- Learn how antihypotensive medications work.
- Identify the main antihypotensive medications (inotropes and vasopressors) that can be used to treat patients suffering from end-organ hypoperfusion.
- Understand how and when to administer antihyoptensive medications.
- Adrenergic: Chemicals that have the characteristics of—or cells that are activated by or secrete—epinephrine or epinephrine-like substances.
- Inotropes: A substance that improves the contractility of muscle, particularly the heart.
- Vasoconstriction: Constriction or narrowing of a blood vessel.
- Vasopressors: A substance that stimulates contraction of the muscular walls of arteries and capillaries, increasing blood pressure.
You’re caring for an acute myocardial infarction patient when she suddenly says she’s feeling worse. You look at the monitor. The numbers and rhythm are unchanged, but the patient is more pale and sweatier than before. The EMT working with you looks up and says, “68 over 32.”
At this point, what do you do? Grab another bag of saline? Reach for dopamine, the only antihypotensive medication in your kit? Drive faster because you’ve got 20 more minutes until you get to the closest primary PCI center?
Or maybe you’re at the home of a 51 year-old male who was bitten by a cat 24 hours ago and now has a high fever, altered mental status and is significantly hypotensive. Are you still going to reach for that dopamine with this patient in obvious septic shock?
Antihypotensive medications are used to improve blood pressure and end-organ perfusion in patients who aren’t able to adequately maintain these functions naturally. Their uses have been well documented in emergency and critical care medicine, but not nearly as well in prehospital emergency care. With proper education and prudent practice by prehospital providers, the use of a variety of these drugs in the care of critically ill patients is just one more tool that affords EMTs and paramedics the opportunity to bring the ICU to the field.
Anatomy & Physiology
Most antihypotensives are adrenergic in origin, meaning they work by activating specific receptors in the body. Normally, these receptors are acted on by the endogenous neuromodulators epinephrine and norepinephrine. These receptors and chemicals are, in part, the driving force behind the fight-or-flight reaction.
In the adrenergic class of medications, the antihypotensives are broken down into those that affect alpha-1 (α1) receptors, those that affect beta-1 (β1) receptors, and those that affect both. Α1 receptors lie mostly with the smooth muscle of vasculature. When drugs activate these receptors, vasoconstriction occurs. Thus, these drugs are known as α1 agonists.
Conversely, β1 receptors are found primarily within the heart. Activation of these receptors can have several effects: a change in heart rate (chronotropy) or a change in the contractile force of the heart (inotropy). These medications are known as β1 agonists. Several of the inotropic drugs are non-adrenergic in origin, and will be discussed later.
In regard to common nomenclature, drugs that act by increasing the amount of blood the heart can eject with each beat (stroke volume) are known as “inotropes.” The others are typically known as “vasopressors” or “pressors,” as they have at least a modest ability to press (cause vasoconstriction) the peripheral vasculature.
The use of pressors in providing thorough, aggressive care isn’t without risk. Careful thought and evidence-based judgment needs to be used in the evaluation of several factors: Which agent is most appropriate? Which agent has the most risk? Does a patient have comorbidities that make one agent better than another? How is the drug going to be administered?
Prior to even considering the use of one of these vasoactive agents, additional thought should be given to how truly and critically hypoperfused is the patient? Are there signs of decreased end-organ perfusion such as cold, clammy skin or altered mentation? Is there an etiology for the decrease in blood pressure?
The whole clinical picture is incredibly important here—not just the numbers (e.g., blood pressure, heart rate). Have less invasive means of increasing perfusion such as supining the patient, stopping exsanguination, crystalloid boluses, or increasing heart rate via atropine or pacing failed? If the patient is indeed critically ill and unresponsive to other indicated forms of increasing perfusion, than the use of an antihypotensive may be called for. However, as a general rule, antihypotensive medications are reserved for patients in hypoperfusion states with a decrease in systolic blood pressure > 30 mmHg.
Next is the issue of the actual physical administration of the medication. Venous access in patients who are hypoperfused is a very real challenge. Shunting and hypovolemia can make for a near impossibility in obtaining peripheral venous access. Even more so, severe tissue necrosis from the extravasation of antihypotensives is a very serious complication when being administered via peripheral IV access. Administration via central venous access is the gold standard for any antihypotensive medication administration, especially all adrenergics. However, obtaining central venous access isn’t plausible in the prehospital environment.
As a temporary means of administration, a large-bore peripheral IV is acceptable if available. If IV access isn’t available, intraosseous (IO) access is a great alternative—it’s reliable, quick and safe in both the prehospital and in-hospital environments. IO cannulations should be considered the preferred site for administration of antihypotensive agents in the field until another means of central access can be achieved later in the ED.
While standard dosages will be covered in this article, all antihypotensives affect every patient differently, and to a greater variance than many other medications. Frequent reevaluation of the patient’s clinical status is a must. Vital signs and cardiac rhythm must be evaluated no less than every five minutes. The site of administration should be regularly monitored for extravasation and infiltration. Simply put, the provider must vigilantly monitor all aspects of the patient’s condition for response, side effects and complications.
Dopamine is the standard go-to antihypotensive for most prehospital systems. It’s a drug that has both inotropic and vasoconstrictive properties. These properties vary by dosing. Dosage starts at 5–10 mcg/kg/min, and at this dose dopamine primarily stimulates β1 receptors and increases cardiac output by increasing stroke volume. At > 10 mcg/kg/min—with 20 mcg/kg/min being the maximum dose—there’s modest α1 effects that cause an increase in systemic vasoconstriction, in turn causing an increase in afterload. Dopamine is generally one of the first-line drugs in patients with acute heart failure with mild hypotensive complication. However, caution should be exercised when using dopamine in the heart failure population at higher doses. An increase in afterload can further weaken the heart and lead to worsened heart failure and cardiovascular collapse.1
One of the main drawbacks from dopamine is its proclivity to cause exaggerated chronotropy and tachyarrhythmias. Dopamine should be used cautiously in patients with significant preexisting heart disease or current tachycardia. There’s currently little evidence to support dopamine as a first-line agent in shock states.
Dobutamine is a synthetic adrenergic with purely β1 agonistic, inotropic effects. There’s also modest chronotropy observed. Different from dopamine, due to increasing stroke volume without any α1 effects, dobutamine causes a reflex peripheral vasodilation. This leads to increased cardiac output with decreased strain on heart muscle. Dobutamine use is generally reserved for advanced heart failure and low cardiac output states after hypotension is corrected, and is contraindicated for distributive shock states.1,2 Dobutamine is generally dosed at 2–20 mcg/kg/min. There’s some evidence to support dopamine/dobutamine dual-therapy in patients with severe acute heart failure. This increases cardiac output with minimal increased strain on the heart.2
Norepinephrine (Levophed) acts on both α1 and β1 receptors, producing both potent vasoconstriction and a moderate increase in cardiac output. However there are no inotropic effects with norepinephrine. Dosages for norepinephrine generally range from 5–30 mcg/min. Norepinephrine is the first-line pressor of choice for both cardiogenic and septic shock. There is measureable decrease in mortality when administered as first-line in both these conditions.2,3 Additionally, while the standard treatment for hypovolemic shock from hemorrhage is fluid and blood product administration, norepinephrine is generally the first-line choice until euvolemia can be achieved.
Providers should be prepared to see a reflex bradycardia due to an increase in vasoconstriction and blood pressure cancelling the heart’s compensatory chronotropy in response to the shock-state. However, this decrease in heart rate is mitigated by the other effects of the drug and does not decrease overall perfusion.1
Phenylephrine (Neo-Synephrine) has purely α1 agonistic qualities and is an extremely effective vasoconstrictor. This vasopressor is reserved primarily for patients suffering from distributive shock of a neurogenic origin such as spinal cord injury or other CNS illness/injury. However, phenylephrine can be used as a second-line agent in other hypoperfusion states that are refractory to norepinephrine or where norepinephrine in contraindicated due to a patient’s predisposition to arrhythmia. A possible reflex decrease in heart rate can also be seen with phenylephrine administration. Dosages of phenylephrine are titrated between 25–200 mcg/min.1
Epinephrine affects both α1 and β1 receptors; however, it has very potent effects on the β1 receptors, in particular. At lower doses, epinephrine increases cardiac output via an increase in inotropy and chronotropy. At this lower dose, there can be a mild reflex vasodilation to the increase of cardiac output. This vasodilatory action along with the substantial increase in cardiac output is very beneficial in cardiogenic shock states. However, at higher doses, α1 effects predominate with profound vasoconstriction.
Epinephrine is the strongest vasoconstrictor of all the vasopressors when all things are equal, thus making it first-line for anaphylaxic shock and generally second-line for septic and cardiogenic shocks. Epinephrine is typically dosed at 1–10 mcg/min with higher doses titrated as needed to maintain end-organ perfusion.1
It’s crucial to understand why epinephrine is the first-line agent for anaphylactic shock.4 Most importantly, with epinephrine being the strongest vasoconstrictor, it’s the best choice for reversing the catastrophic vasodilation that occurs in anaphylactic shock. Additionally, epinephrine is the best drug to prevent or stop the mast cells (white blood cells responsible for hypersensitivity reactions) from propagating the anaphylaxis. And lastly, epinephrine is the only drug that prevents or reverses upper and lower airway obstruction secondary to bronchoconstriction and angioedema
Vasopressin is a naturally occurring chemical in the body that’s also known as antidiuretic hormone. Its uses vary widely due to the unique properties and effects it has within the body. It can be used to stop free-water loss in diabetes insipidus and to stop gastrointestinal bleeding. In addition to these uses, it can also play a role in the shock setting.
Vasopressin is a potent vasoconstrictor with no direct β1 effects. The increase in blood pressure that’s seen with vasopressin is due to its vasoconstricting action. While its efficacy as a vasopressor has yet to be completely established, vasopressin’s ability to cause peripheral vasoconstriction has led to its adoption as a second- and third-line drug in several shock pathologies, mainly those of distributive etiology.
Particularly in anaphylactic shock refractory to epinephrine alone, vasopressin is the second-line choice. Also when used as a second- or third-line agent in distributive shocks, vasopressin is able to reduce the amount of the previous agents used while maintaining the goal blood pressure.1 Vasopressin is traditionally dosed at 0.01–0.04 units/min.
Milrinone is a nonadrenergic inotrope used by patients at home with severe heart failure, in addition to its traditional in-hospital uses. Milrinone belongs to the class of drugs known as phosphodiesterase inhibitors. Its effects are similar to that of dobutamine with the exception of there being decreased risk for cardiac arrhythmia.1 Milrinone increases cardiac output via increased inotropy with very little chronotropic effect. Milrinone also decreases both preload and afterload via direct vasodilatory properties, which is different from many of the other medications reflex effects. Additionally, there’s less of an increase in myocardial oxygen demand than that of its adrenergic counterparts.1 Milrinone is administered as an initial 50 mcg/kg bolus followed by a 0.375–0.75 mcg/kg/min maintenance infusion.
Milrinone is administered for in-hospital and out-of-hospital patients waiting for heart transplants and advanced therapies like ventricular assist devices, or for those who aren’t candidates for more advanced therapies for which milrinone is the destination therapy. Although the current indication for milrinone is for advanced heart failure, there’s a pool of evidence beginning to support its use in the acute shock setting, especially in pediatrics and neonatology.5 When used in shock, an adrenergic vasopressor is typically also needed.6 However, the practice of using milrinone in most shock settings isn’t standard care and more research is needed.5
Allergies to these medications are very rare. Most complications come from one of two things: arrhythmia or ischmia. Most of the adrenergics lead to increased myocardial excitability and/or workload for one reason or another. This can potentially cause tachyarrhythmias such as ventricular tachycardia and fibrillation. Additionally, coronary vasospasm can lead to acute myocardial infarction in certain patients, especially those with preexisting heart disease.
The other common complication is tissue ischemia from vasoconstriction. At higher doses many of the pressors can cause such profound vasoconstriction that skin, entire limbs, the kidneys and the intestine can become ischemic, leading to necrosis. This can progress to the point of limbs being amputated and organs permanently failing. Occasionally, the bowel can become so ischemic, it dies and needs to be resected.
For many of us, some or all of these options aren’t available to use in the prehospital setting. However, these options save lives and improve outcomes. They aren’t very difficult to administer and really have no more increased risk than many of the other drugs we carry. With good evidence-based judgment and care, prehospital providers can use these treatments in their daily practice. If these aren’t available to you, it’s time to have real conversations with your medical director and state agency about bridging the gap into the new age of prehospital critical care and emergency medicine.