CONTENTS
#1) approach to hypertensive emergencies
- [1] Is there a known cause of the HTN?
- [2] Is this actually a hypertensive emergency?
- [3] Re-evaluation for an underlying cause of the HTN.
- [4] Control Bp with IV antihypertensive agents.
- [5] Transition to oral antihypertensives.
- Background
#2) antihypertensive pharmacology in general
- Dihydropyridine CCBs:
- Diltiazem
- Beta-blockers and alpha/beta-blockers
- Alpha-blockers
- Hydralazine
- Nitrates
- ACEi or ARB
- Nitroprusside
- Centrally acting sympatholytics
secondary hypertension
- Secondary hypertension is used here to refer to hypertension which is a result of some other primary process. In most cases, the primary process will be more obvious clinically, dominating the initial clinical presentation (e.g. aortic dissection, sympathetic crashing acute pulmonary edema, cocaine intoxication).
- Treatment will vary widely, depending on the specific context. This will be covered in other chapters regarding these individual conditions. For example:
two criteria are required to diagnose hypertensive emergency:
(a) severe hypertension:
- Usually a MAP of at least >135 mm is needed to cause a hypertensive emergency.(34670853)
- However, this may vary considerably depending on the patient's baseline Bp. The relative change in blood pressure from baseline is more important than its absolute value. Hypertensive emergency can occur at lower MAPs in previously normotensive patients who have acute hypertension (e.g., pregnant women with preeclampsia).(26674757) Alternatively, patients with chronic hypertension may have extremely elevated Bp without hypertensive emergency.
(b) target organ damage, such as:
- [1] Acute kidney injury (often with microscopic hematuria).
- [2] Myocardial ischemia (type-II myocardial ischemia).
- [3] Pulmonary edema.
- [4] Hypertensive encephalopathy (e.g., visual disturbance, seizure, delirium). In situations where this is unclear, the presence of increased optic nerve sheath diameter on ultrasonography might support the diagnosis of hypertensive encephalopathy with increased intracranial pressure.
- 🔑 Epistaxis, proteinuria, chronic renal failure, or headache don't qualify as target organ damage.(34670853)
- 🔑 If there is no target organ damage, then the patient doesn't have a hypertensive emergency.
- The concept of “hypertensive urgency” is discussed further below: ⚡️
causes of severe hypertension include:
- Nonadherence with antihypertensive medications (especially clonidine withdrawal).
- Physiologic stimuli:
- Volume overload.
- Hypercapnia, or nonadherence with CPAP or BiPAP therapy for sleep disordered breathing.
- Pain.
- Anxiety, agitation.
- Urinary obstruction.
- Medications:
- Sympathomimetics (e.g., cocaine, over-the-counter decongestants).
- Calcineurin inhibitors (cyclosporine, tacrolimus).
- Erythropoietin.
- Steroid.
- NSAIDs.
- Metoclopramide.
- Anti-angiogenic medications.
- Monoamine oxidase inhibitors with high dietary tyramine intake.
- Withdrawal:
- Alcohol or benzodiazepine withdrawal.
- Clonidine or tizanidine withdrawal.
- Stroke (e.g., ischemic stroke, intracranial hemorrhage, subarachnoid hemorrhage).
- SCAPE (sympathetic crashing acute pulmonary edema).
- Aortic dissection.
- Preeclampsia.
- Endocrinopathy:
- Pheochromocytoma.
- Hyperaldosteronism.
- Cushing's syndrome.
- Hyperthyroidism.
- Renal:
- Scleroderma renal crisis.
- Acute glomerulonephritis.
- Renal artery stenosis.
- Dysautonomia:
- GBS (Guillain-Barre syndrome).
- Autonomic dysreflexia following spinal cord injury. 📖
evaluation may include:
physical examination
- Repeat blood pressure measurement: Initial Bp measurement in the emergency department is often transiently elevated (possibly reflective of a “white coat hypertension” phenomenon). Simply allowing the patient to rest quietly and repeating the blood pressure will often lead to a substantial reduction.(34670853)
- POCUS:
- Assessment of volume status.
- Evaluation for ultrasonographic papilledema and/or increased optic nerve sheath diameter.
history
- Baseline Bp? (Ask patient & review any electronic records.)
- History of hypertension?
- Antihypertensive regimen?
- Compliance with regimen?
- Any prior episodes of hypertensive emergency?
- Home medications, especially any recent changes? (Including over the counter decongestants.)
- Symptoms (including chest discomfort, dyspnea, weakness, visual disturbance, headache)?
- Illicit drug use? (31279421)
labs
- Chemistries.
- ? Acute kidney injury.
- Complete blood count.
- ? Schistocytes (implies true hypertensive emergency).
- Troponin (only if EKG/clinical evidence to support MI).
- Urinalysis.
- Urine toxicology screen may be considered.
- Pregnancy evaluation as appropriate.
other studies
- EKG.
- Non-contrast head CT, if presentation is worrisome for possible intracranial hemorrhage.
diagnostic/therapeutic management of any obvious causes of hypertension
Before initiation of antihypertensives, consider some simple interventions which may be highly effective in reducing the blood pressure. Overlooking these factors may eventually lead to overshoot hypotension. For example, if pain is driving the hypertension but you initiate therapy with antihypertensives first, when the pain eventually subsides the patient may develop overshoot hypotension.
interventions that may rapidly reduce the blood pressure:
- Pain: Treat with appropriate analgesia.
- Agitation: Treat with antipsychotics or dexmedetomidine.
- Volume overload: Treat with diuresis or dialysis.
- Drug withdrawal: Treat appropriately, for example:
- Alcohol withdrawal: Phenobarbital.
- Clonidine/tizanidine withdrawal: Restart therapy.
- Urinary retention: Foley catheter.
blood pressure goal?
- There isn't solid evidence behind this. The following approach seems reasonable & consistent with guidelines: (29133354, 30165588)
- (#1) The initial goal is to decrease the MAP by ~20% within 1-2 hours.
- (#2) If this reduction is tolerated, then decrease the MAP to ~125 mm (~160/110 mm) over the next 2-6 hours.
- (#3) The blood pressure may subsequently be gradually decreased further over a period of days, as clinically tolerated.
- Bp targets may need to be individualized. Consider what the patient's baseline pressure is, and how rapid the increase in pressure was.
- Chronic severe hypertension: A more gradual approach to lowering the Bp may be wise.
- Acute development of hypertension: More rapid reduction of Bp makes sense.
- 💡 Whenever possible, try to clearly define the baseline Bp (e.g., obtain multiple Bp readings in both arms before starting antihypertensives). Lack of a definite baseline Bp leads to uncertainty regarding all downstream Bp targets.
IV antihypertensives can be divided into three groups:
- (1) Truly titratable agents:
- Duration of action is <<30 minutes.
- The drug must be given as a continuous infusion. It is fairly easy to titrate.
- Examples: Clevidipine, nitroglycerine, esmolol, nitroprusside.
- (2) Quasi-titratable agents:
- Duration of action is <1-2 hours.
- The drug is generally given as a continuous infusion, but it's a bit sluggish to titrate. Care is required to avoid medication accumulation, which may cause hypotension.
- Examples: Nicardipine, diltiazem.
- (3) Bolus agents:
- Duration of action is >1-2 hours
- The most sensible way to give the drug is via intermittent bolus doses. If an infusion is used, it will tend to accumulate and be difficult to titrate.
- Examples: Labetalol, metoprolol, hydralazine.
preferred IV antihypertensive infusion
- [1] Calcium channel infusions are usually the best agents. Most patients have excessive vasoconstriction, a physiologic problem which is corrected by calcium channel blockers.
- Clevidipine might be the best agent, if available.
- Nicardipine is an excellent choice, if clevidipine isn't available.
- [2] PRN doses of labetalol is a reasonable approach if the Bp isn't profoundly elevated.
is an arterial line needed?
- There is no solid data on this.
- Indications for an arterial line might include:
- Very labile blood pressures.
- Profound hypertension (too high to be real?).
- Clinical deterioration despite noninvasive management.
- An arterial line is probably unnecessary in most cases of hypertensive emergency, for the following reasons.
- The pain of arterial line insertion can exacerbate hypertension.
- No prospective evidence exists to show that this procedure is beneficial or necessary.
- Bp targets are arbitrary and poorly defined. It's illogical to tightly chase after an arbitrary target.
if the blood pressure plummets, evaluate for hypovolemia and volume resuscitate if necessary
- Patients often have a combination of:
- (1) Excessive vasoconstriction, which is driving their hypertension.
- (2) Hypovolemia due to the diuretic effect of hypertension (“pressure diuresis”).
- When treated with vasodilation, these patients may develop hypotension (due to unmasking of their hypovolemia). Overall this may lead to wide fluctuations in blood pressure, which is difficult to control. Stabilizing these patients requires addressing both problems:
- (1) Control excessive vasoconstriction with a vasodilator.
- (2) Control hypovolemia with volume administration.
when to start oral titration
- Start oral antihypertensives after the patient has stabilized and improved on IV antihypertensives for several hours.
- Oral antihypertensives may be gradually up-titrated, with simultaneous weaning off IV antihypertensives.
factors to consider when selecting an oral antihypertensive
- [1] How has the patient responded to various IV antihypertensives?
- For example, a favorable response to nicardipine infusion might suggest that the patient will respond favorably to an oral dihydropyridine calcium channel blocker.
- If a high dose of antihypertensive medication has been required, this suggests that fairly high doses of oral antihypertensives will be required.
- [2] Consider the patient's home antihypertensive regimen:
- This may provide some clues regarding the dose and number of agents that will be required.
- In many cases, it may be appropriate to resume some or all of the patient's home antihypertensive regimen (especially if the trigger for the hypertensive emergency was medication nonadherence).
- [3] Does the patient have comorbidities that would benefit from specific antihypertensive agents?
- For example, if the patient has HFrEF this would be an argument to initiate oral carvedilol and/or an ACEi/ARB (rather than a calcium channel blocker).
- [4] Try to choose agents with high efficacy and reasonably rapid onset time.
- The ideal oral antihypertensive will take effect within a few hours. This allows for a prompt up-titration of oral doses, which facilitates rapid weaning of the IV antihypertensive agent.
- Amlodipine takes forever to work – this drug is an absolute slug and has no role here.
- Metoprolol drops the heart rate, but is relatively ineffective for controlling blood pressure.
usually preferred agents
- 🏆 Nifedipine extended release ⚡️
- Generally a good choice (this is essentially an oral equivalent of nicardipine).
- It works rapidly and is effective, especially among patients with a favorable response to nicardipine infusion.
- The main drawback is that nifedipine XR cannot be crushed for administration via an enteral tube.
- Immediate release dihydropyridine calcium channel blockers (isradipine ⚡️ or felodipine ⚡️). These may be used as an alternative to nifedipine XR among intubated patients who cannot swallow pills.
- Alpha/beta blockers: labetalol ⚡️ or carvedilol ⚡️.
- Oral labetalol has faster onset and traditionally has been a workhorse for hypertensive emergency.
- Carvedilol has slightly slower onset, which may prolong weaning off the antihypertensive infusion somewhat. However, carvedilol is a much better medication for chronic use as compared to labetalol. To facilitate weaning, a reasonably high initial dose should be used (discussed further below: ⚡️).
- ACEi/ARB ⚡️: An oral captopril titration may rapidly establish how the patient responds to an ACEi. If the patient responds favorably to captopril then this may be transitioned to an equivalent dose of lisinopril (equal to the total daily captopril dose divided by five).
list of all oral antihypertensive agents:
- Dihydropyridine CCBs:
- Diltiazem
- Beta-blockers and alpha/beta-blockers
- Alpha-blockers
- Hydralazine
- Oral hydralazine plus isosorbide dinitrate
- ACEi or ARB
- Centrally acting sympatholytics
There are several reasons that MAP (mean arterial pressure) is the preferred measurement of blood pressure:
- [1] MAP is what the automated Bp cuff is actually measuring:
- Automated oscillometric Bp cuffs measure the MAP directly (whereas the systolic and diastolic Bp are estimated using proprietary algorithms).
- [2] MAP may be most closely related to the risk of hypertensive emergency:
- We tend to focus on the systolic blood pressure (“she had a systolic of 250!!”). However, the risk of hypertensive emergency seems overall be more closely related to the diastolic pressure than the systolic pressure.
- MAP is probably the single parameter most closely related to the risk of hypertensive emergency.
- [3] MAP is preferred for simplicity in guiding therapy:
- Titrating an antihypertensive infusion against a MAP is simple and sensible.
- In comparison, trying to titrate an antihypertensive infusion against both a systolic and diastolic blood pressure simultaneously is often impossible and confusing (for example, what happens if the systolic target is reached but not the diastolic?).
what is malignant hypertension?
- When chronic hypertension is not treated, it may eventually reach a tipping point where the hypertension itself is causing progressive microvascular damage. This leads to a vicious spiral that, if untreated, will progress to death.
- The term “malignant hypertension” is somewhat outdated (classically this was defined based on the presence of extreme hypertension and hypertensive retinopathy – which was often lethal before the advent of antihypertensives). Nonetheless, as a general concept this remains useful.
- Malignant hypertension is the “purest” form of primary hypertensive emergency.
pathophysiology of malignant hypertension
- The vicious spiral is shown above. The core of this spiral is that hypertension causes microcirculatory damage that impairs renal perfusion, leading to activation of the renin-angiotensin system (RAS). RAS activation, in turn, causes vasoconstriction – which leads to worsening hypertension.
- Clinical implications of this pathophysiology include the following:
- (#1) The primary pathophysiological problem is excessive vasoconstriction. Thus, the optimal treatment may include a vasodilator (most often a calcium channel blocker). Alternatively, use of a beta-blocker will not address this underlying problem.
- (#2) Patients are sometimes intravascularly volume depleted (due to sodium excretion in the kidney that is triggered by the hypertension). When vasoconstriction is treated, this may unmask underlying volume depletion – which is best treated with IV crystalloid administration.
- “Hypertensive urgency” is a term that has been used to refer to patients with severely elevated blood pressure (e.g., >~180/120) who do not have target organ damage. However, this is a misnomer because there is no “urgent” need to reduce the blood pressure, specifically:
- (1) There is NO need for referral to the emergency department.
- (2) There is NO need for hospital admission.
- (3) There is definitely NO need for ICU admission!
- If there is any doubt about this, please see the the AHA/ACC guidelines reproduced below.(29133354) Aggressive reduction in blood pressure is more likely to cause harm than benefit in this clinical context.
- It would probably be ideal to eliminate the term “hypertensive urgency” and replace it with the term “asymptomatic uncontrolled hypertension” (which would discourage over-reacting to this condition).(34670853)
- If a patient with hypertensive urgency is encountered in the outpatient context, it might be reasonable to start them on a low dose of a chronic oral antihypertensive agent with a relatively benign side-effect profile (e.g., amlodipine). It might also be wise to arrange close follow-up with their primary care provider for management of their blood pressure. Obtaining adequate follow-up and ambulatory blood pressure measurement is probably more important than the immediate patient management. This is not a critical care topic, so it's beyond the scope of this book.
indications 💊
- Excellent therapy for most patients with a primary hypertensive emergency. Nicardipine is usually the workhorse agent in hospitals that don't have clevidipine.
contraindications & drawbacks
- Contraindications:
- Cirrhosis (cleared by the liver).
- Acute coronary ischemia (may cause reflex tachycardia).
- Refractory hypoxemia (may impair V/Q matching).
- Drawbacks:
- A longish half-life may give the infusion a tendency to accumulate and cause hypotension. This may be avoided by cutting the infusion back once the target blood pressure is reached (see “dose” section below).
- It may promote volume overload (nicardipine is often provided in a relatively dilute form that may cause substantial volume administration).
- It may cause headache and reflex tachycardia.
pharmacology
- Onset ~5-15 minutes.
- Half-life: 45 hours.
- Duration of action: hours (sources vary).
dose
- Start at 5 mg/hr.
- If Bp is above target, increase by 2.5 mg/hr every 15-30 min, to a maximum rate of 15 mg/hour.
- When Bp reaches target, reduce the infusion to 3-5 mg/hr to prevent accumulation.
- If Bp falls below target, decrease infusion to 2.5 mg/hr or stop entirely.
- If the blood pressure falls substantially below target, stop the infusion entirely.
indications 💊
- Clevidipine is similar to nicardipine but has a shorter half-life, allowing it to be a truly titratable agent.
- Clevidipine is more successful than nicardipine at achieving tight blood pressure control. (18806012) It's easier to use than nicardipine, with a lower risk of overshoot hypotension.
- Clevidipine is cleared by ester hydrolysis within the blood (so its clearance isn't affected by hepatic or renal dysfunction). (Vincent 2023)
- Clevidipine is provided in a milky lipid emulsion (similar to propofol).
contraindications & drawbacks
- Contraindications:
- Hyperlipidemia, lipoid nephrosis, or acute pancreatitis.
- Acute coronary ischemia (may cause reflex tachycardia).
- Drawbacks:
- Unavailable at many hospitals due to cost/acquisition barriers.
- It may cause reflex tachycardia, and headache.
pharmacology
- Onset in ~3 minutes.
- Lasts ~10 minutes.
dose
- Start at 1-2 mg/hour
- Double every 2 minutes until Bp begins approaching the target, then titrate by smaller increments every 5-10 minutes.
- The dose range is 1-32 mg/hour.
These are essentially oral analogues of IV nicardipine or IV clevidipine. Similar to nicardipine or clevidipine, they are widely applicable and generally effective. Amlodipine is not listed here because it requires days to ready steady-state effect, given a half-life of 65-90 hours. Such sluggish pharmacokinetics are well suited to outpatient management but not for the management of acutely ill patients.
isradipine
basics 💊
- Isradipine may generally be conceptualized as a more rapid-acting version of amlodipine.
- The drawback of isradipine is that it is a bit more expensive and less widely available.
pharmacology
- Onset within ~2 hours.
- Half-life is ~8 hours.
- Duration of action is ~12 hours.
- Hepatic metabolism.
dosing
- Start 2.5 mg q12.
- Usual maximum dose is ~5 mg q12.
- Dosing can be increased to 10 mg q12, but most patients show no improvement at doses higher than 5 mg q12.
- Initiation of isradipine in ICU to wean off antihypertensive infusions in the context of hypertensive emergency:
- Start with one dose of 2.5 mg.
- Order a second 2.5 mg dose to be given 2.5 hours later with parameters to discuss with the practitioner prior to administration and hold if the Bp is at goal.
- Re-evaluate in 2-3 hours:
- If Bp remains substantially above target then give another 2.5 mg dose and increase the scheduled dose to 5 mg q12.
- If Bp is at target, then cancel the second dose and utilize 2.5 mg q12 dosing.
felodipine
basics
- Felodipine has a slightly slower onset as compared to isradipine. However, overall it is a very similar drug. (8466725)
- Compared to isradipine, felodipine may not allow for as facile oral up-titration, since it takes longer to have effect.
pharmacology
- Onset in 2-5 hours.
- Half-life of ~15 hours.
- Duration of effect ~24 hours.
- Hepatic metabolism.
dosing
- Initial dose: 2.5-5 mg po daily.
- Usual dose is 5-10 mg daily.
- Maximal dose 20 mg daily.
- Initiation of felodipine in ICU to wean off antihypertensive infusions in the context of hypertensive emergency:
- Start with one dose of 5 mg.
- Re-evaluate in 12 hours, if Bp remains substantially above target then give another 5 mg dose and initiate 5 mg BID. If Bp is at target, then continue with 5 mg q24 dosing.
nifedipine XR
basics 💊
- Contraindicated in patients unable to take oral tablets (cannot be crushed)
- Generally an excellent antihypertensive. This can be used as a once-daily medication, facilitating transition to the ward and outpatient therapy.
- Only ten-fold selective for vascular effects as compared to cardiac effects. Consequently, very high doses could have a minor effect on heart rate and cardiac contractility.
pharmacology
- Onset within ~2-4 hours.
- Half-life of ~10 hours.
- Duration of action ~24 hours.
dosing
- Starting dose is 30-60 mg.
- Maximal dose may vary somewhat depending on formulation (90 mg daily for Adelat CC, or 120 mg daily Procardia XL).
basics
- Diltiazem has a 3:1 selectivity for vascular:cardiac effects (which may be compared, for example, to nifedipine which has a 10:1 for vascular:cardiac effects). (25719531) Although diltiazem is generally similar to metoprolol (in terms of negative inotropic and negative chronotropic effects), it's direct vasodilator effects are unlike pure beta-blockers (and more analogous to alpha-beta blockers).
- Combined vasodilation and negative chronotropic/inotropic effects may increase diltiazem's efficacy for treating hypertension. However, this may also increase the risk of hypotension when diltiazem is utilized as an antiarrhythmic agent.
indications
- [1] Beta-blocker alternative in situations where beta-blockers are contraindicated (e.g., acute cocaine intoxication, severe active asthma).
- [2] Atrial fibrillation rate control (exert no effect on conversion to sinus rhythm).
- Diltiazem may be useful in patients who are hypertensive or more hemodynamically robust, especially patients who have been chronically treated with diltiazem as outpatients.
- [3] AVNRT conversion to sinus rhythm & maintenance therapy.
- Calcium channel blockers are generally regarded as front-line therapy for the management of stable patients with regular, narrow-QRS complex tachycardia.
- Verapamil and diltiazem seem to have equivalent efficacy. In the largest available RCT, verapamil converted 47/48 patients whereas diltiazem converted 52/53 patients. (19261367)
- Diltiazem causes less hypotension than verapamil. In the aforementioned RCT, verapamil dropped the blood pressure by and average of ~13/10 mm (▵SBP/▵DBP) and one patient developed clinically significant hypotension, whereas diltiazem dropped the mean blood pressure by ~5 mm/7 mm and no patients developed hypotension. (19261367)
- [4] Aortic dissection (very rarely, for example if there are contraindications to other agents).
contraindications & drawbacks
- Contraindications to diltiazem:
- [1] Ejection fraction <40%.
- [2] Borderline hemodynamic stability.
- [3] Possible ventricular tachycardia or pre-excited atrial fibrillation.
- [4] Bradycardia.
- [5] Any high-grade heart block.
- [6] Co-medications susceptible to significant drug interactions mediated by p-glycoprotein or CYP3A4. (37345492, 31504425)
- Drawbacks of diltiazem in atrial fibrillation:
- Compared to beta-blockers, diltiazem may be less effective if the arrhythmia is driven by high sympathetic tone.
- Diltiazem tends to cause hypotension. In the only RCT involving diltiazem infusions among ICU patients, 30% of patients treated with a diltiazem infusions developed hypotension which required the diltiazem to be discontinued. (11395591)
pharmacology of diltiazem
- Oral bioavailability: 40%.
- Peak serum time: 2-4 hours (immediate release) or ~11-14 hours (extended release).
- Half-life: 3-4.5 hours (single IV dose).
- Hepatic metabolism.
diltiazem dosing: usual IV & PO regimens
[#1] Initial loading dose
- Traditional loading dose:
- Start with 0.25 mg/kg (max dose 25 mg) IV bolus.
- If inadequate response and blood pressure remains adequate, may re-bolus once after 15 minutes at a dose of 0.25-0.35 mg/kg.
- Continuous loading dose: (validated for AVNRT)
- Dosing protocol for controlled, slow 20-minute infusion: (19261367)
- Diltiazem 2.5 mg/min is infused, for a cumulative dose of up to 50 mg max (or if diltiazem is unavailable, verapamil 1 mg/min infusion up to a total of 20 mg max).
- Cycle blood pressure every two minutes.
- Stop the infusion immediately if cardioversion, hypotension, or another adverse event occurs. For AVNRT, most patients will cardiovert within 5-10 minutes (with a dose of 12.5-25 mg diltiazem).
- A nurse and/or physician should be present and continuously observe the patient during the infusion.
[#2] Infusion
- Infuse at a rate of 2.5-15 mg/hour.
- The optimal infusion rate can be roughly estimated as ~0.18 multiplied by the loading dose (i.e., a 25 mg loading dose correlates roughly with a 5 mg/hour infusion). 📖
- Consider a reduction in the infusion rate after the target heart rate is reached. Especially with hepatic dysfunction, diltiazem may accumulate.
[#3] Transition to oral diltiazem
- Start diltiazem extended-release (diltiazem-ER) at a dose roughly equal to 10[3(infusion rate in mg/hr) +3]. When in doubt, round down. For example:
- 3 mg/hour –> 120 mg/day diltiazem-ER
- 5 mg/hour –> 180 mg/day diltiazem-ER
- 7.5 mg/hour –> 260 mg/day diltiazem-ER
- 10 mg/hour –> 330 mg/day diltiazem-ER
- 15 mg/hour –> 480 mg/day diltiazem-ER
- Wean off infusion over the next few hours.
common indications for beta-blockers & alpha/beta blockers
- Arrhythmia:
- Atrial fibrillation: metoprolol is often used.
- Ventricular tachycardia: Propranolol is probably superior to metoprolol and esmolol because it antagonizes both beta-1 and beta-2 receptors. Patients often have chronic heart failure, which may lead to down-regulation of beta-1 receptors and up-regulation of beta-2 receptors. (36837606) Propranolol may also have superior CNS penetration, further reducing sympathetic outflow. (37257955)
- Type-1 MI: discussed further here: 📖
- HFrEF: Carvedilol and metoprolol XL are shown to reduce mortality.
- Hypertension:
- Beta-blockers are not front-line agents for isolated hypertension.
- Alpha/beta blockers are more effective (labetalol, carvedilol).
- Paroxysmal sympathetic hyperactivity:
- Propranolol is a front-line agent to prevent PSH. Propranolol is lipophilic and exerts direct effects on the brain, making it more effective than most other beta-blockers.
contraindications to beta-blockers
- Contraindications to beta-blockers in general:
- Bradycardia (heart rate <60 b/m).
- Heart block
- PR interval >240 ms.
- Second/third degree heart block.
- Cardiogenic pulmonary edema.
- Low cardiac output (including frank cardiogenic shock).
- Hypotension.
- Acute asthma exacerbation.
- Acute sympathomimetic intoxication (e.g., cocaine).
- Contraindications to nonselective beta-blockers:
- Hyperkalemia (may worsen slightly).
- Asthma (nonselective beta-blockers are higher risk in asthma; judgment is required depending on asthma severity).
choice of beta-blocker
- β1-selective:
- β1/β2 nonselective:
- Alpha plus β1/β2 nonselective:
metoprolol
pharmacology
- Oral bioavailability is ~40% (so there is a 1:2.5 conversion between IV:PO).
- IV metoprolol has an onset of ~5 minutes, whereas PO has a peak plasma time after 1.5-2 hours..
- Duration of action is ~3-6 hours (PO) or ~5-8 hours (IV).
- Hepatic metabolism.
initial IV loading 💊
- Usually start with 5 mg IV, which should take effect within ~5 minutes.
- Additional doses may be given every 5 minutes, titrating to effect (reduction in heart rate, without causing hypotension).
- Generally, no more than 15 mg total will be used initially.
ongoing IV maintenance therapy
- For patients without enteral access, scheduled IV doses may be required.
- The intravenous form wears off faster than the oral form, so more frequent dosing may be required than is usual with oral metoprolol (e.g., the initial loading dose may be repeated q3hr-q6hr, depending on heart rate and blood pressure). (Sadhu 2023)
transition from IV to oral administration
- The initial oral dose may be estimated based on the IV dose required, based on a 1:2.5 conversion from IV to PO: (University of Wisconsin protocol)
- Response to 5 mg IV –> Start metoprolol tartrate 12.5 mg PO q6hr.
- Response to 10 mg IV –> Start metoprolol tartrate 25 mg PO q6hr.
- Response to 15 mg IV –> Start metoprolol tartrate 37.5 mg PO q6hr.
- The first oral dose can be started 20 minutes after the initial IV dose (so it's ordered immediately if the patient responds favorably to IV metoprolol).
- Metoprolol tartrate usually isn't given every six hours. However, starting with more frequent dosing may allow more flexibility in dose adjustment. If the patient responds favorably to q6hr metoprolol tartrate, this can eventually be converted to q12hr metoprolol tartrate or daily metoprolol succinate.
dosing oral metoprolol
- Heart failure:
- Start with metoprolol succinate 12.5-25 mg daily.
- Up-titrate to metoprolol succinate 200 mg daily.
esmolol gtt
indications 💊
- Very short-acting, beta-1 selective beta blocker. This allows it to be used as a titratable agent.
- Uses may include:
- Aortic dissection.
- Ventricular tachycardia storm.
- LV outflow tract obstruction.
- IV esmolol infusion may be used if it's unclear whether the patient will tolerate a beta-blocker. This has the theoretical advantage that if it causes hypotension, it can be stopped and will wear off fairly rapidly (over ~10 minutes). If the patient responds well to esmolol, it may be transitioned to a longer-acting beta-blocker.
- Another simpler option is to use IV metoprolol or IV labetalol. If the patient is unable to tolerate beta-blockade, it may be reversed transiently by using an infusion of low-dose dobutamine or epinephrine.
contraindications
- Same as beta-blockers in general (above: ⚡️)
onset & duration
dose
- [1] The loading dose is 0.5 mg/kg IV (~30-40 mg for 60-80 kg patient) over one minute.
- If there is concern about whether the patient can handle this, you may give half of the loading dose (0.25 mg/kg), wait 5 minutes, then give the remainder.
- [2] Start infusion at 0.05 mg/kg/min = 50 ug/kg/min (~3-4 mg/min for 60-80 kg patient).
- [3] If there is inadequate effect:
- Re-load with 0.5 mg/kg IV (~30-40 mg for 60-80 kg patient) over one minute.
- Up-titrate infusion in increments of 0.05 mg/kg/min every 10 minutes, up to a maximal dose of 0.3 mg/kg/min (~18-24 mg/min for 60-80 kg patient).
propranolol
pharmacology
- Elimination half-life 2-6 hours.
- High lipophilicity.
- Hepatic metabolism.
propranolol dosing for ventricular tachycardia storm 💊
- IV regimen: (10942741, 25745472, 32345562)
- Loading infusion 0.15 mg/kg IV over 10 minutes (~10 mg). Follow heart rate and hold the infusion if the heart rate falls <45 b/m.
- Maintenance: 3-5 mg IV Q6hr.
- Oral regimen:
propranolol dosing for paroxysmal sympathetic hyperactivity
- Oral dosing is preferred, often beginning at a dose of ~40 mg PO q6hr. Uptitration as needed, within a range of 20-80 mg q4-8 hours.
- Intravenous dose: Less information on this is available. 1 mg IV q6hr might be reasonable as a starting dose, with uptitration as clinically indicated. (30429730)
nadolol
general properties
- B1/B2 nonselective beta-blocker.
- May be superior to beta-1 selective beta-blockers for management of arrhythmia (e.g., catecholaminergic polymorphic VT).
- Long half-life compared to propranolol makes nadolol useful as maintenance therapy.
pharmacology:
- Half-life of 10-24 hours.
- Onset 3-4 hours.
- Duration of activity 17-24 hours.
- Renal clearance.
dosing:
- Hypertension: 40-320 mg/day.
- SVT maintenance therapy: 60-160 mg/day.
- Aggressive behavior or variceal hemorrhage: 40-160 mg/day.
- ⚠️ adjust dose in renal insufficiency:
- GFR >50 ml/min: give daily.
- GFR 31-50 ml/min: give q24-q36.
- GFR 10-30 ml/min: give q24-q48 hours.
labetalol
indications 💊
- IV labetalol:
- IV Labetalol is a reasonable agent in most hypertensive emergencies, especially if you're trying to drop the Bp by only a moderate amount (e.g., 10-30 mm). For severe hypertension, IV labetalol is less effective than nicardipine. (21707983)
- ⚠️ The problem with labetalol for hypertensive emergencies is that labetalol often doesn't address the underlying physiological problem. The primary driver of most hypertensive emergencies is excessive afterload (vasoconstriction). However, labetalol works predominantly as a beta-blocker (with negative inotropic and negative chronotropic effects). Beta-blocking someone with excessive afterload could theoretically reduce the cardiac output and thereby promote systemic hypoperfusion. Additionally, high labetalol doses may cause fetal bradycardia (>800 mg per day) (30165588)
- PO labetalol:
- Labetalol is traditionally a preferred oral antihypertensive for hypertensive emergency.
- As an alpha-beta blocker, labetalol is more effective at lowering blood pressure than pure beta-blockers (e.g., metoprolol).
- For patients who respond well to IV labetalol, a transition to oral labetalol makes sense. PRN doses of IV labetalol can be continued after starting oral labetalol for management of breakthrough hypertension. Meanwhile, the dose of oral labetalol may be gradually increased until no additional PRN IV doses are needed.
contraindications & drawbacks
- See section on beta-blockers above: 📖
pharmacology of labetalol
- Ratio of alpha:beta effects:
- Intravenous is 1:7 (so this is mostly a beta-blocker).
- Oral: 1:3 (so this is more of a real alpha-beta blocker).
- IV labetalol:
- PO labetalol
- Onset in ~2 hours.
- Duration of ~10 hours.
dosing of IV labetalol
- (#1) Start with sequential pushes of 20mg, 40mg, 80mg, 80mg, 80mg (q10-15 min PRN).
- Escalating boluses of labetalol can be useful to achieve rapid control of severe hypertension at the bedside if this is needed (e.g., acute Bp spike, which requires immediate control).
- If a total dose of 300mg doesn’t work (20-40-80-80-80), switch to another agent.
- Individual responses vary.
- (#2) Once Bp controlled, may use intermittent boluses to keep the blood pressure in range.
- The optimal bolus dose will vary between patients. This may be determined empirically as described above in #1. The goal of the bolus dose is to drop the Bp effectively, but not excessively.
- The blood pressure must be monitored carefully, with repeat PRN doses used as necessary (figure below).
- Labetalol lasts ~2-4 hours, so it doesn't make sense to give it as a continuous infusion (a continuous infusion will gradually accumulate and eventually cause overshoot hypotension).
dosing PO labetalol
- Start 200 mg q12hr. If no effect is seen following the first dose, an additional dose may be considered after 2-4 hours, followed by a subsequent increase in the maintenance dose.
- Max dose 1,000 mg q12hr. However, in pregnancy high doses may pose a risk of fetal bradycardia.(30165588)
carvedilol
general comments
- Carvedilol is a combined alpha-blocker and a nonselective beta-blocker. The beta-blocking effects may be roughly ten times more potent than the alpha-blocking effects.
- Carvedilol has a high affinity for receptors in the heart, so it remains active in the tissue even after being eliminated from the serum. (22149523)
- Carvedilol also has an array of potentially magical effects (e.g., antioxidant, antiproliferative, reduction of vascular smooth muscle migration and neutrophil infiltration, inhibition of apoptosis). (25719531)
- Carvedilol may be better tolerated than beta-1 selective agents in patients with diabetes. (25719531)
- Hyperkalemia may occur with beta-1/beta-2 nonselective beta-blockers.
dosing
- ⚠️ Evaluate ejection fraction and exercise caution in severe HFrEF.
- For hypertension in general:
- Start 6.25 mg BID.
- Increase to a maximal dose of 25 mg BID.
- For hypertensive emergency in ICU (while down-titrating IV antihypertensive infusion):
- [1] Often start at 12.5 mg BID.
- [2] Re-evaluate before 2nd dose:
- If Bp is already at target, consider dose-reduction to 6.25 BID
- If Bp is slightly above target, continue at 12.5 BID.
- [3] If Bp remains above target after 24 hours, up-titrate. Maximal dose is 25 mg BID.
- For LV dysfunction status post myocardial infarction:
- Start 3.125-6.25 BID.
- Gradually up-titrate to a maximal dose of 25 mg BID.
indications
- [1] Congestive heart failure:
- Alpha-blockers cause vasodilation of arterioles and venous capacitance beds, thereby reducing afterload and preload. Prazosin may also act centrally, to suppress sympathetic outflow. (34327714) Hemodynamic evaluation reveals that prazosin has a similar short-term physiologic effects as compared to sodium nitroprusside. (534583)
- In V-HEFT 1, prazosin failed to improve mortality, whereas a combination of hydralazine plus isosorbide dinitrate did improve mortality. Thus, prazosin may be inferior to a combination of hydralazine plus isosorbide dinitrate.
- [2] Benign prostatic hyperplasia
- [3] Raynaud disease.
contraindications
- Pregnancy: Prazosin is likely safe in pregnancy, but rarely used for preeclampsia (there may be some unproven concern regarding a risk of stillbirth). (34327714)
- Side effects may include:
- Orthostatic hypotension and falls.
- Drowsiness.
- Headache.
- Terazosin or doxazosin may be associated with arrhythmias (e.g., SVT, AF). (26033778)
prazosin
- 🏆 Pharmacokinetics are most amenable to rapid dose-titration:
- Dosing:
- Starting dose 1-2 mg q8-12 hours.
- Usual dose range 6-15 mg per day, divided in two-three doses.
- Maximal dose 10 mg q12. (26033778)
terazosin
- Pharmacokinetics:
- Bioavailability 100%.
- Peak level within one hour, half-life 12 hours.
- Hepatic metabolism.
- Dosing:
- Start 1 mg QHS.
- Usual dose 1-5 mg po QHS.
- Maximal dose 20 mg/day. (26033778)
doxazosin
- Pharmacokinetics:
- Bioavailability 50%.
- Peak effect in 8 hours.
- Half-life of 22 hours.
- Hepatic metabolism.
- Dosing:
- Usual dose 1-4 mg PO daily
- Maximal dose 16 mg/day. (26033778)
- Note: doxazosin XR is indicated for the treatment of benign prostatic hypertrophy, whereas doxazosin IR may be used for treatment of hypertension.
- Doxazosin was associated with an increase in the incidence of heart failure in the ALLHAT trial, but this may have been related to increased rates of peripheral edema and reduced use of diuretic among patients treated with doxazosin. In the ASCOT trial, doxazosin wasn't associated with an increase in heart failure. (37345492)
indications & general comments
- ⚠️ IV hydralazine is usually not a preferred agent for hypertensive emergencies since the response can be erratic.
- Preeclampsia: Hydralazine is generally considered safe in pregnancy and has been used in preeclampsia. However, hydralazine may be associated with an increased risk of fetal distress, as compared with dihydropyridine calcium channel blockers. Overall, hydralazine appears to be inferior to nifedipine or isradipine in preeclampsia. (26033778)
- Hydralazine is an arteriolar vasodilator that decreases systemic vascular resistance and generally increases cardiac output. (25719531)
contraindications & cautions
- Contraindications:
- Hydralazine can cause reflex tachycardia. It is relatively contraindicated in coronary artery disease.
- Aortic dissection (may increase wall shear stress).
- Lupus or connective tissue diseases (hydralazine may cause medication-induced lupus).
- Severe tachycardia with heart failure.
- High-output heart failure.
- Heart failure due to mechanical obstruction (e.g., aortic stenosis).
- Cor pulmonale. (26033778)
- Side-effects may include headache, nausea/vomiting, palpitations, and tachycardia. (26033778)
pharmacology
- IV:PO conversion is roughly 1:2 or 1:3 (oral bioavailability is 30-50%). (26033778)
- IV hydralazine:
- The effect occurs within 5-30 minutes.
- Duration of effect is ~2-4 hours.
- Oral hydralazine:
- Metabolism:
- Metabolized in the liver, with some individual variation between slow vs. fast acetylators.
- ⚠️ Half-life is usually 2-8 hours, but may be prolonged up to ~7-16 hours in patients with GFR <20 ml/min. (26033778)
dosing
- IV hydralazine:
- Initial dose:
- Start with a dose of 10 mg IV.
- Repeat q15-q30 minutes as needed.
- The maximum initial cumulative dose is 40 mg.
- Repeat doses may be given q4-6 hours as needed.
- Initial dose:
- PO hydralazine:
- Start 10-37.5 mg PO q6-8hr.
- Escalate as needed up to max dose 100 mg q6-8hr. (Irwin & Rippe 9th ed.)
advantages & general comments
- Overall physiological effect is similar to an ACE inhibitor, without the risk of nephrotoxicity.
- May be useful in heart failure.
- Short duration of action may facilitate rapid oral titration.
- Long-term adherence with TID medication is challenging. Consequently, this combination may eventually be transitioned to an ACEi/ARB after the patient has stabilized and they are at less risk of acute kidney injury.
contraindications & drawbacks
- Contraindications
- Hydralazine is contraindicated in patients with HOCM (hypertrophic obstructive cardiomyopathy), or left ventricular outflow tract obstruction.
- Drawbacks
- Hydralazine may cause reflex tachycardia and fluid retention.
- Renal dysfunction may cause hydralazine to accumulate over time.
pharmacology
- Hydralazine – discussed above.
- Isosorbide dinitrate 💊
- Onset within ~1-2 hours.
- Duration of ~8 hours.
dosing
- Hydralazine
- Start 25-37.5 mg q6-8hr. (Irwin & Rippe 9th ed.)
- Max dose 100 mg q6-8hr. (Irwin & Rippe 9th ed.)
- Isosorbide dinitrate
- Start 20 mg q6-8hr. (Irwin & Rippe 9th ed.)
- Max dose 40 mg q6-8hr. (Irwin & Rippe 9th ed.)
- Heart failure (V-HEFT I & II trials):
- Initial dosing was hydralazine 37.5 q6hr and isosorbide dinitrate 20 mg q6hr.
- If tolerated, this was doubled to 40 mg isosorbide dinitrate and 70 mg hydralazine q6hr. However, only about half of the patients reached the maximal dose. This regimen led to a mortality benefit among outpatients.
- 💡 Doses may be staggered every four hours (i.e., alternating doses of hydralazine and isosorbide dinitrate every four hours) if there is concern regarding causing an excessive drop in blood pressure.
indications
- Indications in MI:
- Anginal chest pain (or other anginal equivalent).
- Cardiogenic pulmonary edema.
- Possibly hypertension (although hypertension may be managed by other agents supported by more robust evidence, such as beta-blockers or ACE inhibitors).
- SCAPE: high-dose nitroglycerine infusion is a front-line therapy.
- Right ventricular failure: discussed in the chapter on RV failure: 📖
contraindications
- Recent use of phosphodiesterase inhibitors:
- Sildenafil or vardenafil within 24 hours.
- Tadalafil within 48 hours.
- Marked bradycardia or tachycardia. (ESC 2023, 37622654)
- Hypertrophic cardiomyopathy or severe aortic stenosis (relative contraindication – can use in certain situations but exercise caution). (26002298)
- RV infarction (relative contraindication only; can be used with caution).
- ICP elevation or PRES: Nitroglycerine may increase the ICP.
dosing for MI
- [1] Sublingual tablet of 0.4 mg q5 minutes (up to three doses). 💊
- [2] Anginal chest pain: infusion dosing may start at 10-20 ug/min.[2] If the patient responds favorably, may transition to a nitroglycerine infusion. 💊
dosing for SCAPE
- (Sublingual nitroglycerine)
- This may be utilized if a patient experiences SCAPE in a location unable to provide IV nitroglycerine (e.g., a medicine ward).
- The goal of sublingual nitroglycerine is solely to bridge the patient until they are able to receive IV nitroglycerine – not as an alternative or replacement for IV nitroglycerine. Patients should be transported immediately to a location capable of administering definitive therapy (IV nitroglycerine and noninvasive ventilation).
- The optimal dose is unclear, but 3-5 sublingual 400-mcg tablets q5 minutes might be reasonable. (Note that the bioavailability of sublingual nitroglycerine is only ~40%.)
- Loading IV dose:
- Start with an initial loading dose of IV nitroglycerine of ~1,000-2,000 micrograms.(29887195, 31327485) This may be provided in one of two ways:
- (a) Pushing a bolus of 1,000-2,000 mcg nitroglycerine over ~2 minutes.
- (b) Nitroglycerine infusion at 400-800 mcg/min for 2.5 minutes.
- Both approaches are equivalent, with the choice depending on logistics.
- The main risk of nitroglycerine boluses is hypotension. However, this is unlikely if the diagnosis of SCAPE is secure (since these patients are profoundly vasoconstricted). Several studies have found nitroglycerine boluses to be safe in the context of SCAPE. Occasional patients who have SCAPE along with underlying hypovolemia may develop hypotension that usually responds to observation or administration of small volumes of crystalloid – since the nitroglycerine levels will naturally fall within minutes.(34215472)
- IV nitroglycerine boluses have been shown to be safe, even when administered by paramedics in the field.(33023684, 31900011) Consequently, resuscitationists working within the critical care arena should feel quite comfortable with this as well.
- Start with an initial loading dose of IV nitroglycerine of ~1,000-2,000 micrograms.(29887195, 31327485) This may be provided in one of two ways:
- Maintenance infusion:
- The nitroglycerine infusion may be initiated at a rate of ~100-300 mcg/min (depending on the baseline blood pressure and illness severity).(34215472) A high dose of nitroglycerine is required to achieve arterial vasodilation, possibly at least ~150 mcg/min.(14715359) Based on the vicious-spiral physiology of SCAPE, it's generally better to start at a high dose, control the blood pressure promptly, and then back down.
- If blood pressure isn't controlled promptly, up-titrate the nitroglycerine aggressively. Very high doses (e.g., 800 mcg/min) may be required for limited periods of time, to break the cycle of progressive hypertension.(32278569)
- Wean off nitroglycerine as SCAPE resolves:
- Generally the SCAPE will start resolving rapidly (within minutes to a couple of hours), causing the blood pressure to decrease. As quickly as the storm began, it quietly abates.
- Nitroglycerine can usually be titrated off rapidly as SCAPE resolves. In some cases, ongoing hypertension control may require the addition of an oral vasodilator (e.g., ACE inhibitor) – but in many cases this isn't required.
- 💡 Watch the blood pressure very carefully and down-titrate the nitroglycerine infusion accordingly, to avoid hypotension.
indications for ACEi/ARB
- Heart failure:
- Patients with systolic heart failure (HFrEF).
- Patients with SCAPE. Chronic use of an afterload-reducing medication might reduce the likelihood of recurrent SCAPE episodes.
- Status post MI:
- Diabetic nephropathy.
- Scleroderma renal crisis (front line therapy).
contraindications & drawbacks
- Contraindications:
- Hyperkalemia.
- Tenuous renal function (e.g., recent acute kidney injury; renal artery stenosis).
- History of bradykinin-mediated angioedema (especially a contraindication to ACEi).
- Pregnancy or women planning pregnancy. (37345492)
- Bilateral renal artery stenosis, or renal artery stenosis in solitary functional kidney. (37345492)
- Drawbacks:
- ⚠️ ACEi/ARB should generally be avoided among potentially unstable inpatients, since they have a tendency to promote renal failure if any hemodynamic instability develops (but this isn't a concern among patients with end-stage renal disease on hemodialysis).
selection of agent
- Captopril may be useful for oral dose titration (due to rapid action and short duration).
- HFrEF: valsartan may be preferable to facilitate eventual transition to valsartan/sacubitril.
captopril 💊
- Captopril has a fast onset and short duration of action (which allows for facile oral titration). Small captopril doses can be initiated cautiously and up-titrated as tolerated. Once the patient has been stabilized on captopril, this may eventually be transitioned to an equivalent dose of lisinopril using a 5:1 conversion (the total daily dose of captopril divided by five will approximate an equivalent lisinopril dose).(8773158) 🌊 Lisinopril is preferred for chronic therapy, since it can be given once daily.
- Pharmacology:
- Onset in 15-30 minutes (food reduces bioavailability by ~25%). (25719531)
- Half-life ~ 2 hours.
- Duration ~6 hours.
- Renal clearance.
- Acute hypertension: Start at 12.5-25 mg PO, may repeat dose in one hour if insufficient effect.
- Hypertension: Start at 25 mg q8hr-q12hr, may increase up to 150 mg po q8hr (450 mg/day max).
- Heart failure:
- Start 6.25-12.5 mg PO q8.
- Target up-titration to 50 mg q8hr if tolerated.
- Post-MI LV dysfunction: Start 6.25 mg PO, then 12.5 q8hr, target up-titration to 50 mg q8hr if tolerated.
lisinopril 💊
- Pharmacology:
- Half-life 12 hours.
- Renal clearance.
- If transitioning from captopril to lisinopril: The total daily captopril dose divided by five may approximate a roughly equivalent lisinopril dose. When in doubt, round down and begin with a more conservative lisinopril dose.(8773158) 🌊
- Hypertension: initial dose is often 10 mg if not taking a diuretic, with a usual dosing range of 20-40 mg daily.
- Heart failure: 5 mg po daily, or 2.5 mg if sodium <130 mEq/L. Gradual up-titration.
- Post-MI LV dysfunction: initial dose is often 5 mg, with gradual up-titration as tolerated.
PO enalapril 💊
- Pharmacology:
- Half-life 11 hours.
- Renal clearance.
- Hypertension: Start 2.5-5 mg po daily, maintenance 10-40 mg/day either daily or divided BID. (25719531)
- Heart failure:
- Start 2.5 mg q12.
- May titrate up to 10 mg q12.
IV enalaprilat 💊
- Pharmacology:
- Half-life of 1-2 hours.
- Renal clearance.
- Hypertension: 1.25 mg q6hr (with dose ranging up to 5 mg IV q6).
- Heart failure: 1.25-5 mg IV q6hr.
losartan 💊
- Pharmacology:
- Hypertension: start 50 mg/day, or 25 mg/day among patients with volume depletion or on diuretics. Titrate up to a maximal dose of 100 mg/day.
- Heart failure: start at 25-50 mg daily; may up-titrate to 50-100 mg daily.
valsartan 💊
- Pharmacology:
- Peak plasma time: 2-4 hours.
- 25% bioavailable; food markedly decreases absorption (~50%).
- Half-life of 9-24 hours.
- Clearance is mostly hepatic (83%), with renal clearance of 13%. (25719531)
- Hypertension:
- Start at 80-160 mg QD.
- Dose range 80-320 mg QD.
- Heart failure:
- Start 20-40 mg PO BID.
- May titrate as tolerated to 80-160 mg BID.
- Consider simultaneous reduction in diuretic dosing.
- Post-MI: Start 20 mg BID, may increase to 40 mg PO BID within a week, with eventual up-titration to target 160 mg BID (if tolerated). (14610160) The VALIANT trial found that valsartan was non-inferior to captopril in patients with recent MI plus either heart failure or ejection fraction <40%. (14610160)
indications & basics
- Nitroprusside is a balanced arterial, venous, and pulmonary vasodilator with a short half-life (<2 minutes). This makes nitroprusside potentially valuable for fine titration of afterload.
- Prolonged use of high-dose nitroprusside may lead to the accumulation of cyanide or sodium thiocyanate.
- For hypertensive emergencies, higher doses of nitroprusside may be needed – so toxicity becomes a substantial issue. Generally, nitroprusside is not a preferred agent for treating hypertensive emergencies. One meta-analysis found that nitroprusside was associated with a higher mortality rate as compared with clevidipine. (18806012)
- For heart failure, lower doses of nitroprusside are generally sufficient, so toxicity is less problematic.
contraindications
- Stronger contraindications:
- Severe hepatic dysfunction (increases risk of cyanide toxicity).
- Severe renal dysfunction (increases risk of sodium thiocyanate toxicity).
- Severe, refractory hypoxemia (nitroprusside may cause ventilation/perfusion mismatch).
- Congenital (Leber’s) optic atrophy, tobacco amblyopia, or untreated B12 deficiency – these patients may have difficulty metabolizing cyanide.
- Relative contraindications:
- Recent use of phosphodiesterase inhibitors (e.g., sildenafil) – This may increase the hypotensive effects.
- Intracranial pressure elevation:
- Nitroprusside may cause cerebral arterial vasodilation, potentially increasing intracranial pressure. However, it will also decrease the BP.
- Nitroprusside isn't a preferred agent for patients with hypertension and prominent neurological manifestations (e.g., PRES, preeclampsia).
- Alternatives to nitroprusside:
- For control of hypertension: clevidipine or nicardipine infusion.
- For balanced preload and afterload reduction in congestive heart failure:
- [i] Prazosin monotherapy.
- [ii] Hydralazine/isosorbide dinitrate.
- [iii] ACEi/ARB (e.g., oral captopril titration).
- (Further discussion of afterload reduction options here: 📖)
pharmacology
metabolism of nitroprusside (simplified version)
- Nitroprusside rapidly decomposes within the blood into cyanide.
- Cyanide is converted into sodium thiocyanate by the liver.
- The kidneys excrete sodium thiocyanate.
cyanide intoxication 2/2 nitroprusside
- Risk factors:
- Hepatic dysfunction.
- Most often occurs when >5 mcg/kg/min is utilized, but it can happen in some patients on 2 mcg/kg/min for prolonged periods.
- Clinical manifestations may include:
- Neurologic dysfunction (anxiety, restlessness, confusion, headache, eventually stupor and coma).
- Dyspnea, tachycardia, hypertension, diaphoresis, nausea/vomiting.
- Diagnosis:
- Lactic acidosis is a late feature that cannot be used to exclude early toxicity.
- Treatment:
- Consult with poison control.
- May use high-dose hydroxocobalamin.
thiocyanate intoxication 2/2 nitroprusside
- Risk factors:
- Renal dysfunction.
- Prolonged infusion for >24-48 hours (usually, thiocyanate has a half-life of 3-4 days). (18158484)
- Clinical manifestations may include:
- Neurologic dysfunction (altered mental status, tinnitus, paresthesias, headache, seizures, hyperreflexia).
- Anorexia, nausea, fatigue.
- Dyspnea.
- Diagnosis: Elevated thiocyanate levels are diagnostic (if available).
- Treatment: May require dialysis.
other side-effects:
- Thrombocytopenia.
- B12 deficiency.
dosing
- Nitroprusside is very short-acting, making it easily titratable:
- The peak effect occurs within two minutes.
- If discontinued, the effect disappears within a few minutes.
- Dosing: 0-2 ug/kg/min
- Start at 0.25 ug/kg/min infusion. (Brown 2023)
- Up-titrate in increments of 0.25-0.5 ug/kg/min every ~5-10 minutes (depending on the intensity of cardiac monitoring).
- In heart failure, most patients experience a beneficial response at 1-2 ug/kg/min.
- The maximal rate is ~2 ug/kg/min. At higher doses, there is an increasing risk of cyanide or thiocyanate accumulation. (19723460; 25425768, 35944767)
- ⚠️ Avoid prolonged use (>>48 hours) at higher doses to limit toxicity. The duration of safe use will depend on the dose and kidney/liver function. Prompt efforts should be made to transition to another therapy (e.g., hydralazine plus isosorbide dinitrate, ACE inhibitors, or temporary use of nitroprusside to facilitate diuresis).
- Tachyphylaxis often develops within 24-48 hours.
- Monitoring of cyanide and/or thiocyanate levels should be considered if these tests are available. (25425768)
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To keep this page small and fast, questions & discussion about this post can be found on another page here.
- #1 most common mistake = overdiagnosis of hypertensive emergency among patients with scary high Bp but no target organ damage. This isn't a hypertensive emergency, please don't call the ICU for this. Thanks in advance.
- #2 most common mistake = treating hypertensive emergency too aggressively and dropping the Bp too much and too fast.
- #3 most common mistake = trying to transition from an antihypertensive infusion to an oral agent that takes a long time to have any effect on blood pressure (e.g. amlodipine). This causes patients to be stuck in the ICU on an infusion forever. It's also unpredictable when these drugs take effect, so there is a risk of dose-stacking (i.e. you keep up-titrating oral agents and eventually they all kick in simultaneously, causing hypotension).
- Generally avoid IV hydralazine; this has erratic effects and sometimes bottoms out the blood pressure.
- Don't use IV metoprolol for blood pressure control. Metoprolol isn't very effective for control of blood pressure, but it will slow down the heart rate. That actually makes matters worse, because then you can't use labetalol (since the patient is already bradycardic).
Guide to emoji hyperlinks 
= Link to online calculator.
= Link to Medscape monograph about a drug.
= Link to IBCC section about a drug.
= Link to IBCC section covering that topic.
= Link to FOAMed site with related information.- 📄 = Link to open-access journal article.
= Link to supplemental media.
References
- 18158484 Elkayam U, Janmohamed M, Habib M, Hatamizadeh P. Vasodilators in the management of acute heart failure. Crit Care Med. 2008 Jan;36(1 Suppl):S95-105. doi: 10.1097/01.CCM.0000297161.41559.93 [PubMed]
- 18806012 Aronson S, Dyke CM, Stierer KA, Levy JH, Cheung AT, Lumb PD, Kereiakes DJ, Newman MF. The ECLIPSE trials: comparative studies of clevidipine to nitroglycerin, sodium nitroprusside, and nicardipine for acute hypertension treatment in cardiac surgery patients. Anesth Analg. 2008 Oct;107(4):1110-21. doi: 10.1213/ane.0b013e31818240db [PubMed]
- 19261367 Lim SH, Anantharaman V, Teo WS, Chan YH. Slow infusion of calcium channel blockers compared with intravenous adenosine in the emergency treatment of supraventricular tachycardia. Resuscitation. 2009 May;80(5):523-8. doi: 10.1016/j.resuscitation.2009.01.017 [PubMed]
- 19723460 Opasich C, Cioffi G, Gualco A. Nitroprusside in decompensated heart failure: what should a clinician really know? Curr Heart Fail Rep. 2009 Sep;6(3):182-90. doi: 10.1007/s11897-009-0026-4 [PubMed]
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