Shock is a state of decreased organ perfusion that is life-threatening and requires emergent medical intervention. As such, patients who present with shock are hemodynamically unstable and require high acuity care. In critical care and emergency medicine, hemodynamic instability is managed with 30cc per kg boluses of intravenous fluid and vasoactive agents. The ultimate goal of intravenous fluid resuscitation and vasopressors is to prevent multi-system organ failure and to achieve a mean arterial pressure that is greater than 65 mmHg. Refractory hypotension results when patients remain hypotensive despite receiving the appropriate resuscitative fluids and vasopressors. Oral Midodrine has been hailed as an adjunctive therapy in critical care patients with refractory hypotension. It has also been beneficial in patients who become hypotensive during hemodialysis. Nonetheless, Midodrine is only FDA approved for the treatment of symptomatic orthostatic hypotension. The mechanism of action is through alpha-1 adrenergic activation leading to an increase in vascular tone and hypertension. Midodrine does not stimulate cardiac beta-adrenergic receptors, however its use can result in profound bradycardia. 

Review of the current literature suggests that Midodrine causes reflex bradycardia primarily through activation of the baroreceptors. These receptors sense when there is an unusual increase in blood pressure. Physiologically, Blood Pressure (BP) is determined by Stroke Volume (SV), Heart Rate (HR) and Total Peripheral Resistance (TPR) as such BP = SV x HR x TPR. In an unregulated system, increase in TPR through vasoconstriction should directly increase blood pressure. However, when the carotid sinus senses this increase in blood pressure, signals are to the central homeostatic center—the medulla oblongata, which then activates a vagal response. Acetylcholine is released as a result and binds to the M2 muscarinic receptors. These receptors are located on cardiac muscle and act primarily by reducing conduction velocity through the atrioventricular node leading to bradycardia. The electrocardiogram will show signs of delayed depolarization but normal P-R intervals and consistent P-QRS association.

In Critical Care and Progressive Care patients, our goals in correcting hypotension include providing volume support and/or pressure support. In refractory hypotension cases where volume resuscitation does not improve hypotension, we must focus on providing pressure support. Midodrine is a typical first-line agent in providing pressure support through its effects as an agonist on alpha-1 adrenergic receptors. Of note, midodrine’s mechanism of action can be compared to that of phenylephrine, epinephrine and also norepinephrine which predominantly acts as an agonist on alpha-1 adrenergic receptors. Although phenylephrine, epinephrine and norepinephrine are common vasopressor agents used in the setting of Critical Care and Anesthesia, midodrine is not. Due to midodrine’s nature as an oral medication that is commonly used outside of Critical Care and Anesthesia, the effect of reflex bradycardia often seen in vasopressor agents used in Critical Care and Anesthesia can be overlooked. The significance of this is that reflex bradycardia from midodrine administration can worsen hypotension and increase the requirement for further vasopressor agent support. This ultimately prolongs the course of treatment needed in the Critical Care setting.

When discussing our current case, the way in which prolonged Critical Care treatment was mitigated was through the discontinuation of midodrine administration after noting our patient’s bradycardic response. Since the half-life of midodrine is 3-4 hours while the half-life of vasopressor agents used in Critical Care/Anesthesia range from 2-5 minutes, it was important to hemodynamically monitor our patient for the duration of midodrine’s clearance [7]. In our patient’s case, the effect of reflex bradycardia resolved after 24 hours of midodrine discontinuation. Additionally, it is essential to note that our patient did not have an underlying renal pathology which would have prolonged the clearance of midodrine [7,8].