Honored guest presentation: scientific foundations of clinical neurosurgery.
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History, 17th Century↗
Biomedical subjects
Julian T Hoff
Publications and source records attributed to Julian T Hoff.
Iron and iron-handling proteins in the brain after intracerebral hemorrhage.
BACKGROUND AND PURPOSE: Evidence indicates that brain injury after intracerebral hemorrhage (ICH) is due in part to the release of iron from hemoglobin. Therefore, we examined whether such iron is cleared from the brain and the effects of ICH on proteins that may alter iron release or handling: brain heme oxygenase-1, transferrin, transferrin receptor, and ferritin. METHODS: Male Sprague-Dawley rats received an infusion of 100 microL autologous whole blood into the right basal ganglia and were killed 1, 3, 7, 14, or 28 days later. Enhanced Perl's reaction was used for iron staining, and brain nonheme iron content was determined. Brain heme oxygenase-1, transferrin, transferrin receptor, and ferritin were examined by Western blot analysis and immunohistochemistry. Immunofluorescent double labeling was performed to identify which cell types express ferritin. RESULTS: ICH upregulated heme oxygenase-1 levels and resulted in iron overload in the brain. A marked increase in brain nonheme iron was not cleared within 4 weeks. Brain transferrin and transferrin receptor levels were also increased. In addition, an upregulation of ICH on ferritin was of very long duration. CONCLUSIONS: The iron overload and upregulation of iron-handling proteins, including transferrin, transferrin receptor, and ferritin, in the brain after ICH suggest that iron could be a target for ICH therapy.
Animals↗
Deferoxamine-induced attenuation of brain edema and neurological deficits in a rat model of intracerebral hemorrhage.
OBJECT: In the authors' previous studies they found that brain iron accumulation and oxidative stress contribute to secondary brain damage after intracerebral hemorrhage (ICH). In the present study they investigated whether deferoxamine, an iron chelator, can reduce ICH-induced brain injury. METHODS: Male Sprague-Dawley rats received an infusion of 100 microl of autologous whole blood into the right basal ganglia and were killed 1, 3, or 7 days thereafter. Iron distribution was examined histochemically (enhanced Perl reaction). The effects of deferoxamine on ICH-induced brain injury were examined by measuring brain edema and neurological deficits. Apurinic/apyrimidinic endonuclease/redox effector factor-1 (APE/Ref-1), a repair mechanism for DNA oxidative damage, was quantitated by Western blot analysis. Iron accumulation was observed in the perihematoma zone beginning 1 day after ICH. Deferoxamine attenuated brain edema, neurological deficits, and ICH-induced changes in APE/Ref-1. CONCLUSIONS: Deferoxamine and other iron chelators may be potential therapeutic agents for treating ICH. They may act by reducing the oxidative stress caused by the release of iron from the hematoma.
Animals↗
Spontaneous intracerebral hemorrhage: a review.
Spontaneous intracerebral hemorrhage (SICH) is a blood clot that arises in the brain parenchyma in the absence of trauma or surgery. This entity accounts for 10 to 15% of all strokes and is associated with a higher mortality rate than either ischemic stroke or subarachnoid hemorrhage. Common causes include hypertension, amyloid angiopathy, coagulopathy, vascular anomalies, tumors, and various drugs. Hypertension, however, remains the single greatest modifiable risk factor for SICH. Computerized tomography scanning is the initial diagnostic modality of choice in SICH, and angiography should be considered in all cases except those involving older patients with preexisting hypertension in thalamic, putaminal, or cerebellar hemorrhage. Medical management includes venous thrombosis prophylaxis, gastric cytoprotection, and aggressive rehabilitation. Anticonvulsant agents should be prescribed in supratentorial SICH, whereas the management of hypertension is controversial. To date, nine prospective randomized controlled studies have been conducted to compare surgical and medical management of SICH. Although definitive evidence favoring surgical intervention is lacking, there is good theoretical rationale for early surgical intervention. Surgery should be considered in patients with moderate to large lobar or basal ganglia hemorrhages and those suffering progressive neurological deterioration. Elderly patients in whom the Glasgow Coma Scale score is less than 5, those with brainstem hemorrhages, and those with small hemorrhages do not typically benefit from surgery. Patients with cerebellar hemorrhages larger than 3 cm, those with brainstem compression and hydrocephalus, or those exhibiting neurological deterioration should undergo surgical evacuation of the clot. It is hoped that the forthcoming results of the International Surgical Trial in IntraCerebral Hemorrhage will help formulate evidence-based recommendations regarding the role of surgery in SICH.
Adult↗
Nestin expression after experimental intracerebral hemorrhage.
The current study examines nestin expression after intracerebral hemorrhage (ICH), the role of different blood components in nestin upregulation, and the possibility that low doses of thrombin that induce tolerance to brain injury (thrombin preconditioning) might also induce nestin expression. Adult male Sprague-Dawley rats received an intracaudate injection of either whole blood, thrombin (1 or 5 U) or red blood cells (RBCs). Animals were sacrificed for single and double labeling immunohistochemistry to identify which cells express nestin, and for Western blotting to quantify nestin expression. By immunohistochemistry, nestin immunoreactivity was present in large numbers of astrocytes, surrounding the hematoma from day 3 to 1 week after ICH. After 2 weeks, nestin immunoreactivity was co-localized with a neuronal marker (neuronal specific enolase). By Western blot analysis, nestin was strongly expressed at day 3 (P<0.01) and 1 week (P<0.01), and expression persisted for at least 1 month (P<0.05). Intracerebral injection of thrombin or lysed RBCs resulted in a marked increase in nestin expression. Interestingly, injection of a low dose of thrombin that induces brain tolerance also upregulated nestin. The ICH-induced nestin expression in astrocytes may reflect an early response of these cells to injury, while the delayed expression in neurons might be a part of the adaptative response to injury perhaps leading to recovery of function. Nestin induction by a low dose of thrombin suggests that specific receptor-mediated pathways are involved in inducing nestin expression and that nestin may play a role in thrombin preconditioning.
Animals↗
Research by academic surgeons.
Academic surgeons are required to fulfill three basic, interconnected responsibilities: patient care, teaching, and research. Increased demands for patient care and its revenue have severely curtailed the time available to pursue research projects. In order for trainees and junior faculty to discover the fulfillment research can provide, their time must be protected to allow them to find good mentors, projects, and funding essential for success in academic surgery.
Academic Medical Centers↗
Donald J. Reis, MD: research mentor extraordinaire.
Donald J. Reis, M.D., the late internationally reknowned neuroscientist, had a special talent for mentoring researchers early in their academic careers. His "hands-on" approach to laboratory investigation, his extraoridinary patience with novice researchers, his commitment to the scientific method, and his enthusiastic approach to the art of neuroscience all combined to make him the ideal mentor for many budding academics over the past four decades. The beauty of his scientific legacy is that he loved to each research. The following tribute is personal from one whose career was changed by a great mentor.
Animals↗
The impact of provider volume on mortality after intracranial tumor resection.
OBJECTIVE: Policies of regionalization and selective referral for a number of "high-risk" surgical procedures are being explored and implemented as a result of significant variation in postoperative mortality between high- and low-volume providers. The effect of provider volume on outcomes after intracranial tumor resection is unknown and warrants investigation. METHODS: By use of the Nationwide Inpatient Sample for 1996 and 1997, patients (older than 19 yr) who had a diagnosis of a malignant central nervous system neoplasm and underwent craniotomy or craniectomy were included. Hospital volume and surgeon volume were categorized by quartiles (very low, low, high, or very high volume). Unadjusted and case mix-adjusted analyses were performed with regard to postoperative in-hospital mortality. RESULTS: The crude in-hospital mortality was 2.8% for a total of 7547 patients. The mean patient age was 55.8 years (66.5% <65; 33.5% >/=65). Mortality for very low- to very high-volume hospitals was as follows: 3.8, 3.2, 2.4, and 1.8% (P < 0.001). Mortality for very low- to very high-volume surgeons was as follows: 4.1, 3.9, 3.1, and 1.4% (P = 0.003). Predictors of mortality in a logistic regression model were emergent admission (odds ratio [OR], 2.97; 95% confidence interval [CI], 2.02-4.38; P < 0.001), and age 65 years or greater (OR, 1.63; 95% CI, 1.16-2.30; P = 0.005). The risk of mortality was reduced for very high-volume hospitals (OR, 0.58; 95% CI, 0.35-0.97; P = 0.038) and very high-volume surgeons (OR, 0.42; 95% CI, 0.22-0.84; P = 0.012). CONCLUSION: Higher-volume providers have superior outcomes after surgical resection of malignant intracranial tumors. This reduction was maintained despite adjustment for case mix. As the regionalization of high-risk surgery moves forward, it is important for neurosurgeons to maintain leadership roles in the development of specialty-specific data collection and health policy initiatives that improve and reduce variation in outcomes.
Adult↗
Thrombin preconditioning attenuates brain edema induced by erythrocytes and iron.
Pretreatment with a low intracerebral dose of thrombin reduces brain edema after hemorrhagic and thrombo-embolic stroke. We have termed this phenomena thrombin preconditioning (TPC) or thrombin-induced brain tolerance. Red blood cell lysis and iron overload contribute to delayed edema formation after intracerebral hemorrhage. The present study examined whether TPC can attenuate the brain edema induced by lysed red blood cells or iron. It also examined whether TPC is associated with increasing hypoxia inducible factor-1alpha (HIF-1alpha) levels and alterations in two HIF-1alpha target genes, transferrin (Tf) and transferrin receptor (TfR), within the brain. Brain edema was measured by wet/dry weight method. HIF-1alpha, Tf, and TfR were measured by Western blot analysis and immunohistochemistry. We found that TPC reduces the edema induced by infusion of lysed red blood cells and iron. Thrombin increases HIF-1alpha levels through p44/42 mitogen activated protein kinases pathway. Thrombin also increases Tf and TfR levels in the brain. These results indicate that HIF-1alpha and its target genes may be involved in thrombin-induced brain tolerance.
Animals↗
Editorial comment--International variations in surgical practice for spontaneous intracerebral hemorrhage.
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Cerebral Hemorrhage↗
Recombinant activated factor VII for the rapid correction of coagulopathy in nonhemophilic neurosurgical patients.
OBJECTIVE: Coagulopathy is a significant contraindication for neurosurgery. Unfortunately, many coagulopathic patients require urgent neurosurgical intervention. Standard use of blood products, including fresh-frozen plasma or prothrombin complexes, to correct the coagulopathy often leads to significant delays in treatment. Recombinant activated factor VII (rFVIIa) is a medication originally designed to treat bleeding in hemophiliacs but also seems to correct a wide variety of coagulopathies rapidly and safely in nonhemophilic patients. METHODS: The medical records of nine patients with coagulopathy requiring urgent neurosurgical intervention were reviewed retrospectively. Each patient was given a dose ranging from 40 to 90 microg/kg of rFVIIa before undergoing surgery. Pre-rFVIIa coagulation and post-rFVIIa coagulation parameters were obtained. Once correction of the coagulopathy was verified, each patient underwent the appropriate neurosurgical procedure. RESULTS: The average age of the patients was 40.9 years; six were women. The causes of the coagulopathy included anticoagulant medication, liver dysfunction, and dilutional coagulopathy after traumatic hemorrhage. Neurosurgical indications included intraparenchymal/intraventricular hemorrhage, hydrocephalus, diffuse cerebral edema, and epidural hematoma. Post-rFVIIa coagulation parameters obtained as early as 20 minutes after infusion of the medication showed normalization of values. There were no procedural or operative complications and no postoperative hemorrhagic complications. No associated thromboembolic or other complications with the use of rFVIIa were observed. CONCLUSION: The use of rFVIIa for the urgent surgical treatment of coagulopathic patients is quite promising. Further studies, including randomized, prospective trials using rFVIIa to address issues such as optimal dosing, efficacy, surgical indications, cost-effectiveness, morbidity, and mortality are needed.
Adolescent↗
Oxidative brain injury from extravasated erythrocytes after intracerebral hemorrhage.
Intracerebral infusion of lysed erythrocytes causes brain edema without inducing ischemic cerebral blood flow. Reports have indicated that oxidative damage contributes to secondary brain injury in stroke. In the present study, we investigated whether erythrocyte lysis after intracerebral hemorrhage (ICH) might result in oxidative brain damage. This study had four parts. Male Sprague-Dawley rats received an infusion of autologous lysed erythrocytes into the right striatum. Control rats only had a needle insertion. Neurological deficits, brain water and ion contents were determined in the first part. In the second part, hemoxygenase-1 (HO-1), manganese superoxide dismutase (Mn-SOD), copper/zinc SOD (CuZn-SOD) and protein carbonyl levels were determined by Western blot analysis. In the third part, immunohistochemistry was performed for HO-1. DNA damage was examined using DNA polymerase I-mediated biotin-dATP nick-translation (PANT) and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) in the fourth part. Infusion of lysed RBCs induced marked edema in the ipsilateral striatum and profound neurological deficits. Western blot analysis and immunohistochemistry indicated that HO-1 was upregulated 24 h after infusion of lysed red blood cells. Both Mn-SOD and CuZn-SOD contents decreased, protein carbonyl levels increased in the ipsilateral striatum, and there was the appearance of PANT- and TUNEL-positive cells suggesting oxidative mechanisms in the erythrocyte-induced brain injury. In conclusion, oxidative stress caused by components of the lysed erythrocytes contributes to the brain injury after ICH.
Animals↗
Pathophysiology of brain edema formation.
A number of mechanisms seem to be involved in edema formation after an ICH. At least three phases of edema are involved in ICH. These include a very early phase (first several hours) involving hydrostatic pressure and clot retraction, a second phase (first 2 days) involving the activation of the coagulation cascade and thrombin production, and a third phase (after 3 days) involving RBC lysis and hemoglobin-induced neuronal toxicity. Activation of the complement system in brain parenchyma also plays an important role in the second and third phases. There are potential therapeutic strategies to address each of these mechanisms. Because the adverse effect of an ICH seems to result from a toxic effect of blood components on brain tissue, early clot removal may be the best strategy, because it results in the removal of all the toxic components [93]. Hematoma aspiration after tissue plasminogen activator (tPA) infusion has also been shown to be relatively safe and effective in animal models. Kaufman et al [94] reported that tPA lysed the hematoma in minutes and did not cause inflammation or bleeding in rabbits. Because clots lysed with tPA can be aspirated through a needle or catheter, mechanical brain injury by this method is minimized. In a rat model, aspiration of clot with tPA reduced clot volume and brain injury [95,96]. Recently, Wagner et al [97] infused tPA into hematomas in a porcine model at 3 hours after induction and aspirated the liquified clots 1 hour later. Clot removal after tPA treatment resulted in a 72% reduction in hematoma volume compared with untreated controls. Clot removal also reduced brain edema volume and BBB disruption and improved cerebral tissue pressure [93]. Six randomized trials have been accomplished, but surgical evacuation of the clot remains controversial [98-103]. Recently, thrombolysis and aspiration under CT guidance reduced the hematoma volume effectively [104]. Infusion of tPA directly into the hematoma before clot aspiration has also been used in human beings. Up to 90% of the original hematoma volume can be removed [105, 106]. Schaller et al [107] injected tPA directly into a hematoma 72 hours after the ictus in patients. The hematomas were lysed, and the liquified clots were drained in 14 patients. Two patients died, but none had recurrent hemorrhage. In conclusion, much has been learned about the basic mechanisms involved in edema formation after ICH. Animal models indicate that a number of components of blood are capable of inducing brain injury and brain edema. Now, it is time to translate that basic information into clinical trials.
Blood-Brain Barrier↗
Plasminogen activator inhibitor-1 induction after experimental intracerebral hemorrhage.
Serine proteases, such as thrombin and tissue-type plasminogen activator, play an important role in brain injury after intracerebral hemorrhage and other neurologic disorders. Plasminogen activator inhibitor-1 is one of the serine protease inhibitors, or serpins. The balance between serine proteases and serpins may affect the outcome of intracerebral hemorrhage. The purpose of this study was to determine whether plasminogen activator inhibitor-1 and tissue-type plasminogen activator are upregulated after intracerebral hemorrhage and the role that thrombin plays in that induction. Plasminogen activator inhibitor-1 protein levels were upregulated after intracerebral hemorrhage. Brain plasminogen activator inhibitor-1 content also increased after thrombin infusion in a dose-dependent manner. Hirudin, a specific thrombin inhibitor, blocked the upregulation of plasminogen activator inhibitor-1 after intracerebral hemorrhage. Time courses showed that plasminogen activator inhibitor-1 levels around the hematoma peaked at the first day. Plasminogen activator inhibitor-1-positive cells were detected in the perihematomal area and the ipsilateral basal ganglia after thrombin infusion, but not in the contralateral hemisphere. Plasminogen activator inhibitor-1 messenger RNA levels were increased at 24 hours after intracerebral hemorrhage and after thrombin infusion. However, tissue-type plasminogen activator protein levels were the same in the control, whole-blood, and thrombin-infusion groups. In conclusion, intracerebral hemorrhage and thrombin infusion stimulate plasminogen activator inhibitor-1 but not tissue-type plasminogen activator production in the brain. The upregulation of plasminogen activator inhibitor-1 may be neuroprotective by limiting thrombin or other serine protease-induced toxicity.
Animals↗
Thrombin-receptor activation and thrombin-induced brain tolerance.
The authors previously found that pretreatment with a low dose of thrombin attenuates the brain edema induced by a large dose of thrombin or an intracerebral hemorrhage, and reduces infarct volume after focal cerebral ischemia (i.e., thrombin preconditioning). This study investigated whether thrombin preconditioning is caused by activation of the thrombin receptor, also called protease-activated receptor. In the in vivo studies, thrombin-induced brain tolerance was eliminated by RPPGF (Arg-Pro-Pro-Gly-Phe), a thrombin-receptor antagonist. Pretreatment with a thrombin-receptor agonist reduced the amount of edema induced by a large dose of thrombin infused into the ipsilateral basal ganglia 7 days later (81.3 +/- 0.7% vs. 82.6 +/- 0.8% in the control, P < 0.05). In the in vitro study, low doses of thrombin (1 or 2 U/mL) did not induce cell death. However, doses greater than 5 U/mL resulted in dose-dependent lactate dehydrogenase release (P < 0.01). Thrombin and thrombin receptor-activating peptide preconditioning reduced lactate dehydrogenase release induced by a high dose of thrombin (10 and 20 U/mL), whereas RPPGF blocked the effect of thrombin preconditioning in vitro. Western blots indicated that p44/42 mitogen-activated protein kinases were activated after thrombin preconditioning. Finally, inhibition of p44/42 mitogen-activated protein kinases activation by PD98059 abolished the thrombin-preconditioning effect. Results indicate that thrombin-induced brain tolerance is in part achieved through activation of the thrombin receptor. Activation of the thrombin receptor in the brain may be neuroprotective. The protective effect of thrombin preconditioning is achieved through the p44/42 mitogen-activated protein kinase signal-transduction pathway.
Animals↗
Hypoxia-inducible factor-1alpha accumulation in the brain after experimental intracerebral hemorrhage.
Hypoxia-inducible factor-1 (HIF-1), a transcription factor composed of HIF-1alpha and HIF-1beta protein subunits, has been implicated in cellular protection and cell death in cerebral ischemia. The extent to which HIF-1 plays a role in brain pathology during intracerebral hemorrhage (ICH) is unknown. This study determined whether HIF-1alpha is upregulated at different time points in a rat model of ICH and the role of thrombin and red blood cell lysis in upregulation. Recently, thrombin has been implicated as a nonhypoxic regulator of HIF-1alpha in cultured smooth-muscle cells. Male Sprague-Dawley rats received intracerebral infusions of saline, autologous whole blood, blood plus hirudin, thrombin, thrombin plus hirudin, or lysed erythrocytes. Rats were killed at different time points for Western blot analysis, immunohistochemistry, immunofluorescent double staining, and reverse transcription polymerase chain reaction measurements of HIF-1alpha. HIF-1alpha protein levels increased without changing HIF-1alpha messenger RNA levels after intracerebral infusions of blood, thrombin, and lysed erythrocytes. HIF-1alpha positive cells, which proved to be neurons, were found in the brain after ICH. Hirudin, a specific thrombin inhibitor, reduced HIF-1alpha upregulation in response to both thrombin and blood. This study demonstrates that perihematomal HIF-1alpha protein is upregulated after ICH. This phenomenon is an early response of brain parenchyma to the clot. Thrombin and erythrocyte lysate are involved in HIF-1alpha upregulation through reducing HIF-1alpha degradation.
Animals↗
Behavioral tests after intracerebral hemorrhage in the rat.
BACKGROUND AND PURPOSE: In humans, intracerebral hemorrhage (ICH) causes marked perihematomal edema formation and neurological deficits. A rat ICH model, involving infusion of autologous blood into the caudate, has been used extensively to study mechanisms of edema formation, but an examination of behavioral outcome would improve its preclinical utility and provide a more rigorous assessment of the pathological cascade of events over time. The purpose of this study was to use a battery of sensorimotor function tests to examine the neurological effects of ICH in the rat and to examine which components of the hematoma are involved in generating those effects. METHODS: The behavioral tests used were forelimb placing, preference for forelimb use for weight shifts during vertical exploration of a cylindrical enclosure, and a corner turn test. Rats were tested from day 1 to day 28 after injection of autologous whole blood; injection of blood plus hirudin (thrombin inhibitor), packed red blood cells, thrombin, or saline; or needle placement only. RESULTS: The battery of tests indicated that there were marked neurological deficits by day 1 after ICH, with progressive recovery of function over 4 weeks. The forelimb placing score paralleled changes in edema. Injection of thrombin caused and injection of hirudin reduced the ICH-induced neurological deficits. Injection of packed red blood cells, which causes delayed edema formation, induced delayed neurological deficits CONCLUSIONS: These tests allow continuous monitoring of neurological deficits after rat ICH and assessment of therapeutic interventions. The time course of the neurological deficit closely matched the time course of cerebral edema for both ICH and injection of blood components. There was marked recovery of function after ICH, which may be amenable to therapeutic manipulation.
Animals↗
Delayed argatroban treatment reduces edema in a rat model of intracerebral hemorrhage.
BACKGROUND AND PURPOSE: Studies indicate that thrombin plays an important role in intracerebral hemorrhage (ICH)-induced edema formation. Although thrombin is produced as the blood clots, it may be bound to fibrin and only gradually released from the clot. The time window for administration of a thrombin inhibitor to reduce ICH-induced edema is unknown. Whether this time window extends beyond the period when a thrombin inhibitor might exacerbate rebleeding is also unknown. METHODS: This study examines (1) whether argatroban, an inhibitor of both free and fibrin-bound thrombin, can reduce edema formation after intracerebral infusion of 100 micro L of blood in the rat; (2) the therapeutic time window for argatroban; and (3) whether argatroban promotes rebleeding in a model in which ICH was induced by intracerebral injection of collagenase. RESULTS: Intracerebral infusion of blood caused a marked increase in perihematomal water content. Intracerebral injection of argatroban 3 hours after ICH caused a significant reduction in edema measured at 48 hours (80.9+/-1.0% versus 82.6+/-0.8%; P<0.01). The systemic administration of high-dose argatroban (0.9 mg/h) starting 6 hours after ICH also significantly reduced edema (80.3+/-1.1% versus 82.0+/-1.3% in vehicle controls; P<0.05). There was no protection when the onset of argatroban administration was delayed to 24 hours after ICH or if a lower dose of argatroban (0.3 mg/h) was used. Argatroban did not increase collagenase-induced hematoma volume when given into the clot after 3 hours or given systemically at 6 hours. CONCLUSIONS: Our data suggest that argatroban may be an effective therapy for ICH-induced edema.
Animals↗