Mayo, Steven

Background: Elevated intracranial pressure (ICP) is one proposed mechanism leading to poor outcomes in patients with spontaneous intraventricular hemorrhage (IVH). We characterized occurrence and significance of intracranial hypertension in severe IVH requiring extraventricular drainage (EVD). Methods: Prospective analysis of ICP in the first 400 patients enrolled in the CLEAR III trial, a multicenter, double-blind, randomized study comparing EVD plus intraventricular recombinant tissue plasminogen activator (rtPA) vs. EVD plus placebo for treatment of IVH in patients with obstructive IVH and intracerebral hemorrhage (ICH) volume <30cc. Maximum and minimum ICP was recorded every 4 hours in all patients until 7 days post randomization. ICP readings were analyzed at pre-defined thresholds and proportion of high ICP events compared by clinical/radiological variables. Impact on 30 day mortality was assessed. Results: of 17,593 ICP readings, maximum ICP ranged from -4 to 115 mm Hg (median, interquartile range; 11,8); 90.2% (15,861) were ≤ 20 mm Hg, 2.0% were >30, 0.5% were >40, and 0.2% were > 50 mm Hg. Proportion of threshold events > 20 and > 30 mm Hg were more frequent in patients with persistent closure of the lower ventricular system after day 3 (p=0.047 and p=0.04, respectively), but were not correlated with initial or end of treatment (72 hours after last dose of study agent) ICH or IVH volumes. ICP elevation > 20 mm Hg occurred during a required 1 hr EVD closure time after study agent injection in 507/3364 (15.1%) injections although early re-opening of EVDs occurred in only 3.9%. Shunting for hydrocephalus was required in 18% of patients over 1 yr follow-up and was not associated with high ICP events. Percentage of ICP readings per patient > 30 mmHg and ICH/IVH volumes were independent predictors of 30 day mortality after adjustment for other outcome predictors (p=0.01; p=0.04; p<0.001, respectively). Conclusions: ICP is not frequently elevated during monitoring and drainage with an EVD in patients with severe IVH. ICP > 30 mm Hg predicts higher short-term mortality. Early opening of the lower ventricular system may reduce frequency of high ICP events. Injection of thrombolytics can be performed without additional ICP management in the majority of patients.

Background: Elevated intracranial pressure (ICP) and inadequate cerebral perfusion pressure (CPP) are mechanisms causing poor outcomes in spontaneous intraventricular hemorrhage (IVH). We characterized intracranial hypertension in severe IVH requiring extraventricular drainage (EVD). Methods: Prospective analysis of ICP in all 500 patients enrolled in the CLEAR III trial, a multicenter, double-blind, randomized study comparing EVD + intraventricular recombinant tissue plasminogen activator (rtPA) vs. EVD + placebo for treatment of obstructive IVH and intracerebral hemorrhage (ICH) volume <30cc. Maximum and minimum ICP/CPP were recorded every 4 hours until 7 days post randomization (rand), analyzed at pre-defined thresholds and compared by clinical and radiological variables. Results: of 23,406 ICP readings, maximum ICP ranged from 0-97 mmHg (median, IQR; 11,8); 90.7% (21,223) were ≤20mmHg, 1.8% >30, 0.5% >40, and 0.2% > 50mm Hg. Proportion of threshold events >20mmHg were more frequent with persistent closure of the lower ventricular system after day 3 (p=0.02), and was correlated with initial and end of treatment (72 hours post rand) ICH volumes (p=0.01, p=0.04, respectively). ICP elevation >20mmHg occurred during a required 1 hr EVD closure interval after 566/3712 (15.3%) study agent injections. Early re-opening of the EVD occurred in 3.9%. Shunting for hydrocephalus occurred in 18.6% over 1 year follow-up and was associated with % of high ICP events >20 and 30 mmHg (p=0.01 for both). After adjustment for ICH severity factors and IVH volume, % of ICP readings>20 mmHg was significantly associated with 30 and 180 day mortality (p=0.01; p=0.03 respectively), and borderline with modified Rankin Scale (mRS4-6) (p=0.09; p=0.11 respectively). Proportion of CPP readings <70mmHg was associated with day 30 poor mRS (p=0.02), with a weaker association for day 180 mRS (p=0.07). Conclusions: Elevated ICP and inadequate CPP are not infrequent during monitoring and EVD drainage in severe IVH and predict higher short and long-term mortality. Early opening of the lower ventricular system may reduce high ICP events. These results permit future correlation of ICP and CPP with treatment rendered (thrombolysis vs placebo), with upcoming unblinding of the trial.

Objectives: Elevated intracranial pressure and inadequate cerebral perfusion pressure may contribute to poor outcomes in hypertensive intraventricular hemorrhage. We characterized the occurrence of elevated intracranial pressure and low cerebral perfusion pressure in obstructive intraventricular hemorrhage requiring extraventricular drainage. Design: Prospective observational cohort. Setting: ICUs of 73 academic hospitals. Patients: Four hundred ninety-nine patients enrolled in the CLEAR III trial, a multicenter, randomized study to determine if extraventricular drainage plus intraventricular alteplase improved outcome versus extraventricular drainage plus saline. Interventions: Intracranial pressure and cerebral perfusion pressure were recorded every 4 hours, analyzed over a range of thresholds, as single readings or spans (≥ 2) of readings after adjustment for intracerebral hemorrhage severity. Impact on 30- and 180-days modified Rankin Scale scores was assessed, and receiver operating curves were analyzed to identify optimal thresholds. Measurements and Main Results: Of 21,954 intracranial pressure readings, median interquartile range 12 mm Hg (8–16), 9.7% were greater than 20 mm Hg and 1.8% were greater than 30 mm Hg. Proportion of intracranial pressure readings from greater than 18 to greater than 30 mm Hg and combined intracranial pressure greater than 20 plus cerebral perfusion pressure less than 70 mm Hg were associated with day-30 mortality and partially mitigated by intraventricular alteplase. Proportion of cerebral perfusion pressure readings from less than 65 to less than 90 mm Hg and intracranial pressure greater than 20 mm Hg in spans were associated with both 30-day mortality and 180-day mortality. Proportion of cerebral perfusion pressure readings from less than 65 to less than 90 mm Hg and combined intracranial pressure greater than 20 plus cerebral perfusion pressure less than 60 mm Hg were associated with poor day-30 modified Rankin Scale, whereas cerebral perfusion pressure less than 65 and less than 75 mm Hg were associated with poor day-180 modified Rankin Scale. Conclusions: Elevated intracranial pressure and inadequate cerebral perfusion pressure are not infrequent during extraventricular drainage for severe intraventricular hemorrhage, and level and duration predict higher short-term mortality and long-term mortality. Burden of low cerebral perfusion pressure was also associated with poor short- and long-term outcomes and may be more significant than intracranial pressure. Adverse consequences of intracranial pressure-time burden and cerebral perfusion pressure-time burden should be tested prospectively as potential thresholds for therapeutic intervention.