Hi, my name is Elizabeth Webb. I am the clinical coordinator at the Shepherd Center in Atlanta, Georgia, which is a rehab hospital for spinal cord injury and brain injury patients. Today, we're gonna be talking about the management of hypertensive crisis. So our objectives for this lecture are to be able to define hypertensive crisis and talk about medication management strategies and summarize recommendations for blood pressure management during intracerebral hemorrhage and acute ischemic stroke. Here's our table of contents. Here's a cute picture of my dogs. Just to fill that space, we're gonna talk about hypertensive emergency with a focus on intracerebral hemorrhage, acute ischemic stroke, and transitioning to oral therapy, and then also gonna do a brief discussion on autonomic dysreflexia and paroxysmal sympathetic hyperactivity. Here's a list of abbreviations that will be used throughout the presentation. All right, so a brief refresh on hypertensive crisis. So normal blood pressure is less than 120 over 80. Elevated blood pressure would be a systolic from 120 to 129 and diastolic less than 180. And then hypertension, we have two stages. Stage one would be systolic 130 to 139 or diastolic 80 to 89. And stage two, systolic greater than or equal to 140 or diastolic greater than or equal to 90. So diagnosis of hypertension is based on two blood pressure readings on two separate occasions. If systolic and diastolic fall into two different categories, you would use the higher blood pressure category. Once diagnosis is made, our target blood pressure is less than 130 over 80, regardless of any compelling indications. So what are some risk factors for hypertension? Age greater than 50, sex. So until age 64, men are at a higher risk. After age 65, women are at a higher risk. A family history of hypertension, race. African-Americans are at a higher risk for hypertension and African-American females are at a higher risk to develop preeclampsia in pregnancy, which we'll talk about in a few slides, is a type of hypertensive emergency. We all know lifestyle choices, lack of exercise, smoking, excessive alcohol, consumption, unhealthy diet, overweight and obesity, along with chronic kidney disease and sleep apnea. So like I said, once diagnosis is made, our target blood pressure goal is less than 130 over 80 for a type one hypertension and an ASCVD risk of greater than 10%. So ASCVD would be acute coronary syndrome, MI, angina, stroke, any of those types of things. It is recommended to initiate treatment with a single agent along with lifestyle modifications. So for a type two hypertension, which if you all remember is greater than or equal to 140 over 90, it's recommended to start two agents from two different classes and lifestyle modifications. And we're all familiar with lifestyle modifications, weight loss, heart healthy diet, increased physical activity and limiting alcoholics consumption. And interestingly enough, a heart healthy diet has been shown to have the highest impact on reducing systolic blood pressure. So what are our pharmacotherapy options? Our first line agents are our dihydropyridine calcium channel blockers. So amlodipine, nicardipine, nifedipine, nimodipine, which is only used for subarachnoid hemorrhages. You'll probably only see amlodipine and nifedipine in practice. You can also use an ACE or an ARB or a diuretic, which may be especially beneficial in African-American patients. Other options include a beta blocker. These are no longer recommended as first line in the absence of any comorbidities like AFib or Hefref. Here we can also see alpha agonists, aldosterone antagonists and vasodilators. Most patients will require a combination of two drugs, usually an ACE along with a dihydropyridine calcium channel blocker like amlodipine. Calcium channel blockers have been shown to provide superior protection against cardiovascular events when combined with an ACE or a thiazide diuretic. We'll talk more about these when we talk about transitioning from IVs to oral medications. Okay, so what is a hypertensive crisis? We have urgency and emergency. So a hypertensive crisis is defined as acute and severe elevations in blood pressure that can be associated with target organ damage. So an urgency is severe elevation in blood pressure with no target organ damage. And these can usually be managed outpatient with oral medication. And an emergency would be systolic greater than or equal to 180 and or diastolic greater than or equal to 120 with evidence of new or worsening target organ damage. These hypertensive emergencies require ICU management and IV medications. A quarter of all hypertensive crisis are emergency and three quarters are urgency. You find that most urgencies are due to noncompliance with medications. With hypertensive emergency, we're more concerned with the rise in blood pressure more than the actual blood pressure number. Right, so what are some risk factors for hypertensive emergency? We find that being female, obesity, having a history of preexisting hypertension or cardiovascular disease, mental illness, polypharmacy, and just in general non-adherence to their medications. Potential causes for hypertensive emergency, intoxication with amphetamines, cocaine or stimulants. Those can all cause an increase in blood pressure. Withdrawal symptoms, especially from clonidine or beta blockers, pregnancy, preeclampsia and eclampsia, pheochromocytoma, spinal cord injury or traumatic brain injury, and also just simply having a history of hypertension. So we've mentioned target organ damage. So what does target organ damage look like? A whole slew of things. We can see intracerebral hemorrhage, subarachnoid hemorrhage, stroke and encephalopathy. For cardiovascular examples, we can see pulmonary edema, MI or unstable angina, even acute heart failure. We can see acute kidney injury or renal failure. As I mentioned before, we can see pregnancy. In pregnancy, we can see preeclampsia or eclampsia, retinal hemorrhage or papillary edema, as well as help syndrome, aortic aneurysm and dissection. Of these, the most common we're gonna see are stroke, some kind of stroke, whether it's ischemic or hemorrhagic, pulmonary edema, encephalopathy and heart failure. So just wanna touch briefly on hypertensive urgency. These can be managed in an outpatient setting, does not require admission to ICU like hypertensive emergency, simply can be managed by restarting or titrating our hypertension medications as the most common cause is often due to medication non-adherence. The goal is gradual blood pressure reduction over 24 to 48 hours. There's no benefit to rapid aggressive correction. This is especially important in patients with chronic hypertension as their bodies are used to an elevated blood pressure as their normal, and we need to ensure adequate or begin perfusion. All right, so let's talk about hypertensive emergency. Hypertensive emergencies require treatment in an ICU for close monitoring and IV, they require IV medications. We prefer continuous infusions over short acting agents due to disturbances that we can see with tissue perfusion in order to prevent further organ damage, target organ damage. The goal is to, in the first hour, is to reduce systolic blood pressure by 25%. In hours two to six, we wanna maintain blood pressure of 160 over 100 to 110. For hours six to four, six to 24, we wanna maintain this blood pressure. And then 24 to 48 hours, it's reasonable to transition to oral treatment based on the hypertensive guidelines. Reductions by more than 25% have been associated with cerebral ischemia. If you see any type of neurological changes during that initial 25% reduction in the first hour, therapy should be discontinued. Excessive reduction can also cause renal ischemia and coronary ischemia. Aortic, what I was, sorry. There are a few compelling indications that require rapid blood pressure lowering. For the 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. And for acute ischemic stroke, blood pressure must be lowered to less than 185 over 110 to receive TPA. And again, we'll talk more about stroke and ICH in a few slides. So drug selection, we need to consider the rate of target organ damage and does that require any type of treatment? Is there any kind of compelling indication that will require blood pressure to be lowered more rapidly like what we talked about on the previous slide? Are there any kind of comorbidities such as congestive heart failure, renal failure, pregnancy that can dictate drug selection? We need to consider, we want to pick a drug with quick onset of action and a short duration. And we also want to consider a drug's mechanism of action, which we will get to in a couple of slides, as well as the rate of blood pressure decline that is needed. So what are our choices? Calcium channel blockers, vasodilators, we have adrenergic antagonists, doping receptor antagonists, as well as an ACE inhibitor. There's no evidence from randomized controlled trials that show that medications reduce morbidity and mortality in hypertensive crisis. And there's no evidence to show us which agent to choose from, like which agent has more benefit over another. There's been two smaller triangles that show nicartapine may be better than labetalol in achieving blood pressure goals. And this was the CLU trial that compared, I mean, nicartapine with labetalol in the ER department. All right, so you know us pharmacists love our drugs. I'll try to make this as painless as possible for you all. So for calcium channel blockers, we were gonna choose dihydropyridine only. These are potent vasodilators that have little to no effect on conduction or contractility. They're usually well-tolerated with minimal adverse effects. They work by inhibiting calcium from entering slow calcium channels in the vascular smooth muscle and myocardium during depolarization, which causes coronary smooth muscle relaxation and vasodilation. For nicartapine, there's no dosage adjustments recommended with hepatic and renal impairment. It does have a slower onset and longer duration compared to clavitapine. It's contraindicated with advanced aortic stenosis to avoid in patients with heart failure. One plus about nicartapine is that it's available in oral formulation, which would allow for easier conversion down the road. Clavitapine is only available in IV and it's formulated as a 20% fat emulsion. So you need to monitor for hypertriglycidemia. Also increases your risk for pancreatitis. And you also need to avoid with soy or egg allergies. Vasodilators, these are all nitrous oxide dependent. Nitroprusside acts directly on venous and arterial smooth muscles to cause peripheral vasodilation and decrease peripheral resistance, therefore increasing cardiac output and decreasing preload. Prolonged use of sodium nitroprusside can cause cyanide toxicity, which can cause irreversible or neurological damage and cardiac arrest. With infusion rates that are greater or equal to four to 10 micrograms per kilogram per minute or a duration of greater than 30 minutes, it's recommended to administer this along with thiosulfate to prevent cyanide toxicity. You can also develop tachyphylaxis with extended use. It's recommended to use lower dosing in geriatric patients. And case reports have shown an increase in intracranial pressure along with sodium nitroprusside. Nitroglycerin's mechanism is similar to this 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. One of the limitations of this use is inconsistent and transient blood pressure response which reflects tachycardia and it can reduce cardiac output. We want to only use this in acute coronary syndromes or acute pulmonary damage, thinking along the lines of target organ damage. You can develop tachyphylaxis after 20 to 48 hours, which can require frequent dose titrations and increase the risk for potential adverse effects like flushing, headache, erythema. You also need to avoid use in volume-deficited patients. A direct vasodilator, hydralazine. This causes direct vasodilation of arterioles with little effect on veins leading to decreased systemic resistance. The exact mechanism of this is unknown but it's thought to cause inhibition of release of calcium from the sarcoplasmic reticulum and inhibition of myosin phosphorylation. Continuous infusion is preferred for the hypertension guidelines and hydralazine is only given by IV push. So it's not an ideal first agent. Also, it has an unpredictability of response and prolonged duration of action. One thing that hydralazine has going for it, it's available PO. So beta blockers, we're all familiar with these. They antagonize beta receptors and produce decreases in heart rate, contractility, and AV conduction. Esmolol is beta-1 selective, which are only found in the heart. It has a quicker onset and shorter duration of action compared to labetalol. It does require a loading dose though. Labetalol has some alpha blocking potential and it's non-selective, meaning it blocks beta-1 and beta-2. It has a slightly longer onset and longer duration of action compared to Esmolol. It is available in oral formulation, which is a plus. Beta blockers should not be used with radiocardia or decompensated heart failure. And they're also contraindicated with reactive airway disease, COPD, or second or third degree heart block. I'm gonna try to skip through these. Most of fentolamine is really only recommended to be used in emergencies caused by excessive catecholamines like bimochromocytoma, cocaine or methamphetamine overdose or clonidine withdrawal. Fendolipam is really not used that often. It's contraindicated with sulfite allergy, increased intraocular pressure or increased intracranial pressure. Enalaprad is our ACE inhibitor. It's available in IV formulation. These are contraindicated in pregnancy, should not be used in MI or bilateral renal artery stenosis. These are useful if the hypertensive emergency is caused by high plasma renin activity. It has a slow onset of action, unpredictable blood pressure response and a long duration of action. These make it not an ideal treatment of hypertensive emergency. However, there are a lot of ACE inhibitors that are available as oral agents. So looking at drug selection by comorbidity for acute aortic dissection, remember we need rapid lowering of blood pressure to less than 120 within 20 minutes. So our drugs of choice are gonna be the beta blockers. For acute coronary syndrome, we want to avoid using any kind of nitrates if any PD-5 inhibitors have been used because this can cause profound hypertension. And remember, beta blockers are gonna be contraindicated if there's any type of pulmonary edema, any bradycardia, hypertension, heart block or reactive airway disease. For acute renal failure, we want to avoid using ACEs and ARBs, preeclampsia or eclampsia, hydralazine, libidolol and nicotinoprene are all safe to use during pregnancy. We need to avoid ACEs and ARBs and nitroprusside. For perioperative hypertension, this mostly occurs during anesthesia induction and airway manipulation. Our drugs of choice are clavidipine, esmolol and nicardipine and acute sympathetic discharge or catecholamine excess. We're gonna use clavidipine, nicardipine and fentolamine, which we just talked about. So next we want to focus on two instances of hypertensive crisis that I see often in my clinical practice, intracerebral hemorrhage and ischemic stroke. We're gonna focus on IC8 first. Many of these patients present with elevated blood pressure and that is associated with a greater risk of hematoma expansion, deterioration and death. It is important to carefully titrate blood pressure meds to avoid large variabilities in systolic blood pressure. This has been shown to be beneficial in improving functional outcomes. Rapid initiation of treatment and reaching blood pressure goals with one hour can limit expansion and also improve functional outcomes. For mild to moderate ICH and in systolic blood pressure of 150 to 220, guidelines recommended to lower blood pressure to systolic less than 140 and maintain 130 to 150. Lowering to less than 130 has been shown to be potentially harmful and should be avoided. For large ICHs or those requiring surgical intervention like decompression, the safety and efficacy of rapidly lowering blood pressure is not well established. There have been two trials that have looked at lowering blood pressure to less than 140. The ATAC2 trial compared blood pressure goals of 130 to 139 and 140 to 149 and showed that systolic goal of less than 140 did not lead to lower death or disability rates. These patients received IV nicartepine within 4.5 hours after symptom onset and primary outcome was after disability. The study was actually terminated early. The primary outcome was seen in 38.7 in the intensive group and 37.7 in the standard group. The rate of renal adverse effects within seven days was significantly higher in the intensive group with a P-value of 0.002. The INTERACT trial compared intensive blood pressure lowering of less than 140 to standard treatment. The medication was chosen by the physician and they used both IV and PO medications. The primary outcome was the same as the ATAC2 trial, death or disability. There was no difference in primary outcome between the two groups, 52% in the intensive group and 55.6 in the standard treatment group with a P-value of 0.06. Although an ordinal analysis of modified Rankin scores showed an improvement in functional outcomes of the intensive lowering group. So the evidence is not clear. Both trials demonstrated that lowering systolic to less than 140 did not improve mortality or disability. It is important to note that INTERACT2 excluded patients with a systolic greater than 220, which is a limitation. And it also allowed the physicians to choose medications and use both IV and PO, which prevents standardization of this trial. Unfortunately, there is a lack of evidence to help us determine which agent should be used to lower blood pressure after ischemic stroke. 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 leads to improved outcomes. So we also want a drug that is easily titratable. There is no evidence to determine whether we should use IV bolus or continuous infusion. However, a continuous infusion could lead to easy titration and less variability in drug levels. Venous vasodilators could be harmful due to unopposed venodilation and the effect on interest cerebral pressure. So for acute ischemic stroke, our treatment of choice is TPA. And so if patients are eligible for TPA, blood pressure needs to be lowered to less than 185 to 110 prior to administration. So why do we need to lower blood pressure prior to be giving TPA? Observational studies have shown that the risk of hemorrhage after receiving TPA is higher in those with an elevated blood pressure. And this particular blood pressure is what was used in randomized controlled trials, which is why it's used in the guidelines. So after giving TPA, blood pressure must be maintained at 180 over 105 for the first 24 hours after receiving TPA. You need to maintain blood pressure every 15 minutes for the first two hours, then every 30 minutes for the next six hours, and then every hour for the next six minutes. For patients that are not eligible to receive fibroanalytic therapy and are receiving mechanical thrombectomy, it's reasonable to maintain blood pressure less than or equal to 180 over 110. So remember, what agents are we gonna use to try to lower blood pressure? We can use labetalol, nicardipine, and clavidipine. Just a couple of my brief thoughts. Labetalol onset and duration can vary. It is available in single-dose and multi-dose vials, which allows for IV bolus dosing. Clavidipine has a shorter onset and duration. Clavidipine and nicardipine are both only available as IV infusions. Other options we consider are hydralavine and enalaprolat. To maintain blood pressure after TPA administration, we would use the same agents and dosing, except we could give labetalol as a continuous infusion of two to eight milligrams per minute. You could also consider using nitroprusside after giving TPA if your blood pressure is still not at goal. For acute ischemic stroke in patients who are not eligible to receive TPA and have a blood pressure of 220 over 110 and have no comorbid conditions that would require rapid blood pressure lowering, the benefit to starting or resuming hypertensive medications within the first 48 to 72 hours is uncertain. It's considered reasonable to lower blood pressure by 15% in the first 24 hours after a stroke. Dropping blood pressure too low could cause stroke progression by affecting cerebral perfusion and also acute kidney injury by causing renal hypoperfusion. For patients with a blood pressure of less than 220 and 110 who did not receive TPA, multiple trials have shown that starting meds within 48 to 72 hours did not improve functional outcomes or improve mortality. It is worth mentioning, though, that these trials excluded patients with extreme hypertension, so you need to take that with a grain of salt. We would use the same medications here that we previously mentioned, lobetalol, nicartopene, or clovidipine. So transitioning to oral therapy, we would want to use current guidelines as a basis for medication selection and consider if the current IV medication is available in oral form or is there a similar agent. General factors we would consider when switching to oral medications is where is this patient located? Are they in the ICU or have they transitioned to the floor? Is the patient able to swallow? Do they have a feeding tube? We also need to consider cognitive status. Are they on any sedating medications? Has there been any vomiting? Are they on a diet? Are vital signs stable? Other things such as infection, volume status also need to be considered. We also want to consider a patient's race. When thinking about drug selection, it's been shown that African-American patients benefit from calcium channel blockers and diuretics over an ACE or an ARB. And we also choose if patients have any drug allergies or intolerances. And we also need to think about non-adherence in order to prevent reoccurrence or access to medications. For example, would it be better for a patch or once a day versus three times a day administration? So guideline-directed medication therapy. Our first-line agents are ACEs and ARBs, calcium channel blockers, and thiazide diuretics. Like I mentioned, ACEs and ARBs are not considered first-line agents in African-American patients due to limited efficacy, reduced efficacy, and limited outcomes. These African-American patients have been shown to have lower plasmin renin levels, which is the site of activity for both ACEs and ARBs. We want to avoid using calcium channel blockers in patients with decompensated heart failure. Considering using thiazide diuretics in African-American patients, chlorophalidone has the greatest blood pressure-lowering potential compared to HGTZ, which would be preferred due to its longer half-life. And also it's been shown to have the greatest reduction in trials. However, HGTZ is what's used most often in this class. And again, our blood pressure goal is less than 130 over 80. So drug selection and comorbidities. For heart failure, GDMT shows us that we need to use its ACEs, ARBs, and ARNIs, beta blockers, and diuretics. We can also consider aldosterone antagonists. We want to avoid non-dihydropyridine calcium channel blockers in HEF-GREF and HEF-PEF with volume overload. We can also consider diuretics. Chronic kidney disease, ACEs, and ARBs should be considered, especially with albinuria. It's hard to say, greater than 300 to slow progression. And you can try an ARB if a patient is unable to tolerate an ACE. For acute ischemic stroke, it's recommended to resume medication within a few days for secondary prevention. You want to consider using thiazide, ACE, or an ARB, or a combination. For diabetes, consider an ACE or an ARB, especially in the presence of albinuria. For aortic disease, remember beta blockers are preferred agents. And again, with pregnancy, labetalol, methaldopa, and nifedipine are safe to use, and we can also use hydralazine. So for a pharmacist's perspective, just quickly going over each of the agents we mentioned, hydralazine is available as an oral agent. It's not a first-line agent, and we usually reserve this for resistant hypertension. Beta blockers are available in labetalol, specifically available as an oral agent. However, beta blockers are not preferred unless there is a compelling indication, heart failure, half-breath, which in those situations, labetalol is not a preferred agent. Nicartopine can easily be converted into oral dosing, or you can use amlodipine. Calcium channel blockers are considered first-line agents. Clavidipine is only available as an IV, not available as an oral agent. But again, we can switch to amlodipine or nifedipine. Naloprotein can be switched to an oral ACE inhibitor like lisinopril, and ACEs are first-line. Esmolol, the same thing with betalol. Beta blockers are not considered first-line therapy. Nitroglycerin or sodium preside, if these are not available in oral formulation, we can use an oral vavetilator like isosorbide mononitrate or isosorbide dinitrate. But again, these are not first-line agents. All right, I just wanna touch briefly on two hypersensitive emergencies that are unique to the patients we see at Shepherd Center, which again are spinal cord injury and brain injury patients. So first off, autonomic dysreflexia. This is a common complication in spinal cord injury. It is often seen with injuries at level T6 or higher. And again, the higher the level of spinal cord injury, the greater the risk. Up to 90% of spinal cord injury patients experience autonomic dysreflexia, and patients with a complete injury are more likely to experience this than those with incomplete injury. So what is autonomic dysreflexia? It is a sudden and exaggerated increase in blood pressure in response to a stimuli below the level of injury. And the stimuli can be a wide variety of things like bowel or bladder distension, can be a clogged foley, sitting on something in a wheelchair, button or zipper out of place on their clothing, and it can be something very minor. Dysregulation of the nervous system leads to an uncoordinated response to the stimuli, which causes a dramatic increase in blood pressure. This can be life-threatening if not treated. So there's an exaggerated sympathetic response. It is due to a lack of descending compensatory parasympathetic activity. The symptoms that we see are headaches, bradycardia, flushing, sweating, and cold or clammy skin. The headache is often described as sudden, severe, and throbbing, and it's usually bilateral. Blood pressure increase is usually 25 points above the patient's baseline, and a significant episode is systolic greater than 150 or greater than 40 points above their normal. And treatment includes recognition and correction of whatever the stimulus is. Pharmacologic treatment as nitroglycerin placed one to two inches above the level of injury, which needs to be wiped off after the episode has resolved. Other options include a nifedipine 10 milligram capsule that can be bitten to puncture it and release the contents, sublingual captophril or clonidine, IV hydralazine or labetalol if the heart rate, labetalol only if the heart rate is not too low. Our protocol at Shepherd is usually based on the blood pressure response after the first dose of nitroglycerin. You can either give a second dose of nitroglycerin and then give hydralazine oral. Next, we will talk briefly about paroxysmal sympathetic hyperactivity or neurostorming, which can occur after a traumatic brain injury. Storming are episodes of excessive sympathetic activity that causes elevated blood pressure, heart rate, temperature, and respiratory rate. For treatment, we want to try to manage symptoms as well as to prevent future symptoms from occurring. This is commonly referred to as abortive and preventative treatment. So first-line agents include opioids, benzos, gabapentin, beta blockers, and alpha agonists. Opioids can be abortive, such as morphine IV, or preventative, like a fentanyl patch is pretty common, practiced especially in severe, persistent cases of storming. Benzos are primarily abortive treatment, usually IV formulations with a short half-life, such as lorazepam. The most common beta blocker that's 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 brimocryptine, which is a dopamine agonist. In my experience, this drug is not used that often. At Shepherd Center, we also use baclofen quite commonly, that is used to treat rigidity-themed with storming. Atypical antipsychotics, such as halodol, can be used to treat agitation. However, these drugs come with a long list of monitoring parameters and prevent potential adverse reactions. In refractory cases, you can use continuous infusions of propofol, prosthetics, opioids, such as fentanyl, or benzos like Ativan or Versed. All right, so in conclusion, hypertensive emergency treatment goals and drug selection need to be based on current guidelines and comorbidity. There is no clear evidence to determine first-line agents. Rapid blood pressure lowering or low blood pressure goals are associated with worse outcomes and provide no functional gains except in those unique circumstances that we mentioned, like pregnancy and aortic dissection. And when transitioning to oral agents, we want to use evidence-based guidelines that should direct our drug selection. Here are my references. And I welcome any questions you might have. I have included my email address on this slide. Do feel free to email me if you have any questions. Thank you for your time. I appreciate you all attending.

hypertensive crises

intracerebral hemorrhage

acute ischemic stroke

medication strategies

autonomic dysreflexia

paroxysmal sympathetic hyperactivity

blood pressure management