Chapter 44: Management of Systemic Blood Pressure in the NeuroICU

Mental status changes in the setting of poor cerebral blood flow are most often seen with low arterial BP. Cerebral perfusion pressure (CPP), the pressure gradient that influences blood flow to the brain, is the difference between mean arterial pressure (MAP) and intra-cranial pressure (ICP) and is represented by the formula:

where CBF is cerebral blood flow and CVR is cerebrovascular resistance.

Cerebrovascular autoregulation maintains a constant blood flow over a wide range of CPPs. Normally, moderate changes in CPP have little effect on CBF. This is secondary to changes in CVR. An increase in CPP produces vasoconstriction and a decrease produces vasodilation. Typically for adults, CPP ranges between 50 and 100 mm Hg, though some research suggests 70 to 90 mm Hg to be a more accurate number.^1,2,3 In chronically hypertensive individuals, the cerebral arterioles develop medial hypertrophy and lose their ability to dilate effectively at lower pressures.⁴ This can lead to decreased cerebral perfusion when systemic BP falls, even though BP may remain within a range that would provide adequate cerebral perfusion in patients without hypertension.

The mechanisms governing CBF autoregulation are controversial.⁵ Most likely, the autoregulatory vessel caliber changes are influenced by arterial smooth muscle and metabolic mechanisms.^6,7 Perivascular nerves and the vascular endothelium may also play a role.^8,9,10 CBF autoregulation typically operates when mean systemic blood pressure is between 50 and 150 mm Hg² and can be modulated by sympathetic nervous activity and the renin-angiotensin system (RAS).

Central nervous system (CNS) trauma or acute ischemic stroke may impair CBF autoregulation, leaving surrounding CNS tissue vulnerable to over- or underperfusion. Likewise, autoregulation may be lost in the setting of a space-occupying brain lesion such as tumor or hematoma.¹¹ Autoregulation may be regained by hyperventilatory hypocapnia.¹² Patients with diabetes may have impaired CBF autoregulation, probably due to diabetic microangiopathy.¹³ In summary, cerebral autoregulation is a dynamic process affected by a patient's medical condition and, in particular, previous blood pressure control.

Hypertensive encephalopathy (HE) was first described by Oppenheimer and Fishberg in 1928 in the report of a patient with acute glomerulonephritis complicated by neurologic symptoms, convulsions, and severe hypertension.¹⁴ It is a descriptive term referring to reversible cerebral disorders associated with high blood pressure in the absence of cerebral thrombosis or hemorrhage.

Hypertensive encephalopathy occurs most frequently when diastolic BP exceeds 120 mm Hg in a patient with chronic hypertension.¹⁵ (Out-of-office BP control is known to be poor in most patients before they present with hypertensive emergency.^16,17) At this level of diastolic BP, cerebral autoregulation cannot effectively limit blood flow to the brain and clinical symptoms develop.¹⁸ Cerebral edema and microhemorrhages may occur. Hypertensive encephalopathy defines 16.3% of cases of hypertensive emergencies, more than intracranial hemorrhage or aortic dissection.¹⁹ The syndrome is generally precipitated by a severe and rapid rise in BP. After BP reduction all signs and symptoms often resolve.

Two theories have been proposed to account for the clinical and radiologic abnormalities associated with hypertensive encephalopathy. The first proposes that HE results from spasm of the cerebral vasculature in response to acute hypertension; in other words, excessive autoregulation leads to ischemia and edema, particularly in the regions bordering the arterial blood supply.^20,21 A more recent hypothesis suggests the syndrome results from breakthrough of autoregulation.^22,23,24 This would result in interstitial extravasation of proteins and fluids, producing focal vasogenic edema in the peripheral vascular distribution of the involved vessel. Vascular injury, tissue ischemia, and the release of vasoconstrictive mediators worsen the condition.^17,25 Fibrinoid necrosis eventually occurs if the process is not interrupted. Figure 44-1 shows the renal arteriolopathy associated with hypertensive emergency, and Figure 44-2 shows changes associated with chronic hypertension.

Magnetic resonance imaging (MRI) may now allow for a rapid and more specific diagnosis of HE. In uncomplicated cases, brain MRI shows areas of cerebral edema predominately in posterior white matter.²⁶ Lesions may be symmetric or asymmetric. Although not diagnostic, the terms posterior reversible encephalopathy syndrome or reversible posterior leukoencephalopathy syndrome have been adopted for this neuroradiologic finding. Flair imaging is the most sensitive sequence to detect areas of cerebral edema. The lesions are hyperintense on T2-weighted imaging and flair, and iso- to hypointense on T1-weighted imaging.²⁷ Diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) mapping shows the edema in HE to be vasogenic in origin.²⁶ Figure 44-3 demonstrates typical MRI findings of hypertensive encephalopathy.

Some drugs are cerebral vasodilators and have the potential for paralyzing autoregulation and raising intracranial pressure with systemic hypertension. This is seen most commonly with at least some calcium antagonists and hydralazine.^28,29 In particular, hydralazine has multiple cerebral hemodynamic effects. It raises ICP and thus, owing to its effect of also lowering systemic pressure, reduces CPP. Subsequently, CBF may increase, though not necessarily before cerebral underperfusion has occurred.³⁰

Angiotensin-converting enzyme inhibitors improve autoregulation during hypotension, likely by reducing angiotensin II–dependent tone in cerebral resistance vessels. With chronic antihypertensive treatment, CBF autoregulation may return to normal. Angiotensin-converting enzyme inhibitors in particular, when given chronically, may maintain autoregulation at the lower limit of CPP. Apart from this, it is uncertain if there is a beneficial, class-specific pharmacologic effect of antihypertensive drugs directly on the cerebral circulation.

The development of uncontrolled hypertension associated with sudden discontinuation of antihypertensive medications has been described frequently in the medical literature and is referred to as discontinuation syndrome, acute posttreatment syndrome, acute withdrawal syndrome, and rebound hypertension.^31,32,33 This syndrome has been reported to occur with clonidine, methyldopa, propran-olol, and rarely angiotensin-converting enzyme inhibitors.^{34,35,36,37,38,39} Of the medications mentioned, clonidine has been studied the most in determining the mechanism responsible for rebound hypertension following discontinuation. Clonidine is a widely used antihypertensive drug that suppresses the sympathetic nervous system via a central mechanism by agonism of inhibitory α receptors. Sudden discontinuation of clonidine leads to rebound hypertension as a result of secretion of stored norepinephrine.⁴² This effect is amplified in patients also taking propranolol (and possibly other β blockers) because of unopposed peripheral α-receptor activation.⁴³ Mirtazapine, which is a central α-receptor blocker, was reported to produce extreme hypertension in a patient maintained on clonidine, presumably by blocking clonidine's central effect.⁴⁴

Hypertension is associated with impaired cognition, particularly executive functions, and is believed to play a causal role in cognitive decline above and beyond its relationship to stroke.^45,46 Pathologic changes in the brain associated with hypertension include vascular remodeling, impairment of cerebral autoregulation, white matter lesions, unrecognized lacunar infarcts, and Alzheimer-like changes such as amyloid angiopathy and cerebral atrophy.⁴⁷ Hypertension appears to affect the subcortical white matter in particular, and may affect a substantial volume of variably damaged tissue that is potentially salvageable through optimization of blood supply.

Based on the evidence above, it is probable that our patient presents with hypertensive encephalopathy in association with uncontrolled blood pressure secondary to withdrawal of high-dose clonidine, in the setting of atenolol use. This case emphasizes the importance of educating patients about the adverse effects of abrupt discontinuation of antihypertensive agents, particularly clonidine.

Fairly strong evidence supports the deleterious effects of rapid reductions in BP in the early period following an acute stroke.^{48,49,50,51,52} Immediately beyond the area of infarction, the penumbra is at high risk for ischemia and infarct extension.^53,54 A number of factors about BP in patients with a stroke are worth emphasizing. First, BP frequently rises immediately following cerebral ischemia.^54,55 (Proposed mechanisms for increases in blood pressure after stroke generally include excess sympathoadrenal tone from direct neural injury,⁵⁴ altered parasympathetic function, catecholamine release, and cytokine activation.^56,57,58,59) BP typically begins to fall spontaneously within hours to days after stroke without intervention.^56,60 As a result, medication-induced reductions in BP may lead to CPP below a level that allows adequate cerebral perfusion to the penumbra. Exacerbating this tendency, patients with stroke typically have long-standing HTN and, thus, an autoregulatory curve that is shifted to the right.

Not all studies have shown deleterious effects of lowering BP acutely after stroke.^61,62 Small sample size may account for the inconsistent findings in this regard. Furthermore, it is important to recognize that low BP upon presentation may be a surrogate for independent cardiac disease, which may explain, in part, the worse outcomes seen with lower BP in this setting.⁶³ Most consensus guidelines recommend that BP not be treated acutely in the patient with ischemic stroke, except in the case of extreme hypertension (eg, systolic BP > 220 mm Hg or diastolic BP > 120 mm Hg) and end-organ damage. Typical examples of end-organ damage include hypertensive encephalopathy, aortic dissection, acute renal failure, acute pulmonary edema, and acute myocardial infarction. Ongoing studies are evaluating ideal BP control in the setting of acute stroke.⁶⁴

When urgent BP reduction is needed in the setting of a stroke, limited data exist to guide selection of the optimal pharmacologic agent. Many agents have been tested without clear superiority.^1,65,66 Short-term, parenteral medications have the appeal of a quickly titratable effect. Nicardipine, esmolol, and labetalol are frequently used, and the use of these titratable agents is reasonable rather than the frequent bolus therapy. Alternative agents include enalaprilat or fenoldopam.¹¹ Sodium nitroprusside, a previous favorite in the management of HTN emergencies, may dilate both cerebral arterial and venous systems and lead to increased intracranial pressure.⁶⁷ When intravenous medications are used, particularly in states of altered consciousness, intra-arterial blood pressure should be continuously measured. When antihypertensive medication is given acutely to patients with ischemic stroke, MAP should be reduced by no more than 15% within the first 24 hours,^68,69 and reduction of BP should not occur during the acute phase of ischemic stroke. Parenteral antihypertensive agents and some of their properties are listed in Table 44-1.

Preliminary evidence suggests that vasopressors may have a role in maintaining CPP and thus limit infarct extension.^70,71,72 The use of a vasopressor in this setting is not standard of care, however, and has not yet been incorporated into guidelines. Volume expansion, with the goal of improving cerebral perfusion, does not have a role, unless polycythemia is present.^73,74 Many stroke patients are volume depleted on presentation, owing to BP-induced sodium excretion, a phenomenon known as pressure natriuresis. This volume depletion may exacerbate the fall in BP after antihypertensive agents are given.⁷⁵ Low BP in the setting of obvious hypovolemia warrants volume repletion, especially if it is associated with neurologic deterioration in patients with acute stroke. Apart from volume depletion, other causes of hypotension one should consider include arrhythmias, sepsis, and aortic dissection.

Strokes qualifying for thrombolytic therapy have different blood pressure goals, in part because of the increased risk of bleeding with higher BP. Guidelines suggest initiating antihypertensive medications in eligible patients when systolic BP is above 185 mm Hg and diastolic BP is above 110 mm Hg. For the immediate 24 hours after thrombolytic agents are given, the target BP is below 180/105 mm Hg.

The optimal management of BP in hemorrhagic stoke is under active investigation. Initially, BP increases in the setting of intracranial hemorrhage (ICH).⁷⁶ While most patients with ICH have chronic HTN and a shifted autoregulatory curve, there is less of a concern for the ischemic penumbra seen in ische-mic strokes.^77,78 Several clinical studies suggest that it is safe to reduce either the BP to less than 160/90 mm Hg or the MAP to less than 130 mm Hg within 24 hours.^79,80 Some studies even show reduction in hematoma growth with reduction in BP.^81,82 Current guidelines target a BP of 160/90 mm Hg or a MAP of 110 mm Hg in the acute management of intracerebral hemorrhage; as ICP may be elevated, ICP monitoring may be required to ensure CPP is maintained over 60 mm Hg.⁸³

Blood pressure regulation is maintained in large part through autonomic regulation of blood vessel tone and sodium homeostasis. It is not surprising, then, that processes involving the central or peripheral nervous system can affect blood pressure. Brain and spinal cord injury frequently coexist with irregularities in blood pressure, both upward and downward. Beyond pain, proposed mechanisms include excess catecholamine release or sympathetic nervous system activation.^84,85

Autonomic dysreflexia describes the phenomenon of vasoconstriction that occurs in spinal cord injuries above the level of T5. Specifically, a peripheral stimulus initiates a strong sympathetic nervous system discharge.^86,87 Often the stimulus is from the genitourinary tract, such as infection or urinary retention. Mechanisms include excess sympathetic drive, renal vasoconstriction, and an inability to dilate the splanchnic vessels. Flushing and bradycardia are frequent, caused by excess parasympathetic activity above the spinal lesion, mediated, in turn, by carotid barorecptors.⁸⁸ Treatment of the offending stimulus (eg, urinary tract infection) should be the primary focus. Converting to an upright posture may mitigate the hypertension.⁸⁹ When pharmacotherapy is required, consideration should be given to the rapidity with which BP needs to be reduced, the concurrent presence of bradycardia, and the likelihood that the reflex vasoconstriction can be interrupted. Nifedipine has been shown to be effective in treating and preventing the hypertension of autonomic dysreflexia.⁹⁰

The management of HTN in traumatic brain injury is similarly challenging. External factors including pain and stress may affect BP. Assessment of cerebral perfusion based on physical assessments may be limited by the patient's overall medical condition; as a result, CPP estimation through MAP and ICP monitoring is preferred.^11,91 Guidelines based on the best available evidence for BP therapy in various settings, including traumatic brain injury, are listed in Table 44-2. Tissue hypoperfusion, especially in patients whose BP is usually high, should always be considered as a possible complicating factor.