Continuing Education Activity

Due to their negative inotropic and chronotropic actions, beta-adrenergic receptor antagonists are typically indicated in individuals with chronic cardiovascular disease (hypertension, coronary artery disease, congestive heart failure) with a significant reduction in mortality. The FDA-approved indication for labetalol is to treat arterial hypertension, which ranges from acute hypertensive crises (urgent/emergency) to stable chronic hypertension. Labetalol in clinical practice has several common off-label uses that include acute hypertension in pregnancy and hypertension associated with acute ischemic stroke, and intracranial hemorrhage, including subarachnoid hemorrhage. Today, labetalol is usually reserved for the acute management of hypertensive crises. This activity covers labetalol, including mechanism of action, pharmacology, adverse event profiles, eligible patient populations, contraindications, monitoring, and highlights the role of the interprofessional team in the management of labetalol therapy.

Objectives:

• Identify the indications for clinicians to use labetalol.
• Explain the mechanism of action of labetalol.
• Review the contraindications to labetalol therapy.
• Summarize how interprofessional team strategies can improve patient results in cases where labetalol therapy is indicated.

Indications

Due to their negative inotropic and chronotropic actions, beta-adrenergic receptor antagonists (e.g., carvedilol and metoprolol) are typically indicated in individuals with chronic cardiovascular disease (hypertension, coronary artery disease, congestive heart failure) with a significant reduction in mortality.[1]

The FDA-approved indication for labetalol is the treatment of arterial hypertension, which ranges from acute hypertensive crises (urgent/emergency) to stable chronic hypertension. Labetalol in clinical practice has several common off-label uses that include acute hypertension in pregnancy and hypertension associated with acute ischemic stroke, and intracranial hemorrhage, including subarachnoid hemorrhage. Today, labetalol is usually reserved for the acute management of hypertensive crises.

Labetalol is often chosen as treatment of acute hypertension by anesthesia providers peri-operatively as it produces a dose-related decrease in blood pressure without reflex tachycardia without significant reduction in heart rate. These effects are produced through a mixture of its alpha- and beta-blocking effects. The hemodynamic effects of labetalol are variable, with small, insignificant changes in cardiac output seen in some studies and small decreases in total peripheral vascular resistance. This hemodynamic profile is favorable in the perioperative setting when the anesthesia provider desires rapid reduction of blood pressure without the reflex tachycardia, which can potentially further compromise a patient's hemodynamics under general anesthesia. Similarly, labetalol is a common anti-hypertensive given in the post-anesthesia care unit, again due to its HR sparing effects and better control of blood pressure.[2]

Labetalol is one of the most commonly used anti-hypertensives medications used for the treatment of hypertension during pregnancy. Hypertension during pregnancy is an increasingly common and a leading cause of maternal mortality and morbidity worldwide.  Severe hypertension requires prompt treatment with rapid-acting antihypertensive agents such as labetalol to avoid stroke and placental abruption. Previously, intravenous hydralazine was utilized as a first-line drug for this purpose, although there is a growing experience with other agents, including intravenous labetalol and oral nifedipine. There appears to be a growing concern about the neonatal effects of hydralazine. Treatment aims to lower blood pressure during pregnancy into the mild range (less than 160/100 mm Hg), reduce the risk of stroke and other maternal cardiovascular complications.[3][4]

Due to the alpha1-receptor antagonistic activity of labetalol, blood pressure is lowered more in the standing than in the supine position, but this can lead to symptoms of postural hypotension. When deciding to administer intravenous labetalol, the postural component needs to be considered when positioning the patient for treatment. Also, the patient should not be allowed to move to an erect position unmonitored until their ability to do so safely is established.

Mechanism of Action

Labetalol is useful as it contains both selective, competitive, alpha1-adrenergic antagonism and non-selective, competitive, beta-adrenergic (B1 and B2) blocking activity in a single agent. When analyzed in the laboratory, the activity ratio of alpha to beta-blockade has been estimated to be approximately 1 to 3 and 1 to 7 following oral and intravenous (IV) administration, respectively.[5]

Administration

For acute hypertensive events (emergent/urgent), the IV formulation is indicated and an initial dose of a 10- to 20-mg IV push, with repeat boluses administered every 10 minutes until the systolic blood pressure is within the desired range or a maximum dose of 300 mg per 24-hour period is reached. A dose of 20 mg correlates with approximately 0.25 mg/kg in an 80-kg patient. A continuous infusion can also be considered and initially started at 0.5 to 2 mg per minute with the potential to titrate up to 10 mg per minute.[1]

Labetalol is metabolized by the liver resulting in an inactive glucuronide conjugate. It has an onset of action within 2 to 5 minutes, reaches its peak effects at 5 to 15 minutes, has an elimination half-life of 5.5 hours, and a duration of action up to four hours.

For a hypertensive emergency in pregnancy (systolic BP equal to 160 mm Hg or diastolic BP equal to 110 mm Hg), which is officially an off-label use, the initial dosing scheme is reportedly very similar to treating non-pregnant patients with acute hypertension with 20 mg as an initial dose. If blood pressure still exceeds this threshold, it is reasonable to consider increasing the dose every 10 minutes in increments of 20 to 40 mg to a maximum single dose of 80 mg. A maximum total cumulative dose of 300 mg is still recommended in this scenario.

Adverse Effects

Overall, labetalol is usually well tolerated. Most adverse effects are typically mild and transient. As previously described above, symptomatic postural hypotension is a potential occurrence if patients are tilted or allowed to change positions from the supine or seated position to standing too quickly. This is especially important in the post-operative period (PACU or the ward) when managing a hypertensive patient with labetalol who can otherwise ambulate to the bathroom. Increased sweating, as well as flushing, have been reported with the use of labetalol. It seems the incidence of adverse reactions after administering labetalol seems to be dose-dependent.[6]

As with all beta-blockers, labetalol has negative inotropic effects and has the potential to cause acute left ventricular failure if given in sufficiently large enough doses to those patients who have impaired function of the left ventricle. All beta-blockers can exacerbate intermittent claudication and Raynaud phenomenon in patients with coexisting peripheral vascular disease. Another important consideration for anesthesia providers in the perioperative period is that non-selective beta-blockers that interact with beat receptors can result in bronchospasm in patients with a history of asthma or chronic obstructive pulmonary disease due to antagonism of beta receptors. Sudden withdrawal of beta-blockers can result in increased sensitivity to catecholamines. This upregulation can lead to tachyarrhythmias, acute hypertensive crises, and palpitations, although this is more common with chronic use.[7]

Contraindications

As a member of the beta-blocker class, labetalol is contraindicated, and its use is strongly cautioned in patients with bronchial asthma, overt cardiac failure, greater-than-first­ degree heart block, cardiogenic shock, severe bradycardia, as well as other conditions associated with severe and prolonged hypotension. Of course, it should be avoided in patients with a history of hypersensitivity to any component of the drug formulation to avoid any degree of allergic reaction.[8]

Monitoring

There are no specific drug monitoring requirements for labetalol. As it is typically used for severe acute hypertension and not chronic use, no monitoring is necessary. Also, it is a safe drug with a large margin of safety, with dosing permitted to an upper limit of 300 mg per day.[9]

Toxicity

Supportive care and close monitoring are the staples of treatment for an overdose of beta-blockers with the addition of glucagon for severe refractory hypotension and bradycardia.

Glucagon provides several important clinical effects when used for beta-blocker overdose. It provides an increase in HR and improves both myocardial contractility as well as atrioventricular conduction. Its MOA seems to be independent of the beta-adrenergic binding site allowing it to be effective. The recommended initial dose of glucagon to reverse severe symptomatic beta-blockade is 50 mcg/kg IV as a loading dose, followed by an infusion of 1 to 15 mg per hour IV, titrated to clinical response and improvement.[10]

Enhancing Healthcare Team Outcomes

As labetalol is typically used to treat acute hypertension, whether it presents in the emergency department or an outpatient clinic, an interprofessional team approach and effective communication are essential for quality patient care. This interprofessional team can include specialists, other clinicians (MDs, DOs, PAs, NPs), nursing staff, and pharmacists. In the emergency department, swift intake and triage by the nurse or medical technician to identify a patient with dangerously elevated blood pressure and quickly but effectively convey the critical information to a physician or provider are necessary. If hospital admission is warranted, communicating the crucial details of the patient's presentation, medical history, and the treatment and current medical workup that have been completed are important, so time and resources are not wasted on repeating tests and exams. Utilizing an interprofessional team methodology that employs open communication between all team members and coordinated activity will improve patient outcomes and fewer adverse effects, particularly in hypertensive emergencies. [Level 5]