Persistent vasoplegia in the recovery phase of septic shock is often encountered in the intensive care unit. The exact mechanism of vasoplegia is not fully understood, but it is thought to involve a dysregulation of the vascular tone due to various factors such as endothelial dysfunction, nitric oxide excess, cytokine storm, and catecholamine depletion or desensitization. One of the challenges in managing vasoplegia is the difficulty in weaning patients from intravenous (IV) vasopressors, which can have adverse effects such as arrhythmias, ischemia, and tissue necrosis. Moreover, IV vasopressors require continuous monitoring and titration, which can increase the workload and cost of ICU care.
Midodrine is an oral alpha-1 adrenergic agonist that acts on peripheral vascular smooth muscle cells to increase arterial tone and blood pressure. It has been used for the treatment of orthostatic hypotension, neurogenic shock, and hepatorenal syndrome. In addition, several studies have investigated the adjunctive treatment of midodrine to provide haemodynamic support and facilitate intravenous (IV) vasopressor weaning in patients with persistent vasoplegia.
In this blog post, we will review the evidence and rationale for using midodrine in this setting, as well as the potential benefits and risks of this approach.
Rationale for Midodrine in Persistent Vasoplegia
Midodrine may help restore the vascular tone by stimulating the alpha-1 receptors on the vascular smooth muscle cells, which are relatively spared from desensitization compared to the beta receptors. Moreover, midodrine may have synergistic effects with other vasopressors by enhancing their vasoconstrictive action. For example, midodrine may increase the sensitivity of the vascular smooth muscle cells to norepinephrine by upregulating the expression of alpha-1 receptors. Midodrine may also augment the release of endogenous norepinephrine from sympathetic nerve terminals by blocking its reuptake.
Additionally, midodrine may have beneficial effects on other organ systems that are affected by vasoplegia. For instance, midodrine may improve renal perfusion and function by increasing renal arterial pressure and reducing renal venous congestion. Midodrine may also improve cardiac output and oxygen delivery by increasing preload and it increases afterload.
Evidence for Midodrine in Persistent Vasoplegia
Midodrine has been proposed as a potential option in facilitating weaning vasopressors in patients with persistent low-dose vasopressor requirement without signs of end-organ hypoperfusion after initial shock resolution. Multiple case studies, case series, and observational studies indicated possible benefits.
In a prospective, observational study involving 20 adult surgical ICU patients, Levine et al. found out that midodrine treatment significantly increased the rate of decline in IV vasopressor usage without correlating changes in total body fluid balance, heart rate, mean arterial pressure, or white blood cell count . Whitson et al. in a retrospective study revealed that midodrine may reduce the duration of IV vasopressors during recovery phase from septic shock and may be associated with a reduction in length of stay in the ICU .
The MIDAS trial is the largest study to date that was a randomized, double-blind, placebo-controlled trial conducted by Santer and colleagues across three centers in the United States and Australia. Patients on low-dose vasopressors were given either 20 mg of midodrine or a placebo. The study found no significant differences between the midodrine and placebo groups in terms of vasopressor discontinuation, ICU discharge readiness, ICU length of stay, hospital length of stay, or ICU readmission. This study suggests that using midodrine as a transitional oral agent to decrease low-dose vasopressor duration may not effectively reduce ICU stays, and it may paradoxically increase the need for ICU-level monitoring. However, the study was limited by its small sample size and potentially overly heterogeneous population .
It is important to mention that the MIDAS trial excluded patients with liver failure and chronic renal failure. A positive effect was discovered in a post hoc subgroup analysis of patients who received epidural analgesia.
More recently, a small trial was conducted in Irland on 60 patients and found out that midodrine use in septic shock patients reduced IV norepinephrine duration, weaning period, and mortality, making it a cost-effective treatment option .
The MAVERIC study was a pilot trial investigating the feasibility and efficacy of adjunctive midodrine in vasopressor-dependent hypotension patients. The results showed that midodrine was feasible and had an acceptable safety profile, but there was no evidence of physiological or clinical efficacy at the chosen dose .
Potential Risks of Midodrine in Persistent Vasoplegia
Given midodrine is not without potential side effects. In the MIDAS trial, patients on midodrine experienced a higher rate of bradycardic events secondary to vagal reflexes . A retrospective cohort study investigated the clinical impacts of administering midodrine to patients with persistent hypotension on vasopressors after cardiac surgery with cardiopulmonary bypass (CPB). A propensity score-matched control group was formed, and 74 pairs of patients were analyzed in the study. The results showed that midodrine use was associated reduced free-ICU days but higher mortality and longer ICU length of stay. There was no difference in the length of intravenous vasopressors, rate of ICU readmission, or occurrence of severe kidney injury between the groups. The study concluded that administering midodrine for sustained hypotension after cardiac surgery with CPB was linked to negative outcomes, and its routine prescription to hasten ICU discharge should be used with caution until further prospective studies are conducted .
In summary, the evidence on midodrine for persistent vasoplegia after septic shock is mixed, with the largest trial not supporting its routine use. Patients with liver and chronic renal failure were not included in the trial, and further investigation is needed to assess midodrine as a transitional oral agent in these populations. Until more research is conducted, the use of midodrine in these patients should be approached with caution, considering potential risks and benefits on an individual basis.
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Whitson MR, Mo E, Nabi T, Healy L, Koenig S, Narasimhan M, Mayo PH. Feasibility, Utility, and Safety of Midodrine During Recovery Phase From Septic Shock. Chest. 2016 Jun;149(6):1380-3. doi: 10.1016/j.chest.2016.02.657. Epub 2016 Mar 4. PMID: 26953217. Link
Santer P, Anstey MH, Patrocínio MD, Wibrow B, Teja B, Shay D, et al.; MIDAS Study Group. Effect of Midodrine versus Placebo on Time to Vasopressor Discontinuation in Patients with Persistent Hypotension in the Intensive Care Unit (MIDAS): an international randomised clinical trial. Intensive Care Med2020;46:1884–1893. Crossref, Medline, Google Scholar
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