acute hypertensive response in stroke: pathophysiology and ...haemorrhage trial (interact) variables...

Acute Hypertensive Response in Stroke: Pathophysiology and Management


Adnan I. Qureshi

Professor, Neurology, Neurosurgery, and RadiologyPresident, International Society of Interventional Neurology

Adnan I. Qureshi

Professor, Neurology, Neurosurgery, and RadiologyPresident, International Society of Interventional NeurologyPresident, International Society of Interventional Neurology

For the ATACH II Investigators

Zeenat Qureshi Stroke Research Center University of Minnesota, Minneapolis, MN

President, International Society of Interventional Neurology


Zeenat Qureshi Stroke Research Center University of Minnesota, Minneapolis, MN



Qureshi MD

Professor, Neurology, Neurosurgery, and RadiologyPresident, International Society of Interventional Neurology

Qureshi MD

Professor, Neurology, Neurosurgery, and RadiologyPresident, International Society of Interventional NeurologyPresident, International Society of Interventional Neurology


Stroke Research Center University of Minnesota, Minneapolis, MN

President, International Society of Interventional Neurology


Stroke Research Center University of Minnesota, Minneapolis, MN

Initial Systolic Blood Pressure in Patients Presenting to the Emergency Room with Stroke in US

(National Hospital Ambulatory Medical Care Survey 2003)



60%

80%

100%

Prop

ortion

of

patient

s (%

)

0%

20%

40%

60%

All

stroke

IS ICH

Prop

ortion

of

patient

s (%

)

Adapted from: Qureshi AI, et al. Am J Emerg Med 2007;25(1):32.





>220 mm Hg

185-219 mm Hg

140-184 mm Hg

<140 mm Hg

ICH SAH

Adapted from: Qureshi AI, et al. Am J Emerg Med 2007;25(1):32-8.

Acute Hypertensive ResponseAcute Hypertensive Response

• Stroke specific

• Transient

• Prognostic significance

• Stroke specific

• Transient

• Prognostic significance• Prognostic significance• Prognostic significance

(Qureshi AI: Circulation 2008 Jul 8;118(2):

Acute Hypertensive ResponseAcute Hypertensive Response

Prognostic significancePrognostic significancePrognostic significancePrognostic significance

(Qureshi AI: Circulation 2008 Jul 8;118(2):176-87)

Acute hypertensive response:Stroke specific disruption of

autonomic activity


autonomic activity

Disruption: structuraland/or functional

Parasympatheticactivity

Sympatheticactivity

(Qureshi AI: Circulation 2008 Jul 8;118(2):176


autonomic activity


autonomic activity

Disruption: structuraland/or functional

Parasympatheticactivity

Sympatheticactivity

BP

Adaptation: functional


Treatment of acute hypertensive response in ischemic stroke

Treatment of acute hypertensive response in ischemic strokeresponse in ischemic strokeresponse in ischemic stroke


Treatment of acute hypertensive response in ischemic stroke

Treatment of acute hypertensive response in ischemic strokeresponse in ischemic strokeresponse in ischemic stroke


Reduction in cerebral blood flowSPECT scan




Severe hypoperfusion (core)moderate hypoperfusion (penumbra)

alive but at risk

Severe hypoperfusion (core)moderate hypoperfusion (penumbra)

alive but at risk

Severe hypoperfusion (core)-mild to moderate hypoperfusion (penumbra)

alive but at risk

Severe hypoperfusion (core)-mild to moderate hypoperfusion (penumbra)

alive but at risk

Cerebral blood flow and cell deathPerfusion-Diffusion mismatch

Cerebral blood flow and cell deathPerfusion-Diffusion mismatch

Diffusion-weighted MRI

Cerebral blood flow and cell deathDiffusion mismatch

Cerebral blood flow and cell deathDiffusion mismatch

Perfusion-weighted MRI

Hypoperfused but alivesalvageable---

Hypoperfused but alivesalvageable---

Diffusion-weighted MRI

Hypoperfused but alive---potentially ---Penumbra

Hypoperfused but alive---potentially ---Penumbra

Perfusion-weighted MRI

Rapid collateral formation during acute intracranial occlusion(Qureshi AI: J Vasc Intervent Neurol 2008; 1(3):70

Rapid collateral formation during acute intracranial occlusion(Qureshi AI: J Vasc Intervent Neurol 2008; 1(3):70

LEFT ICA INJECTION, AP

FRAME 1/16

FRAME 6/16 FRAME 8/16

Rapid collateral formation during acute intracranial occlusion---residual rCBF (Qureshi AI: J Vasc Intervent Neurol 2008; 1(3):70-72).

Rapid collateral formation during acute intracranial occlusion---residual rCBF (Qureshi AI: J Vasc Intervent Neurol 2008; 1(3):70-72).

Ballooninflation

LEFT ICA INJECTION, APFRAME 4/16

FRAME 8/16 FRAME 13/16

Hypoperfused but alive—BP change---impaired autoregulation

are BP dependant

Hypoperfused but alive—BP change---impaired autoregulation

are BP dependant

SBP=100 mm Hg

—vulnerability to systemic impaired autoregulation—collaterals

are BP dependant

—vulnerability to systemic impaired autoregulation—collaterals

are BP dependant

SBP=100 mm Hg SBP=160 mm Hg

Current guidelines are based on the policy of avoiding further ischemic injury

Current guidelines are based on the policy of avoiding further ischemic injuryof avoiding further ischemic injuryof avoiding further ischemic injury

Current guidelines are based on the policy of avoiding further ischemic injury

Current guidelines are based on the policy of avoiding further ischemic injuryof avoiding further ischemic injuryof avoiding further ischemic injury

Intravenous Nimodipine West European Stroke Trial

(Ahmed et al. Cerebrovasc Diseases 2003;15:235


(Ahmed et al. Cerebrovasc Diseases 2003;15:235

Total anterior circulation infarction(n=106)(n=106)

PlaceboIV nimodipine1 or 2 mg/h

No difference inoutcome

Within 24 hours


(Ahmed et al. Cerebrovasc Diseases 2003;15:235-43)


(Ahmed et al. Cerebrovasc Diseases 2003;15:235-43)

Partial anterior circulation infarction(n=62)(n=62)

PlaceboIV nimodipine1 or 2 mg/h

Diastolic BP reductionassociated with neurological deterioration and outcome

Within 24 hours

BP reductionharmful?

BP reductionno effect?

Courtesy ofDavid S. Liebeskind MD,UCLA StrokeCenter, LA

Acute hypertensive response should not be treated in ischemic stroke

Qureshi AI: Circulation 2008 Jul 8;118(2):176


Qureshi AI: Circulation 2008 Jul 8;118(2):176

A subgroup ofpatients maydeteriorate


Qureshi AI: Circulation 2008 Jul 8;118(2):176-87


Qureshi AI: Circulation 2008 Jul 8;118(2):176-87

Benefit of acute blood pressure

reduction unclear

American Heart Association Guidelines2007 updates


Pending more data, emergency administration of antihypertensive agents should be withheld unless the diastolic blood pressure is >120 mm Hg or unless the systolic blood pressure is >220 mm Hg.


The panel remains concerned by the evidence that aggressive lowering of blood pressure among patients may cause neurological worsening, and the goal is to avoid overtreating patients with stroke until definitive data are available.


American Stroke Association Stroke Council. Stroke. 38(5):1655







American Stroke Association Stroke Stroke. 38(5):1655-711, 2007 May.

Treatment of acute hypertensive response in patients receiving

Treatment of acute hypertensive response in patients receiving response in patients receiving

thrombolysisresponse in patients receiving

thrombolysis


Treatment of acute hypertensive response in patients receiving

Treatment of acute hypertensive response in patients receiving response in patients receiving

thrombolysisresponse in patients receiving

thrombolysis


Acute hypertensive response may increase the risk of post-thrombolysis intracerebral

hemorrhage

Acute hypertensive response may increase the risk of post-thrombolysis intracerebral

hemorrhage

Impaired Reperfusion


Impairedautoregulation+SBP

Reperfusion+coagulopathy

Acute hypertensive response may increase thrombolysis intracerebral

hemorrhage

Acute hypertensive response may increase thrombolysis intracerebral

hemorrhage

Reperfusion


Reperfusion+coagulopathy

SBP and post-thrombolytic ICH

Studies Patients withacute ischemicstroke

ECASS II (Stroke. 2001;32(2):438-41)

793(Stroke. 2001;32(2):438-41)

Multicenter rt-PA stroke survey(Circulation 2002;105:1679-1685)

1205

EPITHET (Stroke. 2010; 41(1):72-7)

97

thrombolytic ICH

withischemic

Intracranial hemorrhage rate

Predictor

60 (8%) Baseline SBP

158 (13%) Pre-treatment SBP

15 (15%) Weighted SBP 1-24 h

American Heart Association GuidelinesThrombolysis

American Heart Association GuidelinesThrombolysis

• Systolic blood pressure is <=185 mm Hg and their diastolic blood pressure is <=110 mm Hg (Class I, Level of Evidence B) before lytic therapy is started.

• Systolic blood pressure is <=185 mm Hg and their diastolic blood pressure is <=110 mm Hg (Class I, Level of Evidence B) before lytic therapy is started.

• Maintained below 180/105 mm Hg for at least the first 24 hours after intravenous rtPA treatment.

• Blood pressure recommendations should be followed in patients undergoing intra(Class I, Level of Evidence C).

• Maintained below 180/105 mm Hg for at least the first 24 hours after intravenous rtPA treatment.

• Blood pressure recommendations should be followed in patients undergoing intra(Class I, Level of Evidence C).

American Stroke Association Stroke Council. Stroke. 38(5):1655

American Heart Association Guidelines-Thrombolysis

American Heart Association Guidelines-Thrombolysis

Systolic blood pressure is <=185 mm Hg and their diastolic blood pressure is <=110 mm Hg (Class I, Level of Evidence B) before lytic therapy is

Systolic blood pressure is <=185 mm Hg and their diastolic blood pressure is <=110 mm Hg (Class I, Level of Evidence B) before lytic therapy is

aintained below 180/105 mm Hg for at least the first 24 hours after intravenous rtPA treatment.

Blood pressure recommendations should be followed in patients undergoing intra-arterial thrombolysis (Class I, Level of Evidence C).

aintained below 180/105 mm Hg for at least the first 24 hours after intravenous rtPA treatment.

Blood pressure recommendations should be followed in patients undergoing intra-arterial thrombolysis (Class I, Level of Evidence C).

American Stroke Association Stroke Stroke. 38(5):1655-711, 2007 May.

Post-hoc analysis of NINDS rtStroke. 29(8):1504


Acute ischemic stroke and received rtSBP >180 mm Hg (3-24 hours after symptom onset)

Antihypertensivetreatment (N=65)

32%Clinical

improvementat 24 hours

hoc analysis of NINDS rt-PA trial Stroke. 29(8):1504-9, 1998 Aug.


Acute ischemic stroke and received rt-PA 24 hours after symptom onset)

No antihypertensive treatment (N=112)

52%





32%Clinical





More severe hypertension


52%


More abrupt decline of BP inresponse to antihypertensive

medication





32%Clinical


Occlusion

BP high





More abrupt decline of BP inresponse to antihypertensive


52%

response to antihypertensivemedication

(recanalization is associatedwith spontaneous BP decline)

Recanalization Reocclusion

BP normal BP high

Special considerationspost thrombolytic patientsSpecial considerations

post thrombolytic patients

• Greater level of susceptibility to blood pressure decline/fluctuations (presumably related to recanalization).

-Mattle HP, et al. Stroke. Feb 2005;36(2):264

• Greater level of susceptibility to blood pressure decline/fluctuations (presumably related to recanalization).

-Mattle HP, et al. Stroke. Feb 2005;36(2):264-Mattle HP, et al. Stroke. Feb 2005;36(2):264

• First 6 hours is the period of maximum fluctuations in blood pressure following thrombolytic treatment.

-Aiyagari V, et al. Stroke. Oct 2004;35(10):2326

-Mattle HP, et al. Stroke. Feb 2005;36(2):264

• First 6 hours is the period of maximum fluctuations in blood pressure following thrombolytic treatment.

-Aiyagari V, et al. Stroke. Oct 2004;35(10):2326

Special considerations-post thrombolytic patientsSpecial considerations-

post thrombolytic patients

Greater level of susceptibility to blood pressure decline/fluctuations (presumably related to recanalization).

Stroke. Feb 2005;36(2):264-268.

Greater level of susceptibility to blood pressure decline/fluctuations (presumably related to recanalization).

Stroke. Feb 2005;36(2):264-268.Stroke. Feb 2005;36(2):264-268.

First 6 hours is the period of maximum fluctuations in blood pressure following thrombolytic treatment.

Aiyagari V, et al. Stroke. Oct 2004;35(10):2326-2330.

Stroke. Feb 2005;36(2):264-268.

First 6 hours is the period of maximum fluctuations in blood pressure following thrombolytic treatment.

Aiyagari V, et al. Stroke. Oct 2004;35(10):2326-2330.

Treatment of acute hypertensive response in

intracerebral hemorrhage


intracerebral hemorrhageintracerebral hemorrhageintracerebral hemorrhage

Re: Qureshi AI: Lancet 2009;373:1632


intracerebral hemorrhage


intracerebral hemorrhageintracerebral hemorrhageintracerebral hemorrhage

Re: Qureshi AI: Lancet 2009;373:1632-44.

Evolution of our understanding of acute hypertensive response

Phase I(1985-1997)

Phase II(1998-2003)

DONOT TREAT BP IN ACUTE ICH-EXPERIMENTA

REDUCE BP –MODESTLY-CASE SERIESICH-

EXPERIMENTAL/CLINICAL RESEARCH

CASE SERIES

PERI-HEMATOMAISCHEMIA

HIGH BP ~HEMATOMA EXPANSION


Phase III(2004-2009)

Phase IV(2010---)

AGGRESSIVEBP REDUCTION EXPLORED-PILOT

AGGRESSIVE BP REDUCTION CONFIRMED-PHASE III

EXPLORED-PILOTSTUDIES

CONFIRMED-PHASE III STUDIES

BPREDUCTION~HEMATOMA EXPANSION

BP REDUCTION ~PATIENT OUTCOMES

Acute Hypertensive Response Should Not Be Treated(Powers WJ. Neurology 1993;43:461

Acute Hypertensive Response Should Not Be Treated(Powers WJ. Neurology 1993;43:461

Perihematomaischemia is a

serious concern

Acute Hypertensive Response Should Not Be Treated(Powers WJ. Neurology 1993;43:461-467)

Acute Hypertensive Response Should Not Be Treated(Powers WJ. Neurology 1993;43:461-467)

Hematoma expansion is uncommon

rCBF

Hibernationstage (0-2 days)

Reperfusionstage (2

Meta

bolism

Qureshi AI, et al. Neurosurg Clin N Am 2002;13:355

Reperfusionstage (2-14 days)

Normalizationstage (>14 days)

Qureshi AI, et al. Neurosurg Clin N Am 2002;13:355-370.


Phase I(1985-1997)

Phase II(1998-2003)




CASE SERIES





Phase IV(2010---)







Hematoma Enlargement(From: Qureshi: N Engl J Med; 344.: 2001.1450

Hematoma Enlargement(From: Qureshi: N Engl J Med; 344.: 2001.1450

Baseline

Hematoma EnlargementQureshi: N Engl J Med; 344.: 2001.1450-1460)

Hematoma EnlargementQureshi: N Engl J Med; 344.: 2001.1450-1460)

6 hours

Elevated systolic blood pressure may predispose to hematoma enlargement

Kazui: Stroke, Volume 28(12).December 1997.2370


Kazui: Stroke, Volume 28(12).December 1997.2370

Prop

ortion

of

patient

s (%

)

30

40

50

Prop

ortion

of

patient

s (%

)

0

10

20

30

Hematomaenlargement


Kazui: Stroke, Volume 28(12).December 1997.2370-2375


Kazui: Stroke, Volume 28(12).December 1997.2370-2375

SBP>200 mm Hg

No hematomaenlargement

Acute Hypertensive Response Should be Treated

(Qureshi et al.: Lancet 2009;373:1632


(Qureshi et al.: Lancet 2009;373:1632

Is there perihematoma

ischemia?


(Qureshi et al.: Lancet 2009;373:1632-44)


(Qureshi et al.: Lancet 2009;373:1632-44)

Hematoma expansion is a reality

Guidelines for the Management of Spontaneous Intracerebral Hemorrhage in Adults. 2007

Guideline From the American Stroke Association Stroke Council



• Until ongoing clinical trials of blood pressure intervention for ICH are completed, physicians must manage blood pressure on the basis of the present incomplete evidence.

• Suspect elevated intracranial pressure

• Until ongoing clinical trials of blood pressure intervention for ICH are completed, physicians must manage blood pressure on the basis of the present incomplete evidence.

• Suspect elevated intracranial pressure• Suspect elevated intracranial pressurepressure <180 mm Hg.

• Do not suspect elevated intracranial pressureblood pressure <160 mm Hg. Regular clinical evaluation.

• Suspect elevated intracranial pressurepressure <180 mm Hg.

• Do not suspect elevated intracranial pressureblood pressure <160 mm Hg. Regular clinical evaluation.

Stroke. 38(6):2001





Until ongoing clinical trials of blood pressure intervention for ICH are completed, physicians must manage blood pressure on the basis of the present incomplete evidence.

Suspect elevated intracranial pressure-keep systolic blood

Until ongoing clinical trials of blood pressure intervention for ICH are completed, physicians must manage blood pressure on the basis of the present incomplete evidence.

Suspect elevated intracranial pressure-keep systolic blood Suspect elevated intracranial pressure-keep systolic blood

Do not suspect elevated intracranial pressure-keep systolic blood pressure <160 mm Hg. Regular clinical evaluation.

Suspect elevated intracranial pressure-keep systolic blood

Do not suspect elevated intracranial pressure-keep systolic blood pressure <160 mm Hg. Regular clinical evaluation.

Stroke. 38(6):2001-23, 2007 Jun.

BP reduction and hematoma enlargementBP reduction and hematoma enlargement

No standard management practicesJauch EC, Stroke. 2006 Aug;37(8):206137%

180 mm Hg Single centerIV nicardipine 5Qureshi AI, Crit Care Med. Jul 2006;34(7):1975

17%

37%

BP reduction and hematoma enlargementBP reduction and hematoma enlargement

No standard management practicesJauch EC, Stroke. 2006 Aug;37(8):2061-5.

Single center-AHA guidelinesIV nicardipine 5-15 mg/hrQureshi AI, Crit Care Med. Jul 2006;34(7):1975-1980.

Intracerebral Hemorrhage Specific Intensity of Care Quality Metrics-

An algorithm that evaluates principles of care using the "best available" evidence in a semi

Variable Quality parameter

Treatment of acute hypertensive response (SBP ≥180

Time interval between two consecutive SBP≥180 mm Hg AND first SBP<180 mm Hg response (SBP ≥180

mm Hg)AND first SBP<180 mm Hg recording

Re: Qureshi AI. Neurocrit Care 2011;14:291

26 quality indicators related to 18 facets of care

Hemorrhage Specific Intensity of Care -BP management

An algorithm that evaluates principles of care using the "best available" evidence in a semi-quantitative manner

Quality parameter 1 points if YES or not applicable

Time interval between two consecutive SBP≥180 mm Hg AND first SBP<180 mm Hg

Achieved target range with 2. 5 hours of second of AND first SBP<180 mm Hg hours of second of the two consecutive measurements OR not applicable

Re: Qureshi AI. Neurocrit Care 2011;14:291-317

26 quality indicators related to 18 facets of care

507090

110130150170190210230

1 2 3 4 5 6 7 8 9 10 11 12

Sys

tolic

blood

pre

ssur

e

(mm H

g)

Time (hours)

Intravenous calcium channel blocker infusion initiated

Figure 3Effective and timely reduction of SBP:Achieved target range with 2. 5 hours

Baseline 2 hours

Time (hours)

12 13 14 15 16 17 18 19 20 21 22 23 24 25

Time (hours)

Intravenous calcium channel blocker infusion initiated

Effective and timely reduction of SBP:with 2. 5 hours =1 point

24 hours

Time (hours)

Intracerebral Hemorrhage Specific Intensity of Care Quality Metrics-VALIDATION STUDY

Score on performance metrics and survival in 50patients with ICH

Low

Re: Qureshiu AI. J Stroke Cerebrovasc Dis. 2012 May 24. [Epub ahead of print]

Low performance

17

Hemorrhage Specific Intensity of Care VALIDATION STUDY

Score on performance metrics and survival in 50patients with ICH

High

Re: Qureshiu AI. J Stroke Cerebrovasc Dis. 2012 May 24.

High performance

26

Intracerebral Hemorrhage Specific Intensity of Care Quality Metrics-26 quality indicators

Score on performance metrics and survival

% s

urviva

l

Re: Qureshiu AI. J Stroke Cerebrovasc Dis. 2012 May 24. [Epub ahead of print]

% s

urviva

lHemorrhage Specific Intensity of Care

26 quality indicatorsScore on performance metrics and survival

Re: Qureshiu AI. J Stroke Cerebrovasc Dis. 2012 May 24.


Phase I(1985-1997)

Phase II(1998-2003)




CASE SERIES





Phase IV(2010---)







Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT)

Variables Intensive SBP<140mmHg

(n=203)

Hematoma expansion (>33% or 12.5 ml)

15%

Variables SBP reduction ≥60 mmHg

(n=32)

Hematoma expansion(>33%)

19%

Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) Study

Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT) Lancet Neurology 2008;7:391-399

SBP<140mmHg AHA-guidelineSBP<180mmHg

(n=201)

p-value

23% 0.05

SBP reduction SBP reduction <60 mmHg

(n=28)

RR (95% CI)

33% 0.6 (0.2, 1.4)

Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) Study. Arch Neurol 2010: 67(5):570-6.



(n=52)


12%

aft

er

onse

t


(n=11)


18%


Tre

ate

d <

3 h

rsaft

er

onse

tIntensive blood pressure reduction in acute cerebral

haemorrhage trial (INTERACT) Lancet Neurology 2008;7:391-399


(n=52)

p-value

27% 0.08


(n=9)

RR (95% CI)

38% 0.5 (0.1, 2.3)




(n=52)


12%

aft

er

onse

t

Attenuation of hematoma expansion with intensive SBP


(n=11)


18%


Tre

ate

d <

3 h

rsaft

er

onse

t

Attenuation of hematoma expansion with intensive SBP reduction. Attenuation most prominent in patients

recruited within 3 h

Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT) Lancet Neurology 2008;7:391-399


(n=52)

p-value

27% 0.08

Attenuation of hematoma expansion with intensive SBP


(n=9)

RR (95% CI)

38% 0.5 (0.1, 2.3)


Attenuation of hematoma expansion with intensive SBP reduction. Attenuation most prominent in patients

recruited within 3 h


Phase I(1985-1997)

Phase II(1998-2003)




CASE SERIES





Phase IV(2010---)







Primary hypothesis: ATACH II

Intensive SBP reduction1 reduces the likelihood of death or disability at 3m2 after ICH by 10% or greater when compared with reduction.reduction.

1. SBP≤140 mmHg using IV nicardipine with treatment within 3.5 h of onset of ICH

2. Defined by mRS score of 4-6 3. SBP≤180 mmHg

Primary hypothesis: ATACH II

reduces the likelihood of after ICH by 10% or

greater when compared with standard SBP

≤140 mmHg using IV nicardipine with treatment initiated and continued for the next 24h

6

Trial design: ATACH IIre. Qureshi AI, Palesch YY. Neurocrit Care. 2011;15(3):559

Trial design: ATACH IIre. Qureshi AI, Palesch YY. Neurocrit Care. 2011;15(3):559

SBP<180 mm Hg

Baseline

SBP<140 mm Hg

: ATACH IIre. Qureshi AI, Palesch YY. Neurocrit Care. 2011;15(3):559-76.

: ATACH IIre. Qureshi AI, Palesch YY. Neurocrit Care. 2011;15(3):559-76.

24 hrs 3 m

Overview of the study design

Patient screened

Patient meets eligibility criteria

Randomize subjects 1:1

Intensive treatment

SBP≤140mmHg

Standard treatmentSBP≤180mmHg using

IV nicardipinetreatment

SBP≤140mmHg using IV

nicardipine±labetalol

SBP≤180mmHg using IV nicardipine±labetalol

mRS and Euro-QOL

Overview of the study design-ATACH II

ED personnel

Site investigator

WebDCUTM system at MUSC

Standard treatmentSBP≤180mmHg using

IV nicardipine

Site investigator SBP≤180mmHg using

IV nicardipinelabetalol

Blinded neurological evaluation by site investigator

FDA-IND-exempt # 107804

INTERACT II

• Onset <6 hours

• SBP 150-220 mm Hgmm Hg

SBP-66% in 6h

SBP90% in 2h

ATACH II

• Onset <4.5 hours

• SBP >180 mm Hg

• Hematoma vol.<60 ccvol.<60 cc

SCORE IT• CT spot sign

SBP-90% in 2h

Intensityof care

Integration: additive OR synergistic?Integration: additive OR synergistic?

ATACH IIINTERACT II

SBP reduction <140 mm Hg<140 mm Hg

Time window

Patient subset

Time to reach SBP goals

Intensity of care

: additive OR synergistic?: additive OR synergistic?

STICH IISurgical evacuationof lobar ICH

Intensity of care

IVH-CLEARIntraventricularhemorrhage+thrombolytics

Treatment of acute hypertensive response:

Choosing the right IV antihypertensive agent


Choosing the right IV antihypertensive agentantihypertensive agentantihypertensive agent

Re: Qureshi AI: Circulation 2008 Jul 8;118(2):176


Choosing the right IV antihypertensive agent


Choosing the right IV antihypertensive agentantihypertensive agentantihypertensive agent

Qureshi AI: Circulation 2008 Jul 8;118(2):176-87.

The search for the ideal regimenThe search for the ideal regimen

• Treats underlying pathophysiology• Rapid onset of action• Predictable dose response• Titratable to desired BP

• Treats underlying pathophysiology• Rapid onset of action• Predictable dose response• Titratable to desired BP • Titratable to desired BP • Minimal dosage adjustments• Minimal adverse effects• No increase in ICP• No coronary or cerebral steal• Easy transition to oral formulation

• Titratable to desired BP • Minimal dosage adjustments• Minimal adverse effects• No increase in ICP• No coronary or cerebral steal• Easy transition to oral formulation

The search for the ideal regimenThe search for the ideal regimen

Treats underlying pathophysiology

Predictable dose responseTitratable to desired BP

Treats underlying pathophysiology

Predictable dose responseTitratable to desired BP Titratable to desired BP Minimal dosage adjustmentsMinimal adverse effects

No coronary or cerebral stealEasy transition to oral formulation

Titratable to desired BP Minimal dosage adjustmentsMinimal adverse effects

No coronary or cerebral stealEasy transition to oral formulation

Systolic blood pressure recordings for 24 IV Labetalol+ Hydralazine


125

150

175

200

225

250

275

Syst

olic b

lood

pre

ssur

e (mm H

g)

0

25

50

75

100

125

0 2 4 6 8 10Time after initiation of antihypertensive treatment (hrs)

Syst

olic b

lood

pre

ssur

e (mm H

g)

From: Qureshi AI. Journal of Intensive Care: 2005;20:34

recordings for 24 hrs in ICH ptsIV Labetalol+ Hydralazine± Nitroprusside


12 14 16 18 20 22 24Time after initiation of antihypertensive treatment (hrs)

From: Qureshi AI. Journal of Intensive Care: 2005;20:34-42



125

150

175

200

225

250

275

Syst

olic b

lood

pre

ssur

e (mm H

g)

IV bolusIV bolus

0

25

50

75

100

125

0 2 4 6 8 10Time after initiation of antihypertensive treatment (hrs)

Syst

olic b

lood

pre

ssur

e (mm H

g)

From: Qureshi AI. Journal of Intensive Care: 2005;20:34



IV bolusIV bolus

IV bolus

12 14 16 18 20 22 24Time after initiation of antihypertensive treatment (hrs)

From: Qureshi AI. Journal of Intensive Care: 2005;20:34-42

� Goals not met� Prominent fluctuations

Hourly mean arterial pressure recordings for the 24hour period in ICH pts (IV nicardipine infusion)

From: Qureshi AI. Critical Care Medicine 2006;34:1975

Hourly mean arterial pressure recordings for the 24-hour period in ICH pts (IV nicardipine infusion)

From: Qureshi AI. Critical Care Medicine 2006;34:1975-80

Hourly mean arterial pressure recordings for the 24hour period after initiating IV nicardipine infusion

Infusion based regimens are more

From: Qureshi AI. Critical Care Medicine 2006;34:1975

Infusion based regimens are moreeffective than bolus based regimens

Hourly mean arterial pressure recordings for the 24-hour period after initiating IV nicardipine infusion

Infusion based regimens are more

From: Qureshi AI. Critical Care Medicine 2006;34:1975-80

Infusion based regimens are moreeffective than bolus based regimens

Antihypertensive medication and intracranial pressureAntihypertensive medication and intracranial pressure

Intracranial mass lesion+ Cerebral blood volume [venous]=ICP

Antihypertensive meds→ Cerebral venous dilation

Antihypertensive medication and intracranial pressureAntihypertensive medication and intracranial pressure

Intracranial mass lesion+ Cerebral blood volume [venous]=ICP

Cerebral venous dilation→ CBV [venous]↑↑

Comparison of IV antihypertensive agentsComparison of IV antihypertensive agentsAgent Mechanism of

action

Cerebral

blood flow

Labetolol α & β-adrenergic

blockers

Hydralazine Direct relaxation

of arteriolar

smooth muscle smooth muscle

Nitroprusside Releases nitric

oxide

Nicardipine Calcium channel

blocker

Esmolol∗∗ β-adrenergic

blocker


Comparison of IV antihypertensive agentsComparison of IV antihypertensive agentsCerebral

blood flowICP Onset of

action

… … 5-10 min

++ ++ 10-20 min

++ ++ Within

seconds

+ … 5-10 min

… … 5 min

Re: Qureshi AI: Circulation 2008 Jul 8;118(2):176-87

SummarySummary


SummarySummary

Qureshi AI: Circulation 2008 Jul 8;118(2):176-87.

Stroke subtype specific BP treatment recommendations:

American Stroke Association, Stroke Council



Acute ischemic stroke

Not a candidate for thrombolysis

Candidate for thrombolysis

Acute Suspect high Acute intracerebral hemorrhage

Suspect high ICP

Do not suspect high ICP

Acute subarachnoid hemorrhage

Aneurysm not secured

Aneurysm secured





SBP<220 mm Hg

SBP<160 mm Hg

SBP<180 mm Hg

SBP<180 HgSBP<180 Hg

SBP<160 mm Hg

SBP<160 mm Hg

Depends upon presence of vasospasmDepends upon

presence of vasospasm





Acute ischemic stroke

Not a candidate for thrombolysis

Candidate for thrombolysis

Acute Suspect high Acute intracerebral hemorrhage

Suspect high ICP

Do not suspect high ICP

Acute subarachnoid hemorrhage

Aneurysm not secured

Aneurysm secured

Early diagnosis and differentiationinto stroke subtypes is key!!





SBP<220 mm Hg

SBP<160 mm Hg

SBP<180 mm Hg

SBP<180 HgSBP<180 Hg

SBP<160 mm Hg

SBP<160 mm Hg

Depends upon presence of vasospasmDepends upon

presence of vasospasm

Early diagnosis and differentiationinto stroke subtypes is key!!

ConclusionsConclusions

� Treatment of acute hypertensive response in patients with stroke represents a widely applicable and cost effective intervention to improve patient outcomes.improve patient outcomes.

� However such benefit is contingent on appropriate interpretation, implementation, and integration of results of on

ConclusionsConclusions

Treatment of acute hypertensive response in patients with stroke represents a widely applicable and cost effective intervention to improve patient outcomes.improve patient outcomes.

However such benefit is contingent on appropriate interpretation, implementation, and integration of results of on-going clinical trials.

Thank you

Zeenat Qureshi Stroke Research Center 2012

Thank you

Zeenat Qureshi Stroke Research Center 2012

INTERACT II

• Onset <6 hours

• SBP 150-220 mm Hgmm Hg

SBP-66% in 6h

SBP90% in 2h

ATACH II

• Onset <4.5 hours

• SBP >180 mm Hg

• Hematoma vol.<60 ccvol.<60 cc

SCORE IT• CT spot sign

SBP-90% in 2h

Intensityof care

acute hypertensive response in stroke: pathophysiology and ...haemorrhage trial (interact) variables...

Documents