HYPERTENSION MANAGEMENT IN - EMCREG-International

HYPERTENSION MANAGEMENT INACUTE NEUROVASCULAR EMERGENCIESArthur M. Pancioli, MDVice Chairman of Research, Associate Professor, Department of Emergency Medicine,University of Cincinnati College of Medicine, Cincinnati, OH, Member, Greater Cincinnati/NorthernKentucky Stroke TeamOBJECTIVES:1. Describe the rationale for lowering blood pressure in hypertensive neurovascularemergencies.2. Describe the potential harm in lowering blood pressure in hypertensive neurovascularemergencies.3. Define the agents of choice in managing hypertensive neurovascular emergencies.INTRODUCTIONManagement of blood pressure in thesetting of neurovascular emergencies isof considerable concern to emergencyphysicians. It is an area of medicine withremarkably little clinical trial data fromwhich to derive evidence-based treatmentapproaches. Thus, clinicians must relyon an understanding of the underlyingpathophysiology and the mechanismof action of therapeutic agents to drivetreatment decisions.When treating patients with neurovascularemergencies and hypertension,two competing concerns must bebalanced. The first is the concern thatacutely elevated blood pressure can lead toinjury in multiple vascular beds, includinghemorrhage in the brain and elsewhere.The second is the concern that reductionof blood pressure can compromise tissuewith marginal perfusion. Factors thatmust be considered in deciding whetherto lower the patient’s blood pressure,and if so to what degree, include 1) thetype of neurovascular emergency, 2) thelevel of hypertension, 3) the patient’sw w w . e m c r e g . o r gpast blood pressure history, and 4) theperceived condition of the patient’s nativeautoregulatory system.The three types of neurovascularemergencies that will be considered hereare acute ischemic stroke, intracerebralhemorrhage and subarachnoidhemorrhage. While all falling into thecategory of neurovascular emergencies,the underlying pathologies differconsiderably as will the blood pressuremanagement decisions required to treatthem.PathophysiologyBefore addressing the individualneurovascular emergencies, someunderlying principles must be outlined.First, neuronal tissue has a very highmetabolic demand and therefore itrequires continuous high volume bloodflow. Normal blood flow to the humancerebral cortex averages 50ml of bloodflow / 100 grams of brain tissue / minute(expressed as: ml/100 g/min). 1 At levelsof perfusion less than 20 ml/100 g/min, neuronal cell membranes becomeimpaired with resulting neurologicalFactors that must beconsidered in decidingwhether to lower thepatient’s blood pressure,and if so to whatdegree, include 1) thetype of neurovascularemergency, 2) the levelof hypertension, 3) thepatient’s past bloodpressure history, and 4)the perceived condition ofthe patient’s nativeautoregulatory system.61

ADVANCING THE STANDARD OF CARE:Cardiovascular and Neurovascular EmergenciesAt levels of perfusionless than 20 ml/100g/min, neuronalcell membranesbecome impaired withresulting neurologicaldysfunction.dysfunction. 1 Despite this impairment,if blood flow is eventually restored, thistissue is largely salvageable. At levelsof blood flow below 10 ml/100 g/min,the neuronal tissue rapidly becomesirreversibly damaged. In the no-flowstate, neuronal death begins within afew minutes. Thus, any attempts toalter neurovascular physiology mustbe performed with the principle ofmaintaining adequate cerebral bloodflow to maintain tissue viability.Without superimposed pathology, thetwo principal factors that affect thevolume of cerebral blood flow are thecerebral perfusion pressure (CPP) andthe brain’s autoregulatory system.Cerebral perfusion pressure is the meanarterial pressure (MAP) minus either theintracerebral pressure (ICP) or the centralvenous pressure (CVP), whichever ishigher.CPP = MAP – (ICP or CVP, whichever is greater)The native autoregulatory system refersto the brain’s ability to keep the cerebralblood flow at a relatively constantlevel over a wide range of CPP. This isaccomplished by varying the resistance inthe pre-capillary arterioles. 2 Notably thismechanism is functional over a very widerange of CPP (Figure 1). 2 Also note inthis figure that a second curve depicts theautoregulatory curve “shifted” to the right.This curve represents the autoregulatoryrange of the patient with significantunderlying hypertension. For chronicallyhypertensive patients, the native systemwill require higher pressures to achievethe same degree of cerebral blood flowthan the non-hypertensive individual. 3In the setting of neurovascularemergencies, multiple deleterious effectscan ensue. First, the brain’s ability tocontinue normal autoregulation canbecome compromised. This can occurdue to CPP being outside of the rangewhere autoregulation can be maintained.Figure 1. Auto regulation and blood flow in patients with and withoutchronic hypertension. Adapted with permission from Powers.Neurology 1993;43(1):461-7.62w w w . e m c r e g . o r g

HYPERTENSION MANAGEMENT INACUTE NEUROVASCULAR EMERGENCIESWhen CPP is below the limits ofautoregulation, ischemic damage canensue. When CPP is above the upper limit,then autoregulatory breakthrough occurswhich leads to increased intracranialblood volume, increased intracranialpressure and vasogenic edema.In addition, the underlying pathology canhave a significant impact on the cerebralblood flow. In the setting of an acuteischemic stroke, an arterial occlusioncompromises flow to the region at risk tovarying degrees depending on collateralcirculation and the degree of occlusion.For intracerebral hemorrhage (ICH), thehematoma behaves as any mass lesionand causes an acute increase in ICP, thusdecreasing CPP unless the MAP is alsoincreased. It is also hypothesized that inthe region immediately surrounding thehematoma the blood flow is compromiseddue to local physical effects of the masslesion. For subarachnoid hemorrhage(SAH) the extravascular blood can raiseICP and can also cause arterial spasmleading to increased vascular resistance,thereby compromising flow. Thus eachof the individual types of neurovascularemergencies has their own uniquepotential to alter blood flow.Many factors, therefore, may influencethe variable that is most important– the cerebral blood flow. In practiceas emergency physicians, however, it isthe systemic blood pressure over whichclinicians have the greatest control andtherefore it is often the primary therapeutictarget. What must be considered is howtreatment of the systemic blood pressurewill alter the truly important variable,the cerebral blood flow, when treatingpatients.w w w . e m c r e g . o r gAcute Ischemic StrokeAs discussed, the high metabolic demandof brain tissue makes it quite susceptibleto ischemia. In the setting of acuteischemic stroke the duration and extentof ischemia will determine the ultimatefate of the affected area of brain tissue.As shown in Figure 2, there is a clearrelationship between duration of ischemiaand level of residual blood flow that willdifferentiate tissue that is salvageable andthat which will die.To further demonstrate the need forcareful use of blood pressure medicationin neurological emergencies, Figure 3illustrates the effect of blood flow on thedegree of injury that can be expected inmarginally perfused tissue. The centrallylocated black curve is adapted from Zivinwho characterized neuronal injury overtime in the setting of ischemia. The redand blue curves demonstrate the changeResidual Cerebral Blood Flowml 100g -1 min -1 30252015105Normal neuronal functionReversible neuronal dysfunctionNeuronal death12Duration of Transient IschemiaFigure 2. Degree of blood flow reduction and durationeffect tissue outcome. Adapted with permission from Powers.Neurology 1993;43(1):461-7.In the setting of acuteischemic stroke theduration and extent ofischemia will determinethe ultimate fate of theaffectedarea of brain tissue.63

ADVANCING THE STANDARD OF CARE:Cardiovascular and Neurovascular EmergenciesMore compelling inmost patients, however,is the concern thataggressive loweringof blood pressure cancause a reduction ofperfusion in the areaof ischemia, which mayexpand the region ofinfarction.in survivability that come with decreasesand increases in blood flow respectively.Thus it is clear that even relatively briefperiods of even relative hypotension mustbe avoided to prevent marked increase ininjury. 4The best summary statement regardingblood pressure management in thesetting of ischemic stroke comes fromthe American Stroke Association’s mostrecent guidelines on the managementof ischemic stroke. The authors state:“Despite the prevalence of arterialhypertension following stroke, its optimalmanagement has not been established.” 5Thus for all ischemic stroke patients,a blanket recommendation is not yetpossible. Clinicians must considerwhat factors should influence treatmentdecisions and then act on a case by casebasis.100Theoretical reasons to consider loweringa patient’s blood pressure include thepotential to reduce the formation of brainedema, lessening the risk of hemorrhagictransformation, and preventing furthervascular damage. More compelling inmost patients, however, is the concern thataggressive lowering of blood pressure cancause a reduction of perfusion in the areaof ischemia, which may expand the regionof infarction. This is well documentedin the literature with adverse clinicaloutcomes with sublingual nifedipine. 6Current expert consensus is that potentialindications for acute reduction of elevatedblood pressure in the setting of acuteischemic stroke include: patients whoare candidates for fibrinolysis to reducethe risk of hemorrhage, patients withsignificant end organ damage (e.g. acuteNRNeurologic Injury (%)755025ET50CR00 100 200 300 400 500Duration of Ischemia (min)Figure 3. Degree of injury in compromised tissue based onperfusion changes. Adapted with permission from Zivin et al.Neurology 1998;50:599-603.64w w w . e m c r e g . o r g

HYPERTENSION MANAGEMENT INACUTE NEUROVASCULAR EMERGENCIESmyocardial infarction, aortic dissection, hypertensiveencephalopathy, acute renal failure, acute pulmonaryedema, etc.), or patients with extremes of blood pressure(systolic above 220 or diastolic above 120). 5The clearest indication for blood pressure lowering inthe setting of acute ischemic stroke is in patients whoare candidates for fibrinolytic therapy. In this population,elevated blood pressure significantly increases the risk ofintracerebral hemorrhage. Fibrinolytic therapy should notbe given to patients who have a systolic blood pressure>185 mm Hg or a diastolic blood pressure >110 mm Hg atthe time of treatment. 5,7 Often stroke patients arrive withvery elevated blood pressure, but it may fall within theseparameters after a few minutes without specific therapy. Ifnot, guidelines for fibrinolytic therapy allow for treatmentof the blood pressure with relatively modest measures,including intravenous labetalol boluses, enalaprilatand some centers are now using nicardipine infusion.However, very aggressive interventions to lower bloodpressure should not be used, so if the above measuresare not effective in achieving the blood pressure targets,then fibrinolytic therapy is contraindicated. If the patientis treated with a fibrinolytic, the blood pressure must bemaintained

ADVANCING THE STANDARD OF CARE:Cardiovascular and Neurovascular EmergenciesSubarachnoid HemorrhageAneurysmal SAH is the one type of neurovascularemergency of which clinicians should absolutely treatelevated blood pressure. Patients with aneurysmalSAH, who do not receive definitive treatment for theiraneurysm, have a risk of rebleeding of 20% at 2 weeksand 30% at one month. 17 While there is little evidencethat uncontrolled blood pressure increases that risk,the potential is all too logical. Clearly, extremes ofblood pressure at admission (MAP> 130 or

HYPERTENSION MANAGEMENT INACUTE NEUROVASCULAR EMERGENCIESNicardipine has been shown to be as effective assodium nitroprusside in controlling blood pressure,but requires fewer dose titrations and does not increaseICP. It has therefore supplanted sodium nitroprussideas a treatment for acute neurovascular emergencies.Dosage is individualized based on the severity of thepatient’s hypertension and the goals for therapy. Forgradual reduction in blood pressure, initiate therapy5.0 mg/hr. If desired blood pressure reduction isnot achieved at this dose, the infusion rate may beincreased by 2.5 mg/hr every 15 minutes up to amaximum of 15.0 mg/hr, until desired blood pressurereduction is achieved. For more rapid blood pressurereduction, initiate therapy at 5.0 mg/hr then the infusionrate may be increased by 2.5 mg/hr every 5 minutesup to a maximum of 15.0 mg/hr, until desired bloodpressure reduction is achieved. Following achievementof the blood pressure goal, the infusion rate shouldbe decreased to 3 mg/hr. For maintenance, the rate ofinfusion should be adjusted as needed to achieve thedesired response.Nicardipine is contraindicated in patients withadvanced aortic stenosis because part of thetherapeutic effect of nicardipine is secondary toreduced afterload. Reduction of diastolic pressurein these patients may worsen rather than improvemyocardial oxygen balance. 20LabetalolLabetalol is an adrenergic receptor blocking agent thathas both selective α 1 - and nonselective β-adrenergicreceptor blocking actions in a single drug. In humans,the ratios of α- to β-blockade have been estimatedto be approximately 1:3 and 1:7 following oral andintravenous administration, respectively. Labetalolproduces dose-related falls in blood pressure withoutreflex tachycardia and without significant reductionin heart rate, presumably through a mixture of its α-blocking and β-blocking effects.For hypertensive emergencies labetalol is given aseither repeated intravenous boluses or as a continuousinfusion. For repeat bolus dosing, labetalol injectionshould begin with a 10-20 mg dose (which correspondsto 0.125-0.25 mg/kg for an 80-kg patient) by IVinjection over a 2-minute period. While much of thepackaging of the agent lists 20 mg as the initial dose,many clinicians begin with a 10 mg dose to ensuresafety of bolus therapy before proceeding to a 20mg dose. Immediately before the injection and at 5and 10 minutes after injection, supine blood pressureshould be measured to evaluate response. Additionalinjections of 40 or 80 mg can be given at 10-minuteintervals until a desired supine blood pressure isachieved or a total of 300 mg of labetalol has beeninjected. The maximum effect usually occurs within5 minutes after each injection. A continuous infusioncan also be given at 2 mg/min and titrated. The halflifeof labetalol is 5 to 8 hours. In the ED, initial bolustherapy followed by infusion may be required.Labetalol is contraindicated in bronchial asthma,overt cardiac failure, greater than first degree heartblock, cardiogenic shock, severe bradycardia, andother conditions associated with severe and prolongedhypotension. 21EsmololEsmolol is a b1-selective (cardioselective) adrenergicreceptor blocking agent with rapid onset, a veryshort duration of action, and no significant intrinsicsympathomimetic or membrane stabilizing activityat therapeutic dosages. Its elimination half-life afterintravenous infusion is approximately 9 minutes.Esmolol inhibits the b1 receptors located chieflyin cardiac muscle, but this preferential effect is notabsolute and at higher doses it begins to inhibit b2receptors located chiefly in the bronchial and vascularmusculature.An initial loading dose of 0.5 milligrams/kg (500micrograms/kg) infused over a minute durationfollowed by a maintenance infusion of 0.05milligrams/kg/min (50 micrograms/kg/min) for thenext 4 minutes is recommended. After the 4 minutesof initial maintenance infusion (total treatmentw w w . e m c r e g . o r g67

ADVANCING THE STANDARD OF CARE:Cardiovascular and Neurovascular Emergenciesduration being 5 minutes), depending upon thedesired response, the maintenance infusion may becontinued at 0.05 mg/kg/min or increased step-wiseto a maximum of 0.2 mg/kg/min with each step beingmaintained for 4 or more minutes.Esmolol is contraindicated in patients with sinusbradycardia, heart block greater than first degree,cardiogenic shock or overt heart failure. 22EnalaprilatEnalaprilat, an angiotensin-converting enzyme (ACE)inhibitor when administered intravenously, is theactive metabolite of the orally administered pro-drug,enalapril maleate. Enalaprilat intravenous results inthe reduction of both supine and standing systolic anddiastolic blood pressure. The onset of action usuallyoccurs within fifteen minutes of administration withthe maximum effect occurring within one to fourhours. The duration of hemodynamic effects appearsto be dose-related. Enalaprilat is indicated for thetreatment of hypertension when oral therapy is notpractical.makes this drug very attractive in the facilitation ofblood pressure reduction. It is exactly this property,however, which makes the drug potentially lessattractive for cases of hypertensive neurologicalemergencies. Of great concern in this setting is thesignificant potential for this agent to not only reducesystemic blood pressure via relaxation of vascularsmooth muscle, but also to cause significant increasesin intracranial pressure due to dilatation of intracranialvasculature via the same mechanism. This increaseis nicely illustrated in Figure 4 adapted from AnileThe dose in hypertension is 1.25 mg every six hoursadministered intravenously over a five minute period.A clinical response is usually seen within 15 minutes.Peak effects after the first dose may not occur for up tofour hours after dosing. The peak effects of the secondand subsequent doses may exceed those of the first.Enalaprilat is contraindicated in patients with a historyof angioedema related to previous treatment withan angiotensin converting enzyme inhibitor and inpatients with hereditary or idiopathic angioedema. Aswith all vasodilators, enalapril should be given withcaution to patients with obstruction in the outflowtract of the left ventricle. 23Why Not Sodium Nitroprusside?Sodium nitroprusside is used frequently in manyEDs for rapid titratable blood pressure control inseverely hypertensive patients. Sodium nitroprussideis a potent vascular smooth muscle relaxant, whichFigure 4. Changes in intracranial pressure withnitroprusside therapy. MICP = mean intracranialpressure. Adapted with permission from Anile et al.Acta Neurochir 1981;58:203-211.68w w w . e m c r e g . o r g

HYPERTENSION MANAGEMENT INACUTE NEUROVASCULAR EMERGENCIESet al. in which preoperative neurosurgical patientswith intraventricular catheters were treated withsodium nitroprusside for blood pressure reduction.The observed increase in intracranial pressure in 9out of 10 patients was both rapid and concerning.Notably, after an initial period of steady incrementalincrease in intracranial pressure, there does appearto be a phenomenon of return toward pre-treatmentintracranial blood pressures. In the majority of cases,however the ICP did not return to normal and, in fact,in some cases remained markedly elevated. Thus, withmultiple other powerful, titratable agents available forblood pressure control in the setting of neurovascularemergencies, the use of sodium nitroprusside isgenerally not recommended. 24-27SUMMARYBlood pressure management in acute neurovascularemergencies has potential for therapeutic benefit aswell as the potential to cause harm if not performedwith great care. 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ADVANCING THE STANDARD OF CARE:Cardiovascular and Neurovascular Emergencies19. Wijdicks EFM. Aneurysmal subarachnoid hemorrhage. Theclinical practice of critical care neurology. Oxford, UH: OxfordUniversity Press; 2003.20. PDL BioPharma, Inc. Nicardipine hydrochloride. 2006; http://www.cardeneiv.info/Cardene_Full_PI.pdf21. Prometheus Laboratories. Labetalol HCl. 2003; http://www.prometheuslabs.com/pi/TrandateInj.pdf22. Drugs.Com. Esmolol hydrochloride. 2006: MicromedexTMand MultumTM; http://www.drugs.com/pdr/ESMOLOL_HYDROCHLORIDE.html23. Drugs.Com. Enalapril. 2006: MicromedexTM and MultumTM;http://www.drugs.com/cons/Enalapril_Systemic.html24. Anile C, Zanghi F, Bracali A, Maira G, Rossi GF. Sodiumnitroprusside and intracranial pressure. Acta Neurochir (Wien).1981;58:203-21125. Candia GJ, Heros RC, Lavyne MH, Zervas NT, Nelson CN. Effectof intravenous sodium nitroprusside on cerebral blood flow andintracranial pressure. Neurosurgery. 1978;3:50-5326. Griswold WR, Reznik V, Mendoza SA. Nitroprusside-inducedintracranial hypertension. JAMA. 1981;246:2679-268027. Turner JM, Powell D, Gibson RM, McDowall DG. Intracranialpressure changes in neurosurgical patients during hypotensioninduced with sodium nitroprusside or trimetaphan. Br J Anaesth.1977;49:419-425Copyright EMCREG-International, 200770w w w . e m c r e g . o r g