OVERVIEW: What every practitioner needs to know. Are you sure your patient has hypertensive encephalopathy? What are the typical findings for this disease?

In pediatric patients, hypertension is defined as persistent (on three separate occasions) systolic or diastolic blood pressure (BP) elevation greater than the 95th percentile for age, sex, and height. Stage 1 hypertension exists if the BP is between the 95th percentile and 5 mm Hg greater than the 99th percentile. Stage 2 (or severe) hypertension, which warrants immediate evaluation and treatment, is defined by BP greater than 5 mm Hg greater than the 99th percentile. In patients with severe/stage 2 hypertension, presentation varies between an urgent medical condition and a life-threatening emergency.

A spectrum exists between these categories, but generally patients who present with severe BP elevation accompanied by signs of acute end-organ damage are considered to have a hypertensive emergency. Affected organs may include the kidney, heart, eyes, and brain; the most commonly affected organ is the brain, producing a phenomenon known as hypertensive encephalopathy (HE). In the setting where MRI is available, the often reversible white matter changes found in the setting of HE are referred to as posterior reversible encephalopathy syndrome (PRES).

HE is characterized by alterations in mental status, visual changes, or seizures associated with severe hypertension. If this medical emergency remains untreated, coma, status epilepticus, and death may develop rapidly. As with any hypertensive emergency, prompt confirmation of the diagnosis of HE, evaluation for antihypertensive contraindications, and initiation of therapy with intravenous medications are essential.

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Current expert opinion-based guidelines recommend close BP monitoring, use of intravenous infusions for titrated reduction of BP, and transfer to a critical care environment for these patients. The goal BP in this situation is an initial reduction by no more than 25% over 8 hours (10% in the first hour, then up to 15% more over the following 7 hours), followed by a more gradual decrease in BP over days to weeks. A more rapid initial decrease of BP may be associated with ischemic conditions, such as stroke, resulting from altered autoregulatory mechanisms.

The symptoms of hypertensive encephalopathy include severe hypertension and neurologic changes caused by cerebral edema. Early symptoms such as headache and nausea will progress to confusion/irritability and ultimately coma and/or seizures if untreated. Acute visual changes may occur in the absence of ocular findings, and with associated T2-weighted magnetic resonance imaging (MRI) findings of parietooccipital leukoencephalopathy (posterior reversible encephalopathy syndrome [PRES]). Although the BP will generally be classified as stage 2 hypertension, rapidly increasing BP may result in symptoms at a lower absolute pressure than what would be expected with chronically elevated BP; thus, any patient with hypertension and altered mental status should be evaluated for possible HE.

Patients with HE may or may not have evidence of other end-organ injury, such as kidney disease (hematuria and/or proteinuria, occasionally acute renal failure), ophthalmic disease (retinal hemorrhages/exudates and/or papilledema), or heart disease (heart failure). Findings in any of these other organ systems would represent a hypertensive emergency even in the absence of neurologic findings, and management should be equally aggressive for these conditions.

What other disease/condition shares some of these symptoms?

All patients with a hypertensive urgency or emergency should be carefully evaluated to ascertain the extent of disease, if any. Urgent hypertension should be treated promptly, but the need for critical care management or intravenous medication administration depends on the circumstances and local resources.

Other conditions that must be ruled out include:

Intracranial mass lesions: These lesions, such as tumor, cerebrovascular accident, or occult trauma, may present with altered mental status and hypertension (as a response to increased intracranial pressure). Differentiation of this condition is essential because pharmacologic lowering of BP in this situation would compromise cerebral perfusion.

Ophthalmic hypertensive emergency: This may result in visual changes in the setting of severe hypertension but without any intracerebral abnormality. The management of this condition is similar to that of HE.

Sympathetic stimulation: Such stimulation can be due to either endogenous causes (e.g., pain, fear/panic disorder), or exogenous agents (e.g., ingestion of sympathomimetic agents), both of which may cause hypertension and mental status abnormalities. Management should center around the primary problem in these circumstances but often also includes BP control.

What caused this disease to develop at this time?

In adult patients, the most common cause of hypertensive emergencies is poorly controlled primary (essential) hypertension. Although this diagnosis is increasing in frequency in children because of the current pediatric obesity epidemic, hypertension in children is far more likely to be a secondary finding in another disease process. HE may thus be caused by the following:

  • Chronic kidney disease or renovascular disease
  • Acute renal disease such as glomerulonephritis
  • Toxidromes such as amphetamine intoxication or serotonin syndrome
  • Excessive catecholamine levels as in pheochromocytoma, hyperthyroidism
  • Drug effects such as from corticosteroids or immunosuppressive agents
  • Preeclampsia/eclampsia

The cerebrovascular circulation is capable of autoregulation—that is, maintaining a constant blood flow over a range of perfusion pressures by adjusting the diameters of cerebral vessels as pressure increases. However, beyond a level of maximal constriction of vessels, the limit of autoregulation is reached, and further pressure increases are directly transmitted to the downstream cerebral vasculature. This results in endothelial damage and cerebral edema, which causes the neurologic findings. With chronically elevated BP, this autoregulatory mechanism is shifted such that autoregulation is maintained at higher BPs (at the expense of autoregulation at lower BPs.

The timing of presentation may be the result of an acute onset of hypertension in a previously normotensive patient or from the eventual failure of a shifted autoregulatory mechanisms in patients with long-standing hypertension. In either case, the primary pathogenesis is BP that has exceeded cerebral autoregulatory mechanisms.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

No laboratory studies are necessary to make the diagnosis of HE; the diagnosis is made based on vital signs (hypertension) and clinical/neurologic examination. However, patients with HE are at risk for other end-organ damage, including heart, kidney, and eye. Therefore, most experts recommend evaluation for these conditions with appropriate testing. Additional testing is directed toward determining the cause of hypertension. A complete evaluation may include the following:

  • Urinalysis for evidence of renal dysfunction
  • Urine human chorionic gonadotropic/pregnancy test to rule out preeclampsia/eclampsia
  • Urine/serum toxicologic screen for ingestions
  • Catecholamine measurement to evaluate for pheochromocytoma
  • Glucose determination to evaluate for diabetes
  • Electrolyte panel and renal function testing

Would imaging studies be helpful? If so, which ones?

Computed tomography (CT) is essential to exclude stroke, tumor, intracerebral hemorrhage, or trauma as alternative diagnoses. In the case of HE, CT may show cerebral edema or may be normal. Chest radiography and electrocardiography should also be performed to evaluate for left ventricular hypertrophy (evidence of long-standing hypertension) or congestive heart failure (acutely related to the hypertensive emergency). Renal ultrasonography and echocardiography may also be useful as adjunctive tests to evaluate for kidney or cardiac pathologic conditions.

Magnetic resonance imaging (MRI) may demonstrate parietooccipital leukoencephalopathy (PRES). However, care should be taken to ensure that appropriate management is never withheld pending MRI results, as MRI testing can be relatively time-consuming and delays in therapy may be catastrophic. Additionally, MRI in pediatric patients often requires sedation or anesthesia, and the risks of undertaking sedation in the patient with altered mental status and hemodynamic lability (as is seen with HE) are significant.

If you are able to confirm that the patient has hypertensive encephalopathy, what treatment should be initiated?

The goals of therapy for the patient with HE (after establishing adequate airway, breathing, and circulation) are threefold:

Before initiation of medical therapy, secondary causes of hypertension must be quickly ruled out as discussed above. For example, analgesic administration for the patient in pain or a specific antidote for a patient who ingested a toxin may resolve BP elevation without need for further intervention.

Within 8 hours of diagnosis, the therapeutic target is reduction of BP by at most 20%-25% of the baseline BP. Most experts recommend a rapid reduction by 10% within the first hour, followed by a slower decrease by up to 15% more over the following 7 hours. Because of shifting of the autoregulation curves, irreversible brain and other end-organ ischemic injury may occur with excessively rapid BP reduction; this goal will reduce the emergent risk of ongoing end-organ hypertensive injury while preserving organ perfusion within the autoregulation zone.

This acute BP control is most carefully achieved with the use of continuous intravenous agents, preferably easily titratable agents such as the calcium channel blocker nicardipine(usual dose 0.5-5 µg/kg/min) or the mixed alpha- and beta-antagonist labetalol (usual dose 0.2-1 mg/kg/h; some authors recommend a bolus dose of 0.2-1 mg/kg at the start of infusion). Some experts prefer nitroprusside (usual dose 0.3-5 µg/kg/min), although this agent has become less popular because of concerns of cyanide toxicity with prolonged or excessive use.

In the subsequent hours to days, the patient should be managed in a critical care setting by a multidisciplinary team consisting of an intensivist and a hypertension expert (generally a pediatric nephrologist or cardiologist, depending on the setting). This management will consist of an expanded evaluation of the cause of hypertension, evaluation for other secondary organ injury, continued gradual reduction of BP to normal levels, and transitioning of antihypertensive agents to a stable enteral regimen for chronic management.

What are the adverse effects associated with each treatment option?

The primary adverse effect of concern to the practitioner is the risk of irreversible end-organ ischemic damage resulting from overaggressive BP reduction. This is best avoided with careful titration of a continuous infusion of medication as discussed above.

Specific adverse effects of medications

Beta-blockers (including labetalol, esmolol, and others) may decrease cardiac output in children. This is particularly true in small infants, in whom cardiac output is dependent on adequate heart rate with a relatively fixed ventricular stroke volume. Beta-blockers may also precipitate bronchospasm in at-risk patients (asthmatics) because of the direct pharmacologic effects of beta-antagonism on bronchial smooth muscle.

Vasodilators (calcium channel blockers, hydralazine, nitroprusside) generally cause a reflex tachycardia in children with intact baroreceptor mechanisms. Prolonged or high-dose nitroprusside administration may precipitate cyanide toxicity. This has limited clinical use of nitroprusside at some centers; however, nitroprusside remains a potent, rapid-acting, and easily titratable second-line agent for management of patients with HE.

What are the possible outcomes of hypertensive encephalopathy?

Patients who present with neurologic dysfunction and hypertension will generally fall into one of three categories. The first group includes those patients with hypertension resulting from an underlying intracranial abnormality (e.g., tumor, elevated intracranial pressure) for which the prognosis depends on the prognosis of the underlying condition.

The second group includes those patients for whom an unrelated cause (e.g., cocaine ingestion) has caused both hypertension and altered mental status. Elimination or reversal of the underlying cause over time will allow a more accurate neurologic evaluation of these patients.

The third group of patients, those with hypertensive encephalopathy, have altered mental status caused directly by the elevation of BP. In many such cases, the neurologic dysfunction and MRI findings are often reversible with BP control; as noted above, providers must use caution to avoid rapid reduction of BP to reduce permanent neurologic sequelae.

In general, the diagnosis of hypertension predicts increased long-term morbidity and mortality for patients; however for any individual patient, the prognosis will depend on the treatment options and prognosis of the underlying disease process. This is particularly true in pediatric patients, for whom secondary hypertension is far more common than primary/essential) hypertension.

What causes hypertensive encephalopathy and how frequent is it?

As discussed above, HE is caused by uncontrolled severe hypertension with overwhelmed cerebral autoregulatory mechanisms. Although hypertension and HE are both more common in adults than in children, the risk of permanent neurologic dysfunction from either uncontrolled HE or from overly aggressive treatment of hypertension is likely similar in children and adults.

Predisposing factors for the development of HE include the same factors that produce hypertension (see above).

How do these pathogens/genes/exposures cause the disease?

Cerebral autoregulation allows for constant blood flow to the brain during a range of BPs. The upper and lower limits of autoregulation may change in disease states (such as chronic hypertension); additionally, there is likely considerable individual variation in these limits. However, for all patients, the risk of HE increases as the upper limit of autoregulation is exceeded; further increases in BP are directly transmitted to the cerebral vasculature, resulting in endothelial dysfunction, capillary leakage, cerebral edema, and subsequent neurologic symptoms.

What complications might you expect from the disease or treatment of the disease?

The primary complications include permanent neurologic sequelae resulting from rapid reduction of BP or severity of hypertension. Secondary complications caused by medication side effects are discussed above.

Even in the absence of intracerebral hemorrhage, a known complication of severe hypertension, untreated HE may progress rapidly (within hours) to unconsciousness, status epilepticus, and death. For this reason, HE must be treated as a true medical emergency, and appropriate specialist consultation is essential.

Are additional laboratory studies available; even some that are not widely available?

All laboratory and radiologic testing should be directed toward evaluation of the severity and cause of HE. There are no confirmatory tests that are specific for HE, although T2-weighted brain MRI findings of reversible parietooccipital leukoencephalopathy (see above) are common.

How can hypertensive encephalopathy be prevented?

In patients with known hypertension, HE can best be avoided with adequate BP control and, for those with secondary hypertension, treatment of the underlying disease process.

Many cases of HE present concomitantly with a new diagnosis of severe hypertension in the emergency department setting. For this population, the most effective prevention may be maintenance of appropriate population screening for hypertension. Targeted screening for hypertension in children at risk (e.g., those with a history of umbilical artery catheterization) may also provide early detection and prevention of severe, uncontrolled hypertension.

What is the evidence?

Vaughan, CJ, Delanty, N. “Hypertensive emergencies”. Lancet. vol. 356. 2000. pp. 411-7. (An overview of hypertensive emergencies.)

Raj, S, Overby, P, Erdfarb, A, Ushay, HM. “Posterior reversible encephalopathy syndrome: incidence and associated factors in a pediatric critical care population”. Pediatr Neurol. vol. 49. 2013. pp. 335-9. (A review of the clinical-radiologic syndrome of PRES, which is associated with and sometimes synonymous with hypertensive encephalopathy.)

Pergonlini, MS. “The management of hypertensive crises: a clinical review”. Clin Ter. vol. 160. 2009. pp. 151-7. (A review of the management of emergent and urgent hypertension for adult patients.)

Ongoing controversies regarding etiology, diagnosis, treatment

The optimal medical management of hypertensive encephalopathy is unknown, particularly for pediatric patients. Although many experts encourage the use of continuous infusions of titratable medications for these patients, other experts advocate bolus intravenous medications (e.g., hydralazine or bolus-dosed labetalol). Further study would be beneficial for building consensus among medical practitioners and determining a reliable treatment algorithm for children with hypertensive encephalopathy and other hypertensive emergencies.