Gary Stier

Ischemic conditioning-induced endogenous brain protection: Applications pre-, per- or post-stroke.

In the area of brain injury and neurodegenerative diseases, a plethora of experimental and clinical evidence strongly indicates the promise of therapeutically exploiting the endogenous adaptive system at various levels like triggers, mediators and the end-effectors to stimulate and mobilize intrinsic protective capacities against brain injuries. It is believed that ischemic pre-conditioning and post-conditioning are actually the strongest known interventions to stimulate the innate neuroprotective mechanism to prevent or reverse neurodegenerative diseases including stroke and traumatic brain injury. Recently, studies showed the effectiveness of ischemic per-conditioning in some organs. Therefore the term ischemic conditioning, including all interventions applied pre-, per- and post-ischemia, which spans therapeutic windows in 3 time periods, has recently been broadly accepted by scientific communities. In addition, it is extensively acknowledged that ischemia-mediated protection not only affects the neurons but also all the components of the neurovascular network (consisting of neurons, glial cells, vascular endothelial cells, pericytes, smooth muscle cells, and venule/veins). The concept of cerebroprotection has been widely used in place of neuroprotection. Intensive studies on the cellular signaling pathways involved in ischemic conditioning have improved the mechanistic understanding of tolerance to cerebral ischemia. This has added impetus to exploration for potential pharmacologic mimetics, which could possibly induce and maximize inherent protective capacities. However, most of these studies were performed in rodents, and the efficacy of these mimetics remains to be evaluated in human patients. Several classical signaling pathways involving apoptosis, inflammation, or oxidation have been elaborated in the past decades. Newly characterized mechanisms are emerging with the advances in biotechnology and conceptual renewal. In this review we are going to focus on those recently reported methodological and mechanistic discoveries in the realm of ischemic conditioning. Due to the varied time differences of ischemic conditioning in different animal models and clinical trials, it is important to define optimal timing to achieve the best conditioning induced neuroprotection. This brings not only an opportunity in the treatment of stroke, but challenges as well, as data is just becoming available and the procedures are not yet optimized. The purpose of this review is to shed light on exploiting these ischemic conditioning modalities to protect the cerebrovascular system against diverse injuries and neurodegenerative disorders.

What's New in Traumatic Brain Injury: Update on Tracking, Monitoring and Treatment.

Traumatic brain injury (TBI), defined as an alteration in brain functions caused by an external force, is responsible for high morbidity and mortality around the world. It is important to identify and treat TBI victims as early as possible. Tracking and monitoring TBI with neuroimaging technologies, including functional magnetic resonance imaging (fMRI), diffusion tensor imaging (DTI), positron emission tomography (PET), and high definition fiber tracking (HDFT) show increasing sensitivity and specificity. Classical electrophysiological monitoring, together with newly established brain-on-chip, cerebral microdialysis techniques, both benefit TBI. First generation molecular biomarkers, based on genomic and proteomic changes following TBI, have proven effective and economical. It is conceivable that TBI-specific biomarkers will be developed with the combination of systems biology and bioinformation strategies. Advances in treatment of TBI include stem cell-based and nanotechnology-based therapy, physical and pharmaceutical interventions and also new use in TBI for approved drugs which all present favorable promise in preventing and reversing TBI.

Isoflurane posttreatment reduces brain injury after an intracerebral hemorrhagic stroke in mice.

BACKGROUND: Intracerebral hemorrhage (ICH) is a devastating stroke subtype affecting 120,000 Americans annually. Of those affected, 40%to 50% will die within the first 30 days, whereas the survivors are left with a lifetime of neurobehavioral disabilities. Recently, it has been shown that volatile anesthetics such as isoflurane can reduce brain injury after an ischemic stroke. As a result, in this study, we investigated the effects of isoflurane as a posttreatment therapeutic modality in ICH-injured mice. Specifically, we investigated whether isoflurane posttreatment can preserve the structural integrity of the brain by reducing apoptotic damage and, in turn, improve functional outcome by amelioration of brain edema and neurobehavioral deficits. METHODS: Male CD1 mice (n = 53) were divided into the following groups: sham (n = 14), ICH (n = 14), ICH treated with 1.5% isoflurane posttreatment for 1 hour (n = 15), and ICH treated with 1.5% isoflurane posttreatment for 2 hours (n = 10). The blood injection ICH model was adapted; this involved extracting autologous blood from the mouse tail and injecting it directly into the right basal ganglia. One hour after surgery, treated mice were placed in a glass chamber maintained at 37°C and infused with 1.5% isoflurane for 1 or 2 hours. At 24 hours postinjury, mice were assessed for neurobehavioral deficits using the Modified Garcia Score and then killed and assessed for brain water content. Double immunofluorescent staining was performed using neuronal marker MAP-2 and TUNEL under a fluorescent microscope to assess for apoptosis. RESULTS: Our results indicated that after 1-hour 1.5% isoflurane posttreatment, there was a significant reduction in brain edema, a decrease in apoptotic cell death, and a significant improvement in neurobehavioral deficits. CONCLUSIONS: Our results suggest that isoflurane may be an effective posttreatment therapeutic option for ICH because of its ability to reduce structural damage and subsequently preserve functional integrity.

Hemodynamic effects of rapid vancomycin infusion in critically ill patients.

The rapid infusion of vancomycin produces histamine release resulting in rash (“red-mans” syndrome) and hypotension. Because this phenomenon has been described primarily in healthy subjects, we prospectively studied the rapid infusion of vancomycin in 16 critically ill patients after open heart surgery in an attempt to document histamine release with resulting hemodynamic changes, and to see if there is any correlation with vancomycin levels. After establishing baseline hemodynamic stability and histamine levels, 1 g vancomycin diluted in 50 mL of 5% dextrose was infused over 30 min. Cardiac index, heart rate, blood pressure, pulmonary venous pressures, and systemic and pulmonary vascular resistances remained unchanged during the infusion. Although the mean plasma vancomycin level increased to a peak of 69 ± 20 μg/mL after 20 min of the infusion before declining, mean plasma histamine levels in 15 of the 16 patients remained within the normal range during the infusion. In one patient a baseline histamine level (2.8 ng/mL) more than three times the normal before the vancomycin infusion increased further during the infusion (3.0, 4.9, and 5.0 ng/mL at t = 10, 20, and 30 min, respectively), and remained elevated (2.9 ng/mL) 30 min after the infusion. This patient developed the red-mans syndrome, although there were no hemodynamic changes. There was no evidence of myocardial depression in any of the patients. In conclusion, we safely infused a concentrated solution of vancomycin into critically ill patients over 30 min without any adverse hemodynamic changes. One patient developed the red-mans syndrome. There was no correlation between peak vancomycin levels and the release of histamine in this patient population.

Telemedicine Pre-anesthesia Evaluation: A Randomized Pilot Trial

OBJECTIVE Pre-anesthesia evaluation allows discovery of conditions affecting perioperative planning, but when inadequate it may be associated with delays, cancellations, and preventable adverse events. Not all patients who could benefit will keep appointments. Telemedicine pre-anesthesia evaluation may provide for safe patient care while reducing patient inconvenience and cost. Herein we investigate the impact of telemedicine pre-anesthesia evaluation on perioperative processes. SUBJECTS AND METHODS This was a single-center prospective randomized trial in 200 adults scheduled for head and neck surgery at Loma Linda University Medical Center, Loma Linda, CA. Consenting patients not meeting criteria for telephone pre-anesthesia evaluation were randomly assigned to the in-person or telemedicine group. The primary outcome measure was inadequate evaluation caused surgical delay or cancellation. Secondary measures included prediction of difficult airway management and concordance of physical examination. RESULTS After consent, 40 patients met criteria for telephone screening. Five patients canceled surgery, none for inadequate pre-anesthesia evaluation; thus 155 were randomized. Delay occurred in 1 telemedicine patient awaiting results performed outside our system. Missing documentation at the time of the visit was less common for telemedicine. Difficult airway management was predicted equally but had low positive predictive value. Heart and lung examinations were highly concordant with day of surgery documentation. Patients and providers were highly satisfied with both evaluation modalities. CONCLUSIONS Telemedicine and in-person evaluations were equivalent, with high patient and provider satisfaction. Telemedicine provides potential patient time and cost saving benefits without more day of surgery delay in our system. A prospective trial of patients from multiple surgical specialty clinics is warranted.

Nitrendipine and Superoxide Dismutase in Ischemic Renal Injury

The effect of the Ca entry blocker nitrendipine, the antioxidant superoxide dismutase (SOD), and a combination of nitrendipine and superoxide dismutase on postischemic renal function was studied in four groups (n = 24) of rats. The rats in group 1 (n = 6) were the ischemic control and received 10 mL of 0.9% NaCl. Group II (n = 6) received SOD 7.0 mg/kg. Group III (n = 6) received nitrendipine 1 mg/kg. Group IV (n = 6) received nitrendipine 1 mg/kg and SOD 7 mg/kg. After administration, both kidneys were rendered ischemic by cross-clamping the renal vessels for 60 min. Comparison of 24-h creatinine clearance (CCr) for 3 days after reversal of ischemia revealed: (a) nitrendipine alone was the most effective in preserving renal function (p < .05); (b) SOD provided some degree of improvement, but only on day 3 (p < .05); (c) a similar result was detected using a combination of nitrendipine and SOD (p < .05); (d) there was no significant difference between SOD and nitrendipine nor between SOD and the combination of nitrendipine/SOD; (e) there was a significant improvement with nitrendipine when compared to the combination of nitrendipine/SOD (p < .05).

Granulocyte Colony-Stimulating Factor Treatment Provides Neuroprotection in Surgically Induced Brain Injured Mice

Surgically induced brain injury (SBI) is a common concern after a neurosurgical procedure. Current treatments aimed at reducing the postoperative sequela are limited. Granulocyte-colony stimulating factor (G-CSF), a hematopoietic growth factor involved in the inflammatory process, has been shown in various animal models to be neuroprotective. Consequently, in this study, we investigated the use of G-CSF as a treatment modality to reduce cell death and brain edema, while improving neurobehavioral deficits following an SBI in mice. Eleven-week-old C57 black mice (n=76) were randomly placed into four groups: sham (n=19), SBI (n=21), SBI with G-CSF pre-treatment (n=15) and SBI with G-CSF pre/post-treatment (n=21). Treated groups received a single dose of G-CSF intraperitoneally at 24, 12 and 1 h pre-surgery and/or 6 and 12 h post-surgery. Postoperative assessment occurred at 24 h and included neurobehavioral testing and measurement for both cell death and brain edema. Results indicated that pre-treatment with G-CSF reduced both cell death and brain edema, while post-treatment reduced neurobehavioral deficits. This study implies that the morphological changes in the brain are effected by pre-treatment; however, in order to activate and/or amplify targets involved in the recovery process, more dosing regimens may be needed.

Endothelin Receptor-A (ETa) Inhibition Fails to Improve Neonatal Hypoxic-Ischemic Brain Injury in Rats

Cerebral hypoxia-ischemia (HI) is an important cause of mortality and disability in newborns. It is a result of insufficient oxygen and glucose circulation to the brain, initiating long-term cerebral damage and cell death. Emerging evidence suggests that endothelin receptor-A (ETA) activation can play an important role in mediating brain damage. In this study, we investigated the role of ETA receptor inhibition using ABT-627 in neonatal HI injured rats. Postnatal day 10 Sprague-Dawley rat pups (n=91) were assigned to the following groups: sham (n=28), HI (vehicle, n=32), and HI with ABT-627 at 3 mg/kg (n=31). The Rice-Vannucci model was used to induce ischemia by ligating the right common carotid artery, followed by a 2 h hypoxic episode using 8% oxygen in a 37°C chamber. Postoperative assessment was conducted at 48 h after injury and again at 4 weeks. At the acute time point, investigative markers included cerebral edema, infarction volume, and body weight change. Neurobehavioral testing was measured at 4 weeks post-injury. Our findings indicated that ABT-627 had no effect on the measured parameters. This study suggests that ETA receptor blockade using ABT-627 post-treatment fails to improve neurological outcomes in neonatal HI injured rats.

3% Hypertonic saline following subarachnoid hemorrhage in rats

BACKGROUND Hypertonic saline (HTS) has been proposed as a treatment after aneurysmal subarachnoid hemorrhage (SAH) to minimize ischemic brain injury due to its osmotic and rheologic properties. Although the benefits of 7.2% HTS use in brain injury have been studied, there is a paucity of data on the use of 3%HTS. METHODS We investigated whether 3%HTS can reduce brain water content and improve neurologic function after SAH in the rodent model compared to 0.9% saline solution (NS). Neurologic testing was conducted at 24 hours post-SAH prior to sacrificing animals for brain water content evaluation. FINDINGS There was significant potentiation of brain water content in the right hemisphere between 3%HTS and NS groups. The modified Garcia score was not significantly different between the two groups; however, the vibrissae-stimulated forelimb placement test showed significantly lower scores in the HTS group. 3%HTS does not decrease brain edema or improve neurologic deficits as compared to NS. In fact, our study showed 3%HTS potentiated brain edema and worsened neurologic deficits in the rat SAH model. CONCLUSIONS Given the potential adverse effects of HTS therapies, including hyperchloremic acidosis, and the lack of benefit found in our study, more investigation is required to evaluate the clinical use of 3%HTS in the setting of SAH.

Simvastatin treatment in surgically induced brain injury in rats

BACKGROUND HMG-CoA reductase inhibitors (Statins) have been shown to reduce blood brain barrier (BBB) disruption and improve neurologic outcome in cerebrovascular disorders. Brain injury due to neurosurgical procedures can lead to post-operative complications such as brain edema and altered neurologic function. The objective of this study was to evaluate whether simvastatin reduces brain edema by preventing BBB disruption and improves neurologic status after surgically-induced brain injury (SBI). METHODS Animals were pretreated for seven days with vehicle or simvastatin i.p. daily, after which they underwent SBI. Neurologic evaluation was assessed at 24 hours post-SBI and the animals were sacrificed for brain water content calculation and BBB evaluation. FINDINGS Brain water content was significantly increased in the right frontal lobe in all SBI groups as compared to the left frontal lobe. There was no significant difference in brain water content in the right frontal lobe between simvastatin and vehicle treated groups. Evans blue testing did not show a significant difference in disruption of the BBB between groups. Neurologic scores were not significantly different. CONCLUSIONS Simvastatin did not reduce brain water content, protect the BBB, or improve neurologic scores after SBI.