Stroke management

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This is a short presentation at Down Town Hospital clinical meeting for DNB Medicine students. It dose not cover the all aspects of stroke care especially Thrombolysis, since it is difficult to practice for Medical specialist, and ischemic stroke is not common in North East India

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  • Stroke is third most common cause of death and most common neurologic emergency throughout the word. Stroke is a medical and occasionally a surgical emergencyThe majority of ischaemic stroke patients do not reach the hospital quickly enoughThe delay between stroke onset and hospital admission is;reduced if the Emergency Medical Systems (EMS) are usedincreased if doctors outside the hospital are consulted first
  • AbstractSummaryBackgroundRecent improvements in the monitoring and modelling of stroke have led to more reliable estimates of stroke mortality and burden worldwide. However, little is known about the global distribution of stroke and its relations to the prevalence of cardiovascular disease risk factors and sociodemographic and economic characteristics. MethodsNational estimates of stroke mortality and burden (measured in disability-adjusted life years [DALYs]) were calculated from monitoring vital statistics, a systematic review of studies that report disease surveillance, and modelling as part of the WHO Global Burden of Disease programme. Similar methods were used to generate standardised measures of the national prevalence of cardiovascular risk factors. Risk factors other than diabetes and disease burden estimates were age-adjusted and sex-adjusted to the WHO standard population. FindingsThere was a ten-fold difference in rates of stroke mortality and DALY loss between the most-affected and the least-affected countries. Rates of stroke mortality and DALY loss were highest in eastern Europe, north Asia, central Africa, and the south Pacific. National per capita income was the strongest predictor of mortality and DALY loss rates (p<0·0001) even after adjustment for cardiovascular risk factors (p<0·0001). Prevalences of cardiovascular risk factors measured at a national level were generally poor predictors of national stroke mortality rates and burden, although raised mean systolic blood pressure (p=0·028) and low body-mass index (p=0·017) predicted stroke mortality, and greater prevalence of smoking predicted both stroke mortality (p=0·041) and DALY-loss rates (p=0·034). InterpretationRates of stroke mortality and burden vary greatly among countries, but low-income countries are the most affected. Current measures of the prevalence of cardiovascular risk factors at the population level poorly predict overall stroke mortality and burden and do not explain the greater burden in low-income countries. FundingWHO. 
  • Indian studies have shown that about 10% to 15% of strokes occur in people below the age of 40 years, which is high compared to other countries.11,12 Cerebral venousthrombosis and rheumatic heart disease are important causes of stroke in the young.12 Subacute tubercular meningitis leading to arteritis or autoimmune angiitis arealso important stroke risk factors.13 Reported risk factors among the young include coagulopathy , elevated lipoprotein(a) and elevated anticardiolipin antibodies.14-16 SomeIndian studies have reported interesting causes of stroke, like viper envenomation and also suggested mechanisms like squatting whilst on the toilet as an important triggeringfactor for stroke in Indians, by raising the blood pressure.17,18Dr SubhashKaul ACNR • VOLUME 7 NUMBER 5 • NOVEMBER/DECEMBER 2007Correlation of regional cardiovascular disease mortality in India with lifestyle and nutritional factorsRajeev Gupta , Anoop Misra, Prem Pais, Priyanka Rastogi, V.P. GuptaReceived 24 February 2005; received in revised form 7 April 2005; accepted 14 May 2005. published online 23 June 2005. Abstract ObjectiveThere is a wide disparity in prevalence and cardiovascular disease mortality in different Indian states. To determine significance of various nutritional factors and other lifestyle variables in explaining this difference in cardiovascular disease mortality we performed an analysis.Methods and resultsMortality data were obtained from the Registrar General of India. In 1998 the annual death rate for India was 840/100,000 population. Cardiovascular diseases contribute to 27% of these deaths and its crude mortality rate was 227/100,000. Major differences in cardiovascular disease mortality rates in different Indian states were reported varying from 75–100 in sub-Himalayan states of Nagaland, Meghalaya, Himachal Pradesh and Sikkim to a high of 360–430 in Andhra Pradesh, Tamil Nadu, Punjab and Goa. Lifestyle data were obtained from national surveys conducted by the government of India. The second National Family Health Survey (26 states, 92,447 households, 301,984 adults) conducted in 1998–1999 reported on various demographic and lifestyle variables and India Nutrition Profile Study reported dietary intake of 177,841 adults (18 states, 75,229 men, 102,612 women). Cardiovascular disease mortality rates were correlated with smoking, literacy levels, prevalence of stunted growth at 3-years (as marker of fetalundernutrition), adult mean body mass index, prevalence of overweight and obesity, dietary consumption of calories, cereals and pulses, green leafy vegetables, roots, tubers and other vegetables, milk and milk products, fats and oils, and sugar and jaggery. As a major confounder in different states is poverty, all the partial correlation coefficients were adjusted for illiteracy, fertility rate and infant mortality rate. There was a significant positive correlation of cardiovascular disease mortality with prevalence of obesity (R=0.37) and dietary consumption of fats (R=0.67), milk and its products (R=0.27) and sugars (R=0.51) and negative correlation with green leafy vegetable intake (R=−0.42) (p<0.05).ConclusionsThere are large disparities in cardiovascular disease mortality in different Indian states. This can be epidemiologically explained by difference in dietary consumption of fats, milk, sugar and green-leafy vegetables and prevalence of obesity.Keywords: Lifestyle, Nutritional factors, Cardiovascular diseases, Coronary heart disease
  • 80% ischemicThrombosisEmbolismHypoperfusion20% hemorrhagicIntracerebralSubarachnoidA recent hospital based multicenter prospective stroke registry in India with an objective to identify and recruit 10,000 acute stroke patients from 100 hospitals within India conducted an interim analysis to determine etiologies, clinical management and outcome with 5301 patients. Analysis found that patients with stroke had high rates of risk factors including high alcohol consumption, tobacco consumption, diabetes, hypertension and dyslipidemia. In addition to this, the study identified that the short term mortality was higher among stroke patients with increased rates of risk factors (Xavier 2012).Stroke subtypes in IndiaThe Indian Collaborative Acute Stroke Study (ICASS), a prospective study on consecutive and CT-confirmed cases of acute stroke from the major university hospitalsin India, reported that up to 80% of stroke patients were ischaemic in nature.19 In a population based study, done in Kolkata, CT scan proved infarction occurred in 68%of cases.20 Among the ischaemic strokes, intracranial atherosclerosis was the most common mechanism in the prospective , hospital based Hyderabad Stroke Registry. This was followedby lacunar, cardio-embolic and extracranial carotid disease respectively.21 While intracranial disease is very uncommon in the West (<5%) and extracranial carotidartery disease is uncommon in far eastern countries like China and Japan (<5%), both vascular patterns are common in Indian stroke patients and this may be called ‘theIndian pattern’. Common risk factors for the development of large and small artery disease are similar and constitute hypertension, diabetes and smoking.21,22 For cardioembolicstroke, rheumatic heart disease , and ischaemic heart disease are dominant risk factors in India.23ACNR • VOLUME 7 NUMBER 5 • NOVEMBER/DECEMBER 2007 Dr SubhashKaul
  • Brain is about 2.3% of body weight, consumes one fifth of cardiac output and oxygen. Blood flow of the brain tissue is very high, about 50ml per 100gm. There is reflex increase in oxygen extraction with falling blood flow till it reaches critical level of 20ml when there is further fall to stop synaptic transmission to protect neuronal cell death. Any fall below 10ml over time leads to progressive death of nerve cell. Reopening of blocked circulation before there is substantial damage improve chance of recovery, however reperfusion after death of neuronal cell and blood vessel leads to severe reperfusion hemorrhage into the ischemic tissue.
  • Part of brain surrounding the core of ischemic insult is call penumbra zone which has synaptic transmission failure with progressive cell death depends on the collateral circulation. There is cascade of biochemical event proceeds during ischemic insult resulting in accumulation of toxic substance like glutamate, free radical and lactate leading to entry of calcium into the cell which itself is suicidal to mitochondrial function. Once there is failure of sodium potassium pump, water enter into the cell causing rupture.5.4 N europrotectantsMany agents have been studied for a potential neuroprotective effect in patients with stroke.There are systematic reviews of glutamate antagonists,92 calcium antagonists,93, 94 the free radicalscavenger tirilazad,95 vinca alkaloids,96 oral citicoline,97 the sodium antagonist lubeluzole,98corticosteroids,99 methylxanthine derivatives (pentoxiffyline, propentofylline and pentofylline),100aminophylline,101 and piracetam102 and phase III RCTs of the free radical spin trap NXY 059,1035HT1a agonist repinotan,104 neutrophilchemotaxis inhibitors enlimomab105 and UK-279,276,106magnesium,107 nalmefene,108 diazepam,109 chlomethiazole,110 cerebrolysin,111 and the free radicalscavenger edaravone.112These agents have widely differing pharmacological actions. For the majority of agents, there wasno evidence of benefit or harm. The exceptions are:Definite harm (increase in odds of death or dependence)ƒ. tirilazad (OR=1.23; 95% CI 1.01 to 1.50)95ƒ. enlimomab (adjusted p=0.004 for worse distribution of Rankin grade).105Possible harmƒ. aptiganel hydrochloride (mortality OR=1.32; 95% CI 0.91 to 1.93)92ƒ. selfotel (mortality OR=1.19; 95% CI 0.81 to 1.74)92ƒ. corticosteroids (OR=1.08; 95% CI 0.68 to 1.72)99ƒ. calcium antagonists (OR 1.07 0.97 to 1.18)94ƒ. gavestinel (mortality OR=1.12; 95% CI 0.95 to 1.32).92Possible benefit (reduced odds of death or dependence)ƒ. citicoline (good outcome OR=1.38; 95% CI 1.10 to1.72)97ƒ. non-cortical stroke syndromes treated with magnesium (poor outcome OR=0.75; 95% CI0.58 to 0.97).107For other agents, there was insufficient evidence to define benefit or harm.;; Neuroprotectant agents should be used only within the context of randomised controlledtrials.
  • Cincinnati Stroke scaleif 1 findings abnormal : probability having stroke >72%if 3 findings abnormal : probability having stroke >85%this scale usually use in prehospital setting.Once the diagnosis of stroke is suspected, time in the field must be minimized.The presence of a patient with acute stroke is a “load and go”.A more extensive examination or initiation of supportive therapies should be accomplished en route to the hospital.Pre Hospital Recommendation Do’sAssess and manage ABCsInitiate cardiac monitoringProvide supplemental oxygen to maintain O2 saturation >94%Establish IV access per local protocolDetermine blood glucose and treat accordinglyDetermine time of symptom onset or last known normal, and obtain family contact information, preferably a cell phoneTriage and rapidly transport patient to nearest most appropriate stroke hospitalNotify hospital of pending stroke patient arrivalDon’t’sDo not initiate interventions for hypertension unless directed by medical CommandDo not administer excessive IV fluidsDo not administer dextrose-containing fluids in nonhypoglycemic patientsDo not administer medications by mouth (maintain NPO)Do not delay transport for prehospital interventions
  • Provisional diagnosis Stroke  Non-stroke (specify) __________________________Note: Stroke is unlikely, but not completely excluded if total scores are ≤0.ROSIER (95% CI) CPSS (95% CI) FAST (95% CI) LAPSS (95% CI)Sensitivity 93 (89-97) 85 (80-90) 82 (76-88) 59 (52-66)Specificity 83 (77-89) 79 (73-85) 83 (77-89) 85 (80-90)Positive PredictiveValue 90 (85-95) 88 (83-93) 89 (84-94) 87 (82-92)Negative PredictiveValue 88 (83-93) 75 (68-82) 73 (66-80) 55 (48-62)Nor et al 2005
  • Edwin Boring wrote: ‘The theory of Gall and Spurzheim is ... an instance of a theory which, while essentially wrong, was just enough right to further scientific thought’ In fact, by as early as the end of the eighteenth century the first attempts had been made to bring together biological and psychological concepts in the study of behavior. Franz Joseph Gall, a German physician and neuroanatomist, proposed three radical new ideas. First, he advocated that all behavior emanated from the brain. Second, he argued that particular regions of the cerebral cortex controlled specific functions. Gall asserted that the cerebral cortex did not act as a single organ but was divided into at least 35 organs (others were added later), each corresponding to a specific mental faculty. Even the most abstract of human behaviors, suchas generosity, secretiveness, and religiosity were assigned their spot in the brain. Third, Gall proposed that the center for each mental function grew with use, much as a muscle bulks up with exercise. As each center grew, it purportedly caused the overlying skull to bulge, creating a pattern of bumps and ridges on the skull that indicated which brain regions were most developed (Figure 1-1). Rather than looking within the brain, Gall sought to establish an anatomical basis for describing character traits by correlating the personality of individuals with the bumps on their skulls. His psychology, based on the distribution of bumps on the outside of the head, became known as phrenology.
  • “Sudden, focal neurologic deficit lasting less than 24 hours, confined to an area of the brain or eye perfused by a specific artery.”Based on assumption that TIAs do not cause infarction or other permanent brain injury.Approx. 10% of patients will have a stroke in 90 days, Half of these in just 2 daysMost TIAs last seconds to 10 minutes, with symptoms lasting greater than 1 hour in only 25% of patientsLess than 15% of patients with symptoms lasting > 1 hour resolve within 24 hoursFollowing TIAs, evidence of infarction is found in 20% by CT imaging and almost 50% with MRIThe “24-hour” rule leads to complacency and delay.“A TIA is a brief episode of neurologic dysfunction caused by focal brain or retinal ischemia, with clinical symptoms typically lasting less than one hour, and without evidence of acute infarction.”Parallel to distinction between angina and myocardial infarction (i.e. depends on the absence of tissue injury rather than the resolution of symptoms)Acknowledges that transient neurologic symptoms may cause permanent brain injurySupports rapid intervention to diagnose and treat acute brain ischemiaMore accurately reflects the presence or absence of brain infarctionAvoids assigning an arbitrary time criterion to define TIA
  • Vertigo/TIAIsolated symptom unlikely to be ischemic (true also for blurred vision or diplopia)Evidence of brainstem dysfunctionAtaxia or nystagmusCranial nerve abnormalityContralateralcorticospinal tract abnormalityTIA / MigraineOnset in middle ageAura without headacheDysfunction in periaqueductal gray region of brainstem, not vascularProgressive visual scintillation affecting both eyesStereotypic episodes or positive family history, especially with familial hemiplegic migraine
  • 15 – 20% of ischemic strokesSmall penetrating branches of circle of Willis, MCA, or vertebrobasilar arteryAtherothrombotic or lipohyalinotic occlusionInfarct of deep brain structuresBasal ganglia, cerebral white matter, thalamus, pons, and cerebellumFrom 3 mm to 2 cmRisk factors DiabetesHypertensionPolycythemiaVariable course progressing over daysFluctuating; progressing in steps; or remittingPreceded by TIAs in 25%Without headache or vomitingManagementLong-term blood pressure controlEmpiric anti-platelet therapyOmega-3 oil 1 gm TID to improve viscosityPrognosisGood recovery of functionSilent progression of lacunes
  • Do CT scan for every patient of suspected stroke with significant neurological deficit or depressed level of consciousness and headache or seizure to detectIschaemia as early as 2 h after stroke onsetCerebral haemorrhage immediatelyOther neurological diseasesDo MRI if planning for thrombolysis
  • Opening the thrombosed vessel ThrombolysisMechanical disruption of clotReducing the size of infarctAntiplatelateAnticoagulantNeuro-protectionBlood pressure controlTreat associated complicationRaised ICTSeizure
  • CPatientWithin 3 hours of onsetNormal CT scan, MRI Diffusion/ perfusion or clinical mismatchBP <180/100 mmHgNo bleeding tendencyDrug/Dose 0.9mg /Kg. (max 90mg), 10% bolus, Rest 60 min. infusionRisk ICH in 6% of patientsPromise Reduced morbidity by 30%Intravenous rtPAIntravenous fibrinolytic therapy for acute stroke is now widely accepted.459–467 The US FDA approved the use of intravenous rtPA in 1996, in part on the basis of the results of the 2-part NINDS rtPA Stroke Trial, in which 624 patients with ischemic stroke were treated with placebo or intravenous rtPA (0.9 mg/kg IV, maximum 90 mg) within 3 hours of symptom onset, with approximately one half treated within 90 minutes.166 In the first trial (Part I), the primary end point was neurological improvement at 24 hours, as indicated by complete neurological recovery or an improvement of 4 points on the NIHSS. In the second trial (Part II), the pivotal efficacy trial, the primary end point was a global OR for a favorable outcome, defined as complete or nearly complete neurological recovery 3 months after stroke. Treatment with intravenous rtPA was associated with an increase in the odds of a favorable outcome (OR, 1.9; 95% CI, 1.2–2.9). Excellent outcomes on individual functional measures were more frequent with intravenous rtPA for global disability (40% versus 28%), global outcome (43% versus 32%), activities of daily living (53% versus 38%), and neurological deficits (34% versus 20%). The benefit was similar 1 year after stroke.468The major risk of intravenous rtPA treatment remains sICH. In the NINDS rtPA Stroke Trial, early minimal neurological symptoms or neurological deterioration temporally associated with any intracranial hemorrhage occurred in 6.4% of patients treated with intravenous rtPA and 0.6% of patients given placebo. However, mortality in the 2 treatment groups was similar at 3 months (17% versus 20%) and 1 year (24% versus 28%).166,469 Although the presence of edema or mass effect on baseline CT scan was associated with higher risk of sICH, patients with these findings were more likely to have an excellent outcome if they received fibrinolytic therapy.470 The presence of early ischemic changes on CT scan was not associated with adverse outcome.148 The likelihood of a favorable outcome also was associated with the severity of deficits and the patient’s age. Patients with mild to moderate strokes (NIHSS score <20) and people <75 years of age had the greatest potential for an excellent outcome with treatment.103 The chances of a complete or nearly complete recovery among patients with severe stroke (NIHSS score of >20) improved with treatment, but such recovery occurred less often in this group of critically ill patients.103 Four subsequent trials, the European Cooperative Acute Stroke Study (ECASS I and ECASS II) and the Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS A and ATLANTIS B), enrolled subsets of patients in the ≤3-hour time period and found largely similar effects in this time window to those observed in the 2 NINDS rtPA trials.92,167,462,471–473Debate about time of initiation of intravenous rtPA treatment merits attention. The NINDS investigators reported a time-to-treatment interaction in a subgroup analysis of the NINDS rtPA Stroke Trial.93 Treatment with intravenous rtPA initiated within 90 minutes of symptom onset was associated with an OR of 2.11 (95% CI, 1.33–3.55) for favorable outcome at 3 months compared with placebo. In comparison, the OR for good outcome at 3 months for treatment with intravenous rtPA initiated within 90 to 180 minutes was 1.69 (95% CI, 1.09–2.62). The investigators concluded that the earlier that treatment is initiated, the better the result. A subsequent pooled analysis of all large, multicenter, placebo-controlled trials of intravenous rtPA for acute stroke confirmed a time effect.468 Investigation of the early time epoch in the NINDS trials revealed a potential confounder in the original data: 19% of the patients treated with intravenous rtPA between 91 and 180 minutes after stroke onset had an NIHSS score of <5 compared with 4% of the placebo patients. On the basis of this observation, it has been suggested that the relative preponderance of mild strokes with a likely good outcome in the intravenous rtPA treatment group may explain the entire benefit reported for patients treated between 91 and 180 minutes. Subsequent reanalysis showed that the imbalance in patients with minor stroke did not explain the difference between treatment and placebo.474 The adjusted OR for 3-month favorable outcome (ORs for treatment compared with placebo) for the subgroup of patients from the 2 NINDS intravenous rtPA stroke trials with NIHSS score of <5 at baseline and time from stroke onset to treatment of 91 to 180 minutes was statistically significant in favor of treatment. Indeed, when all possible subgroups were examined separately, no effect of the severity imbalance could be shown to influence the overall result that intravenous rtPA therapy positively influenced outcome. In separate analyses by independent groups, an identical finding was reached: Baseline imbalances in the numbers of patients with mild stroke did not explain the overall study result.475–477Subsequent to the approval of intravenous rtPA for treatment of patients with acute ischemic stroke, numerous groups reported on the utility of the treatment in a community setting.117,120,122,478–483 Some groups reported rates of intracranial hemorrhage and favorable outcomes that were similar to those found in the NINDS trials, but others did not. It is now clear that the risk of hemorrhage is proportional to the degree to which the NINDS protocol is not followed.120,483,484 In addition to the risk of sICH, other potential adverse experiences include systemic bleeding, myocardial rupture if fibrinolytics are given within a few days of acute myocardial infarction, and reactions such as anaphylaxis or angioedema, although these events are rare.460Orolingualangioedema reactions (swelling of tongue, lips, or oropharynx) are typically mild, transient, and contralateral to the ischemic hemisphere.485Angioedema is estimated to occur in 1.3% to 5.1% of all patients who receive intravenous rtPA treatment for ischemic stroke.464,485,486 Risk of angioedema is associated with angiotensin-converting enzyme inhibitor use and with infarctions that involve the insular and frontal cortex. Empiric monitoring recommendations include inspection of tongue, lips, and oropharynx after intravenous rtPA administration. Empiric treatment recommendations include intravenous ranitidine, diphenhydramine, and methylprednisolone.486The largest community experience, the SITS-ISTR Registry (Safe Implementation of Thrombolysis in Stroke–International Stroke Thrombolysis Register, which incorporates the SITS-MOST [Safe Implementation of Thrombolysis in Stroke–Monitoring Study] Registry), resulted when, in 2002, the European Medicines Evaluation Agency granted license for the use of intravenous rtPA for the treatment of ischemic stroke patients within 3 hours of symptom onset. The approval was conditional on the completion of a prospective registry of patient treatment experience with intravenous rtPA within the 3-hour window from stroke onset. SITS-ISTR reported on 11865 patients treated within 3 hours of onset at 478 centers in 31 countries worldwide.468 The frequency of early neurological deterioration temporally associated with substantial parenchymal hematoma after intravenous rtPA was 1.6% (95% CI, 1.4%–1.8%). The frequency of favorable outcome (combined mRS scores of 0, 1, and 2) at 90 days was 56.3% (CI, 55.3%–57.2%) in the intravenous rtPA patients, comparable to the favorable outcome rate among patients treated within 3 hours in the pooled analysis of the 6 randomized trials.468These findings appear to confirm the safety of intravenous rtPA within the 3-hour window at sites that have an institutional commitment to acute stroke care.With >15 years of fibrinolytic experience in acute ischemic stroke, multiple groups have reported their outcomes in treating patients with “off-label” fibrinolysis.487–493 These groups report the use of fibrinolysis in patients with conditions including extreme age (>80 years), prior stroke and diabetes mellitus, minor stroke, rapidly improving stroke symptoms, recent myocardial infarction, major surgery or trauma within the preceding 3 months, and oral anticoagulation use. Overall, the outcomes in the treated patients with these contraindications were better than nontreated “controls” from registry data. Rates of sICH were not increased in these reports. Because stroke patients continue to present with conditions not specifically stated in the original indications for and usage of intravenous rtPA, further experience may allow consideration for fibrinolysis in these situations.Extended Window for Intravenous rtPASubsequent to the NINDS trials, 5 clinical trials have tested the use of intravenous rtPA up to 6 hours after stroke onset without specialized imaging for patient selection. The first 4 trials, ECASS I, ECASS II, ATLANTIS A, and ATLANTIS B,167,471,473,494 collectively enrolled 1847 patients in the 3- to 6-hour time period. None of these 4 trials was individually positive on its prespecified primary end point. In a pooled individual patient-level analysis of these 4 trials, a benefit of therapy in the 3- to 4.5-hour window was suggested, both in increasing the rate of excellent outcomes (adjusted OR, 1.40; 95% CI, 1.05–1.85) and in improving outcomes along the entire range of poststroke disability.92,495 Fibrinolytic therapy in the 4.5- to 6-hour window produced a statistically nonsignificant increase in the rate of excellent outcomes (adjusted OR, 1.15; 95% CI, 0.90–1.47).92,495 In the 3- to 4.5-hour window, across all trials, rates of radiological parenchymal hematoma were higher with fibrinolytic therapy, 5.9% versus 1.7%, but mortality was not increased at 13% versus 12%. In the 4.5- to 6-hour window, fibrinolytic therapy increased rates of both radiological parenchymal hematoma (6.9% versus 1.0%) and mortality (15% versus 10%). When data from all time windows in the first 6 large intravenous rtPA trials were pooled, a time-to-treatment interaction was shown.92Treatment with intravenous rtPA initiated within 1.5 hours of symptom onset was associated with an OR of 2.81 (95% CI, 1.75–4.50) for favorable outcome at 3 months compared with placebo. The OR for good outcome at 3 months for treatment with intravenous rtPA initiated within 1.5 to 3 hours was 1.55 (95% CI, 1.12–2.15) compared with 1.40 (95% CI, 1.05–1.85) within 3 to 4.5 hours and 1.15 (0.90–1.47) within 4.5 to 6 hours.The ECASS III trial was undertaken to prove or disprove the benefit of intravenous rtPA in the 3- to 4.5-hour window suggested by the pooled analysis of the 4 prior trials. In ECASS III, patients between 3.0 and 4.5 hours from symptom onset were randomized to either intravenous rtPA (n=418) or placebo (n=403).169 The dosing regimen was 0.9 mg/kg (maximum of 90 mg), with 10% given as an initial bolus and the remainder infused over 1 hour.13 The inclusion and exclusion criteria for the trial were similar to those in the existing AHA Stroke Council guidelines for treatment of patients within 3 hours of stroke onset,13 except for the time window and that the trial additionally excluded people >80 years old, those with a baseline NIHSS score >25, those taking oral anticoagulants (even if their INR was <1.7), and those who had the combination of a previous stroke and diabetes mellitus. Patients were permitted to receive low-dose parenteral anticoagulants for prophylaxis of DVT within 24 hours after treatment with intravenous rtPA.Early neurological deterioration likely caused by intracranial hemorrhage was identified in 10 subjects treated with intravenous rtPA (2.4%) and 1 subject administered placebo (0.2%; OR, 9.85; 95% CI, 1.26–77.32; P=0.008).169 However, mortality in the 2 treatment groups did not differ significantly and was nominally higher among the subjects treated with placebo.169 The primary efficacy outcome in ECASS III was excellent 90-day outcome on the mRS global disability scale (mRS score 0–1). This outcome was more frequent with intravenous rtPA (52.4%) than placebo (45.2%; OR, 1.34; 95% CI, 1.02–1.76; risk ratio, 1.16; 95% CI, 1.01–1.34;P=0.04). The ECASS III findings align with preclinical and clinical data that suggest a time dependency for benefit from treatment with intravenous rtPA. The point estimate for the degree of benefit seen in ECASS III (OR for global favorable outcome, 1.28; 95% CI, 1.00–1.65) was less than the point estimate of that found in the pool of patients enrolled from 0 to 3 hours in the NINDS study (OR, 1.9; 95% CI, 1.2–2.9)166,169 and was similar to the pooled analysis of the results of subjects enrolled in the 3- to 4.5-hour window in previous trials of intravenous rtPA (OR, 1.4).92,166,167,471,473,494 Overall, the ECASS III results were consistent with the results of previous trials,92,496,497 which indicates that intravenous rtPA can be given safely to, and can improve outcomes for, carefully selected patients treated 3 to 4.5 hours after stroke.In June 2012, the results from the Third International Stroke Trial (IST-3), the largest randomized, placebo-controlled trial to date of intravenous rtPA, were published.498 The trial enrolled 3035 patients who were randomized to treatment within 6 hours from symptom onset with 0.9 mL/kg in the active arm. Eligibility criteria were similar to other intravenous rtPA trials with several exceptions, including no upper limit to age and broader blood pressure eligibility (systolic blood pressure 90–220 mmHg and diastolic blood pressure 40–130 mmHg). The primary outcome measure, an Oxford Handicap Score of 0 to 2 (alive and independent) at 6 months, was achieved in 37% of patients in the intravenous rtPA group versus 35% in the control group (OR, 1.13; 95% CI, 0.95–1.35; P=0.181). Using an ordinal analysis, there was a significant shift in overall Oxford Handicap Score (OR, 1.27; 95% CI, 1.10–1.47; P=0.001). Within 7 days, fatal or nonfatal sICH occurred in 7% versus 1% in the treatment versus placebo arms, respectively. More deaths occurred within 7 days in the intravenous rtPA group (11%) than in the control group (7%; adjusted OR, 1.60; 95% CI, 1.22–2.08; P=0.001), but by 6 months, 27% of patients had died in both groups.Also in June 2012, Sandercock and colleagues498 published a meta-analysis of 12 intravenous rtPA trials that had enrolled 7012 patients up to 6 hours from symptom onset. The results confirmed the benefits of intravenous rtPA administered within 6 hours from symptom onset, with final follow-up mRS score of 0 to 2 in 46.3% of intravenous rtPA–treated patients compared with 42.1% of patients in the placebo arms (OR, 1.17; 95% CI, 1.06–1.29; P=0.001). The data also reinforced the importance of timely treatment, because the benefit of intravenous rtPA was greatest in patients treated within 3 hours from symptom onset (mRS score 0–2, 40.7% versus 31.7%; OR, 1.53, 95% CI, 1.26–1.86; P<0.0001). As noted in the IST-3 trial, sICH events were more common in the intravenous rtPA group (7.7% versus 1.8%; OR, 3.72, 95% CI, 2.98–4.64; P<0.0001), and death within 7 days was increased in intravenous rtPA patients (8.9%) compared with the placebo arms (6.4%; OR, 1.44, 95% CI, 1.18–1.76; P=0.0003), but by final follow-up, the number of deaths was similar (19.1% versus 18.5%; OR, 1.06, 95% CI, 0.94–1.20; P=0.33). Importantly, the authors found patients of all ages received benefit from intravenous rtPA treatment compared with placebo.Drug regulatory authorities have recently taken contradictory actions with regard to later administration of intravenous rtPA, with the European Medicines Agency expanding approval of intravenous rtPA to the 3- to 4.5-hour window and the US FDA declining to do so. The basis of these decisions currently remains confidential as part of the regulatory process. To inform this update of the guidelines, the AHA/ASA Writing Committee leadership requested and was granted by the US manufacturer (Genentech) partial access to the FDA decision correspondence. The degree of evidence that AHA/ASA requires for a Grade B recommendation is less than for a Grade A recommendation, and the latter generally more closely approximates the level of evidence that the FDA requires for label approval. On the basis of the review, it is the opinion of the writing committee leadership that the existing Grade B recommendation remains reasonable. The sponsor indicated it planned to work with academic investigators to independently replicate the types of analyses undertaken as part of the FDA review process and make the resultant findings public, and this approach was supported by the writing committee.Although the maximum time window in which fibrinolytic therapy may be given in many patients has been expanded to 4.5 hours, preclinical, cerebrovascular imaging, and clinical trial evidence indicate the fundamental importance of minimizing total ischemic time and restoring blood flow to threatened but not yet infarcted tissue as soon as feasible. Experience with acute myocardial infarction and acute ischemic stroke systems of care have demonstrated that health system responsiveness is improved by the establishment and monitoring of a time interval within which most patients should be treated after first presentation to the hospital.499,500 Health systems should set a goal of increasing their percentage of stroke patients treated within 60 minutes of presentation to hospital (door-to-needle time of 60 minutes) to at least 80%.43,501,502Patients With Minor and Isolated or Rapidly Improving Neurological SignsMinor and isolated symptoms are those that are not presently potentially disabling. Although most patients with potentially disabling symptoms will have NIHSS scores ≥4, certain patients, such as those with gait disturbance, isolated aphasia, or isolated hemianopia, may have potentially disabling symptoms although their NIHSS score is just 2.Several studies have now reported that approximately one third of patients who are not treated with intravenous rtPA because of mild or rapidly improving stroke symptoms on hospital arrival have a poor final stroke outcome.503–507 A persistent large-artery occlusion on imaging, despite minor symptoms or clinical improvement, may identify patients at increased risk of subsequent deterioration.508 In light of these observations, the practice of withholding intravenous fibrinolytic therapy because of mild or rapidly improving symptoms has been questioned, which justifies further study.Patients Taking Direct Thrombin Inhibitors and Direct Factor Xa InhibitorsNew classes of anticoagulants are rapidly changing the way physicians treat and prevent disorders of thrombosis. Although most potential agents are in clinical development, the direct thrombin inhibitor dabigatran and the direct factor Xa inhibitor rivaroxaban have been approved for use in the United States. Other factor Xa inhibitors are on the horizon: Apixiban has recently been approved by the FDA, and edoxaban is in the late stages of clinical development. These classes of oral anticoagulants do not require therapeutic monitoring, have fewer side effects (especially lower rates of major hemorrhage), and have fewer drug and food interactions than warfarin.509–512 The challenge for physicians evaluating and considering treatment options for patients with acute ischemic stroke is determining the anticoagulant effect of these agents and estimating the potential increased risk of hemorrhage after reperfusion strategies are initiated.Specific to dabigatran, drug concentrations peak ≈2 to 3 hours after an oral dose. The active moiety has a half-life of 12 to 17 hours and is cleared primarily by renal elimination. In patients with impaired renal function, the half-life may extend to 20 to 30 hours. The challenge for the physician treating acute stroke patients with this agent is estimating the impact of the drug on the coagulation system. Traditional coagulation tests are not reliable for measuring the anticoagulant effect of dabigatran. The effects of dabigatran on the INR are not predictable. Similarly, the effects of dabigatran on aPTT are not predictable. Although there is correlation between dabigatran plasma concentrations and aPTT results, the correlation is nonlinear. TT and ECT both show a good linear correlation with direct thrombin inhibitors, including dabigatran, and are very sensitive. If the TT or ECT is normal, it is reasonable to assume that plasma concentrations of dabigatran are minimal. Regrettably, these tests are not performed routinely in the ED, and results may take hours to become available.Specific to the direct factor Xa inhibitors, rivaroxaban has a half-life of 5 to 9 hours and is cleared by renal, fecal, and hepatic mechanisms, whereas apixaban has a half-life of 8 to 15 hours and is cleared by the cytochrome P450 system. The direct factor Xa inhibitors may cause prolongation of the PT and aPTT, but these indexes are not reliable for measuring the pharmacodynamics effects of these agents. Direct factor Xa activity assays may be able to indicate treatment effects but are not routinely performed in the ED, and results may take hours to become available.Until a simple, fast, and reliable method is determined to measure the clinical impact of the direct thrombin inhibitors and direct factor Xa inhibitors, and more data are collected on use of fibrinolytics and reperfusion strategies in patients taking these classes of drugs, a good medical history will be critical. In patients known to have taken one of these agents in the past, but for whom history or a readily available assay suggests no current substantial anticoagulant effects of the agent, cautious treatment may be pursued. In patients with historical or assay suggestion of at least modest anticoagulant effects of dabigatran, fibrinolytic therapy is likely to be of greater risk and ordinarily would not be undertaken. As other classes of anticoagulants become available for clinical use, similar considerations will be necessary.For instance, as this guideline was undergoing revisions, the results of 2 large phase III trials of oral direct factor Xa inhibitors for the treatment of patients with atrial fibrillation were published.513,514 These medications, rivaroxaban (FDA approved) and apixaban (recently approved), are pharmacologically different from dabigatran. The recommendations made for dabigatran may not be applicable in all cases for these newer agents because of differences in metabolism. We urge caution in applying these recommendations to these new oral direct factor Xa inhibitor agents.Other Fibrinolytic AgentsClinical trials of streptokinase (administered at the treatment dose for acute myocardial ischemia, 1.5 million units) were halted prematurely because of unacceptably high rates of hemorrhage, and this agent should not be used.515–518Other intravenously administered fibrinolytic agents, including reteplase, urokinase, anistreplase, and staphylokinase, have not been tested extensively. Tenecteplase is a modified tissue plasminogen activator with a longer half-life and higher fibrin specificity than alteplase and appears promising as an effective fibrinolytic, with greater reperfusion and major vessel recanalization with fewer bleeding complications than alteplase in pilot studies. Recently, a US phase IIb study of intravenous tenecteplase in acute stroke was terminated prematurely for nonsafety issues, but an Australian phase IIb trial comparing tenecteplase with alteplase showed significantly improved rates of reperfusion and clinical outcomes by use of imaging-based patient selection.519–521Desmoteplase is a fibrinolytic agent isolated from vampire bat saliva. Two phase II trials of desmoteplase provided encouraging safety and potential efficacy data in penumbral imaging–selected patients 9 hours after stroke onset.347,349 However, a larger trial revealed no benefit of either of 2 doses of desmoteplase over placebo, possibly because of a higher than projected good outcome rate in the placebo group. Phase III studies are ongoing.Defibrogenating EnzymesExtracts derived from pit viper venom have been demonstrated to cleave fibrinogen rather than fibrin, reducing plasma fibrinogen, which leads to reduced blood viscosity, increased blood flow, and the prevention of clot formation and/or clot extension. Ancrod, a defibrinogenating agent, has been investigated in patients with acute ischemic stroke.522–526 A systematic meta-analysis of defibrinogenating agents in acute ischemic stroke analyzed 6 trials involving 4148 subjects. The review authors identified a trend toward benefit in reducing death or dependency at the end of the follow-up period (43.7% versus 46.7%, for an absolute risk reduction of 3.0% [95% CI, −0.1% to 5.9%]). The meta-analysis also found that treatment increased early minimal neurological symptoms or neurological deterioration temporally associated with any intracranial hemorrhage (4.9% versus 1.0%, for an absolute risk increase of 3.8% [95% CI, 2.3% to 5.4%]). However, more recently, 2 phase III ancrod trials investigating a refined dosing regimen were stopped after a planned interim analysis found no clinically meaningful difference in outcome between the 2 treatment groups in averting disability.527
  • Only 1-3% of all stroke victims receive treatment with tPA in the US 25% of Acute MI patients receive treatment (lytics or PTCA) in the US Mean time to presentation AMI: 3hrsAcute Stroke: 4-10hrs
  • Patient’s inability to recognize stroke symptoms40% of stroke patients can’t name a single sign or symptom of stroke or stroke risk factor.75% of stroke patients misinterpret their symptoms86% of patients believe that their symptoms aren’t serious enough to seek urgent carePhysician’s lack of experience with stroke treatment and therefore reluctance to “risk” treatmentLack of organized delivery of care in many medical centers throughout the country.
  • 26.01.08: The term “general treatment” refers to treatment strategies aimed at stabilizing the critically ill patient in order to control systemic problems that may impair stroke recovery; the management of such problems is a central part of stroke treatment {The European Stroke Initiative Executive Committee and the EUSI Writing Committee, 2003 #456;Leys, 2007 #773}. General treatment includes respiratory and cardiac care, fluid and metabolic management, blood pressure control, the prevention and treatment of conditions such as seizures, venous thromboembolism, dysphagia, aspiration pneumonia, other infections, or pressure ulceration, and occasionally management of elevated intracranial pressure. However, many aspects of general stroke treatment have not been adequately assessed in randomized clinical trials.RecomondationIntermittent monitoring of neurological status, pulse, blood pressure, temperature and oxygen saturation is recommended for 72 hours in patients with significant persisting neurological deficits (Class IV, GCP)Oxygen should be administered if sPO2 falls below 95% (Class IV, GCP)
  • NIH 2013Volume Expansion, Vasodilators, and Induced HypertensionIschemic stroke results from occlusion of an artery with subsequent reduction in regional cerebral blood flow, demarcated into 2 distinct regions consisting of regional cerebral blood flow alterations: severe reduction (core) and moderate reduction (penumbra).667,668 The penumbra remains viable for hours because some degree of blood flow is sustained through collateral supply and arteriolar dilation.669,670 For >3 decades, investigators have studied interventions aimed at increasing cerebral perfusion in acute ischemic stroke by either improving flow through partially occluded vessels or improving flow through cerebral collateral circulation. These approaches have targeted acute alterations of blood rheology, expansion of blood volume, and increased global or local blood pressure. To date, no acute clinical trial has demonstrated unequivocal efficacy, but several ongoing trials may provide a new, widely applicable therapy for patients with ischemic stroke.Hypervolemia and Hemodilution for Treatment of Acute Ischemic StrokeIncreased viscosity has been observed in the acute period of ischemic stroke because of volume depletion, leukocyte activation, red cell aggregation, elevated fibrinogen levels, and reduced red cell deformability.671–675 A higher hematocrit is associated with reduced reperfusion, greater infarct size, and higher mortality among patients after ischemic stroke.671,674 Hemodilution and volume expansion are proposed as treatment options to reduce the viscosity of blood, improve flow through collateral channels and microvascular circulation, and increase oxygen-carrying capacity.676–682A meta-analysis of 18 trials683 in which hemodilution was initiated within 72 hours of symptom onset was reported. A combination of phlebotomy and plasma volume expanders was used in 8 trials, and volume expansion alone was used in 10 trials. The plasma volume expander was dextran 40 in 12 trials, hydroxyethyl starch in 5 trials, and albumin in 1 trial. Hemodilution did not significantly reduce deaths within the first 4 weeks (OR, 1.1; 95% CI, 0.9–1.4) or within 3 to 6 months (OR, 1.0; 95% CI, 0.8–1.2). The proportion of patients with death, dependency, or institutionalization was similar in both groups (OR, 1.0; 95% CI, 0.8–1.2). There was no increased risk of serious cardiac events among patients with hemodilution.Vasodilatation in Acute Ischemic StrokeTechniques to promote vasodilation have been studied in acute stroke for >4 decades. Initially, vasodilatation was studied as a way to treat and prevent TIAs. More recently, vasodilation with methylxanthine derivatives, specifically pentoxifylline, propentofylline, and pentifylline, has been evaluated in the setting of acute ischemic stroke. In addition to the vasodilatation, the methylxanthine drugs may also reduce blood viscosity, increase erythrocyte flexibility, inhibit platelet aggregation, and decrease free radical production. Most methylxanthine-class trials have investigated the promotion of vasodilation in the subacute time frame. In a small randomized trial of 110 Chinese patients with acute cortical and lacunar strokes, Chan and Kay684 initiated vasodilation using pentoxifylline in combination with aspirin within 36 to 48 hours from stroke onset and continued for 5 days. At 1 week, there was no difference in outcomes for patients with lacunar stroke between the treatment arms. They did report a statistically significant reduction in morbidity in patients with cortical strokes.684 Subsequent studies have failed to reproduce this effect, and a Cochrane review of the 4 pentoxifylline trials and the 1 propentofylline study found there was not enough available evidence to reliably assess the effectiveness and safety of methylxanthine drugs in acute ischemic stroke.685Induced Hypertension for the Management of Acute Ischemic StrokeIncreasing the systemic blood pressure may improve regional cerebral blood flow as a result of augmentation of flow through collaterals and arterioles that do not demonstrate an autoregulatory constrictive response to pathological vasodilation.686–690 The clinical response is varied because of variations in collateral formation and preservation of autoregulatory vasoconstriction, systemic blood pressure response, and presence of a penumbra.Rordorf et al691 retrospectively reviewed a group of patients admitted with the diagnosis of ischemic stroke, of whom 33 were not given a pressor agent and 30 were treated with phenylephrine within 12 hours of symptom onset. There was no significant difference in morbidity or mortality between the 2 groups of patients. In 10 of 30 patients treated with induced hypertension, a systolic blood pressure threshold (mean 156 mmHg) was identified below which ischemic deficits worsened and above which deficits improved. The mean number of stenotic/occluded arteries was greater in patients with an identified clinical blood pressure threshold for improvement subsequent to induced hypertension. A second pilot study692 used phenylephrine to raise the systolic blood pressure in patients with acute stroke by 20%, not to exceed 200 mmHg. Of 13 patients treated, 7 improved by 2 points on the NIHSS. No systemic or neurological complications were observed. Marzan et al693 reported the results of induced hypertension (10%–20% of the initial value) using norepinephrine within a mean period of 13 hours after symptom onset. The dose was gradually reduced after 12 hours of administration and terminated when arterial blood pressure remained stable. Early (within 8 hours of initiation) neurological improvement by ≥2 points on the NIHSS was seen in 9 (27%) of 33 patients. Intracranial hemorrhage occurred in 2 patients. Hillis et al694 randomized consecutive series of patients with large diffusion-perfusion mismatch to induced blood pressure elevation (n=9) or conventional management (n=6). Serial DWI and perfusion-weighted MRI studies were performed before and during the period of induced hypertension. Patients who were treated with induced hypertension showed significant improvement in NIHSS score from day 1 to day 3, cognitive score, and volume of hypoperfused tissue. High correlations were observed between the mean arterial pressure and accuracy on daily cognitive tests. Koenig et al695 reported analysis of 100 patients who underwent perfusion-weighted MRI after acute ischemic stroke, of whom 46 were treated with induced hypertension with various vasopressors. The target mean arterial pressure augmentation of 10% to 20% above baseline was achieved in 35% of the 46 treated patients. Compared with 54 patients who underwent conventional treatment, NIHSS scores were similar during hospitalization and discharge, with no clear difference in rates of adverse events. Shah et al696 reported 3 patients who received induced hypertension, not to exceed 180 mm Hg, after partial recanalization using intra-arterial fibrinolysis and noted favorable outcomes and no complications.The available evidence suggests that a small subset of patients with ischemic stroke in the very acute period may benefit from modest (10%–20%) pharmacological elevation in systemic blood pressure. No clear criteria are validated for selection of such patients, although patients with large perfusion deficits caused by steno-occlusive disease who are not candidates for fibrinolytic and interventional treatments are the best studied, as well as those patients who demonstrate neurological change that correlates with systemic blood pressure changes. A short period (30–60 minutes) of a vasopressor infusion trial may help identify patients who are potential responders to such treatment.Albumin for Treatment of Acute Ischemic StrokeAlbumin exerts its purported neuroprotective effect by reducing both endogenous and exogenous oxidative stress, maintaining plasma colloid oncotic pressure, and preserving microvascular integrity in focal cerebral ischemia.697 In experimental models of focal ischemia, albumin reduces ischemic brain swelling, improves regional cerebral blood flow, reduces postischemic thrombosis, improves microvascular flow, and supplies free fatty acids to the postischemic brain.672,698,699 In several observational studies,700,701 low serum albumin at admission correlated with higher rates of death and disability among patients with ischemic stroke. Subsequently, the ALIAS (Albumin in Acute Stroke) Pilot Clinical Trial evaluated 6 doses (0.34–2.05 g/kg)702,703 of 2-hour infusion of 25% human albumin beginning within 16 hours of stroke onset in patients with acute ischemic stroke. Eighty-two subjects received albumin, and 42 of those patients also received intravenous rtPA. The only albumin-related adverse event was mild or moderate pulmonary edema in 13% of the subjects, which confirms reasonable tolerability among patients with acute ischemic stroke without major dose-limiting complications. After adjustment for the intravenous rtPA effect, the probability of good outcome (defined as mRS score 0–1 or NIHSS score 0–1 at 3 months) at the highest 3 albumin tiers was 81% greater than in the lower-dose tiers and was 95% greater than in the comparable NINDS rtPA Stroke Trial historical cohort. The intravenous rtPA–treated subjects who received higher-dose albumin were 3 times more likely to achieve a good outcome than subjects receiving lower-dose albumin. The trial suggested that high-dose albumin treatment may be neuroprotective after ischemic stroke, with a synergistic effect between albumin and intravenous rtPA. A large, randomized, multicenter, placebo-controlled efficacy trial, the phase III ALIAS2 Trial,704 compared 2.0 mg/kg of 25% albumin administered over 2 hours with placebo, with treatment initiated within 5 hours of stroke onset. The primary efficacy end point was either an NIHSS score of 0 to 1, an mRS score of 0 to 1, or both at 3 months.704 An interim safety analysis of the first 436 subjects led to modifications in the study design to enhance safety and minimize development of congestive heart failure.705 An exploratory efficacy analysis of the part 1 study data suggested a trend toward favorable outcomes in patients in the albumin arm.706 In the fall of 2012, the study’s data safety and monitoring board stopped recruitment after an interim analysis, and further results from the study are pending.Mechanical Flow AugmentationMechanical methods to increase cerebral perfusion through Willisian and leptomeningeal collaterals offer the prospect of improving cerebral blood flow without the complications of vasopressor pharmacological agents. Data from animal models and from human research demonstrate that aortic occlusion, which is commonly performed by cross-clamping the descending aorta for vascular control during aortic surgery, results in net flow diversion to the cerebral from the lower-extremity circulatory beds, thereby increasing cerebral blood flow.707–715This evidence generated the development of a catheter-based device with 2 balloons near its distal tip placed in the infrarenal and suprarenal positions in the descending aorta (NeuroFlo device; CoAxia, Maple Grove, MN). After insertion via the femoral artery, the balloons are inflated sequentially up to ≈70% of the diameter of the aortic lumen over a period of 45 minutes to an hour, followed by removal.716A clinical feasibility study in acute ischemic stroke enrolled 17 patients up to 12 hours after symptom onset and showed an improvement in neurological symptoms in >50% of patients during treatment and at 24 hours.717 A randomized controlled multicenter trial enrolling patients with ischemic stroke within 14 hours of symptom onset was completed in 2010. Results recently published in Stroke failed to show significant differences in clinical outcome, but no issues of safety were noted.718,719 There was a statistically nonsignificant trend in lowering mortality in the treatment group compared with controls (11.3% versus 6.3%, respectively).Another method that shows potential for augmenting cerebral blood flow is extracorporeal counterpulsation therapy, which is approved for patients with ischemic heart disease who have refractory angina. This therapy is provided by a device that inflates pneumatic cuffs on the lower extremities in sequential fashion during each cardiac cycle to augment diastolic flow in the coronary arteries and improve systolic unloading in the periphery.720 There is also evidence that it may develop and recruit collateral vessels in ischemic myocardium.721 In the cerebral bed, studies have demonstrated extracorporeal counterpulsation–induced diastolic augmentation of flow in the carotid arteries722 and, more recently, the MCAs.723 In addition, a small pilot trial of subacute extracorporeal counterpulsation in the first 2 months after stroke onset was encouraging.724 On the basis of these findings, a randomized dose-ranging trial is ongoing in patients with acute ischemic stroke who are outside the therapeutic time window for intravenous fibrinolysis or endovascular therapy.Augmentation of cerebral collateral blood flow is a compelling concept that may hold promise in the treatment of acute ischemic stroke. Although the aforementioned treatments appear to warrant further investigation, there are currently no data to support their use in this population of patients.RecommendationsIn exceptional cases with systemic hypotension producing neurological sequelae, a physician may prescribe vasopressors to improve cerebral blood flow. If drug-induced hypertension is used, close neurological and cardiac monitoring is recommended (Class I; Level of Evidence C). (Revised from the previous guideline13)The administration of high-dose albumin is not well established as a treatment for most patients with acute ischemic stroke until further definitive evidence regarding efficacy becomes available (Class IIb; Level of Evidence B). (New recommendation)At present, use of devices to augment cerebral blood flow for the treatment of patients with acute ischemic stroke is not well established (Class IIb; Level of Evidence B). These devices should be used in the setting of clinical trials. (New recommendation)The usefulness of drug-induced hypertension in patients with acute ischemic stroke is not well established (Class IIb; Level of Evidence B). (Revised from the previous guideline13) Induced hypertension should be performed in the setting of clinical trials.Hemodilution by volume expansion is not recommended for treatment of patients with acute ischemic stroke (Class III; Level of Evidence A). (Revised from the previous guideline13)The administration of vasodilatory agents, such as pentoxifylline, is not recommended for treatment of patients with acute ischemic stroke (Class III; Level of Evidence A).(Unchanged from the previous guideline13)
  • All people with acute stroke should have their hydration assessed on admission, reviewed regularly and managed so that normal hydration is maintained
  • Aspirin (160–325 mg loading dose) should be given within 48 hours after ischaemic stroke (Class I, Level A)If thrombolytic therapy is planned or given, aspirin or other antithrombotic therapy should not be initiated within 24 hours (Class IV, GCP)The use of other antiplatelet agents (single or combined) is not recommended in the setting of acute ischaemic stroke (Class III, Level C)The administration of glycoprotein-IIb-IIIa inhibitors is not recommended (Class I, Level A)AspirinPatients who are not candidates for tPA should be given aspirin promptly in a dose of 325 mg (Adams, 2007 [R]) orally, rectally or by nasogastric tube and should be continued on a similar daily dose (Albers, 2004 [R]). Exceptions to this approach would be justified in those with contraindications to aspirin therapy (e.g., aspirin allergy, gastrointestinal hemorrhage). For patients with an aspirin allergy, 75 mg of clopidogrel may be reasonable. Intravenous or oral loading with 150-600 mg of clopidogrel establishes antiplatelet effect more rapidly; however, efficacy in this setting is unproven.Initiation of aspirin therapy should be withheld for 24 hours for patients who have received tPA. Although the benefits of aspirin therapy for long-term preventive therapy for stroke are well established, the use of aspirin to improve outcome in the acute treatment setting has also been demonstrated. Large randomized controlled trials have identified a small but measurable benefit with use of aspirin in the first 48 hours following ischemic stroke onset (Bath, 2001b [A]; Chinese Acute Stroke Trial Collaborative Group,1997 [A]; International Stroke Trial Collaborative Group, 1997 [A]; Sandercock, 1993 [M]).The studies together demonstrate benefit of small magnitude, but with statistical significance in the following outcome measures:• Early recurrent ischemic stroke – 7 fewer per 1,000 treated (p< 0.0001)• Death from any cause – 4 fewer per 1,000 treated (p=0.05)• Death or early recurrence of non-fatal stroke – 9 fewer per 1,000 treated (p=0.001)• Death or dependency at discharge or six months – 13 fewer per 1,000 treated (p=0.007)Also, the measured hazard appears to be small and statistically insignificant:• Hemorrhagic stroke or transformation – 2 more per 1,000 in ASA treated (p=0.06)Antiplatelet agents : SIGN 20085.2.1 aspirinA systematic review of twelve RCTs of over 40,000 patients showed that aspirin at 160 or 300 mg daily reduced death and disability, recurrent stroke, and improved the likelihood of full recovery in patients with ischaemic stroke.80 Two trials of aspirin (160 or 300 mg) given within 48 hours of stroke onset contributed 94% of the data analysed in the review. One was an open label trial and did not require a CT scan before randomisation. Exclusion criteria for these RCTs were vague and in all of the included trials mortality was lower than in the placebo arm (4-9%), suggesting that major strokes were under-represented.A Aspirin 300 mg daily should be commenced within 48 hours of ischaemic stroke and continued for at least 14 days.5.2.2 aspirin plus clopidogrelA small RCT of 110 patients with carotid stenosis showed that dual therapy with aspirin and clopidogrel significantly reduced the proportion of patients with embolic signals on transcranial Doppler ultrasound. The study was not powered to examine clinical end points.82 The FASTER trial randomised 392 patients with TIA or minor stroke to aspirin or aspirin plus clopidogrel for 90 days, commencing within 24 hours of symptom onset. A non-significant 3.8% absolute risk reduction (ARR) in total stroke was found for the combination therapy.25 Dual therapy with aspirin and clopidogrel given to patients within 48 hours of TIA or minor stroke was one component of several interventions in a prospective study, including early statins, antihypertensives and carotid endarterectomy. The contribution of combined aspirin and clopidogrel to the reduced stroke risk is not clear but there was no increase in the risk of intracerebral or other haemorrhage in the study group overall.24 Insufficient evidence exists to support the routine use of the combination of aspirin and clopidogrel for treating patients in the acute phase of stroke.Aspirin and anticoagulant treatment (NICE 2008)People with acute ischaemic strokeAll people presenting with acute stroke who have had a diagnosis of primary intracerebral haemorrhage excluded by brain imaging should, as soon as possible but certainly within 24 hours, be given: aspirin 300 mg orally if they are not dysphagic oraspirin 300 mg rectally or by enteral tube if they are dysphagic.Thereafter, aspirin 300 mg should be continued until 2 weeks after the onset of stroke symptoms, at which time definitive long-term antithrombotic treatment should be initiated. People being discharged before 2 weeks can be started on long-term treatment earlier. Any person with acute ischaemic stroke for whom previous dyspepsia associated with aspirin is reported should be given a proton pump inhibitor in addition to aspirin.Any person with acute ischaemic stroke who is allergic to or genuinely intolerant of aspirin should be given an alternative antiplatelet agent. Anticoagulation treatment should not be used routinely for the treatment of acute stroke. Aspirin intolerance is defined in NICE technology appraisal guidance 90 (‘Clopidogrel and modified-release dipyridamole in the prevention of occlusive vascular events’; see www.nice/org.uk/TA090) as either of the following:proven hypersensitivity to aspirin-containing medicines history of severe dyspepsia induced by low-dose aspirin.There may be a subgroup of people for whom the risk of venous thromboembolism outweighs the risk of haemorrhagic transformation. People considered to be at particularly high risk of venous thromboembolism include anyone with complete paralysis of the leg, a previous history of venous thromboembolism, dehydration or comorbidities (such as malignant disease), or who is a current or recent smoker. Such people should be kept under regular review if they are given prophylactic anticoagulation. Further details will be included in the forthcoming NICE clinical guideline ‘The prevention of venous thromboembolism in all hospital patients’ (publication expected in September 2009).26.01.08: The results of two large randomized, non-blinded, intervention studies indicate that aspirin is safe and effective when started within 48 hours after stroke {International-Stroke-Trial-Collaborative-Group, 1997 #908;CAST-Collaborative-Group, 1997 #907}. In absolute terms, 13 more patients were alive and independent at the end of follow-up for every 1000 patients treated. Furthermore, treatment increased the odds of making a complete recovery from the stroke (OR 1.06; 95%CI 1.01-1.11): 10 more patients made a complete recovery for every 1000 patients treated. Antiplatelet therapy was associated with a small but definite excess of two symptomatic intracranial haemorrhages for every 1000 patients treated, but this was more than offset by a reduction of seven recurrent ischaemic strokes and about one pulmonary embolism for every 1000 patients treated.In a double-blind phase II, the GPIIb-IIIa inhibitor abciximab produced a non-significant shift in favourable outcomes, as measured by modified Rankin scores (mRS) at 3 months, compared with placebo (OR 1.20; 95%CI 0.84-1.70) {AbESST investigators, 2005 #888}. A phase III study evaluating the safety and efficacy of abciximab has been halted because of an increased rate of bleeding with abciximab {Adams, 2007 #887}. ACUTE ASPIRIN THERAPYAfter brain imaging has excluded intracranial hemorrhage all acute stroke patients should be given at least 160 mg of acetylsalicylic acid (ASA) immediately as a one time loading dose. (RCP, NZ, SIGN13; Evidence Level A)• In patients treated with r-tPA, ASA should be delayed until after the 24-hour post-thrombolysis scan has excluded intracranial hemorrhage. (RCP, NZ; Evidence Level A)• ASA (50-325 mg daily) should then be continued indefinitely or until an alternative antithrombotic regime is started. (RCP; Evidence Level A)• In dysphagic patients, ASA may be given by enteral tube or by rectal suppository. (RCP; Evidence Level A)
  • Early use (<3Hr) may reduce mortality and morbidity.Hemorrhagic transformation is highEarly administration of unfractionated heparin, low molecular weight heparin or heparinoids is not recommended for the treatment of patients with ischaemic stroke (Class I, Level A)IndicationArterial dissectionCardioembolic infarct with or without AFImmediate for small infarct if re-embolization risk is highDelayed 2 weeks for all casesHeparin - 1000 units/hr. PTT 1.5 avoid bolus Enaoxaparin – 40mg SC BDLow dose Enoxaparin 40mg SC OD prophylactic for DVT26.01.08: Subcutaneous unfractionated heparin (UFH) at low or moderate doses {International-Stroke-Trial-Collaborative-Group, 1997 #908}, nadroparin{Kay, 1995 #215;Wong, 2007 #477}; certoparin {Diener, 2001 #53}, tinzaparin {Bath, 2001 #15}, dalteparin {Berge, 2000 #21} and intravenous danaparoid {The Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators, 1998 #216} have failed to show an overall benefit of anticoagulation when initiated within 24 to 48 hours from stroke onset. Improvements in outcome or reductions in stroke recurrence rates were mostly counterbalanced by an increased number of haemorrhagic complications. In a meta-analysis of 22 trials, anticoagulant therapy was associated with about nine fewer recurrent ischaemic strokes per 1000 patients treated (OR 0.76; 95%CI 0.65-0.88), and with about nine more symptomatic intracranial haemorrhages per 1000 (OR 2.52; 95%CI 1.92-3.30) {Gubitz, 2004 #918}. However, the quality of the trials varied considerably. The anticoagulants tested were standard UFH, low molecular weight heparins, heparinoids, oral anticoagulants, and thrombin inhibitors.5.3 a nticoagulants SIGN 2008The administration of anticoagulants is contraindicated during the first 24 hours after IV thrombolytic therapy.83 Although recanalisation may be more successful, the risk of haemorrhage increases. Evidence on adjunctive anticoagulation is limited and neither the safety nor efficacy has been established.835.3.1 unfractionated heparinFixed dose unfractionated heparin (UFH) commenced within 48 hours of ischaemic stroke of any aetiology (including patients with atrial fibrillation) does not reduce the chances of death or dependence after 3-6 months and is not significantly superior to aspirin alone.84 A reduction of recurrent strokes (nine fewer for every 1,000 patients treated) was offset by nine extra symptomatic intracerebral haemorrhages for every 1,000 patients treated, and nine additional major extracranialhaemorrhages for every 1,000 patients treated.High dose UFH given within three hours of stroke onset was associated with a significant reduction in death or dependence. Patients eligible for very early heparin treatment are also likely to be candidates for thrombolysis.855.3.2 L ow Molecular Weight heparins and heparinoidsA non-significant trend towards reduction in death and dependence at 3-6 months was seen for low molecular weight heparins (LMWH) and heparinoids when compared to control, which was a mixture of placebo, aspirin, and unfractionated heparin (OR=0.85; 95% CI 0.66 to 1.08).86 In patients with atrial fibrillation, weight-adjusted high dose LMWH (dalteparin 100 iu/kg) was not superior to aspirin in preventing early stroke recurrence and carried a significantly higher risk of extracerebral haemorrhage.87Symptomatic and asymptomatic venous thromboembolic events are highly significantly reduced by all heparin treatments. Deep vein thrombosis (DVT) is avoided in 281 patients for every 1,000 treated and pulmonary thromboembolisms (PTE) are avoided in four patients per 1,000 treated.84 LMWH and heparinoids are associated with a significantly greater reduction in DVT than UFH without any additional hazard.86 Enoxaparin 40 mg once daily is superior to UFH 5,000 units twice daily and is not associated with any increase in bleeding complications or difference in mortality.885.3.3 heparin plus aspirinCombined treatment with aspirin and UFH reduced recurrent stroke by 10 fewer per 1,000 patients treated, although a significant increase in the number of symptomatic intracranial haemorrhages was also reported (10 more per 1,000 patients). For patients in atrial fibrillation (AF) with acute ischaemic stroke aspirin reduces the risk of further stroke by 21% giving a number needed to treat (NNT) to prevent one stroke of 100 over 2-4 weeks.89 Any benefit of UFH in this situation is offset by the increase in haemorrhagic stroke.895.3.4 WarfarinIn one trial 100 patients received warfarin within two weeks of stroke onset and none had haemorrhagic worsening.89 Large, disabling strokes were under-represented. An arbitrary time limit of two weeks is recommended for delaying warfarin treatment for AF following acute stroke.89The routine use of anticoagulants (UFH, LMWH, heparinoids, oral anticoagulants, direct thrombin inhibitors, fibrinogen-depleting agents) is not recommended for the treatmentof acute ischaemic stroke.ƒ. Anticoagulants are not recommended in patients with progressing stroke.A In patients at high risk of venous thromboembolic disease LMWH should be considered in preference to UFH.D Following administration of IV thrombolysis, heparin should not be given in any formfor 24 hours.C For patients in atrial fibrillation following stroke, anticoagulation with warfarin can be introduced early in patients with minor stroke or TIA, but should be deferred for two weeks after onset in those with major stroke.heparin or heparinoids. There is, as yet, insufficient evidence to decide whether specific subgroups of ischemic stroke (e.g., dissection, cardio-embolism with intra-cardiac clot) will benefit from therapeutic anticoagulation.• If a decision is made to use continuous heparin infusion, boluses should be avoided, and aPTT should be maintained in the 1.5-2 times baseline range.• Low-dose prophylactic parenteral anticoagulation (e.g., enoxaparin, 40 mg subcutaneously daily) is beneficial for prevention of deep vein thrombosis (DVT) or PE (pulmonaryembolism) in stroke patients with limited mobility.Considerations with Heparin UseIn contrast, to the proof of efficacy for aspirin, results from the International Stroke Trial provide powerful evidence against the routine use of any heparin regimen as intensive as the moderate-dose subcutaneous regimen utilized in this very large clinical trial (unfractionated heparin – 12,500 units subcutaneous twice daily) (International Stroke Trial Collaborative Group, 1997 [A]).The commonly cited indications of vertebrobasilar distribution ischemia or ischemic stroke in the setting of atrial fibrillation were analyzed separately and there was no measurable benefit in these specific subgroups.Similarly, the weight of available data regarding use of full-dose low-molecular-weight heparin for the acute treatment of stroke does not support their routine use for limiting disability or decreasing mortality in this setting (Publications Committee for the Trial of ORG 10172 in Acute Ischemic Stroke, 1998 [A]).In summary, the routine use of acute anticoagulation treatment with unfractionated heparin, low-molecularweight heparin, or heparinoid in acute ischemic stroke is not supported by the available evidence (International Stroke Trial Collaborative Group, 1997 [A]). This treatment does not appear to improve clinical outcome from the index stroke. There may be subgroups that benefit, but further studies of this problem are required for confirmation.Despite these discouraging results, the use of continuous heparin infusion in acute stroke has continued to be common in clinical practice (Albers, 2004 [R]; Berge, 2000 [A]; Coull, 2002 [M]; Diener, 2001 [A]).Given these data, if the decision is made to use full-dose continuous heparin infusion for a specific indication (e.g., large vessel atherothrombosis or dissection), physicians are strongly encouraged to discuss with their patients the lack of proof for this therapy and to detail the potential hazards.Heparin use for venous thromboembolism (VTE) prophylaxisFor patients at high risk for VTE where pharmacologic prophylaxis is contraindicated, intermittent pneumatic compression (IPC) should be used if the patient is confined to bed. Thigh-length graduated compression elastic stockings have been shown not to be effective (CLOTS Trials Collaboration, 2009 [A]). See also Annotation #38, "Other Post-Emergency Department Medical Management (First 24-48 Hours)“ (Kamphnisen, 2005 [R]).See the ICSI Venous Thromboembolism Prophylaxis guideline for more information.People with acute venous stroke NICE 2008People diagnosed with cerebral venous sinus thrombosis (including those with secondary cerebral haemorrhage) should be given full-dose anticoagulation treatment (initially full-dose heparin and then warfarin [INR 2–3]) unless there are comorbidities that preclude its use.People with stroke associated with arterial dissectionPeople with stroke secondary to acute arterial dissection should be treated with either anticoagulants or antiplatelet agents, preferably as part of a randomised controlled trial to compare the effects of the two treatments.People with acute ischaemic stroke associated with antiphospholipid syndromePeople with antiphospholipid syndrome who have an acute ischaemic stroke should be managed in same way as people with acute ischaemic stroke without antiphospholipid syndrome.There was insufficient evidence to support any recommendation on the safety and efficacy of anticoagulants versus antiplatelets for the treatment of people with acute ischaemic stroke associated with antiphospholipid syndrome.Reversal of anticoagulation treatment in people with haemorrhagic strokeClotting levels in people with a primary intracerebral haemorrhage who were receiving anticoagulation treatment before their stroke (and have elevated INR) should be returned to normal as soon as possible, by reversing the effects of the anticoagulation treatment using a combination of prothrombin complex concentrate and intravenous vitamin K.Anticoagulation treatment for other comorbiditiesPeople with disabling ischaemic stroke who are in atrial fibrillation should be treated with aspirin 300 mg for the first 2 weeks before considering anticoagulation treatment. In people with prosthetic valves who have disabling cerebral infarction and who are at significant risk of haemorrhagic transformation, anticoagulation treatment should be stopped for 1 week and aspirin 300 mg substituted. People with ischaemic stroke and symptomatic proximal deep vein thrombosis or pulmonary embolism should receive anticoagulation treatment in preference to treatment with aspirin unless there are other contraindications to anticoagulation.People with haemorrhagic stroke and symptomatic deep vein thrombosis or pulmonary embolism should have treatment to prevent the development of further pulmonary emboli using either anticoagulation or a caval filter.
  • Ischemic Brain EdemaAcute cerebral infarction is often followed by a delayed deterioration caused by edema of the infarcted tissue.158,963,964 Depending on stroke location, infarct volume, patient age, and degree of preexisting atrophy, edema may produce a range of clinical findings from being clinically silent and not associated with new neurological symptoms to precipitous fatal deterioration.965,966 Although the cytotoxic edema normally peaks 3 to 4 days after injury,965–967 early reperfusion of a large volume of necrotic tissue can accelerate the edema to a potentially critical level within the first 24 hours, a circumstance termed malignant edema.968 In patients with severe stroke or posterior fossa infarctions, careful observation is required for early intervention to address potentially life-threatening edema.Medical Management of Cerebral EdemaCerebral edema will occur in all infarcts but especially in large-volume infarcts. Several medical interventions have been suggested to minimize edema development, such as restriction of free water to avoid hypo-osmolar fluid, avoidance of excess glucose administration, minimization of hypoxemia and hypercarbia, and treatment of hyperthermia. Antihypertensive agents, particularly those that induce cerebral vasodilatation, should be avoided. To assist in venous drainage, the head of the bed can be elevated at 20° to 30°. The goal of these interventions is to reduce or minimize edema formation before it produces clinically significant increases in ICP.
  • When edema produces increased ICP, standard ICP management practices should be initiated.969 ICP management strategies are similar to those used in traumatic brain injury and spontaneous intracranial hemorrhage, including hyperventilation, hypertonic saline, osmotic diuretics, intraventricular drainage of cerebrospinal fluid, and decompressive surgery.970,971 No evidence indicates that hyperventilation, corticosteroids in conventional or large doses, diuretics, mannitol, or glycerol or other measures that reduce ICP alone improve outcome in patients with ischemic brain swelling. Mannitol 0.25 to 0.5 g/kg IV administered over 20 minutes lowers ICP and can be given every 6 hours. The usual maximal dose is 2g/kg. In a preliminary study by Koenig et al,972 use of hypertonic saline in patients with clinical transtentorialherniation caused by various supratentorial lesions, including ischemic and hemorrhagic stroke, was associated with a rapid decrease in ICP. This stroke-specific study complements very supportive data from the traumatic brain injury literature. Hyperventilation of intubated patients induces cerebral vasoconstriction, which causes a reduction in cerebral blood volume, thus lowering ICP. The target of hyperventilation is mild hypocapnia (PCO2 30–35 mmHg), but even after this goal is reached, the benefit is short-lived. Despite intensive medical management, the death rate in patients with increased ICP remains as high as 50% to 70%; thus, these interventions should be considered temporizing, extending the window for definitive treatments.Decompressive SurgeryHemispheric infarction, often caused by proximal large-vessel occlusions (internal carotid, carotid terminus, proximal MCA), is associated with a large volume of infarction that often involves tissue above and below the sylvian fissure.158,964,973Patients with imaging studies that demonstrate the early appearance of CT scan hypodensity,158 restricted diffusion,974,975 or an absence of perfusion244 in more than two thirds of the MCA territory are at increased risk of delayed herniation. Clinical deterioration is often rapid, with brain stem compression first causing deterioration of consciousness, which may be followed rapidly by a failure of upper brain stem function.965,966 Deterioration of consciousness in this setting is associated with a 50% to 70% likelihood of mortality despite maximal medical management.963,976 Brain stem compression is commonly accompanied by secondary involvement of the frontal and occipital lobes, presumably attributable to anterior cerebral and posterior cerebral artery compression against dural structures.977,978 The resulting secondary infarctions greatly limit the potential for a meaningful clinical recovery or even survival.The role of neurosurgical intervention for the treatment of supratentorial infarction has been controversial. Previously, the long-term functional benefit of surgical decompression was debated, although surgical decompression can reduce mortality from 80% to ≈20%.979–982 Because secondary infarctions limit the potential for recovery, earlier intervention, that is, before signs of herniation, is often recommended on the basis of the volume of tissue that is infarcted and the degree of midline shift.983,984 The merger of 3 randomized controlled trials published in 2007 demonstrated the potential benefit of decompressive surgery. In the study, surgery was performed within 48 hours of stroke onset in patients with malignant infarctions who were 18 to 60 years of age. Surgical decompression reduced mortality from 78% to 29% and significantly increased favorable outcomes.985 Equal benefit was observed in patients with dominant and nondominant hemisphere infarctions. Age impacted outcome, with older patients having worse outcomes.986 The authors stressed, “The decision to perform decompressive surgery should, however, be made on an individual basis in every case”.987–989 Although the surgery may be recommended for treatment of seriously affected patients, the physician should advise the patient’s family about the potential outcomes, including survival with severe disability.When a large infarction of the cerebellum occurs, delayed swelling commonly follows. Although the early symptoms may be limited to impaired function of the cerebellum, edema can cause brain stem compression and can progress very rapidly to a loss of brain stem function. Emergent posterior fossa decompression with partial removal of the infarcted tissue is often lifesaving and produces a clinical outcome with a reasonable quality of life.990–992RecommendationsPatients with major infarctions are at high risk for complicating brain edema and increased ICP. Measures to lessen the risk of edema and close monitoring of the patient for signs of neurological worsening during the first days after stroke are recommended (Class I; Level of Evidence A). Early transfer of patients at risk for malignant brain edema to an institution with neurosurgical expertise should be considered.(Revised from the previous guideline13)Decompressive surgical evacuation of a space-occupying cerebellar infarction is effective in preventing and treating herniation and brain stem compression (Class I; Level of Evidence B). (Revised from the previous guideline13)Decompressive surgery for malignant edema of the cerebral hemisphere is effective and potentially lifesaving (Class I; Level of Evidence B). Advanced patient age and patient/family valuations of achievable outcome states may affect decisions regarding surgery. (Revised from the previous guideline13)Recurrent seizures after stroke should be treated in a manner similar to other acute neurological conditions, and antiepileptic agents should be selected by specific patient characteristics (Class I; Level of Evidence B). (Unchanged from the previous guideline13)Placement of a ventricular drain is useful in patients with acute hydrocephalus secondary to ischemic stroke (Class I; Level of Evidence C). (Revised from the previous guideline13)Although aggressive medical measures have been recommended for treatment of deteriorating patients with malignant brain edema after large cerebral infarction, the usefulness of these measures is not well established (Class IIb; Level of Evidence C). (Revised from the previous guideline13)Because of lack of evidence of efficacy and the potential to increase the risk of infectious complications, corticosteroids (in conventional or large doses) are not recommended for treatment of cerebral edema and increased ICP complicating ischemic stroke (Class III; Level of Evidence A). (Unchanged from the previous guideline13)
  • Hemorrhagic TransformationIschemic infarction is frequently accompanied by petechial hemorrhage without associated neurological deterioration in patients who are not treated with recanalization strategies.993,994 Symptomatic hemorrhage, however, occurs in ≈5% to 6% of patients after use of intravenous rtPA and intra-arterial recanalization strategies and anticoagulant use.480,995–997 Strict adherence to fibrinolytic administration and posttreatment protocols minimizes these risks. Hemorrhagic transformation can also occur in patients who did not undergo reperfusion therapies and who require similar vigilance, especially those patients with larger strokes, of older age, and with a cardioembolic pathogenesis. Signs and symptoms of sICH resemble those of patients with spontaneous ICH, such as worsening neurological symptoms, decreasing mental status, headache, increased blood pressure and pulse, and vomiting.470 Similarly, health providers’ vigilance to immediately detect hemorrhagic complications may allow timely interventions to mitigate the hemorrhage.Most sICHs occur within the first 24 hours after intravenous rtPA; the vast majority of fatal hemorrhages occur within the first 12 hours.470 If a patient demonstrates signs of symptomatic hemorrhage, any remaining intravenous rtPA should be withheld. A standardized guideline for managing fibrinolytic-associated hemorrhages does not exist. Given insights from clinical trials, protocols call for an emergent noncontrast CT scan and blood samples for a complete blood count, coagulation parameters (PT, PTT, INR), type and screen, and fibrinogen levels. Concurrently, other causes of neurological worsening, such as hemodynamic instability, are pursued. Although no study has been conducted to determine the best way to manage post–intravenous rtPA hemorrhage, many rtPA-associated hemorrhage protocols call for the use of cryoprecipitate to restore decreased fibrinogen levels. A recent case report described the use of tranexamic acid in the treatment of an intravenous rtPA–associated hemorrhage in a Jehovah’s Witness stroke patient. After administration, no further hematoma expansion was noted.998Further studies are clearly warranted to define the optimal way to manage fibrinolytic-associated hemorrhages.Although definitive data from clinical trials are lacking, surgical hematoma evacuation may be considered depending on the size and location of the hemorrhage and the patient’s overall medical and neurological condition. Evacuation of a large hemorrhage may be lifesaving, whereas smaller hematomas may be tolerated without clinical relevance.999 As with cerebral edema, cerebellar hemorrhagic conversion is more likely to become symptomatic.1000
  • SeizuresThe reported incidence of seizures after ischemic infarction varies greatly, with most reports indicating an incidence <10%.1001,1002 An increased incidence of seizures after ischemic infarction is reported in patients with hemorrhagic transformation.1003 A great variance is also reported in the incidence of recurrent and late-onset seizures.1004,1005 With few data available on the efficacy of anticonvulsants in the treatment of seizures in stroke patients, current recommendations are based on the established management of seizures that may complicate any neurological illness. No studies to date have demonstrated a benefit of prophylactic anticonvulsant use after ischemic stroke, and little information exists on indications for the long-term use of anticonvulsants after a seizure.RecommendationsProphylactic use of anticonvulsants is not recommended (Class III; Level of Evidence C). (Unchanged from the previous guideline13)Seizures and Antiepileptic DrugsThe incidence of clinical seizures within the first 2 weeks after ICH has been reported to range from 2.7% to 17%, with the majority occurring at or near onset.96–100 Studies of continuous electroencephalography (EEG) have reported electrographic seizures in 28% to 31% of select cohorts of ICH patients, despite most having received prophylactic anticonvulsants.101,102 In a large, single-center study, prophylactic antiepileptic drugs did significantly reduce the number of clinical seizures after lobar ICH.98 However, in prospective and population-based studies, clinical seizures have not been associated with worsened neurological outcome or mortality.97,103,104 The clinical impact of subclinical seizures detected on EEG is also not clear. A recent analysis from the placebo arm of an ICH neuroprotectant study found that patients who received antiepileptic drugs (primarily phenytoin) without a documented seizure were significantly more likely to be dead or disabled at 90 days, after adjusting for other established predictors of ICH outcome.105 Another recent single-center observational study had similar findings, specifically for phenytoin.106 Thus only clinical seizures or electrographic seizures in patients with a change in mental status should be treated with antiepileptic drugs. Continuous EEG monitoring should be considered in ICH patients with depressed mental status out of proportion to the degree of brain injury. The utility of prophylactic anticonvulsant medication remains uncertain.Antiepileptic DrugsSeizures occur commonly after ICH and may be nonconvulsive. The frequency of observed seizures after ICH depends on the extent of monitoring. In a recently published largeclinical series of 761 subsequent patients, early seizures occurred in 4.2% of patients, and 8.1% had seizures within 30 days after onset. Lobar location was significantly associatedwith the occurrence of early seizures.81 In a cohort of ICH patients undergoing continuous electrophysiological monitoring in a neurocritical care unit, electrographic seizures occurred in 18 (28%) of 63 patients with ICH during the initial 72 hours after admission. Seizures were independently associated with increased midline shift after intraparenchymal hemorrhage.82 ICH-related seizures are often nonconvulsive and are associated with higher NIHSS scores, a midline shift, and a trend toward poor outcome.82Treatment of clinical seizures in ICH patients during the hospitalization should include intravenous medications to control seizures quickly, as for any hospitalized patient.Initial choice of medications includes benzodiazepines such as lorazepam or diazepam, followed directly by intravenous fos-phenytoin or phenytoin. The European Federation ofNeurological Societies guidelines provide a detailed step approach to address more refractory cases of status epilepticus.83 A brief period of antiepileptic therapy soon after ICH onset may reduce the risk of early seizures, particularly in patients with lobar hemorrhage.81 Choice of medication for prophylaxis should include one that can be administered intravenously as needed during the hospitalization and orally after discharge.RecommendationsSeizures and Antiepileptic Drugs1. Clinical seizures should be treated with antiepileptic drugs (Class I; Level of Evidence: A). (Revised from the previous guideline) Continuous EEG monitoringis probably indicated in ICH patients with depressed mental status out of proportion to the degree of brain injury (Class IIa; Level of Evidence: B). Patientswith a change in mental status who are found to have electrographic seizures on EEG should be treated with antiepileptic drugs (Class I; Level ofEvidence: C). Prophylactic anticonvulsant medication should not be used (Class III; Level of Evidence:B). (New recommendation)
  • Volume of Intracerebral HemorrhageA Powerful and Easy-to-Use Predictor of 30-Day MortalityJoseph P. Broderick, MD; Thomas G. Brott, MD; John E. Duldner, MD;Thomas Tomsick, MD; Gertrude Huster, MHSBackground and Purpose: The aim of this study was to determine the 30-day mortality and morbidity of intracerebral hemorrhage in a large metropolitan population and to determine the most important predictors of 30-day outcome.Methods: We reviewed the medical records and computed tomographic films for all cases of spontaneous intracerebral hemorrhage in Greater Cincinnati during 1988. Independent predictors of 30-day mortality were determined using univariate and multivariate statistical analyses.Results: The 30-day mortality for the 188 cases of intracerebral hemorrhage was 44%, with half of deaths occurring within the first 2 days of onset. Volume of intracerebral hemorrhage was the strongest predictor of 30-day mortality for all locations of intracerebral hemorrhage. Using three categories of parenchymal hemorrhage volume (0 to 29 cm3, 30 to 60 cm3, and 61 cm3 or more), calculated by a quick and easy-to-use ellipsoid method, and two categories of the Glasgow Coma Scale (9 or more and 8 or less), 30-daymortality was predicted correctly with a sensitivity of 96% and a specificity of 98%. Patients with a parenchymal hemorrhage volume of 60 cm3 or more on their initial computed tomogram and a Glasgow Coma Scale score of 8 or less had a predicted 30-day mortality of 91%. Patients with a volume of less than 30 cm3 and a Glasgow Coma Scale score of 9 or more had a predicted 30-day mortality of 19%o. Only one of the 71 patients with a volume of parenchymal hemorrhage of 30 cm3 or more could functionindependently at 30 days.Conclusions: Volume of intracerebral hemorrhage, in combination with the initial Glasgow Coma Scale score, is a powerful and easy-to-use predictor of 30-day mortality and morbidity in patients with spontaneous intracerebral hemorrhage. (Stroke 1993;24:987-993)KEY WoRDs * intracerebral hemorrhage * survival * tomo
  • Overall Approach to Treatment of ICHPotential treatments of ICH include stopping or slowing the initial bleeding during the first hours after onset; Removing blood from the parenchyma or ventricles to eliminate both mechanical and chemical factors that cause brain injury; Management of complications of blood in the brain, including increased ICP and decreased cerebral perfusion; and good general supportive management of patients with severe brain injury. Good clinical practice includes management of airways, oxygenation, circulation, glucose level, fever, and nutrition, as well as prophylaxis for deep vein thrombosis. However, because of the lack of definitive randomized trials of either medical or surgical therapies for ICH, until recently, there has been great variability in the treatment of ICH worldwide.2004 Stroke June 2007Downloaded from stroke.ahajournals.org by on December 7, 2010
  • Trials of Recombinant Activated Factor VIIrFVIIa is approved to treat bleeding in patients with hemophilia who have antibodies to factor VIII or IX, and it has been reported to reduce bleeding in patients without coagulopathy as well.38 Interaction of rFVIIa and tissue factor stimulates thrombin generation. rFVIIa also activates factor X on the surface of activated platelets, which leads to an enhanced thrombin burst at the site of injury.38,39 Thrombin converts fibrinogen into fibrin, which produces a stable clot. rFVIIa has a half-life of 2.6 hours, and the recommended dose for treatment of bleeding in patients with hemophilia is 90 g/kg intravenously every 3 hours.38 Two small dose-ranging pilot safety studies and a largerdose-finding phase II study focusing on decreasing the growth of ICHs have been published.33,34,40 In the 2 small dose-ranging studies, the overall thromboembolic and seriousadverse event rate in the 88 patients tested at escalating doses from 5 to 160 g/kg was low enough to encourage further testing.The second larger, randomized, dose-escalation trial included 399 patients with ICH diagnosed by CT within 3 hours after onset who were randomized to receive placebo (96patients) or rFVIIa 40 g/kg body weight (108 patients), 80 g/kg (92 patients), or 160 g/kg (103 patients) within 1 hour after the baseline scan. The primary outcome measure was the percent change in the volume of the ICH at 24 hours. Clinical outcomes were assessed at 90 days. Hematoma volume increased more in the placebo group than in the rFVIIagroups. The mean increase was 29% in the placebo group, compared with 16%, 14%, and 11% in the groups given rFVIIa 40, 80, and 160 g/kg, respectively (P0.01 forcomparison of the 3 rFVIIa groups with the placebo group).Growth in the volume of ICH was reduced by 3.3, 4.5, and 5.8 mL, respectively, in the 3 treatment groups versus that in the placebo group (P0.01). Sixty-nine percent of placebotreatedpatients died or were severely disabled (as defined by a modified Rankin Scale score of 4 to 6), compared with 55%, 49%, and 54% of the patients who were given rFVIIa 40, 80, and 160 g/kg, respectively (P0.004 for comparison of the 3 rFVIIa groups with the placebo group). The rate of death at 90 days was 29% for patients who received placebo versus 18% in the 3 rFVIIa groups combined (P0.02). Serious thromboembolic adverse events, mainly myocardial or cerebral infarction, occurred in 7% of rFVIIa-treated patients versus 2% of those given placebo (P0.12). In this moderatesizedphase II trial, treatment with rFVIIa within 4 hours after the onset of ICH limited the growth of the hematoma, reduced the mortality rate, and improved functional outcome at 90 days despite a small increase in the frequency of thromboembolic adverse events. A larger phase III randomized trial of rFVIIa has been completed, and presentation of the results will occur in May 2007 at the American Academy of Neurology Meeting in Boston, Mass.In addition, several case reports of the use of rFVIIa in the setting of warfarin-associated ICH have been published.41,42Although rFVIIa can reverse the elevated INR measurements rapidly, its use in this setting remains investigational. In addition, a normal INR after use of rFVIIa does not implycomplete normalization of the clotting system, and the INR may rise again after the initial rFVIIa dose.43
  • Recommendations 20101. Until ongoing clinical trials of BP intervention for ICH are completed, physicians must manage BP on the basis of the present incomplete efficacy evidence.Current suggested recommendations for target BP in various situations are listed in Table 6 and may be considered (Class IIb; Level of Evidence: C). (Unchanged from the previous guideline)2. In patients presenting with a systolic BP of 150 to 220 mm Hg, acute lowering of systolic BP to 140 mm Hg is probably safe (Class IIa; Level ofEvidence: B). (New recommendation)TABLE 2. Suggested Recommended Guidelines for Treating Elevated Blood Pressure in Spontaneous ICH1. If SBP is 200 mm Hg or MAP is 150 mm Hg, then consider aggressive reduction of blood pressure with continuous intravenous infusion, with frequent blood pressure monitoring every 5 minutes.2. If SBP is 180 mm Hg or MAP is 130 mm Hg and there is evidence of or suspicion of elevated ICP, then consider monitoring ICP and reducing blood pressure using intermittent or continuous intravenous medications to keep cerebral perfusion pressure 60 to 80 mm Hg.3. If SBP is 180 mm Hg or MAP is 130 mm Hg and there is not evidence of or suspicion of elevated ICP, then consider a modest reduction of blood pressure (eg, MAP of 110 mm Hg or target blood pressure of 160/90 mm Hg) using intermittent or continuous intravenous medications to control blood pressure, and clinically reexamine the patient every 15 minutes.SBP indicates systolic blood pressure; MAP, mean arterial pressure.The following algorithm adapted from guidelines for antihypertensive therapy in patients with acute stroke may be used in the first few hours of ICH (level of evidence V, grade C recommendation): If systolic BP s > 230 mmHg or diastolic BP > 140 mm Hg on 2 readings 5 minutes apart, institute nitroprusside. If systolic BP is 180 to 230 mmHg, diastolic BP 105 to 140mm Hg, or mean arterial BP >= 130 mm Hg on 2 readings 20 minutes apart, institute intravenous labetalol, esmolol, or enalapril. Avoid oral or sublingual nifedipine. If systolic BP is < 180 mmHg and diastolic BP is < 105mmHg, defer antihypertensive therapy unless concurrent coronary ischemia is suspected. Choice of medication depends on other medical contraindications (e.g., avoid labetalol in patients with asthma). If ICP monitoring is available, cerebral perfusion pressure should be kept at > 70 mmHg at all times. Any clinical deterioration in association with reduction of BP should prompt reconsideration of ongoing BP management strategy. 210 guideBlood PressureBlood Pressure and Outcome in ICHBlood pressure (BP) is frequently, and often markedly, elevated in patients with acute ICH; these elevations in BP are greater than that seen in patients with ischemic stroke.72,73Although BP generally falls spontaneously within several days after ICH, high BP persists in a substantial proportion of patients.72,73 Potential pathophysiologic mechanisms include stress activation of the neuroendocrine system (sympathetic nervous system, renin-angiotensin axis, or glucocorticoid system) and increased intracranial pressure. 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, although a clear association between hypertension within the first few hours after ICH and the risk of hematoma expansion (or eventual hematoma volume) has not been clearly demonstrated.25,74A systematic review75 and a recent large multisite study in China73 show that a measurement of systolic BP above 140 to 150 mm Hg within 12 hours of ICH is associated with more than double the risk of subsequent death or dependency.Compared with ischemic stroke, where consistent U- or J-shaped associations between BP levels and poor outcome have been shown,76 only 1 study of ICH has shown a pooroutcome at very low systolic BP levels (140 mm Hg).77 For both ischemic stroke and possibly ICH, a likely explanation for such association is reverse causation, whereby very lowBP levels occur disproportionately in more severe cases, so that although low BP levels may be associated with a high case fatality, it may not in itself be causal.Broderick et al Guidelines for Management of Spontaneous ICH in Adults 2005Downloaded from stroke.ahajournals.org by on December 7, 2010Recent Pilot Trial of Acute Blood Pressure ManagementThe optimal level of a patient’s blood pressure should be based on individual factors such as chronic hypertension, ICP, age, presumed cause of hemorrhage, and interval sinceonset. Theoretically, elevated blood pressure may increase the risk of ongoing bleeding from ruptured small arteries and arterioles during the first hours. Blood pressure is correlated with increased ICP and volume of hemorrhage. However, it has been difficult to determine whether elevated blood pressure is a cause of hemorrhage growth or an effect of increasing volumes of ICH and increased ICP. A prospective observational study of growth in the volume of ICH did not demonstrate a relationship between baseline blood pressure and subsequent growth of ICH, but frequent early use of hypertensive agents in that study may have obscured any relationship.15 Conversely, overaggressive treatment of blood pressure may decrease cerebral perfusion pressure (CPP) and theoretically worsen brain injury, particularly in the setting of increased ICP.Powers and colleagues44 studied 14 patients with acute supratentorial ICH 1 to 45 mL in size at 6 to 22 hours after onset. Cerebral blood flow (CBF) was measured withpositron emission tomography and [15O]water. After completion of the first CBF measurement, patients were randomized to receive either nicardipine or labetalol to reduce meanarterial pressure by 15%, and the CBF study was repeated.Mean arterial pressure was lowered by 16.75.4% from 14310 to 11911 mm Hg. No significant change was observed in either global CBF or periclot CBF. The authorsconcluded that in patients with small- to medium-sized acute ICHs, autoregulation of CBF was preserved with arterial blood pressure reductions in the range studied.Blood Pressure ManagementThe previous AHA recommendation for the management of blood pressure after ICH outlined the important concept of selecting a target blood pressure on the basis of individualpatient factors,6 such as baseline blood pressure, presumed cause of hemorrhage, age, and elevated ICP. The primary rationale for lowering the blood pressure is to avoid hemorrhagic expansion from potential sites of bleeding. This is especially true for hemorrhage resulting from a ruptured aneurysm or arteriovenous malformation, in which the risk of continued bleeding or rebleeding is presumed to be highest.However, in primary ICH, in which a specific large-vessel vasculopathy is not apparent, the risk of hemorrhagic expansion with mild blood pressure elevation may be lower andmust be balanced with the theoretical risks of inducing cerebral ischemia in the edematous region that surrounds the hemorrhage. This theoretical risk has been somewhatmuted by prospective observational studies in both animals and human beings44,46 that have dispelled the concept of major ischemia in the edematous tissue surrounding thehemorrhage. Nevertheless, some controversy persists on the basis of human MRI–apparent diffusion coefficient studies of the perihemorrhagic region,47 which indicate arim of tissue at risk for secondary ischemia in large hematomas with elevated ICP.Nonetheless, for primary ICH, little prospective evidence exists to support a specific blood pressure threshold. The previous recommendation was to maintain a systolic bloodpressure 180 mm Hg and/or mean arterial pressure 130 mm Hg. The evidence to support any specific recommendation can be briefly summarized as follows: (1) Isolatedsystolic blood pressure 210 mm Hg is not clearly related to hemorrhagic expansion or to neurological worsening.48 (2)Reduction in mean arterial pressure by 15% (mean 14210 to 11911 mm Hg) does not result in CBF reduction in humans as measured by positron emission tomography.44 (3)In one prospective observational study,49 reduction of systolic blood pressure to a target 160/90 mm Hg was associated with neurological deterioration in 7% of patients and withhemorrhagic expansion in 9% but was associated with a trend toward improved outcome in those patients in whom systolic blood pressure was lowered within 6 hours of hemorrhage onset. (4) Baseline blood pressure was not associated with growth of ICH in the largest prospective study of ICH growth and in the Recombinant Activated Factor VII Intracerebral Hemorrhage Trial.15,16,50 (5) Hemorrhagic enlargement occurs more frequently in patients with elevated systolic blood pressure, but it is not known whether this is an effect of increased growth of ICH with associated increases in ICP or a contributing cause to the growth of ICH.51 (6) A rapid decline in blood pressure during the acute hospitalization was associated with increased death rate in one retrospective study.52 (7) Experience in traumatic brain hemorrhage, as well as spontaneous ICH, supports preservation of the CPP 60 mm Hg.53–56 Thus, whether more aggressive control of blood pressure during the first hours after onset of ICH can decrease bleeding without compromising the perfusion of brain surrounding the ICH remains unknown. The Antihypertensive Treatment in Acute Cerebral Hemorrhage (ATACH) Pilot Study, begun in2005, has been funded by the National Institute of Neurological Disorders and Stroke to investigate the control of blood pressure in patients with ICH. This study will involve a3-dose–tiered trial of reducing systolic blood pressure to 3 predetermined levels: 170 to 200, 140 to 170, and 110 to 140 mm Hg. In addition, the phase III randomized international INTERACT study (Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage) is planned to begin in 2006. The goal of this study is to determine whether lowering high blood pressure levels after the start of ICH will reduce the chances of a person dying or surviving with a long-term disability. The study includes patients with acute stroke due to spontaneous ICH with at least 2 systolic blood pressure measurements of 150 mm Hg and 220 mm Hg recorded 2 or more minutes apart and who are able to commence a randomly assigned blood pressure–lowering regimen within 6 hours of ICH onset.AbstractObjective: To determine the feasibility and acute (i.e., within 72 hrs) safety of three levels of systolic blood pressure reduction in subjects with supratentorial intracerebral hemorrhage treated within 6 hrs after symptom onset.Design: A traditional phase I, dose-escalation, multicenter prospective study.Settings: Emergency departments and intensive care units.Patients: Patients with intracerebral hemorrhage with elevated systolic blood pressure ≥170 mm Hg who present to the emergency department within 6 hrs of symptom onset.Intervention: Intravenous nicardipine to reduce systolic blood pressure to a target of: (1) 170 to 200 mm Hg in the first cohort of patients; (2) 140 to 170 mm Hg in the second cohort; and (3) 110 to 140 mm Hg in the third cohort.Primary outcomes of interest were: (1) treatment feasibility (achieving and maintaining the systolic blood pressure goals for 18–24 hrs); (2) neurologic deterioration within 24 hrs; and (3) serious adverse events within 72 hrs.A total of 18, 20, and 22 patients were enrolled in the respective three tiers of systolic blood pressure treatment goals. Overall, 9 of 60 patients had treatment failures (all in the last tier). A total of seven subjects with neurologic deterioration were observed: one (6%), two (10%), and four (18%) in tier one, two, and three, respectively. Serious adverse events were observed in one subject (5%) in tier two and in three subjects (14%) in tier three. However, the safety stopping rule was not activated in any of the tiers. Three (17%), two (10%), and five (23%) subjects in tiers one, two, and three, respectively, died within 3 monthsConclusions: The observed proportions of neurologic deterioration and serious adverse events were below the prespecified safety thresholds, and the 3-month mortality rate was lower than expected in all systolic blood pressure tiers. The results form the basis of a larger randomized trial addressing the efficacy of systolic blood pressure reduction in patients with intracerebral hemorrhage.Effects of BP-Lowering TreatmentsThe strong observational data cited previously and sophisticated neuroimaging studies that fail to identify an ischemic penumbra in ICH78 formed the basis for the INTensive BloodPressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT) pilot study, published in 2008.79 INTERACT was an open-label, randomized, controlled trial undertaken in404 mainly Chinese patients who could be assessed, treated, and monitored within 6 hours of the onset of ICH; 203 were randomized to a treatment with locally available intravenous BP-lowering agents to target a low systolic BP goal of 140 mm Hg within 1 hour and maintained for at least the next 24 hours, and 201 were randomized to a more modest systolic BP target of 180 mm Hg, as recommended in an earlier AHA guideline.80 The study showed a 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. In addition, 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, including disability and quality of life between groups, although the trial was not powered to detect such outcomes. The study provides an important proof of concept for early BP lowering in patients with ICH, but the data are insufficient to recommend a definitive policy.
  • Mechanism of raised intracranial pressureThe presence of hematoma initiates edema and neuronal damage in the surrounding parenchyma. Fluid begins to collect immediately around the hematoma resulting in edema which usually persists for five days,[5] but may last for two weeks. Early edema around the hematoma results from the release and accumulation of osmotically active serum protein from the clot.[6],[7] Cytotoxic and vasogenic edema follow, owing to failure of the sodium pump, death of neurons and disruption of the blood brain barrier.[8] Mass effect as a result of the volume of the hematoma, edema surrounding the hematoma and obstructive hydrocephalus may subsequently result in midline shift and herniation. This is the major cause of death during the first few days after ICH. The local increase in volume following ICH is initially accomodated by ventricular and subarachnoid spaces and later a marked progressive elevation of intracranial pressure (ICP) is seen, especially in patients with massive ICH. Localized mechanical damage and even transtentorialherniation may be seen in the absence of global increase in intracranial pressure.[9],[10] The major cause of mortality in ICH in acute stage is raised ICP. Various medical and surgical procedures have been undertaken to tide over this problem. In this review, the current status of osmotic therapy will be discussed.REVIEW ARTICLEYear : 2003  |  Volume : 51  |  Issue : 1  |  Page : 104--109Current status of osmotherapy in intracerebral hemorrhage J Kalita, P Ranjan, UK Misra  Department of Neurology, Sanjay Gandhi PGIMS, Lucknow, IndiaIntracerebral hemorrhage (ICH) is the most serious form of stroke, with more than two-thirds of the patients either dying or left permanently disabled from the condition. Despite considerable research effort, there is still no treatment of proven efficacy for ICH and the chances of surviving an ICH has failed to improve in recent decades. The brain damage from the initial hematoma is considered largely irreversible, which is because of the early time window of opportunity for treatment benefit and the modest potential effects of any medical therapy that limits hematoma growth. Knowledge has accumulated regarding the nature of secondary effects of the perihematomal edema in ICH, making it an attractive therapeutic target. The pathophysiology of ICH-related perihematomal edema is complex: a number of different mechanisms are involved from the initial hydrostatic pressure of the hematoma to the subsequent toxic effects of breakdown products resulting from coagulation cascade activation and erythrocyte lysis as part of the natural process of hematoma resolution. Although perihematomal edema and hematoma volumes are strongly correlated, there is less and conclusive evidence regarding the independent prognostic role of perihematomal edema per se. Patient management is primarily supportive and aimed at reducing resulting increases in intracranial pressure. No therapies have been shown to definitely influence outcome, and all are associated with some hazard. Further studies are required to clarify the relationship between perihematomal edema and outcome in ICH, and to translate the positive results of therapies identified in the laboratory into the clinical domain.Of the various pathological stroke types, intracerebral hemorrhage (ICH) is themost devastating and least treatable, causing death, disability, and long-term suffering in most of those affected.1 Despite considerable research effort, there is still a paucity of evidence regarding the efficacy of pharmacological and surgical interventions for ICH, and the chances of surviving ICH does not appear to have improved in recent decades.1,2 Although ICH constitutes about 10–15% of strokes in Western populations, its impact in terms of acute and long-term medical care costs as well as productivity loss is high, estimated at US$6 billion annually in the United States alone.3 In Asian populations, where rates of ICH are higher and people tend to be affected at younger ages, the impact of ICH is likely to be enormous. The heavy burden of ICH, coupled with the lack of proven therapies, underpins the need to develop novel strategies to improve outcomes. A better understanding of the underlying pathophysiological and pathochemicalsequelae of ICH should aid in this endeavor. The following processes have been shown to occur in ICH:early hematoma expansion and secondary edema-induced brain compression and consequent neuronal death; Cytotoxic (intracellular) and vasogenic (extracellular) edema resulting from disruption of the blood–brain barrier; Reductions in cerebral perfusion pressure (CPP) from mass effect and raised intracranial pressure (ICP); brain herniation; and finally, in those who survive, residual brain atrophy from the original lesion.4,5 Along with hematoma expansion, perihematomal edema is implicated in many of the fundamental processes driving the neuronal damage in ICH (Figure 1), although the prognostic significance of perihematomal edema on its own remains uncertain.6,7 However, while it is widely accepted that hematoma-induced brain damage is irreversible, the injury arising from perihematomal edema may be reversible, and thereby presents a potential therapeutic target for intervention.This review examines ICH-related perihematomal edema: pathophysiology and the factors influencing growth; its contribution to neurological deficits; and what potential therapeutic measures are currently available to limit its growth and enhance its resolution.ICH-related perihematomal edema growth is a progressive process, with multiple mechanisms implicated in its pathophysiology encompassing the hematologic, immunologic,and inflammatory pathways. Although the significance of perihematomal edema as a prognostic indicator per se is as yet uncertain, its secondary effects on ICP are clear and emphasize the consideration of treatment options that are largely supportive and aimed at reducing ICP and associated complications, most notably of brain herniation-related death. Further studies are therefore required to elucidate the prognostic significance of perihematomal edema in ICH and to translate the results the considerable experimental animal research into the clinical domain.Thus, treatment of the ICP resulting from perihematomaledema is primarily directed at the underlying cause, especially if there is hydrocephalus or mass effect from the hematoma. Because of limited data regarding ICP in ICH, management principles for elevated ICP are borrowed from traumatic brain injury guidelines that emphasize maintaining a CPP of 50–70 mmHg depending on the status of cerebral autoregulation.96 ICH patients with a Glasgow Coma Scale (GCS) score of 8 or less, those with clinical evidence of transtentorialherniation, or those with significant intraventricular hemorrhage or hydrocephalus may be considered for ICP monitoring and treatment.
  • Mechanism of raised intracranial pressureThe presence of hematoma initiates edema and neuronal damage in the surrounding parenchyma. Fluid begins to collect immediately around the hematoma resulting in edema which usually persists for five days,[5] but may last for two weeks. Early edema around the hematoma results from the release and accumulation of osmotically active serum protein from the clot.[6],[7] Cytotoxic and vasogenic edema follow, owing to failure of the sodium pump, death of neurons and disruption of the blood brain barrier.[8] Mass effect as a result of the volume of the hematoma, edema surrounding the hematoma and obstructive hydrocephalus may subsequently result in midline shift and herniation. This is the major cause of death during the first few days after ICH. The local increase in volume following ICH is initially accomodated by ventricular and subarachnoid spaces and later a marked progressive elevation of intracranial pressure (ICP) is seen, especially in patients with massive ICH. Localized mechanical damage and even transtentorialherniation may be seen in the absence of global increase in intracranial pressure.[9],[10] The major cause of mortality in ICH in acute stage is raised ICP. Various medical and surgical procedures have been undertaken to tide over this problem. In this review, the current status of osmotic therapy will be discussed.Problem with raised ICTEarly hematoma expansion and secondary edema-induced brain compression and consequent neuronal death; Cytotoxic (intracellular) and vasogenic (extracellular) edema resulting from disruption of the blood–brain barrier; Reductions in cerebral perfusion pressure (CPP) from mass effect and raised intracranial pressure (ICP); Brain herniationREVIEW ARTICLEYear : 2003  |  Volume : 51  |  Issue : 1  |  Page : 104--109Current status of osmotherapy in intracerebral hemorrhage J Kalita, P Ranjan, UK Misra  Department of Neurology, Sanjay Gandhi PGIMS, Lucknow, IndiaIntracerebral hemorrhage (ICH) is the most serious form of stroke, with more than two-thirds of the patients either dying or left permanently disabled from the condition. Despite considerable research effort, there is still no treatment of proven efficacy for ICH and the chances of surviving an ICH has failed to improve in recent decades. The brain damage from the initial hematoma is considered largely irreversible, which is because of the early time window of opportunity for treatment benefit and the modest potential effects of any medical therapy that limits hematoma growth. Knowledge has accumulated regarding the nature of secondary effects of the perihematomal edema in ICH, making it an attractive therapeutic target. The pathophysiology of ICH-related perihematomal edema is complex: a number of different mechanisms are involved from the initial hydrostatic pressure of the hematoma to the subsequent toxic effects of breakdown products resulting from coagulation cascade activation and erythrocyte lysis as part of the natural process of hematoma resolution. Although perihematomal edema and hematoma volumes are strongly correlated, there is less and conclusive evidence regarding the independent prognostic role of perihematomal edema per se. Patient management is primarily supportive and aimed at reducing resulting increases in intracranial pressure. No therapies have been shown to definitely influence outcome, and all are associated with some hazard. Further studies are required to clarify the relationship between perihematomal edema and outcome in ICH, and to translate the positive results of therapies identified in the laboratory into the clinical domain.Of the various pathological stroke types, intracerebral hemorrhage (ICH) is themost devastating and least treatable, causing death, disability, and long-term suffering in most of those affected.1 Despite considerable research effort, there is still a paucity of evidence regarding the efficacy of pharmacological and surgical interventions for ICH, and the chances of surviving ICH does not appear to have improved in recent decades.1,2 Although ICH constitutes about 10–15% of strokes in Western populations, its impact in terms of acute and long-term medical care costs as well as productivity loss is high, estimated at US$6 billion annually in the United States alone.3 In Asian populations, where rates of ICH are higher and people tend to be affected at younger ages, the impact of ICH is likely to be enormous. The heavy burden of ICH, coupled with the lack of proven therapies, underpins the need to develop novel strategies to improve outcomes. A better understanding of the underlying pathophysiological and pathochemical sequelae of ICH should aid in this endeavor. The following processes have been shown to occur in ICH:early hematoma expansion and secondary edema-induced brain compression and consequent neuronal death; Cytotoxic (intracellular) and vasogenic (extracellular) edema resulting from disruption of the blood–brain barrier; Reductions in cerebral perfusion pressure (CPP) from mass effect and raised intracranial pressure (ICP); brain herniation; and finally, in those who survive, residual brain atrophy from the original lesion.4,5 Along with hematoma expansion, perihematomal edema is implicated in many of the fundamental processes driving the neuronal damage in ICH (Figure 1), although the prognostic significance of perihematomal edema on its own remains uncertain.6,7 However, while it is widely accepted that hematoma-induced brain damage is irreversible, the injury arising from perihematomal edema may be reversible, and thereby presents a potential therapeutic target for intervention.This review examines ICH-related perihematomal edema: pathophysiology and the factors influencing growth; its contribution to neurological deficits; and what potential therapeutic measures are currently available to limit its growth and enhance its The role of ventriculostomy has never been studied prospectively, and its use has been associated with very high mortality68 and morbidity69 rates. When an intraventricularcatheter is used to monitor ICP, CSF drainage is an effective method for lowering ICP, particularly in the setting of hydrocephalus. When an intraventricular catheter is used tomonitor ICP, CSF drainage is an effective method for lowering ICP. This can be accomplished by intermittent drainage for short periods in response to elevations in ICP.The principal risks associated with ventriculostomy are infection and hemorrhage. Most studies report rates of bacterial colonization rather than symptomatic infection that rangefrom 0% to 19%.60,70 The incidence of ventriculostomyassociated bacterial meningitis varies between 6% and 22%.70,71Analgesia and SedationIntravenous sedation is needed in unstable patients who are intubated for maintenance of ventilation and control of airways, as well as for other procedures. Sedation should betitrated to minimize pain and increases in ICP, yet should enable evaluation of the patient’s clinical status. This is usually accomplished with intravenous propofol, etomidate,or midazolam for sedation and morphine or alfentanil for analgesia and antitussive effect.c. Barbiturate coma can result in respiratory and cardiovascular depression.91Neuromuscular BlockadeMuscle activity may further raise ICP by increasing intrathoracic pressure and obstructing cerebral venous outflow. If the patient is not responsive to analgesia and sedation alone,neuromuscular blockade is considered. However, the prophylactic use of neuromuscular blockade in patients without proven intracranial hypertension has not been shown toimprove outcome. It is associated with an increased risk of complications such as pneumonia and sepsis and can obscure seizure activity.b. Induced neuromuscular paralysis can reduce agitation and restlessness and allows use of assisted ventilation, but increases the risk of complications such as pneumonia and sepsis, and can obscure the degree of neurological deficit and any underlying seizure activityHyperventilationHyperventilation is one of the most effective methods available for the rapid reduction of ICP. The CO2 reactivity of intracerebral vessels is one of the normal mechanisms involvedin the regulation of CBF. Experimental studies using a pial window technique have clearly demonstrated that the action of CO2 on cerebral vessels is exerted via changes inextracellular fluid pH.74 Molecular CO2 and bicarbonate ions do not have independent vasoactivity on these vessels. As a result, hyperventilation consistently lowers ICP. Despite the effectiveness of hyperventilation in lowering ICP, broad and aggressive use of this treatment modality to substantially lower PCO2 levels has fallen out of favor, primarily because of the simultaneous effect on lowering CBF. Another characteristic of hyperventilation that limits its usefulness as a treatment modality for intracranial hypertension is the transient nature of its effect. Because the extracellular space of the brain rapidly accommodates to the pH change induced by hyperventilation, the effects on CBF and on ICP are short-lived. In fact, after a patient has been hyperventilated for 6 hours, rapid normalization of arterial PCO2 can cause a significant rebound increase in ICP. The target levels of CO2 for hyperventilation are 30 to 35 mm Hg. Lower levels of CO2 are not recommended.75Barbiturate ComaBarbiturates in high doses are effective in lowering refractory intracranial hypertension but ineffective or potentially harmful as a first-line or prophylactic treatment in patients withbrain injuries. High-dose barbiturate treatment acts by depressing cerebral metabolic activity. This results in a reduction in CBF, which is coupled to metabolism, and a fall inICP. The use of barbiturates in the treatment of refractory intracranial hypertension requires intensive monitoring and is associated with a significant risk of complications,76 the most common being hypotension. Cerebral electrical activity should ideally be monitored during high-dose barbiturate treatment, preferably on a continuous basis, with burst suppression activity providing a physiological end point for dose titration.d. Systemic hypothermia is potentially neuroprotective, often used following global anoxic brain damage after cardiac arrest, but is associated with a relatively high risk of cardiac,immunologic, hematologic, andmetabolic complications.93Corticosteroids, namely, dexamethasone, have traditionally been used for the treatment of cerebral edema, as they are purportedly beneficial in extracellular (vasogenic) edema through the inhibition of inflammatory mediator release, which limits blood–brain barrier permeability and suppresses the extracellular buildup of fluid.27 The approach has been regarded as predominantly preventative and thereby more efficacious in the early stages of edema formation.27 IronSystemic treatment with the iron chelatordeferoxamine ameliorates ICH-induced changes in markers of DNA damage, attenuates brain edema, and improves functional recoveryin rat models of ICH.107–111 A few studies have examined the role of iron in ICH patients and reported that high serum ferritin levels are associated with poor outcome after ICH112 and correlate with the perihematoma edema volume.113,114 Limiting iron-mediated toxicity is a promising therapeutic target in ICH. Besides chelating iron, deferoxamine exhibits other neuroprotective properties.115 It induces transcription of heme oxygenase-1 and inhibits hemoglobin-mediated glutamate excitotoxicity and hypoxia inducible factor prolylhydroxylases. 116–119 Further studies in this area are warranted, but no current therapeutic recommendation can be made at present.
  • Osmotic TherapyThe most commonly used agent is mannitol, an intravascular osmotic agent that can draw fluid from both edematous and nonedematous brain tissue. In addition, it increases cardiac preload and CPP, thus decreasing ICP through cerebral autoregulation. Mannitol decreases blood viscosity, which results in reflex vasoconstriction and decreased cerebrovascular volume. The major problems associated with mannitol administration are hypovolemia and the induction of a hyperosmotic state. Target serum osmolality has often been recommended as 300 to 320 mOsm/kg, but definitive data on the effectiveness of specific thresholds are lacking. A few principles seem certain. First, brain volume falls as long as there is an osmotic gradient between blood and brain. Second, osmotic gradients obtained with hypertonic parenteral fluids are short-lived because each of the solutes reaches an equilibrium concentration in the brain after a delay of only a few hours. Third, the parts of the brain most likely to "shrink" are normal areas; thus, with focal vasogenic edema, the normal regions of the hemisphere shrink but edematous regions with increased capillary permeability do not. Fourth, a rebound in the severity of the edema may follow use of any hypertonic solution because the solute is not excluded from the edematous tissue; if tissue osmolality rises,the tissue water is increased. Finally, there is scant rationale for chronic use of hypertonic fluids, either orally or parenterally, because the brain adapts to sustained hyperosmolality with an increase in intracellular osmolality due to the solute and to idiogenicosmoles.There is some uncertainty about the size of an increase in plasma osmolality that causes a therapeutically significant decrease in brain volume and intracranial pressure in humans. Acute increases as small as 10 mOsm/L may be therapeutically effective. It should be emphasized that accurate dose-response relationships in different clinical situations have not been well defined with any of the hypertonic agents.Mechanism of osmotic agents in ICP reductionThe physiological principle underlying the ICP-lowering effect of various osmotic agents is the same. The solute must be relatively restricted in its entry across the blood brain barrier. An osmotic gradient is necessary to draw water from the brain cell to the site of higher osmolality, the plasma [Figure:1].[11],[12] Once the solute has reached equilibrium in both plasma and brain cell, the intracellular volume returns to its initial state and the intracranial pressure returns, to its initial level. Dimattio et al in 1975 showed in cats that a minimum of 10 per cent change in serum osmolality, i.e. about 30 mosm/L was needed to increase or decrease the water content of the brain.[13] However, smaller osmotic gradients have been shown to provide effective therapy in man. In a clinical study of Glycerol therapy, Rottenberg et al in 1977 reported that an osmotic gradient of just 10 mosm/L, was effective in reducing the intracranial pressure.[14] In addition to its complex effects on brain volume and metabolism, hyperosmolality in laboratory animals has also been shown to inhibit the formation of CSF within the ventricular system.[11],[13] The data on human beings regarding the quantitative importance of such an effect, however, is lacking.The progressive entry of the administered solute from the plasma into the damaged brain tissue as a result of altered blood brain barrier increases the osmolality of brain tissue. As a result, there is increased influx of water from plasma to this area leading to increasing brain edema.The solute also reaches equilibrium in CSF. It's exit from the CSF is slower than from the plasma. This results in greater osmolality of the CSF as compared to plasma, more water influx into the CSF, result in higher CSF pressure.Appearance of new idiogenicosmoles within brain cells increase intracellular osmolality and favor water retention.Defective blood brain barrier leads to rapid entry of solutes into extravascular brain tissue, thus obliterating the osmotic gradient. This results in influx of water into the brain tissue. This produces swelling of edematous brain and shrinkage of normal brain resulting in more midline shift and herniations.
  • Mannitol: Mannitol has a molecular weight of 182 Dalton and was introduced in neurological practice by Wise and Chater in 1962.[43] It is relatively cleared from CSF and brain because of its higher molecular weight, which reduces the rebound phenomenon. Rebound however has been noted in clinical practice.[44] Rebound occurs when large dose of mannitol is given at a frequency that exceeds its urinary exertion rate. If sustained hyperosmolality of the brain is obtained, rebound is likely to occur when the plasma osmolality falls more rapidly than the brain. Mannitol in a dose of 1 gm/kg of body weight, given intravenously over a period of 10 to 15 minutes results in raised serum osmolality of approximately 20 to 30 mosm/L, which returns to normal level in about 3 hrs. A dose of 1.5 to 2 gm/kg lowers CSF pressure significantly for 3 to 8 hrs. Lower dosage of mannitol (0.5 gm/kg or less) is desirable to avoid excessive hyperosmolarity and rebound.[44] Miller and Leech reported 8 patients studied before and after the administration of mannitol (0.5 gm/kg). The ventricular CSF pressure was reduced in all 8 patients; the maximum reduction (35%) occurred 15 min after administration and it persisted for 45 min. The pressure volume response tested by injecting 1 ml saline in one second into the ventricular fluid showed maximum reduction at 15 minutes. It was concluded that not only mannitol influenced ICP, but also intracranial compliance. Thus an improvement in the neurological status may occur following osmotherapy in spite of little measurable effect on ICP.[45]Rheological effects of mannitolIntravenous infusion of mannitol causes influx of extravascular water into the circulation. This leads to acute expansion of plasma volume and increase in cerebral blood flow. This is counterbalanced by compensatory vasoconstriction leading to reduction in CBF, which also results in reduction of ICP. Mannitol results in 15% shrinkage of RBCs, improves deformation and cell wall flexibility thereby improves tissue oxygenation.[46],[47] This may be important for marginally perfused and hypoxic tissue.The side effects of mannitol are related to its mechanisms of action as osmotic diuretic and by intra vascular volume expansion. Water may move back into the extravascular space, but much will be lost via renal excretion. Thus hemodilution and positive effect on the viscosity of blood following mannitol are lost as the circulating blood volume decreases. This effect may not be obvious after a single dose of mannitol in the newly resuscitated and over hydrated patient, but as dehydration occurs, mannitol becomes less effective, later associated with rebound. Therefore, the diuresed fluid after mannitol administration, must be replaced ml for ml and the smallest effective dose of mannitol should be used. Inadequate fluid replacement may result in renal tubular toxicity. This toxicity is reversible but when high dose of mannitol is combined with vasopressor, aminoglycosides or other nephrotoxic drugs, especially in the presence of hypoxic or hypotensive episodes, devastating nephrotoxicity may occur.Controversies regarding mannitol therapyHematoma or large hemispheric infarction with surrounding edema act as space occupying lesion producing mass effect and brain herniation. Compartmentalized ICP difference is an important cause of neurological deterioration rather than a global increase in ICP.[48],[49] Every hypothetical mechanism of action of mannitol has a maximal effect in the normal hemisphere which can lead to potential aggravation of dangerous pressure difference because of differential lowering of compartmentalized ICP. It has been suggested that mannitol may aggravate midline shift and lead to neurological deterioration.[50] Garcia et al in their experimental study found that a high dose of mannitol led to 21% ICP reduction over the injured hemisphere and 26% reduction over the normal hemisphere.[51] Videen et al studied 6 patients who had acute middle cerebral arterial infarction and CT evidence of midline shift measured using the brain boundary shift on sequential T1weighted images acquired before and after a 1.5 gm/kg bolus infusion of mannitol. At 50 to 55 minutes after the baseline scan, total brain volume significantly decreased. The non-infarcted hemisphere shrank more compared to the infarcted hemisphere. However, the clinical implication of this study could not be ascertained.[52] Kauffman et al in an experimental study investigated the pharmacokinetics of mannitol administered for treatment of vasogenic cerebral edema. Control animals received no mannitol, while the treated group received either a single dose or five doses of 0.33 gm /kg of radiolabeled mannitol administered 4-hourly. Water content measurement showed that a single dose of mannitol failed to reduce cerebral water content or edema progression at 4 hrs, while multiple doses produced 3% increase in water content in edematous region. It was concluded that reversal of the osmotic concentration gradient between edematous brain and plasma develops following multiple mannitol injections, which was associated with exacerbation of vasogenic cerebral edema.[53]Manno et al evaluated the effect of a single large dose of mannitol on midline shift after large cerebral infarction in seven patients. The final average change in midline shift compared to the initial displacement was only 0.0 + 1 mm in horizontal and 0.25 + l.3 mm in vertical. Stroke scale improved in two, Glasgow coma scale score improved in three and pupillary light reactivity returned in two patients. No patient worsened. They concluded that a single large dose of mannitol used in patients with infarction did not alter midline shift or worsen neurological status.[54] Similarly, Paczynski et al, demonstrated in the rat model that repeated mannitol infusion reduced the water content of both edematous and normal brain tissue in contrast to earlier studies. Though midline shift was not directly measured in this model, the mean difference in water content between hemispheres was small when mannintol was used in a dose of 0.33 gm/kg. Large and repeated dosing of mannitol however, led to progressive increase in water loss from the normal hemisphere.[55]Despite the fact that mannitol has been widely used to decrease elevated ICP in both ischemic and hemorrhagic strokes, randomized clinical trials are very few. Most of the trials were confounded and a randomized clinical trial of mannitol in intracerebral hemorrhage is lacking.[56] Wang studied 44 cases of acute hemorrhagic stroke treated with FCMCK therapy and compared them with 44 cases treated with mannitol. The mortality rate of the FCMCK treated group was 4.5% which was significantly lower than that of the mannitol group (47.7%).[57] Gigliuto et al reviewed 20 patients with ICH admitted to intensive care units with raised ICP. They concluded that there was no significant therapeutic benefit using mannitol osmotherapy.[58] Based on these small clinical and experimental trials, no conclusion can be drawn. The American Heart Association, in their guidelines for the management of spontaneous intracerebral heamorrhage, recommend mannitol 20% (0.25 gm/kg every four hours) in patients with type B ICP waves, progressively increasing ICP and clinical deterioration due to mass effect.[59] However, enough evidence is lacking for the routine use of mannitol in ICH.
  • Mannitol Use in Acute Stroke Case Fatality at 30 Days and 1 YearDánielBereczki, MD, PhD, DHAS; LászlóMihálka, MD, PhD; SzabolcsSzatmári, MD, DSci;KláraFekete, MD; David Di Cesar, MD; BélaFülesdi, MD, PhD;LászlóCsiba, MD, PhD, DHAS; IstvánFekete, MD, PhD(Stroke. 2003;34:1730-1735.)Background and Purpose—Mannitol is used worldwide to treat acute stroke, although its efficacy and safety have not beenproven by randomized trials.Methods—In a tricenter, prospective study, we analyzed the 30-day and 1-year case fatality with respect to mannitol treatment status in 805 patients consecutively admitted within 72 hours of stroke onset. Confounding factors were compared between treated and nontreated patients.Results—Two thirds of the patients received intravenous mannitol as part of their routine treatment (mean dose, 4722 g/d; mean duration, 63 days). The case fatality was 25% versus 16% (P0.006) at 30 days and 38% versus 25% (P0.001) at 1 year in the-mannitol treated and nontreated groups, respectively. Mannitol treatment effect was adjusted for age, stroke severity, fever in the first 3 days, and aspirin treatment (for ischemic strokes) in logistic regression models. Depending on the factors entered into the model, either no effect or harm could be attributed to mannitol. When the analysis was restricted to those admitted within 24 hours (n568), case fatality differed significantly only at 1 year (35% in treated and 26% in nontreated patients, P0.044). Although the prognostic scores of the Scandinavian Neurological Stroke Scale were similar in treated and nontreated patients, both in ischemic and hemorrhagic strokes, the patient groups differed in several factors that might also have influenced survival. Conclusions—Based on the results of this study, no recommendations can be made on the use of mannitol in acute stroke,and properly randomized, controlled trials should be performed to come to a final conclusion.
  • Design:Randomized, controlled, double-blind study. Inclusion CriteriaPatients with CT proven primary supratentorial ICH within 6 days of ictus. Exclusion CriteriaPatients with renal and hepatic failure, hyperglycemia >250 mg%, past history of ICH, infratentorial hematoma, vascular malformation, tumor or anticoagulant bleed. Patient Involvement:All the patients were subjected to detailed neurological evaluation, and consciousness was assessed by Glasgow coma scale (GCS) and severity of stroke by Canadian Neurological Scale (CNS). Patients were then randomized into the treatment and the control groups. The study group received mannitol 20%, 100 ml every 4 h for 5 days, tapered in the next 2 days. The control group received sham infusionPrimary Outcome: One-month mortality. Secondary Outcome: Functional disability at 3 months assessed by Barthel index score, with a BI score below 12 as a poor outcome, partial BI=12–19, and complete BI=20Low dose mannitol did not seem to be beneficial in patients with ICHJ Neurol Sci. 2005 Jul 15;234(1-2):41-5.
  • Effect of single mannitol bolus in intracerebral hemorrhageU. K. Misra1, J. Kalita1, A. Vajpayee1, R. V. Phadke2, A. Hadique2, V. Savlani2European Journal of NeurologyVolume 14, Issue 10, pages 1118–1123, October 2007Because of existing controversy about use of mannitol in intracerebral hemorrhage (ICH) this open exploratory trial with blinded outcome assessment of single mannitol bolus in ICH was undertaken. CT proven primary supratentorial ICH patients having midline shift of ≥3 mm were randomized into 20% mannitol (1.5 g/kg) and control groups. Clinical evaluation included Glasgow coma scale (GCS) score, Canadian Neurological scale (CNS) score, pupils, breathing, extensor posturing and contra-lateral pyramidal signs. On cranial MRI horizontal (HS), superior sagittal sinus to pontomesencephalic junction (SSS-PMJ) distance and edema hematoma complex were measured. Twelve patients each were in mannitol and control groups. The age, sex, GCS score, CNS score, pupillary asymmetry, contra-lateral pyramidal signs, HS and SSS-PMJ distance in mannitol and control groups did not differ significantly. Mannitol infusion resulted clinical improvement in five patients, which lasted for 30–60 min. HS and SSS-PMJ distance in mannitol and control groups did not change at 30 or 60 min from the baseline. The change in HS and SSS-PMJ distance were also not significantly different between the two groups both at 30 and 60 min. Mannitol led to transient clinical improvement in five patients without significant reduction in HS or SSS-PMJ distance at 30 and 60 min.Is Mannitol useful in ICH Annals of Indian Academy of Neurology, 2007 by J. Kalita, U. K. Misra, R. V. Phadke, A. Vajpayee Summary: Background: Mannitol is used and recommended in stroke by most physicians and academic bodies without any evidence. Our studies on low dose manniol (0.5 mg/kg) for 1 week in ICH did not reduce 1 month mortality nor it significantly lead to blood flow changes as evaluate by SPECT. Objective: Due to existing controversy about use of mannitol in intracerebral hemorrhage (ICH) this open exploratory trial with blinded outcome assessment of single mannitol bolus in ICH was undertaken. Design: CT proven primary supratentorial ICH patients having midline shift of &rt; 3 mm were randomized into 20% mannitol (1.5 g/kg) and control groups. Clinical evaluation included Glasgow coma scale (GCS) score, Canadian Neurological scale (CNS) score, pupils, breathing, extensor posturing and contra-lateral pyramidal signs. On cranial MRI horizontal (HS) and superior sagittal sinus to pontomesencephalic junction (SSS-PMJ) distance were measured. Results: Twelve patients each were in mannitol and control groups. The age, sex, GCS score, CNS score, pupillary asymmetry, contralateral pyramidal signs, and SSS-PMJ distance in mannitol and control groups did not differ significantly. Mannitol infusion resulted clinical improvement in 5 patients, which lasted for 30-60min. HS and SSS-PMJ distance in mannitol and control groups did not change at 30 or 60min from the baseline. The change in HS and SSS-PMJ distance were also not significantly different between the two groups both at 30 and 60 min. Conclusion: Mannitol led to transient clinical improvement in 5 patients without significant reduction in HS, SSS-PMJ distance or EHC at 30 and 60min.ABSTRACT FROM AUTHOR Copyright of Annals of Indian Academy of Neurology is the property of Medknow Publications & Media Pvt. Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.
  • Effect of mannitol on early enlargement of hematoma following hypertensive cerebral hemorrhageWang Minzhong,PangZaiying,FengYabo,et alTo study the effect of mannitol on early enlargement of hematoma following hypertensive cerebral hemorrhage The emergency patients with hypertensive cerebral hemorrhage were devided into group A(36 cases)and group B(35 cases) The mannitol was used in group A and the furosemide was used in group B All patents were examined two times by cranial CT It was found that 33 3% patients(12 cases)in group A had enlargement of hematoma and 17 1% patients(6 cases)in group B had it So the inapt use of mannitol may be one reason of the early enlargement of hematoma following hypertensive cerebral hemorrhage
  • Hypertonic saline: In 1919, Weed and Mc Kibben reported immediate shrinkage of brain parenchyma on gross visualization after intravenous injection of 30% saline solution in anaesthetized cats. Maximum shrinkage was observed 15-20 min after completion of injection.[25] Wilson et al in 1951 reported the effect of various hypertonic salt solutions on cisternal pressure in a group of dogs. The authors evaluated the effect of iso-osmolar doses of 1 M NaCl (5.8%), 1 M Na Lactate (11.2%) and 2/3 M Na succinate (18%) on ICP. The ICP decreased by approximately 10 cm of H2O after administration of hypertonic solutions. The cisternal pressure remained low for 2.5 to 4 hours.[26] Besides its osmotic effect, hypertonic saline also improved regional cerebral blood flow.[27],[28] Hypertonic saline restores normal resting membrane potential by normalizing intracellular concentration of Na and Cl.[29] Theoretically, membrane stabilization may help in preserving blood brain barrier; however, this remains unproven.[30]The potential complications of hypertonic saline are both neurological and systemic. Abrupt changes in serum osmolality and sodium concentration may result in coma and seizures.[31] Both subdural and intracerebral hemorrhages have been observed after abrupt changes in serum sodium.[32] Rapid correction of preexisting hyponatremia has been linked to central pontinemyelinolysis.[33] Prolonged or repeated administration can also result in rebound phenomenon.[34] Rapid volume expansion may precipitate congestive cardiac failure in patients with cardiac dysfunction.[35] Hypokalemia and hypochloremicacidemia can occur when large amounts of sodium chloride are infused without concomitant potassium replacement.[36] The prolongation of prothrombin and activated partial thromboplastin time with decreased platelet aggregation can lead to bleeding complication.[37] This is seen when hypertonic saline replaces normal plasma. It also results in phlebitis[38] and renal failure.[39]Quereshi et al compared equiosmolar dosage of mannintol, 3% NaCl and 23.4% NaCL in a canine model of intracerebral hemorrhage. ICP reduction was most prominent after 23.4% NaCl administration. After 2 hours of administration, only 3% NaCl had a sustained effect on ICP. The ICP in the mannitol group exceeded the pretreatment level. The cerebral perfusion pressure at 2 hours was significantly higher in the 3% NaCl treated group compared to mannitol. The water content in the affected white matter after 2 hrs was also lowest in the 3% NaCl group. The presence of a focal lesion and relative preservation of blood brain barrier may account for the favorable effect of hypertonic saline.[40]In a prospective study, Quershi et al did not find any beneficial effect of continuous infusion of 3% saline acetate in 14 patients who had suffered massive stroke.[41] Schwartz et al evaluated the effect of hypertonic saline in 6 stroke patients with increased intracranial pressure in whom mannitol was ineffective.[42] The maximum ICP reduction after 35 minutes of infusion was 9.9 mm of Hg; thereafter ICP began to rise. Cerebral perfusion pressure was increased although there was no effect on mean arterial blood pressure. They concluded that 75 ml of 10% hypertonic saline reduces ICP and increases cerebral perfusion pressure in stroke patients in whom mannitol was ineffective. All human studies on hypertonic saline for the treatment of cerebral edema and elevated ICP, are based on case reports, case series and small controlled groups. There is no large randomized double blind placebo controlled study on the use of hypertonic saline. A uniform concentration of hypertonic saline has not been studied, dose response curve is lacking and its safety and efficacy need further evaluation.
  • Adults 2009Downloaded from stroke.ahajournals.org by on December 7, 2010Class II1. Treatment of elevated ICP should include a balanced and graded approach that begins with simple measures, such as elevation of the head of the bed andanalgesia and sedation. More aggressive therapies to decrease elevated ICP, such as osmotic diuretics (mannitol and hypertonic saline solution), drainage of CSF via ventricular catheter, neuromuscular blockade, and hyperventilation, generally require concomitant monitoring of ICP and blood pressure with a goal to maintain CPP >70 mm Hg (Class IIa, Level of Evidence B).3. 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. Current suggested recommendations for target blood pressures in various situations and potential medications are listed in Tables 2 and 3 and may be considered (Class IIb, Level of Evidence C).4. Treatment with rFVIIa within the first 3 to 4 hours after onset to slow progression of bleeding has shown promise in one moderate-sized phase II trial; however, the efficacy and safety of this treatment must be confirmed in phase III trials before its use in patients with ICH can be recommended outside of a clinical trial (Class IIb, Level of Evidence B).5. A brief period of prophylactic antiepileptic therapy soon after ICH onset may reduce the risk of early seizures in patients with lobar hemorrhage (Class IIb,Level of Evidence C).Conclusion Over the years, some of the treatment options for raised ICP such as barbiturates or hyperventilation have lost their significance. Hypertonic solutions such as urea, hypertonic saline, glycerol and mannitol have been used to lower ICP for a long time. A large number of clinical and experimental studies demonstrated that a single dose of mannitol reduces elevated ICP transiently. The enthusiasm about mannitol for patients with ICH however is dampened by several factors: 1) Most of the clinical studies on mannitol are on patients with head injuries; 2) No randomized study on ICH patients has been undertaken, and the long-term beneficial effect of mannitol is unknown; and 3) There is evidence that repeated infusion of mannitol may even aggravate brain edema. Hypertonic saline infusion has been reported to reduce ICP when mannitol fails. However, this observation is based on small series and case reports. A properly designed randomized placebo controlled study is therefore needed to evaluate the role of mannitol and hypertonic saline in different concentrations, to address this issue. References1Dennis MS, Burn JP, Sandercock PA, BamfordJm, Wade DT, Warlow CP. Long term survival after first ever stroke: the Oxfordshire community stroke project. Stroke 1993;24:796-800.2Broderick JP, Brott T, Tomsick T, Huster G, Miller R. The risk of subarachnoid and intracerebral haemorrhage in blacks as compared to whites. N Eng J Med 1992;326:733-6.3Misra UK, Kalita J. Recurrent hypertensive intracerebral haemorrhage. Am J Med Sci 1995;1:156-7. 4Brott T, Broderick J, Kothari R, et al. Early haemorrhage growth in patients with intracerebral haemorrhage: incidence and time course. Stroke 1997;28:1-5.5Yang GB, Betz AL, Chenevert TL, Brunberg JA, Hoff JT. Experimental intracerebral haemorrhage relationship between brain oedema, blood flow and blood barin barrier permeability in rats. J Neurosurg 1994;81:93-102.6Zazulia AR, Diringer MN, Derdeyn CP, Powers WJ. Progreession of mass effect after intracerebral haemorrhage. Stroke 1999;30:1167-73.7Wagner KR, XiG, Hau Y, et al. Lobar intracerebral haemorrhage models in pigs: rapid oedema development in perihaematomal white matter. Stroke 1996;27:490-7.8Wagner KR, Xi G, Hau Y, Kleinholz M, et al. Early metabolic alterations in edematous perihaematomal brain region following experimental intracerebral haemorrhage. J Neurosurg 1998;88:1058-65.9Janny P, Papo I, Chazal J, Colnet G, Barretto LC. Intracranial hypertension and prognosis of spontaneous intracerebral haematomas:a correlative study of 60 patients. ActaNeuroChir (Wien) 1982;61:181-6.10Papo I, Janny P, Caruselli G, Colonet G, Luongo A. Intracranial pressure time course in primary intracerebral haemorrhage. Neurosurg 1979;4:504-11.11Hochwald, G M, Wald A, Malhan C. The sink action of CSF volume flow effect on brain water content. Arch Neurol 1976;33:339-44.12Rosenberg GA. Brain fluid and metabolism. New York: Oxford University Press; 1990. pp. 207.13Dimattio J, Hochwald GM, Malhan. C, Wald A. Effect of changes in serum osmolality on bulk flow of fluid into cerebral ventricles and on brain water content. P fluegers Arch 1975;359:253-64.14Rottenberg DA, Hurwitz BJ, Posner JB. The effect of oral glycerol on intraventricular pressure in man. Neurology 1977;27:600-8.15MC Dowell, ME, Wolf AV, Steer A. Osmotic volumes of distribution Idiogenic changes in osmotic pressure associated with the administration of hypertonic solution. Am J Physiol 1955;180:545-56.16Chan PH, Fishman RA. Elevetion of rat brain aminoacids, ammonia and ideogenicosmoles induces by hyperosmolality. Brain Res 1979;161:293-302.17Weed LH, MC Kibben PS. Pressure changes in the CSF following intravenous injection of solutions of various concentration. Am J Physiol 1919;48:512-30.18Bullock, LT, Gregerson MI, Kinney R. The use of hypertonic sucrose solution intravenously to reduce CSF pressure without a secondary rise. Am J Physiol 1935;112:82-96.19Reed DJ, Woodburg DM. Effect of urea and acetazolemide on brain volume and CSF pressure. J Physiol (Lond) 1962;164:265-73.20Cantore G, Guidetti B, Virno M. Oral glycerol for the reduction if intracranial pressure. J Neurosurg 1962;21:278-83.21Tourtellote WW, Reinglass JL, Newkirk TA. Cerebral dehydration action of glycerol. ClinPharamacolTherp 1972;13:159-71.22Mathew NT, Meyer JS, Rivera VM, et al. Double blind evaluation of glycerol therapy in acute cerebral infarction. Lancet 1972;2:1327-9.23Larsson, O, Marinovich N, Barber K. Double blind trial of glycerol therapy in early stroke Lancet 1976;1:832-4.24Yu, YL, Kumana CR, lauder IJ, Cheung YK, Chan FL, Kou MHV, et al. Treatment of Acute cerebral haemorrhage with intravenous glycerol-A double blind, Placebo controlled, Randomised trial. Stroke 1992;23:967-71.25Weed LH, McKibben PS. Experimental alteration of brain bulk. Am J Physiol 1999;48:531-58.26Wilson BJ, Jones RF, Coleman ST, et al. The effects of various hypertonic sodium salt solution on cisternal pressure. Surgery 1951;30:361-6.27Shackford SR, Zhuang J, Schrroker J. Intravenous fluid toxicity: effect on intracerebral pressure, cerebral blood flow, and cerebral oxygen delivery in focal brain injury. J Neurosurg 1992;76:91-8.28Shackford SR, Schmoker JD, Zhuang J. The effect of hypertonic resuscitation on pial arteriolar tone after brain injury and shock. J Trauma 1994;37:899-908.29Nakayama S, Kramer GC, Carlsen RC, et al. Infusion of very hypertonic saline to bleeding rats. Membrane potential and fluid shifts. J Surg Res 1985;38:180-6.30Gurmar W, Jonesson O, Merlotti G, et al. Head injury and haemorrhagicshock:studies of blood brain barrier and intracranial pressure after rescuscitation with normal saline solution, 3% saline solution and dextran 40. Surgery 1988;103:398-407.31Schell RM, Applegate RL II, Cole DJ. Salt, starch and water on the brain. J NeurosurgAnaesthesiol 1996:8:178-82.32Finberg L. Dangers to infants caused by changes in osmotor concentration. Paediatrics 1967;40:1031-4. 33Laureno R. experimental pontine and extrapontinemyelinolysis. Trans Am Neurol Assoc 1980;105:354-8. 34Qureshi AI, Suarez JI, Bhardwaj A. Malignant cerebral edema in patients with hypertensive intracerebral haemorrhage associates with hypertonic saline infusion. A rebound phenomenon? J NeurosurgAnaesthesiol 1998;10:188-92.35Suarez JI, Qureshi AI, Bhardwaj A, et al. Treatment of refractory intracranial hypertension with 23.4% saline, Crit Care Med 1998;26:1118-22. 36Shackford SR, Fortlage DA, Peters RM, et al. Serum osmolar and electrolytes changes associated with large infusion of hypertonic sodium lactate for intravascular volume expansion of patients undergoing aortic reconstruction. SurgGynecolObstet 1987;164:127-36. 37Reed RL II, Johnston TD, Chen Y, et al. Hypertonic saline alters plasma clotting times and platelet aggtregation. J Trauma 1991;31:8-14. 38Vasar MJ, Perry CA, Holocroft JW. Analysis of potential risk associated with 7.5% sodium chloride resuscitation of traumatic shock. Arch Surg 1990;125:1309-15.39Huang PP, Stucky FS, Dimick AR, et al. Hypertonic sodium resuscitation is associated with renal failure and death. Ann Surg 1995;221:543-54. 40Qureshi AD, Wilson DA, Traystman RJ. Treatment of elevated intracranial pressure in experimental intracerebral haemorrhage,Comparison between mannitol and hypertonic saline. Neurosurg 1999;44:1055-64.41Qureshi AI, Suuarez JI, Bhardwaj A, Misski M, Schnitzer MS, Hanley OF, et al. Use of hypertonic (3%) saline/acetate infusion in the treatment of cerebral edema. Effect on intracranial pressure and lateral displacement of the brain. Crit Care Med 1998:26:440-6.42Schwarz S, Georgiadis D, Aschoff A, Schwas S. Effect of hypertonic (10%) saline in patients with raised intracranial pressure after stroke. Stroke 2002;33:136-40.43Wise BL, Chater M. The nature of hypertonic mannitol solution in decreasing brains mass and lowering of cerebrospinal fluid pressure. J Neurosurg 1962;10:1038-43. 44Mc Graw CP, Alexander EP, Howard C. Effect of dose and dose schedule on the response of intracranial pressure to mannitol. SurgNeurol 1978;10:127-30.45Miller TD, Leech P. The effect of mannitol and steroid therapy on intracranial volume pressure relationship in human. J Neurosurg 1975;42:274-81.46Mendehow AD, Teasdale GM, Russel T, Floof J, Paterson J, Murnay GD. Effect of mannitol on cerebral perfusion pressure in human head injury. J Neurosurg 1985;63:43.47Muizelaar JP, Wei EP, Kontos HA, Becker DP. Mannitol causes compensatory vasoconstriction and vasodilatation in response to blood viscosity changes. J Neurosurg 1983;59:822.48Cardaso ER, Kupchak JA. Evaluation of intracranial pressure gradient by mean of transcranialdoppler ultrasonography. ActaNeurochiro 1992;55:1-5.49Weaver DD, Winn HR, Jane JA. Differential intracranial pressure in patients with unilateral mass lesion. J Neurosurg 1982:56;660-5.50Frank JI. Large hemispheric infarction, deterioration, and intracranial pressure. Neurology 1995;45:1286-90.51Garcia BR, Pulido P, Cepille P. The immediate and long term effect of mannitol and glycerol: a comparative experimental study. ActaNeurochir (Wien) 1991;109:114-21.52Videen TU, Zazulia AR, Manno EM, Derdeyn CP, Adams RE, Diringer MN, et al. Mannitol bolus preferentially shrinks non infarcted brain in patients with ischaemic stroke. Neurology 2001;57:2120-2.53Kaufmann AM, Cardaso ER. Aggravation of vasogenic cerebral edema by multiple dose of mannitol. J Neurosurg. 1992;77:584-9.54Manno EM, Adamas RE, Derdeyn CP, Powers WJ, Diringer MN. The effect of mannitol on cerebral edema after large hemispheric cerebral infarction. Neurology 1999;52:583-7.55Paczynski PP, Hc YY, Diringer MN, Hsu EY. Multiple dose mannitol reduces brain water content in a rat model of cortical infarction. Stroke 1997;28:1437-44.56Bereezki D, Liu M, Prado GFD, Fekete I. Cochrane report, a systematic review of mannitol therapy for Acute ischaemic stroke and cerebral parenchymalhaemorrhage. Stroke 2000;31:2719-22.57Wang J. Medical treatment of acute haemorrhagic stroke. Observation of 44 cases with FCMCK therapy. ZhongguoyixuekexueyuanxueBao 1990;12:61-7.58Gigliuto CM, Stone KE, Algus M. The use of mannitol in intracerebral bleed in the medical ICU. N J Med 1991;88:48-51.59Broderick JP, Adams JR HP, Barsan U, et al. Guidelines for the management of spontaneous intracerebral haemorrhage-a statement for health care professional from a special writing group of the stroke council, American Heart Association. Stroke 1999;30:905-15.
  • Incidence at onset -> 2 weeks: 3-17% Electrographic seizure 28-31% (on AET)One study prophylactic AE reduce clinical Sz. after Lobar hematomaProspective population based studies did not show clinical Sz and worsened neurological outcome or mortality.Subclinical Sz.: one study showed prophylactic PHY increased disability and death at 90 days.RecommendationsSeizures and Antiepileptic Drugs1. Clinical seizures should be treated with antiepileptic drugs (Class I; Level of Evidence: A). (Revised from the previous guideline) Continuous EEG monitoringis probably indicated in ICH patients with depressed mental status out of proportion to the degree of brain injury (Class IIa; Level of Evidence: B). Patientswith a change in mental status who are found to have electrographic seizures on EEG should be treated with antiepileptic drugs (Class I; Level ofEvidence: C). Prophylactic anticonvulsant medication should not be used (Class III; Level of Evidence:B). (New recommendation)
  • Stroke management

    1. 1. Management of Stroke Dr PS Deb MD, DM GNRC Guwahati
    2. 2. Stroke Burden - Disability- Adjusted Life Years[DALYs]
    3. 3. Stroke in India10% -15% of strokes below the age of 40 Y• Rheumatic heart disease• Cerebral venous thrombosis• Tubercular meningitis• Autoimmune angiitis• Coagulopathy ,• Elevated lipoprotein(a)• Elevated anticardiolipin antibodies.• Snake bite• Squatting posture of defecation Dr Subhash Kau l ACNR • VOLUME 7 NUMBER 5 • NOVEMBER/DECEMBER 2007
    4. 4. Stroke Types in India (ICASS) India NE India Infarction Infarction Hematoma Hematoma • Caused by• Type • Hypertension • Atherosclerosis extra and intracranial • Alcoholism • Lacunar • Diabetes • Cardioembolic • Tobacco • RHD, IHD The Indian Collaborative Acute Stroke Study (ICASS)
    5. 5. CBF (ml/100g brain) Normal flow, normal function 50 Low flow, raised O2 extraction, normal function 20 Synaptic transmission failure 10 Membrane pump failure 0 1 2 3 4 5Time in hours
    6. 6. Ischemic cell death Ischaemia - 02  glucose   lactate Anoxic depolarisation Ca2+ i  Hi  Free Fe2+ Glutamate Lipolysis NO synthase ProteolysisNA, Dopamine Free radicals
    7. 7. Pre-hospital care Diagnosis Monitoring TransportCincinnati Stroke scale
    8. 8. Emergency Room : Is it Stroke? 1. Hypoglycemia 2. Seizure 3. Migraine 4. Other focal pathology (Trauma, demyelination, tumor, infectio n) 5. Psychogenic 6. Toxic
    9. 9. Where is the lesion? Phrenology.Franz Joseph Gall, a German physician and neuroanatomist
    10. 10. What is the size of lesion?Features Large Medium Small Coma + - - Deficit Dense Dense Mild
    11. 11. What is the pathology? Intracerebral Age Sex Intraventricular Onset : at rest/sleep or activityHemorrhagic Subarachnoid Level of consciousness Subdural Headache, vomiting Extradural Seizure at onset Thrombosis Arterial Fever, neck stiffness Ischemic Embolic Venous + Hypertension, cardiac disease, pregnancy, Alcohol
    12. 12. Transient Ischemic Attack (TIA)Duration < 24hr• Most TIA < 10min• < 25% last for 1hr• 15 % > 1hr resolve in 24hr20% CT, 50% MRI +ve for infarction• 10% develop stroke in 90days• 5% develop stroke in 2 daysAdvantage: Gives time to act
    13. 13. TIA - Differential Diagnosis MigraineAnxiety (panic attack) Orthostatic hypotensionHyperventilation SyncopeNeuropathy (ischemic) Arrhythmias (ischemia)Vertigo SeizuresDisequilibrium Conversion disorder
    14. 14. Lacunar StrokesVariable course• Fluctuating; progressing in steps; or remitting• Preceded by TIAs in 25%• Without headache or vomitingWell-defined syndromes• Pure motor hemiparesis (with dysarthria)• Pure sensory stroke (loss or paresthesias)• Dysarthria-clumsy hand (with contralateral face and tongue weakness)• Ataxia-hemiparesis (contralateral face and leg weakness)• Isolated motor-sensory stroke
    15. 15. What mode of Imaging? Head injury CT Seriously ill Claustrophobic Hyperacute stroke Small stroke MRI Brain stem stroke Pregnancy
    16. 16. CT Scan Hyperacute InfarctLoss of the left insular ribbon (solid Loss of normal left lentiform nuclear Follow-up CT confirms a left basal ganglia arrows), consistent with cytotoxic attenuation (solid arrows) consistent infarction edema, as compared with the with cytotoxic edema, as compared normal-appearing right insular with the normal-appearing right ribbon (open arrows). lentiform nuclei (open arrows).
    17. 17. Hyperdense MCA Hyperdense middle cerebral artery (MCA) sign of acute thrombus formation
    18. 18. Multimodal CT Imaging CT PCT CTATissue Perfusion Status VesselStatus Status
    19. 19. Multimodal MRI Imaging DWI PWI MRA Tissue Perfusion Vessel Status Status StatusDWI, diffusion-weighted imaging; PWI, perfusion-weighted imaging; MRA, magnetic resonance angiography.
    20. 20. InvestigationsAll Patients Selected Patients (<40, Female) 1. Blood glucose 1. TT and/or ECT if it is suspected 2. Oxygen saturation the patient is taking direct 3. Serum electrolytes/renal thrombin inhibitors or direct function tests* factor Xa inhibitors 4. Complete blood count, 2. Pregnancy test including platelet count* 3. Arterial blood gas tests (if 5. Markers of cardiac hypoxia is suspected) ischemia* 4. Electroencephalogram (if 6. Prothrombin time/INR* seizures are suspected) 7. Activated partial 5. Lumbar puncture (if thromboplastin time* subarachnoid hemorrhage is 8. Liver Function test suspected and CT scan is 9. ECG* negative for blood 10. Chest X ray 6. Toxicology screen
    21. 21. Approach to Ischemic Stroke Rx Reperfusion • Thrombolysis • Mechanical disruption of clot Reducing the size of infarct • Neuro-protection • Blood pressure control Preventing recurrence • Anti-platelet • Anticoagulant Treat associated complication • Raised ICT • Hemorrhagic transformation • Seizure control
    22. 22. Thrombolysis in acute stroke Within 3-4.5 hour of No occlusion Stroke Lacunar StopMedium Vessel Large Vessel C-D/ D-P mismatch IV rTPA/URK IA rTPA/URK
    23. 23. Challenges of thrombolysisLack of awareness: • Patient • PhysicianOut of scope • Not reaching in time • Not suitable for thrombolysisOperational issue • Emergency team • Imaging teamFailure of medical thrombolysisRe-closure of opened vessel: (Stenting)Reperfusion injury with toxic edema and hemorrhage
    24. 24. Overcoming challengesEducation• Patient• PhysicianAlternative approach in failed cases• Mechanical disruption of clot: Primary angioplasty• Transcranial Doppler and thrombolysis• Surgical emergency endarterectomyStenting to prevent re-occlusion
    25. 25. Intensive Care of Stroke Monitoring Monitoring • Heart rate • Breathing rate • O2 saturation Medications • Blood pressure • Blood glucose • Vigilance Tests (GCS), pupils • Neurological status
    26. 26. Pulmonary function Don’t use oxygen routinely. Use oxygen if their O2 saturation drops below 94% by administration of > 2 l O2 .
    27. 27. Cardiac workupHolter monitoring for detection of atrial fibrillation(AF). Routine monitoring is not enough.Echocardiography to detect potential causes ofstroke,• CAD• Valvular heart disease• Aortic disease, and• ASD, PFO with suspected paradoxical embolismTransoesophageal echocardiography (TOE) ifavailable.
    28. 28. Blood Pressure controlDon’t reduce blood pressure < 220/120mmHg,185/100 for thrombolysis)Cautious blood pressure lowering when (IVLabetalol, IV Enalepril) avoid venodilators• BP >220/120 mmHg• Severe cardiac failure• Aortic dissection• Hypertensive encephalopathyDon’t reduce blood pressure abruptly
    29. 29. Circulatory supportIn systemic hypotension producing neurologicalsequelae, vasopressors can be used to improve cerebral blood flowwith close neurological and cardiac monitoring is recommended • Class I; Level of Evidence CHemodilution by volume expansion is not recommended fortreatment of patients with acute ischemic stroke • Class III; Level of Evidence AThe administration of vasodilatory agents, such as pentoxifylline, isnot recommended for treatment of patients with acute ischemicstroke • Class III; Level of Evidence A
    30. 30. Fluid balanceRegular monitoring of fluid balance andelectrolytes with severe stroke with swallowingproblems.Use Normal saline (0.9%) for fluid replacementduring the first 24 hours after stroke.Don’t use Dextrose saline or Dextrose.
    31. 31. Glucose metabolismMonitor serum glucose levelsTreat serum glucose levels >180mg/dl (>10mmol/l)with insulin.Treat severe hypoglycaemia (<50 mg/dl) withintravenous dextrose or infusion of 10–20% glucose.Don’t use glucose as maintenance IV fluid.
    32. 32. TemperatureSearch for infection if pyrexia >37.5°C.Treat pyrexia (>37.5°C) with paracetamol and fanning.Don’t use Antibiotic prophylaxis in immunocompetentpatients.
    33. 33. Dysphagia and feedingDon’t use dietary supplements routinely.Oral dietary supplements only for non-dysphagicstroke patients who are malnourished.Nasogastric (NG) feeding (within 48 hours) withimpaired swallowingDon’t do percutaneous enteral gastrostomy (PEG)feeding in the first 2 weeks.
    34. 34. Antiplatelet therapyUse Aspirin (160–325 mg loading dose) within 48hours after ischaemic stroke.Clopidogrel if already taking aspirin or sensitive/bronchial reactivity, gastritis
    35. 35. AnticoagulantsDon’t use anticoagulants routinely.Don’t use Anticoagulants in patients with progressingstroke.Use anticoagulation for patients with atrial fibrillationwith warfarin early after minor stroke or TIA.Use LMWH when there is high risk of venousthromboembolic disease.
    36. 36. Lipid managementDon’t use statin within 48 hours of strokeContinue statin those who were alreadyreceiving before onset of stroke
    37. 37. Ischemic Brain EdemaCytotoxic edema takes 3-4daysEarly reperfusion -> malignant edema in 24hrsPost fossa infarction needs careful monitoring for life threatening edemaPrevention: Avoid • Hypo-osmolar fluid • Glucose administration • Hypoxemia and hypercarbia • Hyperthermia • Vasodilator antihypertensive agentsRaise head end to 20-30 degree
    38. 38. Antiedema RxHyperventilationOsmotic diuretics No evidence indicates that hyperventilation, corticosteroids in conventional or large doses,Hypertonic saline diuretics, mannitol, or glycerol or other measures that reduceIntra-ventricular drainage of CSF ICP alone improve outcome in patients with ischemic brainDecompressive surgery swelling• Cerebellar infarction• Malignant edema
    39. 39. Hemorrhagic TransformationPetechial hemorrhage common after recanalization without any deterioration5-6% cases symptomatic hemorrhage after rTPALarge stroke of older age and cardioembolicNeurological worsening, headache, increased BP, pulse and vomitingNo guideline , stop rTPA if develop during administration, check coagulationprofileSurgical evacuation of large hemispheric or cerebellar hematoma may be lifesaving
    40. 40. SeizuresIncidence varies <10%More after hemorrhagic transformation, embolic strokeLate onset seizure incidence also variableControl seizure like other neurological illnessProphylactic use of anticonvulsants is not recommended• Class III; Level of Evidence C
    41. 41. Atrial fibrillation (AF)Aspirin to reduces stroke in patients with non-valvular AFWarfarin (INR 2.0-3.0) in valvular heart diseases.Don’t use aspirin in valvular heart disease.Don’t use Combination of aspirin and clopidogrel, it isless effective than warfarin and has a similar bleeding rate.
    42. 42. Asymptomatic carotid artery stenosisAspirin in asymptomatic carotid artery diseasewith stenosis less than 80%.Refer patients with a more than 80% stenosisfor carotid artery Surgery (or Angioplsaty).
    43. 43. Hemorrhagic StrokesIntra-cerebral hemorrhage (ICH)• > 10% of all strokes much higher in NE 30-40%• Risk Factors • HTN • Increasing Age • Race: Asians and Blacks • Amyloidosis- esp. in the elderly • AVMs or tumors • Anticoagulants/Thrombolitic use • History of previous stroke • Tobacco, Alcohol
    44. 44. Early hemorrhage growth in patients with intracerebral hemorrhage. • This 66-year-old white man with a baseline GCS score of 14 and NIH Stroke Scale score of 20 had a putaminal hemorrhage with a baseline ICH volume of 10 mL (top row) • The ICH volume on the 1-hour CT was 27 mL (bottom row). However, the 17-mL increase in ICH volume was not accompanied by any change in the 1-hour GCS (14) and NIH Stroke Scale (20) scores. Brott, T. et al. Sroke 1997;28:1-5Copyright ©1997 American Heart Association
    45. 45. Hematoma volume 30d outcome Type ICH Vol. mL Coma Prognosis I < 30 - Good II 30-60 - Fair III 30-60 + Poor >60 +(Joseph P. Broderick et al Stroke 1993;24:987-993)
    46. 46. Approach to Treatment of ICHStopping or slowing the initial bleeding• Factor VIIa• Blood pressure controlReducing raised ICT due to Hematoma and Edema• Evacuation of hematoma• Osmotherapy• NeuroprotectionControl of Seizure and other associated complication
    47. 47. Factor VIIa TrialUseful in Hemophilia with Ab to factor VII or IXProduce clotting by stimulating coagulation cascade in normalUsed in cased of ICH secondary to coagulopathyThere is mild reduction in progression of hematoma, morbidity and mortality(Phase II, III trial)INR may return to normal transiently it require repeated doseRoutine use in Primary ICH remains investigational
    48. 48. Blood Pressure controlHypertension is common during earlystates of ICH -> Expansion, Peri- Recommendationhematoma edema and re-bleeding AHA 2010A systolic BP above 140 to 150 mm • In patients presentingHg within 12 hours of ICH is with a systolic BP ofassociated with more than double therisk of subsequent death or 150 to 220 mmdependency. Hg, acute lowering of systolic BP to 140 mmAssociation of low BP and Hg is probably safedeterioration is not consistent likeischemic stroke. • Class IIa; Level of Evidence: B
    49. 49. Raised ICT Early hematoma expansion and secondary edema-induced brain compression and consequent neuronal death; Cytotoxic (intracellular) and vasogenic (extracellular) edema resulting from disruption of the blood–brain barrier;The Monro-Kellie doctrine Reductions in cerebral perfusion pressure (CPP) from mass effect and raised intracranial pressure (ICP); Brain herniation
    50. 50. Approach to raised ICT Neuromuscular blockHead end elevation Barbiturate comaOsmotherapy Hypothermia CorticosteroidHyperventilation Surgical evacuation of hematomaAnalgesia and sedation CSF drainage
    51. 51. Osmo-therapyBrain volume falls as long as there is an osmotic gradient between blood andbrain.Short lived action few hours.Normal brain shrink (White/ Gray)Rebound edema.Dose not clear: 10 mOsm/L change in osmolality may be effectiveChronic use not recommended as brain adapt
    52. 52. MannitolWise and Chater in 1962Cleared from brain and CSF due to large molecular wt(182Dalton), less rebound phenomenon.Rebound phenomenon with increasing dose to sustainhyperosmolality of brain, as serum osmolality fallsDose: 1g/kg increases serum osmolality 20-30 mOsm/L for 3-4hours.• Higher dose 1.5-2gm/kg lower CSF pressure for longer time with increased rebound phenomenon.• Lower dose 0.5gm/kg has less rebound
    53. 53. Mannitol Use in Acute Stroke Case Fatality at 30 Days and 1 Year In a tricenter, prospective study, 809 patient with ICH within 72 hours were analyzed 30-day and 1-year case fatality with respect to mannitol treatment in 2/3rd casesNo recommendations can be made on the use of mannitol in acute stroke.Stroke. 2003;34:1730-1735.
    54. 54. Mannitol in ICH Randomized, controlled, double-blind study. 25 20 15 10 5 Mannitol 0 Control Control MannitolMannitol 20% 100ml q6h within 6 days of ictus for 5 days, tapered innext 2 days Mannitol did not seem to be beneficial in patients with ICH JNeurol Sci. 2005 Jul 15;234(1-2):41-5.
    55. 55. Effect of single mannitol bolus in intracerebral hemorrhageCT scan >3cm midline shift in ICHRandomized with bolus dose of Mannitol /Saline.Superior sagittal sinus to pontomesencephalic junction (SSS-PMJ) distance and edemahematoma complex were measured.Mannitol led to transient clinical improvement in five patients without significantreduction in superior sagittal sinus to pontomesencephalic junction (SSS-PMJ)distance at 30 and 60 min. • U. K. Misra et al Department of Neurology, Sanjay Ghandi PGIMS, Lucknow, India Eur J Neurol. 2007 Oct;14(10):1118-23. Epub 2007 Aug 28.
    56. 56. Effect of mannitol on early enlargement of hematoma following hypertensive cerebral hemorrhage Enlargement ofHypertensive cerebral hemorrhage cases were Hematomarandomized• Group A 36 – Mannitol• Group B 35 – furosemide 15Two follow-up CT were done 10 5Result: Enlargement of hematoma 0 Enlargement… Mannitol Control• Group A : 33 3% patients(12 cases)• Group B: 17 1% patients(6 cases)The inapt use of mannitol may be one reasonof the early enlargement of hematomafollowing hypertensive cerebral hemorrhage• Wang Minzhong,Pang Zaiying,Feng Yabo,et al
    57. 57. Hypertonic SalineUsed in head injury and when Mannitol or Hyperventilation failedAbrupt change in serum osmolality may leads • Coma, • Seizure and • Subdural hematoma • Pontine myelinolysisVolume expansion • Cardiac failureAltered coagulation parameters -> bleeding • Prolongation of PT, TT • Decreased platelet aggregationRebound phenomenon
    58. 58. Recommendation: Raised ICTConservative• An elevation of the head of the bed• Analgesia and sedationAggressive therapies• Osmotic diuretics (mannitol and hypertonic saline solution),• Drainage of CSF via ventricular catheter,• Neuromuscular blockade,• Hyperventilation, generally require concomitant monitoring of ICP and blood pressure with a goal to maintain CPP >70 mm Hg • Class IIa, Level of Evidence B
    59. 59. Seizure controlClinical seizures should be treated with antiepileptic drugs • Class I; Level of Evidence: AContinuous EEG monitoring in patients with depressed mental status outof proportion to the degree of brain injury • Class IIa; Level of Evidence: BPatients with a change in mental status who are found to haveelectrographic seizures on EEG should be treated with antiepileptic drugs • Class I; Level of Evidence: CProphylactic anticonvulsant medication should not be used • Class III; Level of Evidence:B
    60. 60. Summary - ICH RxBlood pressure control remains the mainstay of management inhemorrhagic strokeOsmotherapy has doubtful role and routine use is not indicatedin minor bleed.Clinical and subclinical seizure with EEG abnormality shouldbe treated.Surgical evacuation of hematoma andSupportive and critical care of patient during acute state is mostimportant to reduce morbidity and mortality

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