Indications of Midodrine in Hepatorenal Syndrome
Midodrine is indicated as an alternative treatment for hepatorenal syndrome type 1 (HRS-AKI) when terlipressin is unavailable, and must always be combined with octreotide and albumin—never used as monotherapy. 1, 2
Primary Indication: Alternative Therapy for Type 1 HRS
Midodrine serves as a second-line vasoconstrictor option specifically when first-line terlipressin is not accessible. 1, 2 The American Association for the Study of Liver Diseases explicitly recommends this combination for type 1 HRS, which is characterized by rapid progressive renal impairment with serum creatinine >2.5 mg/dL or doubling within 2 weeks. 1
Dosing Protocol
- Start midodrine at 7.5 mg orally three times daily 1
- Titrate up to maximum 12.5 mg three times daily based on blood pressure response 1, 2
- Must be combined with octreotide 100-200 μg subcutaneously three times daily 1, 2
- Must be combined with albumin 10-20 g IV daily for up to 20 days 1, 2
- Administer last dose 3-4 hours before bedtime to minimize supine hypertension 3
Key Advantage: Outpatient Administration
A critical advantage of midodrine over norepinephrine is that it can be administered outside the ICU setting and even at home, making it accessible for patients who don't require intensive monitoring. 1, 2 This contrasts sharply with norepinephrine, which requires ICU-level monitoring with central venous access. 2
Evidence Quality and Comparative Efficacy
The evidence supporting midodrine is notably weaker than for terlipressin. Recent high-quality evidence from 2021 demonstrates that norepinephrine is significantly more effective than midodrine/octreotide, with full response rates of 57.6% versus 20% (p=0.006). 4 However, norepinephrine requires ICU admission, which may not be feasible for all patients. 2
Retrospective data from 2009 showed that midodrine/octreotide/albumin improved median survival to 101 days versus 18 days in untreated controls (p<0.0001), supporting its use as a bridge to transplantation. 5
Critical Precautions Specific to HRS Patients
Supine Hypertension Risk
Patients must be counseled to sleep with the head of bed elevated and avoid lying flat, as midodrine can cause dangerous supine hypertension. 3 Symptoms include cardiac awareness, pounding in ears, headache, and blurred vision—patients should discontinue immediately if these occur. 3
Renal and Hepatic Considerations
In cirrhotic patients with renal impairment (which defines HRS), start with a reduced dose of 2.5 mg due to renal elimination of the active metabolite desglymidodrine. 3 Pharmacokinetic studies demonstrate significantly altered AUC and Cmax values in cirrhotic patients with ascites compared to healthy volunteers. 6
Drug Interactions
Avoid concurrent use with MAO inhibitors, and monitor carefully if using with cardiac glycosides (risk of bradycardia/AV block) or other vasoconstrictors like pseudoephedrine. 3 Alpha-blockers (prazosin, terazosin, doxazosin) can antagonize midodrine's effects. 3
When NOT to Use Midodrine
European guidelines from 2025 actually discourage the midodrine/octreotide combination, preferring terlipressin first-line and norepinephrine as the alternative. 2 This reflects the weaker evidence base compared to these alternatives.
Never use octreotide as monotherapy—two definitive studies show octreotide alone provides no benefit; it requires midodrine to be effective. 1
Monitoring Requirements
- Check serum creatinine every 2-3 days to assess response 1, 2
- Monitor blood pressure carefully for supine hypertension 3
- Watch for bradycardia (pulse slowing, increased dizziness, syncope) 3
- Complete response is defined as creatinine ≤1.5 mg/dL on two occasions 1
- Partial response is creatinine decrease ≥25% but still >1.5 mg/dL 2
Duration of Therapy
Continue treatment until complete response or for a maximum of 14-20 days. 1, 2 If no response after this period, consider escalation to norepinephrine (if ICU available) or prioritize liver transplantation evaluation. 2
Role in Hypotensive Patients
While midodrine's mechanism involves alpha-1 agonism to increase vascular tone and blood pressure (standing systolic BP elevated by 15-30 mmHg at 1 hour), 3 its primary indication in HRS is renal function improvement through increased renal perfusion pressure, not simply blood pressure support. 1, 2 The hypotension in HRS reflects splanchnic vasodilation and effective arterial underfilling—midodrine addresses this pathophysiology when combined with albumin and octreotide. 1