Najwa Al-Bustani Neurology PGY-3

INTRACEREBRAL HEMORRHAGE: Bleeding into the parenchyma of the brain that may extend into the ventricles and, in rare cases, the subarachnoid space.

LOCATIO NS Subcortical/lo bar: 20 % Putamen % Thalamus 15 % Pons 8 % Cerebellum 8 %

PATHOPHYSIOLOGY: 2 main concepts: 1. Haemorrhages continue to grow and expand over several hours after onset of symptoms—a process known as early haematoma growth. 1. Brain injury and swelling that happens in the days after ICH is the result of inflammation caused by thrombin and other coagulation end- products. Lancet Neurol 2005; 4: 662–72

INCIDENCE & MORTALITY: Each year, approximately 37,000 to 52,400 people in the United States. The case-fatality rate 34.6% at 7 days. 50.3% at 30 days. 59.0% at 1 year. ( Stroke. 2009;40:00-00)

RISK FACTORS: Hypertension %. Cerebral Amyloid Angiopathy- 15 %. Heavy alcohol consumption. Hypercholesterolemia. Anemia. Smoking/anti-platelet agents >> merging evidence.

PREDICTORS OF OUTCOME: ( Stroke. 2009;40:00-00)

MANAGEMENT: Medical: 1. Supportive care. 2. BP control. 3. Prevention of Hematoma growth. 4. ICP Surgical options.

BP MANAGEMENT: Hypertension theoretically could contribute to hydrostatic expansion of the hematoma, peri- hematoma edema, and rebleeding, all of which may contribute to adverse outcomes in ICH.

Assessed 76 consecutive patients with hypertensive ICH retrospectively. Attempted to lower SBP below targets of 140, 150, or 160 mm Hg. Recordings of serial BP from admission until the second CT scan were assessed. Hematoma enlargement was defined as an increase in volume of 140% or 12.5 cm 3.

RESULT S: Hematoma enlargement occurred in 16 patients. Maximum SBP was significantly associated with hematoma enlargement. After adjustment for other factors, maximum SBP was independently associated with hematoma enlargement. Target SBPs of 160 mm Hg were significantly associated with hematoma enlargement compared with those of 150 mm Hg. ( Stroke. 2004;35: )

CONCLUSION: Findings suggest that elevated BP increases the risk of hematoma enlargement. Efforts to lower SBP below 150 mm Hg may prevent this risk. ( Stroke. 2004;35: )

INTERACT: Open-label, randomized, controlled trial undertaken in 404 mainly Chinese patients. 203 randomized to lower BP to target a low systolic BP goal of 140 mm Hg within 1 hour and maintained for at least the next 24 hours. 201 randomized to a more modest systolic BP target of 180 mm Hg, as recommended in an earlier AHA guideline.

INTERCT: There was trend toward lower relative and absolute growth in hematoma volumes from baseline to 24 hours in the intensive treatment group compared with the control group. There was no excess of neurological deterioration or other adverse events related to intensive BP lowering, nor were there any differences across several measures of clinical outcome.

ANTIHYPERTENSIVE AGENTS: Lancet Neurol 2005; 4: 662–72

HAEMOSTATIC THERAPY: Use of anticoagulation. Reversal of anticoagulation.

N.ENGL.J MED. 358;20, may 15, 2008

AIM: Phase 3 trial to confirm a previous study in which recombinant activated factor VII (rFVIIa) reduced growth of the hematoma and improved survival and functional outcomes. N.ENGL.J MED. 358;20, may 15, 2008

METHODS: Randomly assigned 841 patients with ICH to receive placebo (268 patients), 20 μg of rFVIIa per kilogram of body weight (276 patients), or 80 μg of rFVIIa (297 patients) within 4 hours after the onset of stroke. The primary end point was poor outcome, defined as severe disability or death according to the modified Rankin scale 90 days after the stroke. Exclusion criteria: secondary ICH, anticoagulation use, GCS <5, pregnancy, previous disability. N.ENGL.J MED. 358;20, may 15, 2008

RESULTS: The mean estimated increase in volume of the ICH at 24 hours was 26% in the placebo group, as compared with 18% in the group receiving 20 μg of rFVIIa/Kg and 11% in the group receiving 80 μg. Growth in volume of ICH was reduced by 2.6 ml in the group receiving 20 μg of rFVIIa/Kg and by 3.8 ml in the group receiving 80 μg, as compared with the placebo group. N.ENGL.J MED. 358;20, may 15, 2008

RESULTS: Despite the reduction in bleeding, there was no significant difference among the three groups in the proportion of patients with poor clinical outcome (24% in the placebo group, 26% in the group receiving 20 μg of rFVIIa/Kg, and 29% in the group receiving 80 μg). Overall frequency of thromboembolic serious adverse events was similar in the three groups; however, arterial events were more frequent in the group receiving 80 μg of rFVIIa than in the placebo group. N.ENGL.J MED. 358;20, may 15, 2008

CONCLUSIO N: Haemostatic therapy with rFVIIa reduced growth of the hematoma but did not improve survival or functional outcome after intracerebral hemorrhage.

WARFARIN ASSOCIATED ICH: 7- to 10-fold higher than in patients not receiving warfarin therapy. Risk reaches 1% to 2% per year, and increases to 4.2% in patients older than 75 years. Mortality - 60%. INR 3.0 had greater hematoma volume. Neurology 2008;71;

REVERSAL OF ANTICOAGULATION: Therapy within 1.5 hours, early reversal by 2 hours. No randomized trials. Management Varies. ( Stroke. 2006;37: )

REVERSAL OF ANTICOAGULATION: Therapy chosen: Discontinuation of warfarin FFP PCC VIIa Time to OAC reversal: 5-14 days 3 - 6h for infusion & h for reversal min infusion & 15 min for reversal 15 min post bolus IV

PROTHROMBIN COMPLEX CONCENTRATE (PCC): Octaplex: Factors II, VII, IX, X, Protein C,S, Heparin. Dose: Initial dose is 40 mL (1000 IU Factor IX activity) and 10 mg vitamin K intravenously. If the INR is greater than 1.5 after initial or subsequent doses and the patient continues to bleed, consider administering an additional dose of 20 mL (500 IU Factor IX activity). The rate of infusion should not exceed 2-3 mL/min.

OCTAPLEX IN MNI: 60ml/hr over 5 minutes. If no interaction >> ml/hr. Vitamin K to be given. Octaplex lasts 6 hours, vitamin K starts within 8 hours, lasts hours.

FFP: Volume of 1 Unit Plasma: mL. 1 mL plasma contains 1 unit of coagulation factors. Unit contains 220 unit coagulation factors. Dose: ml/Kg. Volume overload: infusion rate 1 ml/Kg/hour.

Hold Warfarin. PCCs have not shown improved outcome compared with FFP but may have fewer complications compared with FFP and are reasonable to consider as an alternative to FFP (Class IIa; Level of Evidence: B). rFVIIa is not routinely recommended as a sole agent for OAC reversal in ICH (Class III; Level of Evidence: C).

Although rFVIIa can limit the extent of hematoma expansion in noncoagulopathic ICH patients, there is an increase in thromboembolic risk with rFVIIa and no clear clinical benefit in unselected patients. Thus rFVIIa is not recommended in unselected patients. (Class III; Level of Evidence: A)

Usefulness of platelet transfusions in ICH patients with a history of antiplatelet use is unclear and is considered investigational (Class IIb; Level of Evidence: B). Patients with ICH should have intermittent pneumatic compression for prevention of venous thromboembolism in addition to elastic stockings (Class I; Level of Evidence: B).

After documentation of cessation of bleeding, low dose subcutaneous low-molecular-weight heparin or unfractionated heparin may be considered for prevention of venous thromboembolism in patients with lack of mobility after 1 to 4 days from onset (Class IIb; Level of Evidence: B).

RESTARTING WARFARIN: All experts favored resumption of warfarin therapy within 3 to 10 days of ICH in stable patients in whom subsequent anticoagulation is mandatory. No general agreement occurred regarding sub- sequent anticoagulation of patients with atrial fibrillation who survived warfarin-associated ICH. Mayo Clin Proc. 2007;82(1):82-92

SURGICAL OPTIONS: The usefulness of surgery is uncertain (Class IIb; Level of Evidence: C). Cerebellar hemorrhage, brainstem compression/hydrocephalus >> should undergo surgical removal of the hemorrhage as soon as possible (Class I; Level of Evidence: B), ventricular drainage alone rather than surgical evacuation is not recommended. Patients presenting with lobar clots >30 mL and within 1 cm of the surface, evacuation of supratentorial ICH by standard craniotomy might be considered (Class IIb; Level of Evidence: B). ( Stroke. 2010;41:00-00.)

SURGICAL OPTIONS: No clear evidence at present indicates that ultra-early removal of supratentorial ICH improves functional outcome or mortality rate. Very early craniotomy may be harmful due to increased risk of recurrent bleeding (Class III; Level of Evidence: B). Intraventricular administration of recombinant tissue-type plasminogen activator in IVH appears to have a fairly low complication rate, efficacy and safety of this treatment is uncertain and is considered investigational (Class IIb; Level of Evidence: B). ( Stroke. 2010;41:00-00.)

IN SUMMARY: Be aware of early hematoma growth. BP control crucial >> mmHg. Reversal of anticoagulation. rFVIIa controversial. PCC coming into action, may replace FFP >> less volume overload. Surgical options = ??

RAISED ICP TREATMENT: Limited evidence for the monitoring and management of ICP after ICH. Majority of the evidence base and consensus guidance for the treatment of intracranial hypertension relates to traumatic brain injury. Limited studies for stroke. (Anesth Analg 2010;110:1419–27)

RAISED ICP TREATMENT: Osmotic therapy. Hyperventilation. Surgery. ?? Controversial.

HEAD ELEVATION: May reduce ICP by promoting venous outflow. Helps in TBI patients >> 30° head elevation. Cannot be easily translated to patients with acute ischemic stroke, as head elevation may also result in reduced cerebral perfusion pressure (CPP). Postgrad Med J :

OSMOTHERAPY: Create an osmotic gradient across the BBB, drawing water from the interstitial and intracellular space within the brain. Agents which produce a more favorable osmotic gradient are those which are excluded by the intact BBB to a greater degree. Postgrad Med J :

OSMOTHERAPY: Problems may arise in areas where the BBB is disrupted, resulting in reversal of the osmotic gradient and rebound cerebral edema, especially on treatment withdrawal. Relevant in acute stroke where large areas of the BBB may be disrupted, and may also cause preferential effects on the normal hemisphere where BBB remains intact, thus worsening tissue shifts. Postgrad Med J :

MANNITOL: Cochrane review: 3 randomized trials, 226 patients. Insufficient evidence to guide the routine use of mannitol in acute stroke. Effect on stroke outcome unclear, use based on expert opinion/non-randomized trials. Postgrad Med J :

MANNITOL: 20% solution, given as a bolus of g/Kg. Repeat dosing 0.25 to 0.5 g/Kg as needed, Q.1- 6H/4-8H. Target serum osmolality of mOsm/l. Effects: within minutes, peak at about one hour, and last 4 to 24 hours. J.Intensive Care Med : 55

HYPERTONIC SALINE: Limited data surrounding the use of hypertonic saline for stroke related edema in clinical practice. Excluded from the BBB > Mannitol  more potent osmotic agent. Complications: severe hype-Na, rebound hypo-Na on withdrawal, CHF, cardiac arrhythmia. Dose: 0.5 to 2.0 ml/kg 23.4% hypertonic saline, repeat 1-6H PRN.

HYPERVENTILATION: Hypoxia & hypercarbia >> potent cerebral vasodilators. Hyperventilation lowers ICP by inducing hypocarbia >> vasoconstriction. Demonstrated in TBI patients, outcome data lacking. Use for acute ICHT, temporizing measure pCO 2 30 – 35 mm Hg >> no response >> 25-30mmHg. pCO 2 > vasoconstriction

HYPERVENTILATION IN STROKE: Potential worsening of the hypoxic injury due to vasoconstriction. Possibility of rebound vasodilatation after treatment discontinuation resulting in further ICP elevation. Generally not recommended, may be considered as a holding measure until more definitive treatment is initiated.

Stroke 2007;38;

DECOMPRESSIVE SURGERY: DECIMAL, DESTINY, HAMLET >> increase in favorable outcome in the surgery group. Significantly reduced mortality, at the expense of an increase in moderate disability.

DECOMPRESSIVE SURGERY: Patients should be referred within 24 h of symptom onset, and treated within a maximum of 48 h.

TAKE HOME MESSAGE: ICPT- more data for TBI. Osmotherapy: limited information in stroke >> could be useful, ? Outcome change. Hyperventilation >> temporizing solution. Surgery >> to be considered in certain population.