R. Morgan Stuart

Cerebral Perfusion Pressure Thresholds for Brain Tissue Hypoxia and Metabolic Crisis After Poor-Grade Subarachnoid Hemorrhage

Background and Purpose— To identify a minimally acceptable cerebral perfusion pressure threshold above which the risks of brain tissue hypoxia (BTH) and oxidative metabolic crisis are reduced for patients with subarachnoid hemorrhage (SAH). Methods— We studied 30 poor-grade SAH patients who underwent brain multimodality monitoring (3042 hours). Physiological measures were averaged over 60 minutes for each collected microdialysis sample. Metabolic crisis was defined as a lactate/pyruvate ratio >40 with a brain glucose concentration ⩽0.7 mmol/L. BTH was defined as PbtO2 <20 mm Hg. Outcome was assessed at 3 months with the Modified Rankin Scale. Results— Multivariable analyses adjusting for admission Hunt-Hess grade, intraventricular hemorrhage, systemic glucose, and end-tidal CO2 revealed that cerebral perfusion pressure ⩽70 mm Hg was significantly associated with an increased risk of BTH (OR, 2.0; 95% CI, 1.2–3.3; P=0.007) and metabolic crisis (OR, 2.1; 95% CI, 1.2–3.7; P=0.007). Death or severe disability at 3 months was significantly associated with metabolic crisis (OR, 5.4; 95% CI, 1.8–16; P=0.002) and BTH (OR, 5.1; 95% CI, 1.2–23; P=0.03) after adjusting for admission Hunt-Hess grade. Conclusions— Metabolic crisis and BTH are associated with mortality and poor functional recovery after SAH. Cerebral perfusion pressure levels <70 mm Hg was associated with metabolic crisis and BTH, and may increase the risk of secondary brain injury in poor-grade SAH patients.

Intracortical electroencephalography in acute brain injury.

Continuous electroencephalography (EEG) is used in patients with neurological injury to detect electrographic seizures and clinically important changes in brain function. Scalp EEG has poor spatial resolution, is often contaminated by artifact, and frequently demonstrates activity that is suspicious for but not diagnostic of ictal activity. We hypothesized that bedside placement of an intracortical multicontact electrode would allow for improved monitoring of cortical potentials in critically ill neurological patients.

Neurostimulation techniques for painful peripheral nerve disorders.

Disorders of the peripheral nervous system often present a unique challenge to the clinician or surgeon, because the neuropathic pain associated with them can be extremely resistant to typical pain treatments. Painful peripheral nerve disorders often have pain in a particular peripheral nerve distribution, and thus an optimal treatment modality is one that delivers targeted relief to the precise distribution of the pain. To that end, peripheral nerve stimulation (PNS) has undergone several refinements in recent years. New types of stimulation, such as techniques for cranial nerve stimulation and spinal nerve root stimulation (SNRS), have enabled the treatment of painful peripheral nerve problems that until fairly recently were either untreatable or poorly treated with traditional spinal cord stimulation (SCS) techniques. In this article, PNS techniques are described in detail for the stimulation of the occipital and trigeminal nerves for intractable craniofacial pain, as well as emerging techniques for the selective stimulation of spinal nerve roots and subcutaneous peripheral nerve stimulation. The increasing spectrum of disorders and pain syndromes amenable to PNS also is discussed.

Cerebral inflammatory response and predictors of admission clinical grade after aneurysmal subarachnoid hemorrhage

Poor admission clinical grade is the most important determinant of outcome after aneurysmal subarachnoid hemorrhage (aSAH); however, little attention has been focused on independent predictors of poor admission clinical grade. We hypothesized that the cerebral inflammatory response initiated at the time of aneurysm rupture contributes to ultra-early brain injury and poor admission clinical grade. We sought to identify factors known to contribute to cerebral inflammation as well as markers of cerebral dysfunction that were associated with poor admission clinical grade. Between 1997 and 2008, 850 consecutive SAH patients were enrolled in our prospective database. Demographic data, physiological parameters, and location and volume of blood were recorded. After univariate analysis, significant variables were entered into a logistic regression model to identify significant associations with poor admission clinical grade (Hunt-Hess grade 4-5). Independent predictors of poor admission grade included a SAH sum score >15/30 (odds ratio [OR] 2.3, 95% confidence interval [CI] 1.5-3.6), an intraventricular hemorrhage sum score >1/12 (OR 3.1, 95% CI 2.1-4.8), aneurysm size >10mm (OR 1.7, 95% CI 1.1-2.6), body temperature 38.3 degrees C (OR 2.5, 95% CI 1.1-5.4), and hyperglycemia >200mg/dL (OR 2.7, 95% CI 1.6-4.5). In a large, consecutive series of prospectively enrolled patients with SAH, the inflammatory response at the time of aneurysm rupture, as reflected by the volume and location of the hemoglobin burden, hyperthermia, and perturbed glucose metabolism, independently predicts poor admission Hunt-Hess grade. Strategies for mitigating the inflammatory response to aneurysmal rupture in the hyper-acute setting may improve the admission clinical grade, which may in turn improve outcomes.

High-dose intra-arterial verapamil for the treatment of cerebral vasospasm after subarachnoid hemorrhage: Prolonged effects on hemodynamic parameters and brain metabolism

BACKGROUND: Studies attempting to establish the safety and efficacy of standard and high-dose intra-arterial infusions of calcium channel blockers for treatment of cerebral vasospasm have focused on hemodynamic changes during the angiographic procedure. OBJECTIVE: To evaluate longer-term drug effects over the hours following infusion and the effects on brain tissue oxygen tension or cerebral metabolism. METHODS: We studied 11 patients with poor-grade aneurysmal subarachnoid hemorrhages who underwent multimodality brain monitoring and angiography with infusion of high-dose intra-arterial verapamil (≥15 mg total dose). Hourly intracerebral microdialysis measurements and continuously recorded mean arterial pressure (MAP), intracranial pressure (ICP), cerebral perfusion pressure (CPP), and Pbto2 were analyzed for 6 hours before and 12 hours following treatment. RESULTS: A median dose of 23 mg (range, 15-55 mg) of intra-arterial verapamil was given. Compared with baseline values, reductions in CPP and MAP were maximal at 3 hours postangiography (from 105 ± 13 mm Hg to 95 ± 15 mm Hg and from 116 ± 12 mm Hg to 106 ± 16 mm Hg, P < .01) and persisted for up to 6 hours (P < .04); increases in vasopressor therapy were required in 8 procedures (53%). ICP significantly increased during the first 3 hours post angiography (P < .03). Brain glucose increased by 33% by hour 9 (P < .001). There were no significant changes in Pbto2 or the lactate/pyruvate ratio. CONCLUSION: High-dose intra-arterial verapamil causes increases in ICP and reductions in CPP, followed by an increase in brain glucose levels, without altering brain oxygen tension or oxidative metabolism. Patients undergoing high-dose intra-arterial verapamil therapy warrant close hemodynamic and ICP monitoring for at least 12 hours following treatment.

Effect of mannitol on brain metabolism and tissue oxygenation in severe haemorrhagic stroke

Background The impact of osmotic therapies on brain metabolism has not been extensively studied in humans. The authors examined if mannitol treatment of raised intracranial pressure will result in an improvement in brain metabolism together with the expected drop in intracranial pressure (ICP). Methods This is a retrospective review of prospectively collected data. Twenty episodes of raised ICP (>20 mm Hg) resistant to standard therapy that required infusions of mannitol were studied in 12 comatose patients with multimodality monitoring including ICP, PbtO2 and microdialysis. The authors compared mean arterial blood pressure, ICP, cerebral perfusion pressure, PbtO2, brain lactate, pyruvate and glucose using cerebral microdialysis, for 3 h preceding and 4 h after hyperosmolar therapy. Time-series data were analysed using a multivariable general linear model utilising generalised estimating equations for model estimation to account for within-subjects and between-subjects variations over time. Results 20% mannitol solution (1 g/kg) was administered at the discretion of the attending neurointensivist. ICP decreased 30 min (from 27±13 to 19±16 mm Hg, p<0.001) and cerebral perfusion pressure increased 45 min (from 73± 18 to 85±22 mm Hg, p=0.002) after the start of mannitol infusions, whereas mean arterial blood pressure and PbtO2 did not change significantly. The peak lactate–pyruvate ratio was recorded at the time of initiating osmotherapy (44±20) with an 18% decrease over 2 h following mannitol therapy (35±16; p=0.002). Brain glucose remained unaffected. Conclusions Mannitol effectively reduces ICP and appeared to benefit brain metabolism as measured by the lactate–pyruvate ratio.

Prolonged intracerebral convection-enhanced delivery of topotecan with a subcutaneously implantable infusion pump

Intracerebral convection-enhanced delivery (CED) of chemotherapeutic agents currently requires an externalized catheter and infusion system, which limits its duration because of the need for hospitalization and the risk of infection. To evaluate the feasibility of prolonged topotecan administration by CED in a large animal brain with the use of a subcutaneous implantable pump. Medtronic Synchromed-II pumps were implanted subcutaneously for intracerebral CED in pigs. Gadodiamide (28.7 mg/mL), with or without topotecan (136 μM), was infused at 0.7 mL/24 h for 3 or 10 days. Pigs underwent magnetic resonance imaging before and at 6 times points after surgery. Enhancement and FLAIR+ volumes were calculated in a semi-automated fashion. Magnetic resonance spectroscopy-based topotecan signature was also investigated. Brain histology was analyzed by hematoxylin and eosin staining and with immunoperoxidase for a microglial antigen. CED of topotecan/gadolinium was well tolerated in all cases (n = 6). Maximum enhancement volume was reached at day 3 and remained stable if CED was continued for 10 days, but it decreased if CED was stopped at day 3. Magnetic resonance spectroscopy revealed a decrease in parenchymal metabolites in the presence of topotecan. Similarly, the combination of topotecan and gadolinium infusion led to a FLAIR+ volume that tended to be larger than that seen after the infusion of gadolinium alone. Histological analysis of the brains showed an area of macrophage infiltrate in the ipsilateral white matter upon infusion with topotecan/gadolinium. Intracerebral topotecan CED is well tolerated in a large animal brain for up to 10 days. Intracerebral long-term CED can be achieved with a subcutaneously implanted pump and provides a stable volume of distribution. This work constitutes a proof of principle for the safety and feasibility for prolonged CED, providing a means of continuous local drug delivery that is accessible to the practicing neuro-oncologist.

Relationship between brain interstitial fluid tumor necrosis factor-α and cerebral vasospasm after aneurysmal subarachnoid hemorrhage

Tumor necrosis factor-alpha (TNF-alpha) has a crucial role in the onset of hemolysis-induced vascular injury and cerebral vasoconstriction. We hypothesized that TNF-alpha measured from brain interstitial fluid would correlate with the severity of vasospasm following aneurysmal subarachnoid hemorrhage (aSAH). From a consecutive series of 10 aSAH patients who underwent cerebral microdialysis (MD) and evaluation of vasospasm by CT angiogram (CTA) or digital subtraction angiography (DSA), TNF-alpha levels from MD were measured at 8-hour intervals from aSAH days 4-6 using enzyme-linked immunosorbent assay. An attending neuroradiologist blinded to the study independently evaluated each CTA and DSA and assigned a vasospasm index (VI). Five patients had a VI<2 and 5 patients had a VI>2, where the median VI was 2 (range 0-13). The median log TNF-alpha area under the curve (AUC) was 1.64pg/mL *day (interquartile range 1.48-1.71) for the VI<2 group, and 2.11pg/mL *day (interquartile range 1.95-2.47) for the VI>2 group (p<0.01). Thus, in this small series of poor-grade aSAH patients, the AUC of TNF-alpha levels from aSAH days 4-6 correlates with the severity of radiographic vasospasm. Further analysis in a larger population is warranted based on our preliminary findings.