Introduction with a clinical conundrum
An elderly woman is admitted to the ICU with urosepsis. By ICU day #3 she is dramatically improved, but having difficulty weaning off vasopressors. At this point, she has been requiring between 2-4 ug/min of norepinephrine for one day. Whenever the norepinephrine is stopped, her MAP falls into the mid-50s. What is the best approach to this?
- [a] Bolus her with fluid and attempt to wean off norepinephrine.
- [b] Perform bedside ultrasonography and give fluid if the IVC has lots of respiratory variability, then try to wean off norepinephrine.
- [c] Stop norepinephrine and see if she can continue to produce urine despite hypotension.
- [d] Continue norepinephrine infusion.
Until recently, these were the usual approaches to this situation. However, none of them is perfect:
Choice A: Fluid challenge This may be the worst approach. By the time someone has been in a North American ICU for three days with urosepsis, it is essentially impossible that they will be volume depleted.
Choice B: Ultrasound-guided resuscitation Also not a great approach. Ultrasound-guided fluid resuscitation may be helpful during the initial resuscitation, but not on ICU day #3. By this point, she has already received lots of fluid. Therefore, two possibilities exist:
- Ultrasound shows that she is intravascularly fluid replete. In this case, fluid is not indicated.
- Ultrasound shows that she is intravascularly fluid depleted. However, we know that she has already received a lot of fluid during her hospital course. Therefore, if she remains intravascularly depleted, this means that the fluid given to her has leaked out of her capillaries. Thus, she still won’t benefit from additional fluid. Additional fluid will work great for a few hours, but then it too will leak out of her vasculature.
Choice C: Wean vasopressors for urine output This isn’t a bad approach, but it’s not perfect either. Even if the kidneys continue to produce urine, there is still a possibility that they could become injured due to hypotension. Furthermore, regardless of her kidneys, if she remains hypotensive this may inhibit physical therapy and transfer to the ward.
Choice D: Continue norepinephrine: This was previously my usual approach. There are some patients who develop persistent vasodilation (a.k.a., “vasoplegia”), which takes a few days to resolve. With patience, this will resolve. Sometimes the safest approach is to wait it out.
Newer approach to weaning vasopressors: Oral midodrine
Midodrine is an oral agent which functions as an alpha-1 agonist. It has been used in a variety of situations including autonomic dysfunction, hepatorenal syndrome, and dialysis-induced hypotension. Over the past few years there has been increasing interest in using midodrine to facilitate weaning off vasopressors.
Carotid artery stenting often causes several hours of hypotension due to vagal stimulation, requiring intravenous vasopressors in an ICU. This is a case series of four patients who were treated with oral midodrine in a telemetry unit, to prevent the requirement for receiving intravenous vasopressor therapy. All patients were treated with midodrine 10 mg q8hr for 24 hours, with excellent results and no complications.
Liu 2010 (abstract)
This was a retrospective descriptive study comparing 20 patients with shock who were weaned from IV vasopressors using midodrine versus 20 patients weaned without midodrine. The average duration of intravenous vasopressor use was 0.3 days shorter in patients receiving midodrine (p=0.049).
This was a prospective observation study of midodrine use in the surgical ICU at Massachusetts General Hospital. Twenty patients were treated after they had improved and met ICU discharge criteria, aside from requiring low doses of vasopressors (either <150 ug/min phenylephrine or <8 ug/min norepinephrine). Reasons for vasopressor requirement were diverse (including neurogenic shock, medication effect, and systemic inflammation).
Midodrine was successful in allowing discontinuation of intravenous vasopressors within 24 hours in 70% patients. The rate of weaning off vasopressors was significantly faster after starting midodrine, suggesting that this wasn’t merely coincidental. Hemodynamics remained stable throughout the transition. The median duration of midodrine use during the entire hospitalization was four days, with a range of 3-7 days. No complications were noted.
This was a retrospective observational study of patients weaned from vasopressors using midodrine following the resolution of septic shock. 140 patients weaned using midodrine were compared to 135 patients weaned without midodrine. Prior to starting midodrine, the average vasopressor requirement was either 0.09 +/- 0.09 mcg/kg/min norepinephrine or 1.05 +/- 0.77 mcg/kg/min phenylephrine. Although the study wasn’t randomized, the two groups were fairly well matched (Table 1 on right).
Midodrine use correlated with a lower duration of IV vasopressor use and ICU length of stay (Table 3 on right). Transitioning to midodrine also correlated with a lower rate of re-starting intravenous vasopressors (5% vs. 15%). Perhaps most provocative, midodrine was associated with a lower rise in serum creatinine (0.5 vs. 0.8 mg/dL, p=0.048).
There were no complications associated with midodrine except for transient bradycardia in one patient, which resolved following discontinuation. 87% of patients discontinued midodrine while in the hospital, with an average duration of six days treatment.
This retrospective study cannot prove causality. For example, it is possible that more robust patients were selected for midodrine therapy. Nonetheless, it is notable that patients treated with midodrine experienced less hemodynamic instability (defined as hypotension requiring re-initiation of IV vasopressor) and less renal impairment. This suggests that using midodrine to perform a more gradual vasopressor wean could improve perfusion and renal function. Alternatively, patients weaned without midodrine may have been under pressure to terminate vasopressor therapy prematurely, in order to facilitate transfer out of the ICU (as in choice [C] above).
Physiologic effect of midodrine
Midodrine is essentially an oral equivalent of phenylephrine, another alpha-1 agonist. It is commonly feared that alpha-1 agonists may decrease cardiac output and impair renal function. However, this fear does not appear to be justified regarding the use of low doses of alpha-1 agonists in vasodilatory shock.
As explored previously, alpha-1 agonists have a similar mechanism of action compared to norepinephrine. Specifically, they may increase both preload and afterload, with a tendency to maintain or increase cardiac output in sepsis. Midodrine is known to improve renal function in hepatorenal syndrome, a vasodilatory state similar to septic vasoplegia. Overall, midodrine should be able to substitute for a low dose of phenylephrine, vasopressin, or norepinephrine.
Pharmacology & dosing
Following oral administration, >90% of midodrine is rapidly absorbed. Midodrine is an inactive prodrug, which is rapidly converted to its active metabolite desglymidodrine. Levels of desglymidodrine peak within 1-2 hours, with a subsequent half-life of 3-4 hours (80% being excreted in the urine). Midodrine is typically administered every eight hours when used in the ICU for blood pressure support (not “three times daily with meals,” which will generate uneven dosing intervals). The half-life of desglymidodrine increases up to 10 hours in end-stage renal disease, which may require extending of dosing interval (House 2011).
Whitson 2016 utilized an initial dose of 10 mg q8hr, with an average required dose of 19 +/- 10 mg q8hr (the maximum allowed dose was 40 mg q8hr). Levine 2013 also reported that the most commonly required dose was 20 mg q8hr. Thus, a reasonable approach may be to start dosing at 10 mg q8hr with rapid escalation to 15-20 mg q8hr if needed. Among patients with severe renal dysfunction, the dosing interval may be extended, for example from q8hr to q12hr (1).
Benefits of liberation from IV vasopressor
Oral vasopressors may potentially reduce ICU length of stay, while avoiding complications such as central line infection and delirium. Faster transition from the ICU could facilitate greater mobility, avoiding deconditioning.
Oral vasopressors could also reduce costs. One day in the ICU costs roughly $2,500, whereas midodrine costs under $50/day. Now, let’s suppose that oral midodrine might reduce ICU length of stay by an average of one day for every patient admitted with septic shock who don’t require intubation (2). Multiplied out over 180,000 such admissions per year in the US, this could save $441 million dollars per year in the US.
Safety & contraindications
Potential complications of midodrine include supine hypertension, reflex bradycardia, urinary retention, piloerection, shivering, and paresthesias. Overall, midodrine is a fairly safe medication, which has been prescribed to outpatients since the early 1980s. This supports the safety of titrating midodrine in the ICU with close monitoring. Contraindications to midodrine include urinary retention, pheochromocytoma, and thyrotoxicosis.
- Some patients recovering from septic shock develop a state of persistent vasodilation (“vasoplegia”) which may take a few days to resolve. This delays discharge from ICU due to a persistent requirement for low-dose intravenous vasopressors.
- Midodrine is an oral alpha-1 agonist, with the same mechanism of action as phenylephrine. It is a fairly safe drug which has been used among outpatients for decades.
- Several reports support the use of midodrine to facilitate weaning off intravenous vasopressors in appropriately selected patients with careful monitoring. This may reduce ICU length of stay, avoiding ICU complications (e.g. central line infection and delirium).
This is the second of a four-part series on hemodynamics. Stay tuned for the next installments, which will be administered q2weeks barring any unforeseen adverse events.
- Hemodynamics I: An alternative viewpoint on phenylephrine infusions (PulmCrit)
- Vasopressor Basics (EMCrit)
- Early initiation of norepinephrine in septic shock (PulmCrit) Note: the rationale for starting norepinepinephrine early also argues for continuing a vasopressor for a longer duration with gradual taper.
- Collapsed IVC doesn’t equal hypovolemia (PulmCrit)
- Renal failure is not necessarily a contraindication (for example, midodrine has proven efficacy when given immediately prior to hemodialysis to reduce intra-dialytic hypotension and Whitson 2016 included some patients on hemodialysis in their study). However, the ideal dosing regimen in renal failure is unclear. One approach might be to extend the dosing interval from q8hr to q12hr, with re-assessment of vital signs prior to each dose. Thoughtful manual titration to effect should avoid the risk of drug accumulation.
- My guess is that midodrine wouldn’t reduce the ICU length of stay so much for patients who require intubation, because weaning from the ventilator is more often the factor delaying transfer out of the ICU.