 (67) | 311 (34) | |
| Yes | Randomized to MID or placebo until ICU discharge. DC’ed with stable at goal blood pressure at discretion of clinical team per a standardized weaning protocol (decrease dose every 1–2 d from 20 mg to 10 mg every 8 h, then 5 mg every 8 h, then DC) | 20 mg every 8 h | 20 mg every 8 h | Fixed | After at least 24 h of IVP | 1.77 (0.98, 2.97) | PO | NR | No | |
| No | No protocol | 10 mg TID (for n=61, 82.4%) | Only n=2 with doses >10 mg; All TID | Majority fixed. Progressive tapering for n=19 (26%) | After at least 12 h of IVP | 1.67 (0.96, 3.04) | NR | 17 (23) | NR | |
| No | No protocol | 10 mg every 8 h | 40 mg every 8 h | Titration | After at least 24 h of IVP |
6.15 For patients who were not discharged on MID (n=117, 86.7%) |
NR | Yes | 18 (13.3) | |
| Wood 2022 | No | Started on MID at discretion of treatment team. If enrolled, MID administered until at least 24 h after DC of IVP | 20 mg every 8 h | 20 mg every 8 h | Fixed | After | NR | PO | NR | NR |
Intravenous Vasopressor Use
|
MID 30 (100) Control 30 (100) |
1 (NE only) | NR; inclusion criteria <8 mcg/min NE |
MID 79.2 ± 31.7 Control 166.3 ± 55.7 p<0.001 |
NR | |
|
MID 32 (100) Control 30 (100) |
1 (NE or metaraminol) | NR; inclusion criteria <10 mcg/min NE or <100 mcg/min metaraminol |
MID 16.5 (7.2, 27.5) Control 19 (12.2, 38.5) p=0.32 |
MID 6 (18.8) Control 4 (13.3) p=0.73 |
|
|
MID 15 (100) Control 13 (100) |
1 (NE only) |
Midodrine median NEE 0.14 mcg/kg/min Control median NEE 0.13 mcg/kg/min |
MID 96 (48, 192) Control 120 (72, 264) p=0.36 |
MID 4 (26.7) Control 5 (38.5) p=0.39 |
|
|
MID 30 (100) Control 30 (100) |
1 (NE only) |
Midodrine median NEE 0.08, range 0.04–0.21 mcg/kg/min Control median NEE 0.11, range 0.02–0.35 mcg/kg/min |
MID 26 (14, 106) Control 78.5 (32, 280) p<0.001 |
MID 3 (10%) Control 3 (10%) |
|
| All 73 (48.3) | NR | NR | NR | NR | |
|
MID 11 (52.4) Placebo 10 (47.6) |
NR | NR |
Requiring IVP at 12 h: MID 41.2% vs Control 60% p=0.29 |
NR | |
| MID 20 (100) | 1 (NE or PE) | Midodrine mean NEE 4.1 mcg/min | MID 17 (7, 38.4) | NR | |
| MID 23 (52.3) | NR | Midodrine mean NEE 0.1 mcg/kg/min | NR | NR | |
|
MID 94 (100) Control 94 (100) |
MID: 1 (40.4%), 2 (41.5%), 3+ (18.1%) Control: 1 (62.8%), 2 (24.4%), 3+ (12.8%) |
Midodrine median NEE 0.05 (0.03, 0.08) mcg/kg/min Control median NEE 0.05 (0.03, 0.08) mcg/kg/min |
MID 28.8 (12, 67.2) Control: NR |
MID 42 (44.7) Control: NR |
|
| MID 663 (59.0) | NR | Midodrine median NEE 0.24 mcg/kg/min | Requiring IVP at 24 h: 48% | NR | |
| MID 587 (58.1) | NR | Midodrine median NEE 0.19 mcg/kg/min | NR | NR | |
|
MID 66 (100) Placebo 66 (100) |
1 (NE, PE, or metaraminol) |
Midodrine median NEE 0.03 (0.02, 0.06) mcg/kg/min Control median NEE 0.03 (0.02, 0.06) mcg/kg/min |
MID 23.5 (10.4, 44) Control 22.5 (10.4, 40) p=0.62 |
NR | |
|
MID 74 (100) Control 74 (100) |
MID: 1 (85.1%), 2 (13.5%), 3 (1.4%) Control: NR |
All patients median NEE 0.05 (0.03, 0.09) mcg/kg/min | MID 19 (4, 44) | MID 16 (21.6) | |
|
MID 135 (100) Control 140 (100) |
1 (NE or PE) |
Midodrine mean NEE 0.09 mcg/kg/min Control mean NEE NR |
MID 69.6 ± NR Control 91.2 ± NR p<0.001 |
MID 7 (5.2) Control 21 (15) p=0.007 |
|
| Wood 2022 |
MID 19 (100) Control 42 (100) |
1 (NE or metaraminol) |
Midodrine median NEE 0.05 mcg/kg/min Control median NEE 0.08 mcg/kg/min |
MID 26 (22, 36) Control 24 (17, 93) p=0.511 |
NR |
Quality appraisal for included studies by study design
| Yes | No | No | Unclear | No | Yes | Unclear | Yes | Yes | Yes | Yes | Yes | |
| Yes | Yes | Yes | Unclear | No | Yes | Unclear | Yes | Yes | Yes | Yes | Yes | |
| Yes | Unclear | Yes | Unclear | Unclear | Yes | Unclear | Yes | Yes | Yes | Yes | Yes | |
| Yes | Yes | Yes | No | No | Yes | Unclear | Yes | Yes | Yes | Yes | Yes | |
| Yes | Yes | No | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | |
| Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | |
Reported Side Effects
| No definition | NA |
MID Day 1: 117 ± 14.2, MID Mid-study: 103.77 ± 16.65, MID Last Day: 79 ± 16.9 Control Day 1: 120.43 ± 14.64 Control Mid-study: 97.1 ± 16.65 Control Last Day: 96.73 ± 18.75 |
NA | NR | NR | NR | NR | |
| Bradycardia: ≤50 bpm; Severe bradycardia: <40 bpm |
Bradycardia within 24 h: MID 10 (31.2) Control 2 (6.7) p=0.02 |
Baseline MID HR: 76 (70, 85) Baseline Control HR: 77.5 (65.5, 85) p=0.61 MID HR over 24 h: 69 (62, 82) Control HR over 24 h: 74 (67, 83) p=0.21 |
None; episodes of bradycardia, except one, were transient and deemed clinically insignificant | NR | NR | NR | NO | |
| <60 bpm | NO | NR | NA | NR | NR | NR | NR | |
| <50 bpm | NR | NR | NA | NR | NR | NR | NR | |
| NR | NR | NR | NA | NR | NR | NR | NR | |
| <40 bpm and symptomatic | NO | NR | NA | NO | NO | NO | NO | |
| No definition | NR |
Before MID HR 82 ± 13 After MID HR 81 ± 15 p=0.66 |
NA | NR | NR | NR | NR | |
| <50 bpm | NO | NR | NA | 1 (2.3) | NO | NR | NR | |
| <60 bpm for two consecutive readings |
MID: 12 (12.8) Control: NR |
NR | NR | NR | NR | NR | NR | |
| ≤50 bpm; ≤40 bpm |
≤50 bpm: 172 (15.4) ≤40 bpm: 100 (9) Lowest HR: 39 (33, 44) bpm |
NR | None | 2 (0.18) | NR | NO | NR | |
| NR | NR | NR | NA | NR | NR | NR | NR | |
| <40 bpm or ≥20% decrease from a pre-specified goal |
MID: 5 (7.6) Control: 0 (0) p=0.02 |
NR | NR | NR | NR | NR | NR | |
| No definition | NR | NR | NA | 2 (2.7) | NR | NR | NR | |
| No definition |
MID: 1 (0.7) Control: NO |
NR | MID discontinued and bradycardia resolved. | NR | NR | NR | NR | |
| Wood 2022 | <40 bpm or ≥20% decrease from a pre-specified goal |
MID: 4 (22) Control: 1 (2.4) p=0.025 |
No significant change | NR | NR | NR | NR | NR |
Where midodrine may be consider and avoided
| Orthostatic hypotension | Vasopressor sparing | Cardiogenic shock | Pheochromocytoma |
| Hemodialysis hypotension | Mixed shock | Cerebral vasospasm | Thyrotoxicosis |
| Septic Shock | Renal failure | Unknown enteral absorption | Urinary retention |
| Vasopressor weaning | Lactate clearance | Mechanical circulatory support | |
| Hepatorenal syndrome | Bradycardia | Daily dose >120 mg | |
| Fixed dosing regimen | Dosing every four hours | ||
| Hepatic impairment | |||
| Titrated dosing regimen |