Hello everyone, my name is Elizabeth Webb. I am the Clinical Pharmacist Coordinator at the Shepherd Center, which is a rehabilitation hospital for brain and spinal cord injuries located in Atlanta, Georgia. Today, we will be discussing the management of hypertensive crisis. I have nothing to disclose. The objectives for this presentation are to define hypertensive urgency and emergency, identify treatment goals for hypertensive emergencies, including stroke and intracranial hemorrhage, and to list pharmacological agents that are used to manage hypertensive crisis. Here is a list of abbreviations that will be used throughout my presentation. So first, a quick refresh on hypertension. The definition of hypertension per the most recent guidelines in 2018 is a systolic blood pressure of less than 120 and a diastolic blood pressure of less than 80. Elevated blood pressure would be systolic 120 to 129 and diastolic of less than 80. Hypertension is divided into two stages, with stage 1 being systolic 130 to 139 or diastolic 80 to 89, and stage 2 is systolic blood pressure greater than or equal to 140 or diastolic blood pressure greater than or equal to 90. The diagnosis of hypertension is based on two blood pressure readings on two separate occasions. If the systolic and diastolic blood pressure fall into two categories, we use the higher blood pressure category. Once diagnosis of hypertension is made, target blood pressure goal is less than 130 over 80, regardless of any compelling indication. For stage 1 hypertension and an ASCVD risk of greater than 10%, it is recommended to initiate treatment with a single agent along with lifestyle modifications. For stage 2 hypertension, it is recommended to start two agents from two different classes, as well as lifestyle modifications. Here are our pharmacotherapy options for hypertension. Our first-line agents would be calcium channel blockers, including dihydropurities, ACE inhibitors, and ARBs, and the other options are listed below. Pharmacological therapy can provide a 50% relative risk reduction in heart failure, 30 to 40% relative risk reduction in stroke, and a 20 to 25% relative risk reduction in MI. Most patients will need two drugs. A combination of an ACE inhibitor and a calcium channel blocker may provide superior protection against cardiovascular events than compared with an ACE and a thiazide. We will talk more about these agents when we discuss transitionings from IV to oral medications. So, hypersensitive crisis. Hypersensitive crisis is defined as acute and severe elevations in blood pressure that can be associated with target organ damage. Hypersensitive urgency is severe elevation in blood pressure with no target organ damage. This can be managed outpatient with oral medication. Hypersensitive emergency would be a systolic greater than or equal to 180 or a diastolic greater than or equal to 120 with evidence of new or worsening target organ damage. This requires management in the ICU and IV medication is preferred. Of hypersensitive crisis, a quarter are hypersensitive emergency and three-quarters will be classified as urgency. 80% of the U.S. population has hypertension, and of these, 1 to 2% will experience a hypersensitive crisis in their lifetime. The rise in blood pressure is more important than actual blood pressure numbers. Risk factors to experience one of these two situations are being female, obesity, having a past medical history of hypertension, or coronary artery disease, a history of mental illness, a history of non-pharmacy, meaning taking multiple anti-hypersensitive medications, or a history of non-adherence, non-compliance with your blood pressure regimen. Possible causes of either of these situations besides being non-compliant with your medications would be acute intoxication, including cocaine, amphetamines, or stimulants, withdrawal syndromes from an agent like Clonidine or beta blockers, pregnancy, pheochromocytoma, spinal cord injury, or lupus. Some areas where we might see target organ damage would be neurological, meaning intracerebral hemorrhage or subarachnoid hemorrhage, stroke or encephalopathy, cardiovascular, we could see pulmonary edema, MI, or unstable angina, as well as acute congestive heart failure. We could see acute kidney injury or acute kidney failure. We could see Holtz syndrome, which is hemolysis, elevated liver enzymes, and low platelet counts. We could also see retinal hemorrhage, the clemsia, and as well as aortic dissection. The most common examples of target organ damage are stroke, pulmonary edema, encephalopathy, and acute congestive heart failure. The treatment goals for hypertensive urgency, which can be managed in an outpatient setting and do not require admission to the ICU, would be to restart or titrating up their antihypertensive medication. As we discussed, this is often due to medication noncompliance. The goal is gradual blood pressure reduction over 28 to 48 hours. Studies have shown that there is no benefit to a rapid, aggressive correction. This is especially important in patients with chronic hypertension, as their bodies are used to functioning at an elevated blood pressure, and this blood pressure is needed to ensure adequate organ perfusion. Treatment goals for hypertensive emergency. Continuous infusion is preferred for the IV route, as well as, like we discussed, an ICU admission. The continuous infusion route is preferred over short-acting titratable agents due to disturbances with tissue perfusion and to prevent further target organ damage. Oral lonely doses can often lead to delayed hypertension. The goal in the first hour is to reduce mean arterial pressure by 25%. In hours 2 to 6, the goal is to reduce blood pressure to 160 over 100 to 110. For hours 6 to 24, the goal is to maintain blood pressure at this 160 to over 100 to 110. After a total of 4 to 48 hours, it is reasonable to transition to oral treatment based on the most recent hypertensive guidelines. Reductions in blood pressure by more than 25% have been associated with cerebral ischemia. Neurological changes developed during the initial 25% reduction in the first hour. Therapy should be discontinued. Excessive reduction can also cause renal endocrine disorders. For certain compelling conditions that require rapid blood pressure lowering, for acute aortic dissection, it is recommended to lower systolic blood pressure to less than 120 within the first 20 minutes. Other indications, such as preeclampsia, are not recommended. For acute aortic dissection, it is recommended to lower systolic blood pressure to less than 120 within the first 20 minutes. Other indications, such as preeclampsia, eclampsia, and pheochromocytoma, guidelines recommend lowering systolic blood pressure to less than 140 in the first hour. For acute ischemic stroke, blood pressure must be lowered to less than 185 or over 110 to receive TPA. We will discuss stroke and intracerebral hemorrhage in more detail in the next few slides, in a few more slides. So, how do we select a drug? Things we must consider are degree of target organ damage, presence of comorbidities, including congestive heart failure, renal failure, and pregnancy. We want to select a drug with a quick onset of action and a short duration. We also need to consider the rate of target organ damage. And if there is a compelling indication that we mentioned a few slides ago that will require blood pressure to be lowered more rapidly. We also need to consider the mechanism of action of the drug, as well as the pharmacokinetics, including onset and duration. What are our choices? So, for high blood pressure, we want to select a drug with a quick onset of action and a short duration. What are our choices? So, for hypersensitive emergency, we can use calcium channel blockers, including nicarbidipine and clavidipine, basal dilulators, nitroglycerin, sodium nitroprusside, and hydralazine. Oxygen-derivative antagonists, esmolol, duvetolol, and clitolamine, a dopamine receptor antagonist, venodopam, as well as the only ACE inhibitor that's available, IV, and naleprolat. No evidence from randomized controlled trials that shows medications reduce mortality and morbidity in hypersensitive emergencies. And there's no evidence to show which first-line agents we should be using and which agents show more benefit. There have been two smaller trials that have shown that nicarbidipine may be better than clavidolol in achieving short-term blood pressure goals, and this was seen in the CLU trial, which compared IV nicarbidipine with clavidolol in the emergency department. So, our first class of medications we're going to talk about is the calcium channel blockers. These are dihydropyridine-only calcium channel blockers. These agents are vasodilators and have little to no effect on conduction or contractility. They're usually well-tolerated with minimum adverse side effects. They work by inhibiting calcium from entering slow calcium channels in vascular smooth muscle and myocardium during depolarization, causing coronary vascular smooth muscle relaxation and vasodilation. Therefore, they are potent vasodilators. Nicarbidipine is contraindicated in advanced aortic stenosis, and you may want to avoid in patients with heart failure. There are no dosage adjustments required with renal and patic impairment, but it is recommended to titrate the dose slowly. It is available in an oral formulation, which would allow for easier conversion. Clavidipine is available in IV formulation only and is formulated as a 20% lipid emulsion, which brings about being contraindicated in lipid metabolism deficiencies such as pancreatitis and lipoid nephrosis. There is also a need to monitor for hypertriglyceridemia, as this puts you at risk for pancreatitis. It is also contraindicated with soy or egg allergies. Vasodilators we have sodium nitroprestide and nitroglycerin. Nitroprestide acts directly on venous and arterial smooth muscle to cause peripheral vasodilation and decrease peripheral resistance, increase cardiac output, and decrease afterload. Prolonged use can lead to cyanide toxicity, which can result in irreversible neurological damage and cardiac arrest. You can use thiosulfate with infusion rates greater than or equal to 4 to 10 micrograms per kilogram per minute or durations greater than 30 minutes to prevent this cyanide toxicity. Patients can also develop tachyphylaxis to this drug and you want to use lower doses in geriatric patients. Case reports have also shown an increase in interstitial pressure with nitroprestide use. Nitroglycerin's mechanism of action is similar to nitroprestide with more prominent effects on veins. It reduces cardiac oxygen demand by decreasing preload and can improve coronary blood flow to ischemic regions by vasodilation of coronary arteries. Limitations of use include inconsistent and transient blood pressure response, reflux tachycardia, and it can reduce cardiac output. It should only be used in acute coronary syndrome or acute pulmonary edemia. Tachyphylaxis can also develop with this drug, which requires frequent dose titrations and puts patients at risk for potential adverse events such as flushing, headache, erythema, and nausea and vomiting. The next vasodilator is hydralazine. Hydralazine causes direct vasodilation of arterioles with little effect on veins, leading to decreased systemic resistance. The best mechanism of hydralazine is unknown, but it is thought to cause inhibition of release of calcium from the sarcoplasmic reticulum and inhibition of myosin phosphorylation. It is not an ideal agent due to its thermokinetic profile with a delayed onset and longer duration. However, it can be given IM and is available in an oral formulation. It is not given by continuous infusion, which is recommended by the guidelines. Our next class of drugs we're going to talk about are beta blockers. Beta blockers antagonize beta receptors and produce decreases in heart rate, contractility, and AV conduction. Esmolol, which is a beta-1 selective with beta-1 receptors, are found only in the heart. Beta-1 has mixed activity with alpha and non-beta-1 selective antagonism. Meaning it blocks both alpha receptors and beta receptors. Beta blockers should not be used with bradycardia or decompensated heart failure. They are also contraindicated with reactive airway disease, COPD, and second- or third-degree heart block. Lobetalol is another agent that is available in an oral formulation, looking ahead to transitioning to oral therapy. Our next few drugs kind of fall under a miscellaneous category. Phentolamine is a non-selective alpha-antagonist and competitively prevents norepinephrine and epi from binding in alpha-adrenergic receptors and therefore can reduce hypertension. It should not be used in cases that are caused by excessive catecholamines, such as pheochromocytoma, cocaine, or methamphetamine overdose. It is only given by ibuprofen. Phenobopam is a dopamine-1 receptor antagonist, which decreases peripheral resistance by increasing renal blood flow, diuresis, and naturesis. Majority of effects at a particular infusion rate is seen within 15 minutes of that infusion rate. It is contraindicated with sulfite allergy, increased ocular pressure, or inflammation. Inalaprolat is an ACE inhibitor, which causes competitive inhibition of angiotensin-converting enzyme, which prevents conversion of angiotensin-1 to angiotensin-2, which is a potent vasoconstrictor. It is useful if the hypertension is caused by high plasma renin activity. It has a slow onset of action in plasma renin activity. However, there are a wide variety of ACE inhibitors available as oral agents. It is useful if the hypertension is caused by high plasma renin activity. It has a slow onset of action in approximately 15 minutes, unpredictable blood pressure response, and a long duration of action. Slow onset and long duration of action are not ideal for treatment of hypertensive emergency. Here we are looking at drug selection based on comorbidity. For aortic dissection, you need rapid blood pressure lowering, so beta blockers are preferred. For pulmonary edema, beta blockers are contraindicated. For acute coronary syndrome, you need caution with using nitrate if the patient has used a PB5 inhibitor, which can cause profound hypertension. Beta blockers would also be contraindicated if there is pulmonary edema present with left ventricular dysfunction, bradycardia, hypotension, poor peripheral perfusion, second or third degree heart block, or reactive airway disease. Acute renal failure, caution with using ACE inhibitors, preeclampsia or eclampsia. The drugs of choice are hydralazine, levadolol, and nicarbapine. You need to avoid ACE inhibitors and nitroprostate. Periop hypertension, which is defined as blood pressure greater than or equal to 160 over 90 or systolic increase greater than 25% of pre-op value that lasts for 15 minutes or more. It occurs most often during anesthesia induction and airway manipulation. For acute sympathetic discharge or catecholamine excess, our drugs of choice would be the calcium channel blockers or fentolamine. OK, we're going to focus on intracerebral hemorrhage. Initiating treatment within two hours of the hemorrhage and reaching your target blood pressure within one hour can limit hematoma expansion and improve functional outcomes. If your blood pressure is greater than 220 or systolic, continuous IV infusion is preferred. For mild to moderate ICH with a systolic blood pressure of 150 to 220, lowering systolic blood pressure to a target of less than 140 is considered safe. For a large ICH that requires surgical decompression, safety and efficacy of intense blood pressure lowering is not well established. Careful titration of medication is needed to ensure less systolic blood pressure variability and to avoid large peaks has been shown to be beneficial. For intracerebral hemorrhage, intensive blood pressure reduction has been linked with greater functional recovery at three months when compared with lowering blood pressure based on guidelines. However, lowering systolic blood pressure greater to less than 140 has not been shown to reduce death or disability. The antihypertensive treatment for acute cerebral hemorrhage, hemorrhage trial, or APAC-2, compared with blood pressure goals of 110 to 130 and 140 to 149 and showed that systolic blood pressure less than 140 did not lead to lower death or disability rate. Patients received ivenocardipine within four and a half hours after symptom onset and primary outcome was death or disability. The study was terminated early. There was no difference in either group in the primary outcome. The rate of renal events is higher in the intensive group with the P value being .002. In the interop trial, patients were assigned to intensive blood pressure lowering or standard treatment group and medication was assigned based on, medication was chosen by the physician. Both IV and P medication were used. The primary outcome was the same as the APAC-2 trials, death or disability, and there was no difference seen between the two. So, an ordinal analysis of modified Rankin scores showed an improvement in functional outcomes within intensive lowering group. The evidence is not clear, although both trials demonstrated that systolic to a value of less than 140 does not improve mortality or disability. It is important to note that interop excluded patients with systolic greater than 220, which is a limitation of the study, also allowing physicians to choose their own medication would prevent standardization of this trial. ICH. For medications, there's a lack of evidence to help us determine which agent to use to lower blood pressure. Key characteristics to consider are onset of action and duration. Ideally, we need a drug with a rapid onset and short duration of action. Studies have shown that limiting blood pressure availability has led to improved outcomes, so we also want a drug that is easily titratable. There's no evidence to determine if IV boluses or IV continuous infusion should be used. However, a continuous infusion could allow easy titration and less variability in drug levels. For acute ischemic stroke, in order for patients to receive TPA, blood pressure must be lowered to less than 185 over 110. Some studies have suggested the risk of hemorrhage after receiving TPA is higher in patients with elevated blood pressure, which is the reason why blood pressure must be lowered. The 185 over 110 is the number that was used in these randomized control trials. The blood pressure must be maintained at 180 over 105 for at least 24 hours after receiving TPA. These are the drugs that are recommended to be given prior to receiving TPA. The target blood pressure, as I said, is less than 185 over 110. Well, beta-lol onset and duration can vary. However, it is available in single-dose and multi-dose vials, which allows for IV boluses and clovidipine has a shorter onset and duration. Both nicotinamide and clovidipine are only available as IV infusions. Something else to consider about clovidipine is it must be used within 12 hours of puncturing the vials, so tubing and vials must be departed after 12 hours. To maintain blood pressure less than 180 over 105, we would use the same agents and dosing except for labetalol. A continuous infusion can be used of 2 to 8 microgastroen and after a 10 milligram IV bolus can be started. If blood pressure is still not at your goal, we can consider using sodium nitroprusside. For patients who are ineligible for TPA and their blood pressure is greater than 210 over 120, it's recommended to lower blood pressure by 15% in the first 24 hours after stroke. For patients that were ineligible and their blood pressure is less than 220 over 120, it's recommended to start or resume hypertensive medications within the first 48 to 72 hours after stroke. And this would only be patients that do not have a condition that requires urgent blood pressure lowering like preeclampsia. Too rapid of a drop in blood pressure could lead to decreased cerebral perfusion and hyperperfusion of organs like kidneys. We're going to use the same medications previously mentioned, labetalol, nicartepine, or clavidipine. Multiple randomized controlled trials and meta-analysis have shown that starting or resuming hypertensive medications is safe but does not improve mortality or functional outcomes. Things to consider when we're transitioning to the oral route. Use current guidelines as a basis for medication selection. And something else to consider is, is the current IV medication available in an oral formulation? We would also want to consider the patient's prior hypertensive medications, any comorbidities that they might have. Other factors that we would consider when switching to oral medications is, where is this patient located? Are they in the ICU? Are they on the floor? Are they able to swallow medications? Do they have feeding tube access? Are there any cognitive issues that should be considered? And also, are they on any sedating medications? Are they having any issues with vomiting? Are they on a diet? Are vital signs stable? Other diagnoses such as infection and volume status must be considered as well as patient's ethnicity, which we'll get to in a second, and any history of drug allergies or intolerances. First-line agents for blood pressure are ACEs or ARBs, calcium channel blockers. We could also consider thiazide diuretics in African-Americans. ACEs and ARBs should not be considered as first-line in African-American patients. They are shown to have reduced efficacy and limited outcomes. African-American patients have been found to have lower plasma renin levels, which is the site of activity for both ACEs and ARBs. Chlorothaladone has greater blood pressure-lowering activity compared to HCTZ. However, HCTZ is most often used in the thiazide class. The blood pressure goal, again, is less than 130 over 80. So for comorbidities and drug selection for heart failure, PDMP would include ACEs, ARBs, RNAs, beta blockers, and diuretics. We could also consider aldosterone antagonists. For chronic kidney disease, ACEs and ARBs should be considered, especially if they're albinuria, acute ischemic stroke. We would want to resume medications within a few days to reduce the risk of another stroke. Diabetes, we would consider ACEs and ARBs for renal protection, especially in the presence of albinuria. It's such a hard word to say. Aortic disease, beta blockers are preferred agents, and pregnancy, hydralazine, and labetalol are preferred agents. So from a pharmacist's perspective, hydralazine and labetalol are both available as oral agents. Nacardopine is also available in an oral formulation, and that could also be converted to once-daily amlodipine or nifedipine, which is available in its XL or multi-TID dosing. Clavidipine is not available as an oral agent, but can also be switched to amlodipine or nifedipine. Enaloprilat can be switched to oral enalopril or another ACE inhibitor that's more commonly seen, such as lisinopril. Esmolol is not available as an oral agent, but could be transitioned to another beta blocker, such as carvedilol. Nitroglycerin or sodium nitroprusside are not available in an oral formulation, but another option could be isosorbide mononitrate or isosorbide dinitrate. So, since I work at Shepherd Center, I wanted to bring up two unique situations that we see that cause high blood pressure. The first is autonomic dysreflexia, which is a common complication of spinal cord injury. It is seen in individuals with injuries at level T6 or higher. The higher the risk, the level of spinal cord injury, the greater the risk. Up to 90% of SCI patients can experience autonomic dysreflexia, and patients that have an incomplete injury are more likely to experience this than those with an incomplete injury. It is a sudden and exaggerated increase in blood pressure in response to stimuli below the level of injury. The stimuli can be a wide variety of issues, like bowel or bladder distention, like a cleft foley, or something as simple as sitting on something in their wheelchair or button or zipper out of place on their clothing. Dysregulation of the nervous system leads to an uncoordinated response to the stimuli, which causes a dramatic increase in blood pressure, which can be life-threatening if not treated. There is a sympathetic response that is exaggerated due to a lack of descending, compensatory parasympathetic activity. Symptoms include headache, bradycardia, flushing, sweating, and cold or clammy skin. Headache is often the most common symptom and can be described as sudden, severe, and throbbing. It is usually bilateral. The blood pressure increase is defined as greater than 25 points above the patient's baseline, and a significant episode is systolic greater than 150 or greater than 40 points above their baseline. Treatment includes recognition and correction of the noxious stimuli, as well as our first line agent would be nitro paste, one to two inches of nitro paste directly above the level of injury, and this can be wiped off after the episode has resolved. Another option would be hydralazine capsule that can be punctured or bitten in order to release the contents quickly, sublingual capillary quantity, and hydralazine IV oral beta-law. Those also can both be given orally. Our protocol at Shepherd specifically is based off of a blood pressure scale. After the first dose of nitroglycerin, you can give a second dose of nitroglycerin, and then the third option would be to give hydralazine PO. The other situation we want to talk about is paroxysmal sympathetic hyperactivity, or commonly called to as neurostorming. This commonly occurs after traumatic brain injury, and it is episodes of excessive sympathetic activity that cause elevated blood pressure, heart rate, temperature, and respiratory rate that can often lead to posturing. For treatment, we want to manage symptoms as well as try to prevent future situations from occurring. This is commonly referred to as abortive and preventive treatment. Our first-line agents are opioids, benzos, gabapentin, beta-blockers, and alpha-agonists. Opioids can be abortive, such as morphine, or preventative along the lines of a fentanyl patch. That's pretty common practice in severe and persistent cases of storming. Benzos are also used as abortive treatment, ideally IV formulations, and agents with a short half-life, such as lorazepam. The most common beta-blocker used is propranolol due to its lipophilic properties that allow it to cross the blood-brain barrier. Alpha-agonists, such as clonidine, can also be used. Second-line agents include rimocryptine, which is a dopamine agonist. In my experience, this is not used that often. Atypical antipsychotics, such as halodol, purine, can be used. However, these drugs come with a robust list of monitoring parameters and adverse, potential adverse reactions. In refractory cases, continuous infusions of propofol, presidix, and opioids, such as fentanyl or benzodiazepines, like Ativan, can be used. So, in conclusion, hypersensitive treatment goals and drug selection should be based on current guidelines and comorbidities. There's no clear evidence to determine first-line agents. Rapid blood pressure lowering or too low of blood pressure goals are associated with worse outcomes and provide no functional gains. And when transitioning to oral agents, we want to consider evidence-based guidelines as well as patients' comorbidities to direct drug selection. Here are my references, and here is my email address if anyone has any questions. Thank you.

hypertensive crisis

hypertensive urgency

hypertensive emergency

treatment goals

pharmacotherapy options

target organ damage

medication selection