Large Volume Intrathecal Bolus: CSF Pressure and Implications for Safety

Abstract

ObjectivesLarge volume intrathecal (IT) bolus administrations yield an efficient method of therapeutic delivery to the cerebral CSF from a clinically accessible injection site. In non‐human primates, high volume bolus can translocate up to 90% of the administered substance to the cerebro‐cervical CSF immediately. It is known that administration of up to ca. 20% of the total CSF volume is safe for humans and monkeys; however, the safety parameters detailing the volume and underlying mechanistic limits have not been studied. The goal of the present work is to characterize the relationship between administered volumes and rates and intracranial pressure (ICP) as a safety parameter in rats and monkeys.MethodsICP was measured in the cisterna magna (rats) and the subcutaneous injection port leading to the lumbar CSF (monkeys) utilizing a 1F piezoresistive diffused semiconductor pressure sensor mounted at the tip of a 20 cm long 0.8 F polyimide catheter (Millar, Inc). Signal processing was carried out using a FE221 Bridge Amplifier coupled with a PowerLab 4/35 (ADInstruments). Control of both modules and waveform analysis was performed using LabChart 8 software (ADInstruments).ResultsICP in rats and monkeys was characterized by a periodic waveform of classical shape with spectrally resolved P1, P2, and P3 components (Fig. 1). Mean baseline ICP in rats was 9.3±2.3 mmHg. The adaptability of rats to varying ICPs was studied by plotting the time‐averaged amplitude of the P1 component against the mean ICP. Correlation between these two variables formed three distinctive zones: (1) low synchronization (good compensatory reserve) at low ICP, (2) good synchronization (poor compensatory reserve) at higher ICP, and (3) negative correlation (impaired compensatory mechanisms) at ICP > 32.3±6.5 mmHg (Fig. 1). The determined terminally “critical” ICP was then used to ascertain safe infusion rates and volumes in a separate group of rats. We found that infusion rates of up to 40 mkL/min could be used to safely administer volumes of at least 50% of CSF volume, whereas significantly smaller volumes could be infused at higher rates (Fig. 2). Our previous studies showed that monkeys tolerated bolus injections of 0.5 mL/kg body weight given at ca. 2 mL/min. Administration of this volume in a group of N=4 resulted in an ICP elevation by 47.5±5.9 mmHg. In rats and monkeys, the elevated post‐bolus ICP exponentially relaxed to the baseline within 11.3±8.1 min and 12.3±8.1 min, respectively.ConclusionsICP is a function of the rate and volume of fluid administration in the CSF and can safely be tolerated up to 32.3±6.5 mmHg (3.5‐fold) in rats. Comparable ICP relaxation times in monkeys and rats suggest similarities in the mechanisms of volume accommodation (hydrostatic compliance in the cervical region) and ICP adaptation (likely accelerated CSF drainage). The obtained data can improve the prediction of the safety of large‐volume IT drug administration and can be instrumental for identifying mechanisms regulating ICP adaptability.Support or Funding InformationThis study was supported by MGH ECOR Formulaic Award (2015) and NIH grants R01NS092838 and R21NS090049.