Spontaneous Intracerebral Hemorrhage ICH Is Common High Risk

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					                  Spontaneous Intracerebral                                                                                ICH Is Common
                        Hemorrhage                                                                            Incidence Predicted to Increase
                                                                                                                                                                                                                                100%
                                                                                                                                                                                                                              Increase
              Raul G Nogueira, MD                                                                 ICH Proportion of Strokes                                         100,000
                                                                                                            (US)




                                                                                                                                                   No. of Persons
Vascular and Critical Care Neurology                                                                                                                                 75,000
 Interventional Neuroradiology and                                                                                     ICH       SAH
     Endovascular Neurosurgery                                                                                          9%       3%                                  50,000

       Massachusetts General Hospital
          Harvard Medical School                                                                                                                                     25,000
               Boston, MA
                                                                                                                                                                                                    0
                                                                                                700,000 Total Strokes Annually                                                                              2000                2050
                                                                                                                                                                                                                      Year


                                                                                             Qureshi AI, et al. N Engl J Med. 2001;344:1450-1460; Thom T, et al. Circulation.
                                                                                             2006;113:e85-e151.




                        High-Risk Populations                                                         Traditionally High Mortality and
              ●   Hypertensive patients (especially poorly controlled)                                       Limited Recovery
              ●   Anticoagulant users
                                                                                             • Mortality
              ●   Patients with multiple comorbid risk factors                                                                                                                                    100%
                                                                                                  – 6-month, 30%-50%
              ●   Age >55 years                                                                   – 1-year, 50%
                                                                                                                                                                                                  90%

                                                                                                                                                                                                  80%
              ●   Patients with cerebral microangiopathy (eg, cerebral




                                                                                                                                                                     Proportion of patients (%)
                  amyloid angiopathy)                                                        • Only 20% of ICH patients                                                                           70%


              ●   Patients with dementia                                                       are independent at 6                                                                               60%

                                                                                                                                                                                                  50%
              ●   Certain ethnic populations                                                   months vs 60% of
                     – African Americans                                                       ischemic stroke patients                                                                           40%


                     – Hispanics                                                                                                                                                                  30%


                     – Asians (especially Japanese)                                           • Medical costs                                                                                     20%

                                                                                                                                                                                                  10%
              ●   Alcohol abusers                                                                  – US$125,000 lifetime cost per
                                                                                                     person (1990)                                                                                 0%
              ●   Smokers                                                                                                                                                                                       ICH           Ischemic
                                                                                                   – Direct and indirect costs (lost
              ●   Patients with renal or liver failure                                               productivity + caregiver burden)                                                                    Dead     Dependent     Independent

    Hart RG, et al. Stroke. 1995;26:1471-1477; Steiner T, et al. Stroke. 2006;37:256-262;
    Mayer SA, Rincon F. Lancet Neurol. 2005;4:662-672; Qureshi AI, et al. N Engl J Med.      Manno EM, et al. Mayo Clin Proc. 2005;80:420-433; Mayer SA, Rincon F. Lancet Neurol.
    2001;344:1450-1460; Labovitz DL, et al. Neurology. 2005;65:518-522; Kissela B, et al.    2005;4:662-672; Qureshi AI, et al. N Engl J Med. 2001;344:1450-1460; Taylor TN, et al.
    Stroke. 2004;35:426-431; Koennecke HC. Neurology. 2006;66:165-171.                       Stroke. 1996;27:1459-1466; Reed SD, et al. Neurology. 2001;57:305-314.




                        Predictors of Outcome                                                                Sites of Spontaneous ICH
                                                                                                                                                                                                                                    Thalamic
                                                                                                                                                                                                                                    Hemorrhage
                                                                                                                                                                                                                                    (20%)
●    Hematoma volume                                                                        Lobar
                                                                                            Subcortical
●    GCS                                                                                    Hemorrhage
                                                                                            (25%)
●    Intraventricular
     hemorrhage                                                                                                                                                                                                                     Pontine
                                                                                                                                                                                                                                    Hemorrhage
●    Age                                                                                    Putaminal                                                                                                                               (7%)
                                                                                            Hemorrhage
●    ICH location (deep)                                                                    (35%)


●    Increased cerebral edema
     (midline shift, herniation)                                                                                                                                                                                                    Cerebellar
                                                                                                                                                                                                                                    Hemorrhage
                                                                                                                                                                                                                                    (8%)



    Manno EM, et al. Mayo Clin Proc. 2005;80:420-433; Garibi J, et al.                      Mayer SA, Rincon F. Lancet Neurol. 2005;4:662-672;
    Br J Neurosurg. 2002;16:355-361.                                                        Qureshi AI, et al. N Engl J Med. 2001;344:1450-1460.




                                                                                                                                                                                                                                                 1
Recurrence Risk Distinguishes Lobar                                                                               Mechanisms of Injury
          from Deep ICH
                                                                                            Early hematoma growth
                                                                                               – Hematoma
                                                                                                 enlargement
                                                                                               – Increase in ICP,
                                                                                                 tissue disruption
                                                                                                 and shear forces
                                                                                            Edema and toxic effects
                                                                                            of blood products
                                                                                               – Osmotically active
                                                                                                 serum products
                                                                                               – Thrombin
                                                                                            Inflammatory response



                 Viswanathan Neurology 2006;66:206                                          Qureshi AI, et al. N Engl J Med. 2001;344:1450-1460.




                 Hematoma Expansion                                                                           Hematoma Expansion
                                                                                                  Contrast extravasation is independently
                                                                                                  associated with hematoma expansion and
                                                                                                  worse outcomes!
                                                                                            Patient with spot sign, demonstrating extravasation and hematoma expansion




       • 72% have some hematoma expansion over the first 24 hours
       • 38% have significant (>33%) expansion over 24 hours
           • In 26% of these cases, the enlargement is within 1 hour

                                                                                                      Wada, R. et al. Stroke 2007;38:1257-1262
Davis SM, et al. Neurology. 2006;66:1175-1181;
Brott T, et al. Stroke. 1997;28:1-5.
                                                                                                      Goldstein JN Neurology. 2007 Mar 20;68(12):889-94.
                                                                                        9                                                                                              10




               Common Etiologies of ICH                                                                    Common Etiologies of ICH
                            Primary Hypertension                                                                Cerebral Amyloid Angiopathy
                        Features and Characteristics                                                                   Features and Characteristics
                                                                                                                                                      Location
                                                         Typical sites                                                                                  – Lobar hemorrhage
                                                            – Putamen – 50%                                                                             – Multiple, bilateral
                                                            – Thalamus – 15%                                                                            – Parieto-occipital location
                                                            – Lobar – 15%                                                                             Associated with dementia/AD
                                                            – Cerebellum – 10%
                                                                                                                                                      Elderly patients (>70 years)
                                                            – Pons – 10%
                                                                                                                                                      Typically less severe than
                                                         Typically more severe than                                                                   HTN-related ICH
                                                         cerebral amyloid angiopathy-
                                                         related ICH                                                                                  Risk of recurrence
                                                                                                                                                      5%-15% annually
                                                         Risk of recurrence ~2%
                                                         annually (if BP controlled)                                                                  Microbleeds on
                                                                                                                                                      gradient-echo MRI
Woo D, et al. Stroke. 2002:33:1190-1195; Labovitz DL, et al. Neurology.                      Labovitz DL, et al. Neurology. 2005;65:518-522; Mayer SA, Rincon F. Lancet Neurol.
2005;65:518-522; Mayer SA, Rincon F. Lancet Neurol. 2005;4:662-672;                          2005;4:662-672; Yen CP, et al. Acta Neurochir. 2005;147:393-399; Woo D, et al. Stroke.
Qureshi AI, et al. N Engl J Med. 2001;344:1450-1460.                                         2002;33:1190-1195.




                                                                                                                                                                                            2
            Common Etiologies of ICH                                                                                                      Common Etiologies of ICH
       Acquired Coagulopathy – Anticoagulation                                                                              Acquired Coagulopathy – Thrombolytic Therapy
                                                                                                                                                                              tPA increases risk of ICH
                                                                                     Warfarin and Hematoma                                                                    (6% absolute risk in NINDS trial)
                                                                                           Expansion                                                                          18.5% of bleeds at sites distant
                                                                                                                                                                              from stroke

                                                    Hematoma Expanders
                                                                         1.00
                                                                                    No Warfarin (n=9)

                                                       Proportion of                                                                                                          Risk factors
                                                                         0.75

  Warfarin indicated in DVT, PE, AF                                                                                                                                            – Age >70 years
                                                                         0.50                                 P<.001
  Incidence of anticoagulant-associated
  ICH rose from 5% to 18% of cases of                                    0.25
                                                                                                                                                                               – Serum glucose >300 mg/dL
  spontaneous ICH in 1990s                                                                   Warfarin (n=7)
                                                                                                                                                                               – NIHSS >20
  INR 2.5-4.5 increases risk of ICH 10X                                  0.00
                                                                                0       12      24      36     48      60                                                      – Early ischemic changes
  Associated with longer duration of ICH                                                          Time (h)                                                                       detected on CT
  expansion
  Doubles ICH mortality!                                                                                                                                                       – Not time to treatment!
Hart RG, et al. Stroke. 1995;26:1471-1477; Steiner T, et al. Stroke. 2006;37:256-262;
reproduced with permission from Flibotte JJ, et al. Neurology. 2004;63:1059-1064;
Rosand J, et al. Arch Intern Med. 2004;164:880-884; Flaherty ML, et al. Stroke.
                                                                                                                            NINDS t-PA Stroke Study Group. Stroke. 1997;28:2109-2018.
2006;37:623.




                                                                                                                                              Other Etiologies of ICH
                     Other Etiologies of ICH
                                                                                                                                   Hemorrhagic                              ICH
                                        Drug-related                                                                              conversion of
                                                                                                                                 ischemic stroke
              Cocaine                                                                                                                                           Neoplasms
                                                                                                                                                                Melanoma
              Amphetamines
                                                                                                                                                                Renal Cell Ca
                                                                                                                                                                                            Head trauma
              Other illicit drugs                                                                                                                               Thyroid Ca
              (eg, talwin-pyribenzamine, phencyclidine)                                                                                                         ChorioCa
                                                                                                                                                                Lung Ca
              MAO inhibitors




                                                                                                                                       Pial Arteriovenous Malformations
                     Other Etiologies of ICH                                                                                61 y/o man p/w acute onset of speech difficulties and right HH in
                                                                                                                            the setting of a left tempo-occipital ICH
                                   Vascular lesions
              Cerebral aneurysm
              Arteriovenous malformations
              Dural A-V fistulas
              Cavernous malformation
              Venous angioma/capillary telangectasia




                                                                                                                                                                                                                  3
              Dural Arteriovenous Fistula
                                                                                                     Other Etiologies of ICH
                                          59 y/o female p/w severe left-sided
                                          h/a f/by expressive aphasia in the
                                                                                                                   Other Etiologies
                                          setting of a L frontotemporoparietal                Vasculitis
                                          ICH
                                                                                              Other vasculopathies (post partum,
                                          DAVF with Cortical Venous Reflux                    pheocromocytoma, etc)
                                                                                              Mycotic aneurysm
                                                                                              Moya-moya
                                                                                              Intracranial dissection
                                                                                              Dural venous sinus thrombosis




45 YEAR OLD MAN PRESENTS WITH HEADACHES AND CONFUSION                            45 YEAR OLD MAN PRESENTS WITH HEADACHES AND CONFUSION

                                                                                 BASELINE ANGIOGRAM




                                                                                 ANGIOGRAM POST REMOVAL OF PHEOCROMOCYTOMA




                          Screening for ICH                                                        ICH Management in ED
                              Clinical Symptoms                                                      Assessment and Stabilization
            The likelihood of ICH doubles* when one of the                                            Activate Stroke Team Prior to Arrival
            following is present:
                                                                                               Immediate General Assessment/Stabilization
                  ● Impaired level of consciousness
                                                                                    •   Assess ABCs/vital signs, monitor BP closely
                  ● Vomiting                                                        •   O2 (if hypoxic)
                  ● Severe headache                                                 •   IV access and labs (coagulation, platelets, CBC, electrolytes)
                  ● Warfarin therapy                                                •   Check glucose and treat (if indicated)
                  ● SBP >220 mm Hg                                                  •   Quick history
                                                                                    •   Neurologic screening assessment (GCS, NIHSS)
                  ● Hyperglycemia (glucose >170 mg/dL)
                                                                                    •   Emergent CT scan of brain (ASAP)
                      in nondiabetic patients
                                                                                    •   12-lead ECG
*Likelihood ratio 2.4; 95% CI, 1.8-3.2.
 Goldstein LB, Simel DL. JAMA. 2005;293:2391-2402.                                AHA Adult Stroke Guidelines. Circulation. 2005;112(suppl 24):IV-111-IV-120.




                                                                                                                                                                4
                            Diagnosis of ICH                                                                                                    Diagnostic Imaging
                              AHA Guidelines (2007)                                                       “Blood in the Brain” – What Type of Hemorrhage?
     • Vomiting, early change LOC, and ↑ BP suggest ICH
     • CT or MRI are both first choice for initial evaluation
     • MRI and MRA in selected patients
            – Suspected cavernous malformation in normotensive
              surgical candidates with lobar hemorrhage
     • Consider angiography (CTA or angiogram)
            – All surgical candidates without clear cause
            – Particularly young, clinically stable patients                                                 Intracerebral                               Intraventricular         Subarachnoid
            – Timing depends on factors including clinical state                                           hemorrhage (ICH)                             hemorrhage (IVH)        hemorrhage (SAH)


    Broderick JP, et al. Stroke. 1999;30:905-915.
    Broderick JP, et al. Stroke 2007;38;2001-2023.                                                     Images courtesy of i TEAM Scientific Committee.




                                                                                                                                   ICH Mortality Rate Is Reduced
            General Management of ICH
                                                                                                                                    With Admission to an NICU
         Goals        Provide general supportive care in the                                                                   1.0

         ED and ICU/NICU to manage the primary brain injury                                                                                           Non-NICU admission is associated
         and limit the secondary brain injury                                                                                                         with increased in-hospital mortality
                                                                                                             Cumulative Survival


                                                                                                                                   .9
                                                                                                                                                      (OR, 3.4; 95% CI, 1.65-7.6)
                   •   Continue to support ABCs
                                                                                                                                   .8
                   •   Monitoring (BP, fever, ICP, labs)
                                                                                                                                                                                        Neuro
                   •   Intubation                                                                                                                                                       General
                   •   BP management                                                                                               .7

                   •   Seizure management
                   •   Reverse anticoagulation immediately                                                                         .6
                                                                                                                                        0   5   10 15 20 25 30 35 40 45 50
                                                                                                                                                         Day
                                                                                                        Diringer MN, Edwards DF. Crit Care Med. 2001;29:635-640.




         Should BP Be Lowered in ICH?                                                                                 Should BP Be Lowered in ICH?
•   Current data are inconclusive as to whether BP lowering is useful and about
    defining a target
•   Potential benefits
        –    Limit hematoma growth
        –    Decrease perihematoma edema
               • Isolated SBP ≤210 mmHg not clearly related to hemorrhagic expansion or to
                 neurological worsening
               • Baseline BP not associated with ICH growth in the largest prospective study of ICH
                 growth

•   Potential downside
        –    Create or exacerbate perihematoma ischemia
               • No significant change was observed in either global CBF or periclot CBF as measured
                 by PET after 15% MAP reduction


•   Even if BP lowering isn’t harmful, does it help?
        –    Antihypertensive Treatment in Acute Cerebral Hemorrhage (ATACH) Study
        –    INTERACT study (Intensive Blood Pressure Reduction in Acute Cerebral
             Hemorrhage)

•   Different approaches based on ICH etiology (AVM, aneurysm, CAA)?                                    Broderick JP, et al. Stroke. 1999;30:905-915; Broderick JP, et al. Stroke
                                                                                                        2007;38;2001-2023 Manno EM, et al. Mayo Clin Proc. 2005;80:420-433; Mayer
                                                                                                        SA, Rincon F. Lancet Neurol. 2005;4:662-672; Qureshi AI, et al. N Engl J Med.
                                                                                                        2001;344:1450-1460.




                                                                                                                                                                                                   5
                           Seizures and ICH
                                                                                                               Management of Seizures
   • Seizures are more frequent                       • Poorer outcomes
     in ICH than in ischemic                                                                              AHA guidelines recommend administering
     stroke                                                – Neuronal injury and
                                                             destabilization of                           anticonvulsants for seizure at onset of ICH
   • Seizure risk is 8% after ICH                            critically ill patient
   • Most seizures at onset or                             – Nonconvulsive seizures                       Consider anticonvulsants for ≤1 month in
     ≤24 h of ICH                                            may contribute to coma
                                                                                                          selected patients with lobar hemorrhage
   • More commonly associated                              – Seizures associated
     with lobar than deep ICH                                with deterioration of
                                                             NIHSS and increase in
                                                             midline shift



Vespa PM, et al. Neurology. 2003;60:1441-1446; Mayer SA, Rincon F. Lancet Neurol.
2005;4:662-672; Passero S, et al. Epilepsia. 2002;43:1175-1180; Qureshi AI, et al.             Broderick JP, et al. Stroke. 1999;30:905-915; Qureshi AI, et al. Stroke.
N Engl J Med. 2001;344:1450-1460; Broderick JP, et al. Stroke. 1999;30:905-915.                2001;33:1916-1919; Passero S, et al. Epilepsia. 2002:43:1175-1180.




                              ICH Expansion                                                                                 ED Management:
                                                                                                            Preventing Hematoma Expansion



                                                                                                   • Warfarin reversal
                                                                                                   • Hemostatic therapy (clinical trial)
                                                                                                   • Blood pressure control (clinical trial)




         First CT (50 minutes)                          Second CT (160 minutes)




              Reversing Warfarin Effect:                                                                                     ED Management:
                    Time Counts!                                                                    Should All Patients Be Reversed?
        •    69 consecutive patients with warfarin-related ICH
        •    All patients had repeated INR measures and were
             treated aggressively for ICH in the MGH ED                                                     Because of the high mortality of
                                                                                                             OAT-ICH and high risk of
                                       INR reversed at 24 hours
                                                                                                             hematoma expansion, ALL OAT-
        Characteristic                   No (N=12)             Yes (N=57)            p value                 ICH patients should receive rapid
        Door to CT (min)                                                                                     and complete reversal of
          (Median (25-75%))              65 (30-90)            40 (25-85)            0.5
        CT to FFP (min)                  210 (100-375)         90 (60-205)           0.02
                                                                                                             anticoagulant effect in the
        FFP dose (units)                 2 (1-5)               4 (2-6)               0.1                     Emergency Department.
        CT to Vitamin K (min)            245 (37-361)          87 (25-210)           0.2




                                                                                                                                                                          6
      Reversing Warfarin Effect in the
                                                                                                           Reversing Anticoagulation
         Emergency Department
                                                                                                     ICH in any patient on warfarin (with INR ≥1.5)
        Current MGH Guidelines for ICH patients                                                         should be considered life-threatening
        •    Vitamin K 10 mg IV over 10 minutes STAT
                                                                                                 Goal              Normalize INR to <1.4 ASAP
        •    FFP 10 ml/kg over 90 minutes (Prothrombin Concentrate may
             be substituted for FFP.)                                                            • Time until initiation of warfarin reversal is the
                                                                                                      strongest predictor of 24-h coagulation reversal
        •    Team must designate a single physician to take personal
             responsibility for ensuring that these therapies are administered
             as fast as possible.                                                                • Reversal may not occur in 1 of 6 patients
        •    As soon as FFP ordered, “runner” dispatched to blood bank to
             collect FFP.

        www.stopstroke.org
                                                                                               Goldstein JN, et al. Stroke. 2006;37:151-155.
            Hanley. J Clin Path 2004;57:1132-39




  Reversing Anticoagulation (cont.)                                                            Reversing Anticoagulation (cont.)
      • Discontinue warfarin                                                                            • ASA-related coagulopathy
      • Agents used for reversal                                                                             – Platelet transfusion
             –   Fresh frozen plasma (FFP)
             –   Vitamin K                                                                              • No antidote for clopidogrel-related coagulopathy
             –   Prothrombin complex concentrates (PCC)
             –   Recombinant factor VIIa                                                                • Thrombolytic therapy-related coagulopathy
                                                                                                             – Stop thrombolytic agent
      • Issues to consider                                                                                   – 6-8 units of cryoprecipitate containing factor VIII
             – Normalization with FFP may take hours to days
             – FFP carries viral risk                                                                        – 6-8 units of platelets
             – PCC factor concentrations vary by batch/manufacturer                                     • Heparin- and enoxaparin-induced anticoagulation
             – PCC and rFVIIa have smaller volumes and more rapid
               administration than FFP                                                                       – Protamine sulfate
             – Vitamin K is commonly used with the other 3 approaches

Ansell J, et al. Chest. 2001;119(suppl 1):22S-38S; Hanley JP. J Clin Pathol. 2004;57:1132-
1139; Baker RI, et al. Med J Aust. 2004;181:492-497; Mayer SA, Rincon F. Lancet Neurol.
                                                                                              Manno EM, et al. Mayo Clin Proc. 2005;80:420-433; Makris M, et al. Br J Haematol.
2005;4:662-672; Steiner T, et al. Stroke. 2006;37:256-262;Freeman WD, et al. Mayo Clin
                                                                                              2000;80:420-433.
Proc. 2004;79:1495-1500; Huttner HB, et al. Stroke. 2006;37:1465-1470.




   Reducing Hematoma Expansion                                                                  Reducing Hematoma Expansion
                 Many Potential Hemostatic Agents                                                    Early Hemostatic Therapy With Factor VIIa
                                                                                                 •   Currently approved for use in hemophiliacs; initiates hemostasis
    • Aminocaproic acid                                  • DDAVP (Desmopressin)                  •   Well suited for limiting early hematoma growth in ICH
    • Prothrombin-complex                                • Tranexamic acid                       •   Local effects in endothelial disruption and vascular injury
       concentrates                                      • Cryoprecipitate                       •   Reduces bleeding in patients without coagulopathy
        – Concentrated                                                                           •   Rapidly normalizes INR in anticoagulant-associated ICH
          vitamin K–dependent
                                                         • Aprotinin (Trasylol)
                                                                                                 •   Has been studied as a therapy for ICH in:
          factors (factors II, VII,                                                                   – 2 phase IIa dose-escalation studies
          IX, X)                                                                                      – Phase IIb global dose-response study
    • Recombinant factor VIIa                                                                         – Phase III

                                                                                             Mayer SA. Stroke. 2003;34:224-229; Micieli G, et al. Neurol Sci. 2005;26(suppl 1):S34-S36;
                                                                                             Conti S, et al. Clin Lab Haematol. 2005;27:283-285; Mayer SA, et al. Stroke. 2005;36:74-79;
                                                                                             Mayer SA, et al. N Engl J Med. 2005;352:777-785; Busani S, et al. Thromb Haemost.
                                                                                             2005;93:381-382; Stroke Trials Registry. Internet Stroke Center. Available at:
                                                                                             http://www.strokecenter.org/trials.




                                                                                                                                                                                           7
                               rFVIIa Dose-Response Study                                                                     rFVIIa Phase IIb Dose-Response Study
                                                                                                                                    Change in Hematoma Volume at 24 Hours
     3 Hours                                    60 Min               24 Hours           90 Days
                                                                                                                                                  Percent Change in ICH Volume: Baseline → 24 Hours
                                                                                                                               35

                                                          Placebo                             Clinical outcome                 30
                                                           n=100                              • Mortality
                                                                                              • mRS                                          29%
                                                                                                                               25
                                                                                              • Barthel Index




                                                                                                                 % Increase
                                                           rFVIIa                             • E-GOS                          20
                                                          40 g/kg                             • NIHSS                                                         P=.07
                                                                           Efficacy           • GCS                                                                         P=.049                        P=.012*
                                                           n=100
N=400                                Baseline                              Percent change     • Euro-QOL
                                                                                                                               15
                                                                                                                                                            16%                            P=.015*
randomized                           CT scan                               in ICH volume                                                                                    14%                            14%
                                                           rFVIIa          on 24-hour CT                                       10
                                                          80 g/kg                             Safety                                                                                        11%
                                                           n=100                              Adverse events                    5
                                                                                              until discharge
                                                                                              Serious adverse
                                                           rFVIIa                                                               0
                                                                                              events until                                   Placebo       40 g/kg          80 g/kg        160 g/kg      Combined
                                                          160 g/kg                            day 90                                                                                                     Treatment
                                                            n=100                                                                                                                                         Groups
                                                                                                                              *ICTR values




Mayer S, et al. N Engl J Med. 2005;352:777-785.                                                                     Mayer S, et al. N Engl J Med. 2005;352:777-785.




                               rFVIIa Dose-Response Study                                                                               rFVIIa Dose-Response Study
                                                Survival at 90 Days                                                                               Functional Outcome at 90 Days
                               1.0
                                                                                                                                                              Modified Rankin Scale
                               0.9
                                                                                                                              160 g/kg
                               0.8
        Proportion Surviving




                               0.7
                                                                                                                                80 g/kg
                               0.6                 38% ↓ mortality
                               0.5                 (P=.02)
                                                                                                                                40 g/kg
                               0.4
                                                                                 Placebo                                        Placebo
                               0.3
                                                                                 rFVIIa, 40 /kg
                               0.2                                               rFVIIa, 80 /kg
                                                                                                                                             0%         20%           40%            60%     80%         100%
                               0.1                                               rFVIIa, 160 /kg
                               0.0                                                                                               0-1 no significant disability                4-5 moderate–severe-to-severe disability
                                     0      15           30     45         60      75       90
                                                                                                                                 2-3 slight-to-moderate disability            6 dead
                                                               Days

Reproduced with permission from Mayer SA, et al. N Engl J Med. 2005;352:777-785.                                    Adapted with permission from Mayer SA, et al. N Engl J Med. 2005;352:777-785.




    rFVIIa Phase IIb Dose-Response
           Study: Conclusions
   ● Compared with placebo, rFVIIa treatment
      – Significantly reduced hematoma growth (P=.01)
      – Significantly reduced mortality: 38% decrease (P=.02)
      – Significantly improved patient outcome
   ● Thromboembolic serious adverse events, mainly myocardial and
     cerebral infarction, occurred in 7% of rFVIIa patients compared
     with 2% of placebo patients (P=.12)
   ● Thromboembolic serious adverse events that were possibly or
     probably related to treatment and that were fatal or disabling
     occurred in 2% of rFVIIa-treated patients and in 2% of the
     placebo group




Mayer S, et al. N Engl J Med. 2005;352:777-785.




                                                                                                                                                                                                                         8
       Management of Increased ICP                                                             Restarting Anticoagulation After ICH
                               Treatment Options                                                    ACC/AHA 2006 Guideline
     • Osmotherapy                                    • Positional factors                 • Discontinue anticoagulants and antiplatelets ≥1-2 weeks
        – 3% or 23.4% saline                             – Raise head of bed 30º
        – Mannitol bolus                                 – Keep head at midline            • Reverse anticoagulation as soon as possible
          0.25-0.5 g/kg q4h                              – Avoid head and neck positions      (vitamin K, FFP)
        – Target 310 mOsm/L                                that compress jugular veins
        – Avoid hypo-osmolar fluids
        – Maintain euvolemia
                                                         – Avoid flat-supine position
                                                         – Tracheostomy/ETT ties loose
                                                                                           • If required, resume oral anticoagulation after
                                                                                              3-4 weeks (rigorous monitoring, INR in lower range); if
     • Hyperventilation                               • Sedation, short-term
                                                        neuromuscular paralysis               anticoagulation is needed sooner after ICH, IV heparin
        – Temporary measure as bridge
          for definitive intervention                 • Ventricular drain                     (with PTT 1.5 to 2.0 times normal) or LMWH may be better
        – Prolonged use can cause                       (especially for hydrocephalus)        acute therapy than oral warfarin
          cerebral ischemia
                                                                                           • Higher risk of recurrent ICH if anticoagulation resumed in
Broderick JP, et al. Stroke. 1999;30:905-915; Manno EM, et al. Mayo Clin Proc.                lobar ICHs, microbleeds, and suspected CAA on MRI
2005;80:420-433; Mayer SA, Rincon F. Lancet Neurol. 2005;4:662-672; Manno EM, et al.
Mayo Clin Proc. 2005;80:420-433; Audibert G, et al. Ann Fr Anesth Reanim. 2005;24:
492-501; Qureshi AI, et al. Neurosurgery. 1999;44:1055-1063; Saltarini M, et al.
Eur J Emerg Med. 2002;9:262-265.                                                           Adapted from Sacco RL, et al. Stroke. 2006;37:577-617.




Other Issues in Medical Management
 •   Steroids – No
 •   Fever is bad                                                                                     Surgical Intervention in ICH
       – Does controlling fever help?
       – Important in first 24 hours
 •   Hyperglycemia
                                                                                                  Goal      Remove as much blood clot as
       – Insulin infusions are en vogue in ischemic stroke
       – Little data for ICH either way
                                                                                                  possible, as quickly as possible, with the
 •   Don’t forget DVT prophylaxis                                                                 least amount of brain trauma
       – When can heparin be started?
            • Some say never and to use TEDS/SCDs
            • Others start SQ heparin or LMWH sometime after 48 hours
            • DVT = IVC Filter
 •   Don’t forget nutrition!
 •   Start rehab early
       – Begin range-of-motion exercises in ICU, even in comatose patients
       – Extent of rehab activities will depend on patient’s condition
Hemphill JC, et al. Stroke. 2006;37:724; Mayer SA, et al. Lancet Neurol. 2005;4:662-672;
Qureshi AI, et al. N Engl J Med. 2001;344:1450-1460.                                       Broderick JP, et al. Stroke. 1999;30:905-915.




                   Surgical Modalities:                                                                                Surgical Issues
                 Craniotomy, Stereotactic                                                         •   Evidence that it works?
Open craniotomy                                         + Gets all the blood                      •   Careful diagnosis
                                                        – Invasive, disrupts tissue               •   Timing of intervention: ultra-early, early, late
                                                                                                  •   Site of hemorrhage
Endoscopic aspiration                                   + Visualization
                                                        – Slow, leaves volume                     •   Technique – craniotomy, stereotactic
                                                                                                  •   Consistent, good medical management
Stereotactic evacuation                                 + No disruption                                – Monitoring
                                                        – Slow, leaves volume                          – Preventing re-bleeding
Intra-hematoma thrombolysis?                                                                           – Managing BP
                                                                                                  • Understand pathophysiology
Qureshi AI, et al. N Engl J Med. 2001;344:1450-1460; Broderick JP, et al. Stroke.
1999;30:905-915; Vespa P, et al. Neurocrit Care. 2005;2:274-281; Y Nievas MC, et al.       Hankey GJ, et al. Stroke. 1997;28:2126-2132;
Neurol Res. 2005;27:755-761; Nasser JA, et al. Arq Neuropsiquiatr. 2002;60:362-366.        Fernandes HM, et al. Stroke. 2001;31:2511-2516.




                                                                                                                                                          9
                                          STICH                                                                                                                                                             STICH
  International Surgical Trial in Intracerebral Hemorrhage                                                   International Surgical Trial in Intracerebral Hemorrhage
                                        1033 patients with ICH randomized                                                                                                 1.0
• Randomized
  prospective trial
                                                                                                                                                                          0.9                                                        No overall benefit
                                                                                                                                                                          0.8
                                                                                                                                                                                                                                     from early surgery




                                                                                                                                                Probability of survival
                                   503 allocated to                      530 allocated to
• N=1033                            early surgery                      initial conservative                                                                               0.7
                                                                                                                                                                                                                                     vs conservative
                                                         7 lost to           treatment
                                                                                                                                                                          0.6
• Early surgery                                         follow-up                              1 lost to                                                                                                                             treatment
                                                                                              follow-up                                                                   0.5
  (24 h to surgery;                 496 analyzed
  >96 h from onset) vs
                                     at 2 weeks                           529 analyzed
                                                                           at 2 weeks
                                                                                                                                                                          0.4                  Early surgery                         Benefit in subgroup
                                                        19 lost to                                                                                                                             Initial conservative
  initial conservative                                  follow-up                             24 lost to                                                                  0.3                                                        with hematoma
                                                                                              follow-up
  treatment                         477 followed                          505 followed
                                                                                                                                                                          0.2                                                        ≤1 cm from
                                   up at 6 months
• GCS >5 and ICH
                                                        9 alive but      up at 6 months
                                                                                              8 alive but
                                                                                                                                                                          0.1
                                                                                                                                                                                                                                     cortical surface
                                                          status                                status
  diameter ≥2 cm                                        unknown                               unknown
                                                                                                                                                                           0
                                                                                                                                                                                0   30    60    90   120    150    180   210   240
                                                                                                                                                                                                                                     (absolute benefit,
                                    468 analyzed at                      497 analyzed at
                                      6 months:                            6 months:                                                                                                                 Days                            8%; 95% CI, 0-15)
• 1º outcome =                     6 early follow-up                    4 early follow-up                   Numbers at risk (alive)
  death or disability            327 timely follow-up
                                  135 late follow-up
                                                                      347 timely follow-up
                                                                       146 late follow-up
                                                                                                            Early surgery 477 366 337                                                          321   314 309 304 304 304
                                                                                                            Initial
                                                                                                                                                                               505 380 349     339   329 324 319 316 316
                                                                                                            conservative

  Reproduced with permission from Mendelow AD, et al; for the STICH Investigators.
  Lancet. 2005;365:387-397.                                                                                 Reproduced with permission from Mendelow AD, et al. Lancet. 2005;365:387-397.




                 Stereotactic Treatment of Deep ICH
                               BEFORE                                                                                                                                               Reduction in Mass Effect

                                                                                                                                                              100
                                                                                                                   mm (midline) or cc (edema,vol)

                                                                                                                                                                          90
                                                                                                                                                                          80
                                                                                                                                                                          70
                                                                                                                                                                          60
                                                                                                                                                                                                                                                      Initial
                                                                                                                                                                          50
                                                                                                                                                                                                                                                      Final
                                           AFTER                                                                                                                          40
                                                                                                                                                                          30
                                                                                                                                                                          20
                                                                                                                                                                          10
                                                                                                                                                                          0
                                                                                                                                                                                         Edema                    ICH Volume          Midline shift




                                                                                                                 Vespa et al Neurocritical Care 2005;2:274-81




                      Surgical Candidates
                           AHA Guidelines (2007)                                                                                                                                         Treatment of ICH
   •   Cerebellar hemorrhage >3 cm with neurological deterioration or                                          • Prevention
       brain stem compression and/or hydrocephalus should have surgical
                                                                                                                                           – Modify risk factors
       removal of the hemorrhage ASAP (Class I, Level of Evidence B).
                                                                                                                                              • Control hypertension
   •   Lobar clots within 1 cm of the surface, evacuation of supratentorial
       ICH by standard craniotomy might be considered (Class IIb, Level of                                                                    • Limit anticoagulation
       Evidence B).                                                                                            • Acute intervention when it occurs
   •   No clear evidence indicates that ultra-early craniotomy improves                                                                    – Alter hemostasis
       functional outcome or mortality rate. Operative removal within 12                                                                      • rFVIIa for acute ICH
       hours, particularly by less-invasive methods, has the most                                                                             • Rapid reversal of coagulopathy in warfarin-
       supportive evidence, but the number of subjects treated within this                                                                      related ICH
       window is very small (Class IIb, Level of Evidence B).
                                                                                                                                           – Surgery
   •   Very early craniotomy may be associated with an increased risk of
       recurrent bleeding (Class IIb, Level of Evidence B).
                                                                                                                                              • Alternatives to craniotomy
                                                                                                                                           – Neuroprotection, rehabilitation, etc.

 Broderick JP, et al. Stroke 2007;38;2001-2023




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Thank you for your
    attention!




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