Friess, Stuart H
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Publication Neurocritical Care Monitoring Correlates with Neuropathology in a Swine Model of Pediatric Traumatic Brain Injury(2011-11-01) Friess, Stuart H; Ralston, Jill; Eucker, Stephanie A; Helfaer, Mark A; Margulies, Susan S; Smith, ColinBACKGROUND—Small animal models have been used in traumatic brain injury (TBI) research to investigate the basic mechanisms and pathology of TBI. Unfortunately, successful TBI investigations in small animal models have not resulted in marked improvements in clinical outcomes of TBI patients. OBJECTIVE—To develop a clinically relevant immature large animal model of pediatric neurocritical care following TBI. METHODS—Eleven 4 week old piglets were randomized to either rapid axial head rotation without impact (N=6) or instrumented sham (N=5). All animals had an intracranial pressure monitor, brain tissue oxygen (PbtO2) probe, and cerebral microdialysis probe placed in the frontal lobe and data collected for 6 h following injury. RESULTS—Injured animals had sustained elevations in intracranial pressure and lactatepyruvate ratio (LPR), and decreased PbtO2 compared to sham. PbtO2 and LPR from separate frontal lobes had strong linear correlation in both sham and injured animals. Neuropathologic examination demonstrated significant axonal injury and infarct volumes in injured animals compared to sham at 6 hours post-injury. Averaged over time, PbtO2 in both injured and sham animals had a strong inverse correlation with total injury volume. Average LPR had a strong correlation with total injury volume. CONCLUSION—LPR and PbtO2 can be utilized as serial non-terminal secondary markers in our injury model for neuropathology, and as evaluation metrics for novel interventions and therapeutics in the acute post-injury period. This translational model bridges a vital gap in knowledge between TBI studies in small animal models and clinical trials in the pediatric TBI population.Publication Diffuse Optical Monitoring of Hemodynamic Changes in Piglet Brain With Closed Head Injury(2009-05-04) Eucker, Stephanie A; Durduran, Turgut; Yu, Guoqiang; Ralston, Jill; Friess, Stuart H; Ichord, Rebecca N; Margulies, Susan S; Zhou, Chao; Yodh, Arjun G.We used a nonimpact inertial rotational model of a closed head injury in neonatal piglets to simulate the conditions following traumatic brain injury in infants. Diffuse optical techniques, including diffuse reflectance spectroscopy and diffuse correlation spectroscopy (DCS), were used to measure cerebral blood oxygenation and blood flow continuously and noninvasively before injury and up to 6 h after the injury. The DCS measurements of relative cerebral blood flow were validated against the fluorescent microsphere method. A strong linear correlation was observed between the two techniques (R=0.89, p < 0.00001). Injury-induced cerebral hemodynamic changes were quantified, and significant changes were found in oxy- and deoxy-hemoglobin concentrations, total hemoglobin concentration, blood oxygen saturation, and cerebral blood flow after the injury. The diffuse optical measurements were robust and also correlated well with recordings of vital physiological parameters over the 6-h monitoring period, such as mean arterial blood pressure, arterial oxygen saturation, and heart rate. Finally, the diffuse optical techniques demonstrated sensitivity to dynamic physiological events, such as apnea, cardiac arrest, and hypertonic saline infusion. In total, the investigation corraborates potential of the optical methods for bedside monitoring of pediatric and adult human patients in the neurointensive care unit.Publication Early Cerebral Perfusion Pressure Augmentation With Phenylephrine After Traumatic Brain Injury May Be Neuroprotective in a Pediatric Swine Model(2012-08-01) Friess, Stuart H; Kilbaugh, Todd; Ralston, Jill; Helfaer, Mark A; Smith, Colin; Margulies, Susan S; Frangos, Suzanne GObjective: Cerebral perfusion pressureage, and current guidelines recommend maintaining cerebral perfusion pressure between 40 mm Hg–60 mm Hg. Although adult traumatic brain injury studies have observed an increased risk of complications associated with targeting a cerebral perfusion pressure >70, we hypothesize that targeting a cerebral perfusion pressure of 70 mm Hg with the use of phenylephrine early after injury in the immature brain will be neuroprotective. Design: Animals were randomly assigned to injury with a cerebral perfusion pressure of 70 mm Hg or 40 mm Hg. Diffuse traumatic brain injury was produced by a single rapid rotation of the head in the axial plane. Cerebral microdialysis, brain tissue oxygen, intracranial pressure, and cerebral blood flow were measured 30 min–6 hrs postinjury. One hour after injury, cerebral perfusion pressure was manipulated with the vasoconstrictor phenylephrine. Animals were euthanized 6 hrs posttraumatic brain injury, brains fixed, and stained to assess regions of cell injury and axonal dysfunction. Setting: University center. Subject: Twenty-one 4-wk-old female swine. Measurements and Main Results: Augmentation of cerebral perfusion pressure to 70 mm Hg resulted in no change in axonal dysfunction, but significantly smaller cell injury volumes at 6 hrs postinjury compared to cerebral perfusion pressure 40 (1.1% vs. 7.4%, p < .05). Microdialysis lactate/pyruvate ratios were improved at cerebral perfusion pressure 70 compared to cerebral perfusion pressure 40. Cerebral blood flow was higher in the cerebral perfusion pressure 70 group but did not reach statistical significance. Phenylephrine was well tolerated and there were no observed increases in serum lactate or intracranial pressure in either group. Conclusions: Targeting a cerebral perfusion pressure of 70 mm Hg resulted in a greater reduction in metabolic crisis and cell injury volumes compared to a cerebral perfusion pressure of 40 mm Hg in an immature swine model. Early aggressive cerebral perfusion pressure augmentation to a cerebral perfusion pressure of 70 mm Hg in pediatric traumatic brain injury before severe intracranial hypertension has the potential to be neuroprotective, and further investigations are needed.Publication The Anesthetic Effects on Vasopressor Modulation of Cerebral Blood Flow in an Immature Swine Model(2013-04-01) Kilbaugh, Todd; Margulies, Susan S; Bruins, Benjamin; Friess, Stuart HBACKGROUND: The effect of various sedatives and anesthetics on vasopressor modulation of cerebral blood flow (CBF) in children is unclear. In adults, isoflurane has been described to decrease CBF to a lesser extent than fentanyl and midazolam. Most large-animal models of neurocritical care use inhaled anesthetics for anesthesia. Investigations involving modulations of CBF would have improved translatability within a model that more closely approximates the current practice in the pediatric intensive care unit. METHODS: Fifteen 4-week-old piglets were given 1 of 2 anesthetic protocols: total IV anesthesia (TIVA) (midazolam 1 mg/kg/h and fentanyl 100 μg/kg/h, n = 8) or ISO (isoflurane 1.5%–2% and fentanyl 100 μg/kg/h, n = 7). Mean arterial blood pressure, intracranial pressure (ICP), CBF, and brain tissue oxygen tension were measured continuously as piglets were exposed to escalating doses of arginine vasopressin, norepinephrine (NE), and phenylephrine (PE). RESULTS: Baseline CBF was similar in the 2 groups (ISO 38 ± 10 vs TIVA 35 ± 26 mL/100 g/min) despite lower baseline cerebral perfusion pressure in the ISO group (45 ± 11 vs 71 ± 11 mm Hg; P < 0.0005). Piglets in the ISO group displayed increases in ICP with PE and NE (11 ± 4 vs 16 ± 4 mm Hg and 11 ± 8 vs 18 ± 5 mm Hg; P < 0.05), but in the TIVA group, only exposure to PE resulted in increases in ICP when comparing maximal dose values with baseline data (11 ± 4 vs 15 ± 5 mm Hg; P < 0.05). Normalized CBF displayed statistically significant increases regarding anesthetic group and vasopressor dose when piglets were exposed to NE and PE (P < 0.05), suggesting an impairment of autoregulation within ISO, but not TIVA. CONCLUSION: The vasopressor effect on CBF was limited when using a narcotic-benzodiazepine–based anesthetic protocol compared with volatile anesthetics, consistent with a preservation of autoregulation. Selection of anesthetic drugs is critical to investigate mechanisms of cerebrovascular hemodynamics, and in translating critical care investigations between the laboratory and bedside.Publication Diffuse optical monitoring of hemodynamic changes in piglet brain with closed head injury(2009-06-04) Eucker, Stephanie A; Durduran, Turgut; Yu, Guoqiang; Ralston, Jill; Friess, Stuart H; Ichord, Rebecca N; Margulies, Susan S; Zhou, Chao; Yodh, Arjun G.We used a nonimpact inertial rotational model of a closed head injury in neonatal piglets to simulate the conditions following traumatic brain injury in infants. Diffuse optical techniques, including diffuse reflectance spectroscopy and diffuse correlation spectroscopy (DCS), were used to measure cerebral blood oxygenation and blood flow continuously and noninvasively before injury and up to 6 h after the injury. The DCS measurements of relative cerebral blood flow were validated against the fluorescent microsphere method. A strong linear correlation was observed between the two techniques (R=0.89, p<0.00001). Injury-induced cerebral hemodynamic changes were quantified, and significant changes were found in oxy- and deoxy-hemoglobin concentrations, total hemoglobin concentration, blood oxygen saturation, and cerebral blood flow after the injury. The diffuse optical measurements were robust and also correlated well with recordings of vital physiological parameters over the 6-h monitoring period, such as mean arterial blood pressure, arterial oxygen saturation, and heart rate. Finally, the diffuse optical techniques demonstrated sensitivity to dynamic physiological events, such as apnea, cardiac arrest, and hypertonic saline infusion. In total, the investigation corraborates potential of the optical methods for bedside monitoring of pediatric and adult human patients in the neurointensive care unit.Publication Premedication With Meloxicam Exacerbates Intracranial Hemorrhage in an Immature Swine Model of Non-impact Inertial Head Injury(2012-04-01) Friess, Stuart H; Naim, Maryam Y; Kilbaugh, Todd; Ralston, Jill; Margulies, Susan SMeloxicam is a cyclo-oxgenase-2 preferential non-steroid anti-inflammatory drug with very effective analgesic and anti-inflammatory effects in swine. Previous reports in piglets have demonstrated that meloxicam also inhibits cyclo-oxgenase-1 and reduces production of thromboxane significantly. We use pre-injury analgesia in our immature swine (3–5 day old piglets) model of brain injury using rapid head rotations without impact. In 23 consecutive subjects we found that premedication with meloxicam (N=6) produced a significantly higher mortality rate (5/6 or 83%) than buprenorphine (N =17, 1/17 or 6%, p < 0.02). On gross neuropathologic examination of the meloxicam-treated swine, we observed massive subdural and subarachnoid bleeding which were not present in buprenorphine-premedicated animals. To our knowledge there are no previous reports in swine of increased bleeding or platelet inhibition associated with meloxicam administration and further research is needed to define mechanisms of action in piglets. We caution the use of meloxicam in swine when inhibition of platelet aggregation might adversely affect refinement of experimental research protocols, such as in stroke, trauma, and cardiac arrest models.