Clinical factors associated with unexpected critical care management and prolonged hospitalization after elective cervical spine surgery.

OBJECTIVES: To determine preoperative and operative factors associated with the need for unanticipated critical care management and prolonged hospitalization after cervical spine surgery. DESIGN: Retrospective, case controlled study with data collection over 5 yrs. SETTING: Intensive care unit at a Veterans Affairs hospital. PATIENTS: A total of 109 patients who underwent elective cervical decompression for degenerative disease. INTERVENTIONS: Anterior or posterior cervical spine surgery. MEASUREMENTS AND MAIN RESULTS: Data were recorded with regard to pre- and postoperative neurologic function, extent of surgery, length and cost of hospitalization and critical care, and preoperative co-morbidities. Of 109 patients, 16 (15%) required critical care management in the early postoperative phase (group I). The remainder (n = 93) represented group II. Group I had an average hospital stay of 18.5 days as compared with 6.1 days for group II (p <.001) and a cost difference of approximately $26,000. The incidence of preexisting myelopathy (69%) and the extent of decompression (2.38 levels) were greater in group I than group II (27%, p <.005; 1.67 levels, p <.01). The presence of pulmonary disease (p <.03), hypertension (p <.02), cardiovascular disease (p <.05), and diabetes mellitus (p <.002) all were associated with the need for critical care management and longer hospitalization. CONCLUSIONS: In those patients undergoing decompressive cervical surgery for degenerative disease, the following factors were linked to the need for unanticipated, postoperative critical care and longer hospitalization: multilevel decompression, preexisting myelopathy, pulmonary disease, cardiovascular disease, hypertension, and diabetes mellitus.

Neuronal, but not microglial, accumulation of extravasated serum proteins after intracerebral hemolysate exposure is accompanied by cytochrome c release and DNA fragmentation.

Vasogenic edema after oxidative injury has been accompanied by intracellular accumulation of serum proteins and nuclear damage. This study sought to determine whether serum protein accumulation, along with other markers of brain injury, was present after exposure to intracerebral hemolysate, an oxidant model of intracerebral hemorrhage (ICH). Saline (n = 24) or hemolysate (n = 30) was injected into the caudate-putamen of adult Sprague-Dawley rats. Compared with saline, hemolysate deposition was associated with intracellular accumulation of serum proteins as evidenced by Evans blue uptake in neurons and microglia at 4 and 24 hours. Intracellular Evans blue colocalized with DNA fragmentation detected by nick end-labeling and whose presence was confirmed by gel electrophoresis. Immunoblots of cytosolic fractions confirmed cytochrome c release. Immunostaining established colocalization of cytosolic cytochrome c and intracellular Evans blue at 4 hours. At 24 hours, cytosolic cytochrome c was evident in astrocytes surrounding Evans blue-positive cells. Immunoblot analysis and immunostaining revealed HSP70 induction at 24 hours in regions adjacent to intracellular serum accumulation. Neuronal accumulation of extravasated serum proteins in this model of ICH was associated with cytochrome c release, DNA fragmentation, and cell death. Stress protein induction in adjacent regions suggested that vasogenic edema might have exacerbated cellular dysfunction and cell death after ICH.

Increased cytochrome c-mediated DNA fragmentation and cell death in manganese-superoxide dismutase-deficient mice after exposure to subarachnoid hemolysate.

BACKGROUND AND PURPOSE: We sought to investigate the mechanisms for oxidative injury caused by subarachnoid hemolysate, a pro-oxidant. METHODS: Injection of 50 microL of subarachnoid hemolysate or saline was performed in CD1 mice (n=75), mutant mice deficient in Mn-superoxide dismutase (Sod2+/-; n=23), and their wild-type littermates (n=23). Subcellular location of cytochrome c was studied by immunocytochemistry, immunofluorescence, and immunoblotting of cellular fractions. DNA fragmentation was assessed though DNA laddering and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL). Cell death was examined through basic histology. RESULTS: Cytochrome c immunoreactivity was present in the cytosol of neurons at 2 hours after hemolysate injection and increased by 4 hours compared with saline-injected animals (P:<0.02). Cytosolic cytochrome c was more abundant in Sod2+/- mutants. DNA fragmentation was evident at 24 hours, but not 4 hours, after hemolysate injection as determined by DNA laddering and TUNEL staining (P:<0.02). DNA fragmentation colocalized to cells with cytosolic cytochrome c and iron. In Sod2+/- mutants, the extent of fragmentation was increased as determined by TUNEL staining (52% increase; P:<0.02) and DNA laddering (optical density=0.819 versus 0.391; P:<0.01). Cell death was evident on basic histology as early as 4 hours after hemolysate injection. No cell death was evident in controls. In Sod2+/- mutants, cell death was increased by 51% compared with wild-type littermates (P:<0.05). CONCLUSIONS: These results demonstrate that subarachnoid blood products are associated with the presence of cytochrome c in the cytosol and subsequent cell death in neurons. It appears that Mn-superoxide dismutase plays a role in preventing cell death after exposure to subarachnoid blood products.

Infratentorial traumatic brain hemorrhage: may outcome be predicted by initial GCS?

BACKGROUND: Overall prognosis of nonpenetrating traumatic brain hemorrhage may be predicted by neurologic function days after insult. The relationship between immediate function and outcome has not been examined for infratentorial traumatic brain hemmorhage (iTBH) identified on computed tomographic (CT) scan. Given the severity of brain stem injury, it is conceivable that immediate function may be predictive. METHODS: A retrospective review of 1,500 brain injuries occurring at our institution identified 18 patients (1.2%) with iTBH on CT scan (eight brain stem, five cerebellum, five both). Demographics, supratentorial injuries, and outcome at 6 months (Glasgow Outcome Scale) were recorded. RESULTS: Initial Glasgow Coma Scale (GCS) in 11 patients was less than 5 (group I). Seven patients had GCS scores greater than or equal to 6 (group II). Nine patients in group I either died or were vegetative. In group II, one died; none were vegetative (p < 0.02). Regression analysis demonstrated a strong correlation between initial GCS and Glasgow Outcome Scale scores at 6 months for all patients (p < 0.001). CONCLUSION: We conclude that initial GCS score may be predictive of long-term outcome in patients with CT scan evidence of iTBH-a relationship to be explored further for prognostic information.

Cell death after exposure to subarachnoid hemolysate correlates inversely with expression of CuZn-superoxide dismutase.

BACKGROUND AND PURPOSE: Subarachnoid hemolysate (SAH) has been associated with oxidative brain injury, cell death, and apoptosis. We hypothesized that over-expression of CuZn-superoxide dismutase (CuZn-SOD) would protect against injury after SAH, whereas reduction of its expression would exacerbate injury. METHODS: Saline (n=16) or hemolysate (n=50) was injected into transgenic mice overexpressing CuZn-SOD (SOD1-Tg), CuZn-SOD heterozygous knockout mutants (SOD1+/-), and wild-type littermates (Wt). Mice were killed at 24 hours. Stress gene induction was evaluated by immunocytochemistry and Western blotting for hemeoxygenase-1 and heat shock protein 70. Apoptosis was evaluated by 3'-OH nick end-labeling and DNA gel electrophoresis. Cell death was quantified through histological assessment after cresyl violet staining. RESULTS: Histological assessment demonstrated neocortical cell death in regions adjacent to the blood injection. Overall cell death was reduced 43% in SOD1-Tg mutants (n=6) compared with Wt littermates (n=6; P<0.02). In contrast, cell death was increased >40% in SOD1+/- mutants (n=6; P<0.05). Both hemeoxygenase-1 and heat shock protein 70 were induced after SAH. Apoptosis was also present after SAH, as evidenced by 3'-OH end-labeling and DNA laddering. However, the degree of stress gene induction and apoptosis did not vary between Wt, SOD1-Tg, and SOD1+/- mice. CONCLUSIONS: The extent of CuZn-SOD expression in the cytosol correlates with cell death after exposure to SAH in a manner separate from apoptosis. Overexpression of CuZn-SOD may potentially be an avenue for therapeutic intervention.

Subarachnoid hemolysate produces DNA fragmentation in a pattern similar to apoptosis in mouse brain.

Stroke and traumatic brain/spinal cord injuries are often associated with hemorrhage. Despite the relative frequency of hemorrhage in the central nervous system (CNS), little is known about what role blood and hemoglobin (Hb) play in mediating cellular injury. Since Hb and hemolysate have been associated with generation of oxidative stress and cell injury, we examined whether apoptosis was present after cortical exposure to subarachnoid hemolysate. Subarachnoid hemorrhage (SAH) was induced in CD-1 mice (n=25) by injection of 50 microl of autologous hemolysate over the right parietal cortex. Saline-injected mice (n=13) were used as controls. Subjects were sacrificed at 24 h. Transcardiac perfusion fixation was performed on a subgroup of hemolysate- (n=15) and saline-injected (n=9) animals. Sections were stained for DNA fragmentation using the terminal deoxyuridine nick end-labeling (TUNEL) method and also immunostained for the hemeoxygenase-1 (HO-1) protein to assess blood distribution. In the remaining animals (n=6 SAH, n=4 saline), DNA was extracted and precipitated from 40 mg of tissue and subjected to electrophoresis on a 1.5% agarose gel. DNA fragmentation was evident on TUNEL staining in 10/15 subjects injected with hemolysate as compared to 0/9 subjects injected with saline (p<0.01, Fisher exact test). TUNEL-positive cells were most abundant closest to the site of cortical SAH, as evidenced by HO-1 immunoreactivity. TUNEL-positive cells were also seen remotely in the hippocampus and basal forebrain. The presence of apoptosis was suggested by DNA laddering on electrophoresis in the hemolysate-injected subjects (4/6 animals). No laddering was evident in saline-injected subjects (n=4). These results provide evidence that the presence of subarachnoid blood products is associated with DNA fragmentation and apoptotic cell death.

Heme oxygenase-1 and heat shock protein 70 induction in glia and neurons throughout rat brain after experimental intracerebral hemorrhage.

OBJECTIVE: Current experimental evidence demonstrates the development of ischemic regions adjacent to and spatially remote from an intracerebral hematoma. The cause of this ischemia is uncertain. Because ischemia is a known inducer of stress genes, we investigated the induction of two stress proteins, heme oxygenase (HO)-1 and heat shock protein (Hsp) 70, after intracerebral hemorrhage in the rat. METHODS: Immunocytochemistry for HO-1, Hsp70, and HO-2, the constitutive isoform of the HO enzyme, was performed 1, 2, and 4 days after striatal injection of saline, whole blood, or lysed blood. Immunocytochemistry for HO-1, HO-2, and Hsp70 was also performed 1 day after cortical injection of saline, whole blood, or lysed blood. RESULTS: After striatal injection of lysed and whole blood, the HO-1 protein was induced in glia throughout the hemisphere ipsilateral to the hematoma, and HO-1 immunoreactivity persisted for at least 4 days. After cortical injection of lysed and whole blood, HO-1 was induced in glia throughout the neocortex. Neuronal induction of HO-1 was also observed after cortical injection of lysed blood but not whole blood or saline. After striatal injection of lysed blood, Hsp70 was induced in glia surrounding the hematoma and in neurons from the neocortex overlying the hematoma and the striatum adjacent to the hematoma. After cortical injection of lysed blood, Hsp70 was induced in neurons throughout the neocortex and hippocampus bilaterally. In contrast, after whole blood and saline injection into cortex, Hsp70 induction was observed only in scattered neurons surrounding the hematoma cavity. CONCLUSION: Our results demonstrate that blood in the brain parenchyma induces the HO-1 stress protein but does not significantly alter HO-2 immunostaining. Our results also demonstrate that lysed blood induces Hsp70 in multiple regions of the brain and that the stress response of the brain differs depending on whether lysed blood is injected into the cortex or striatum. These results suggest that blood lysis may play an unforeseen role in the stress response of the brain to intracerebral hemorrhage.

Monitoring in traumatic brain injury.

In the past several years, improvements in technology have advanced the monitoring capabilities for patients with TBI. The primary goal of monitoring the patient with TBI is to prevent secondary insults to the brain, primarily cerebral ischemia. Cerebral ischemia may occur early and without clinical correlation and portends a poor outcome. Measurement of ICP is the cornerstone of monitoring in the patient with TBI. Monitoring of ICP provides a measurement of CPP and a rough estimation of CBF. However, with alterations in pressure autoregulation, measurement of CPP does not always allow for determination of CBF. To circumvent this problem, direct measurements of CBF can be performed using clearance techniques (133Xe, N2O, Xe-CT) or invasive monitoring techniques (LDF, TDF, NIRS). Although direct and quantitative, clearance techniques do not allow for continuous monitoring. Invasive CBF monitoring techniques are new, and artifactual results can be problematic. The techniques of jugular venous saturation monitoring and TCD are well established and are powerful adjuncts to ICP monitoring. They allow the clinician to monitor cerebral oxygen extraction and blood flow velocity, respectively, for any given CPP. Use of TCD may predict posttraumatic vasospasm before clinical sequelae. Jugular venous saturation monitoring may detect clinically occult episodes of cerebral ischemia and increased oxygen extraction. Jugular venous saturation monitoring optimizes the use of hyperventilation in the treatment of intracranial hypertension. Although PET and SPECT scanning allow direct measurement of CMRO2, these techniques have limited application currently. Similarly, microdialysis is in its infancy but has demonstrated great promise for metabolic monitoring. EEG and SEP are excellent adjuncts to the monitoring arsenal and provide immediate information on current brain function. With improvements in electronic telemetry, functional monitoring by EEG or SEP may become an important part of routine monitoring in TBI.

Focal hyperexpression of hemeoxygenase-1 protein and messenger RNA in rat brain caused by cellular stress following subarachnoid injections of lysed blood.

Induction of the hemeoxygenase-1 (ho-1) stress gene is of importance for rapid heme metabolism and protection against oxidative injury in vitro and in vivo. Although ho-1 expression is observed in glia following exposure to whole blood and oxyhemoglobin, expression is mild, and other stress genes are not induced simultaneously in this setting. Hemeoxygenase-1 can be induced by several other physiological stresses in addition to heme. In the brain, ho-1 induction has been observed in the penumbra following focal cerebral ischemia. Because lysed blood is a spasmogen, the authors studied focal hyperexpression of the ho-1 gene after injection of lysed blood, whole blood, or saline into the cisterna magna of adult rats. Immunocytochemical analysis of HO-1 was performed at 1, 2, 3, and 4 days after the injections. Because the 70-kD inducible heat shock protein (HSP70) is induced by cellular stress, alternate sections were immunostained for HSP70 to assess whether focal hyperexpression was a stress phenomenon. An oligonucleotide probe was also used for in situ hybridization to demonstrate that ho-1 messenger (m)RNA was present. Focal HO-1 immunostained areas were observed after lysed blood injection only and were located mainly in the basal cortex and cerebellar hemisphere, although focal hyperexpression was also found in many other regions. The intensity of staining and the number of regions were maximum at 1 day. Double-labeled immunofluorescence revealed that many HO-1-immunoreactive cells were microglia. The HSP70 immunostaining of adjacent sections from the same animals demonstrated focal regions of immunoreactivity whose topography corresponded exactly with the topography of the HO-1-immunostained areas. Conventional histology in regions of HO-1 hyperexpression was often normal. In situ hybridization using the same oligonucleotide demonstrated that ho-1 mRNA was induced in focal areas of forebrain and in large regions of cerebellum within 6 hours of injection. These results demonstrate that focal hyperexpression of the ho-1 stress gene occurs after lysed blood injection and appears to be an indicator of cellular stress and injury in regions in which infarction does not occur. These results also suggest that cellular injury that occurs after injection of lysed blood may go undetected using conventional histology. Although direct heme metabolism was not investigated, our results indicate that rapid metabolism of heme, both intracellular and extracellular, may prove to be beneficial after subarachnoid hemorrhage.

Diagnosis and treatment of iatrogenic spinal accessory nerve injury.

Although iatrogenic injury to the spinal accessory nerve in the posterior cervical triangle is a well-described phenomenon, diagnosis can prove difficult and is often incorrect or delayed. We describe a series of six men and three women (mean age 40 years; range, 20 to 52 years) with iatrogenic spinal accessory nerve injuries. Injuries resulted from lymph node biopsies in the posterior cervical triangle in eight patients and posterior foss surgery in one. Eight patients lost the ability to abduct their arm but could still shrug their shoulder, a pattern that resulted in an incorrect initial diagnosis in five patients. The average delay from injury to referral was 8 months. Seven patients underwent nerve exploration an average of 9.7 months after injury. Five had transected nerves that could be repaired; three of these patients required a nerve graft. Pain was greatly relieved in the five patients who had severe pain before surgery, and weakened shoulder abduction improved in four of six patients. Nerve exploration should be considered when the patient's clinical exam does not improve within 3 months of injury. Nerve repair frequently reduces pain and improves shoulder abduction, even 12 months after injury.

Induction of HSP70 in rat brain following subarachnoid hemorrhage produced by endovascular perforation.

Current experimental research on subarachnoid hemorrhage (SAH) has been limited by the lack of a small-animal model that physiologically resembles SAH and consistently demonstrates acute and delayed cellular injury. Recently, a model for inducing SAH by endovascular perforation of the internal carotid artery has been developed in the rat. This model physiologically resembles SAH. However, little histological data detailing cellular injury after SAH are available in this or other models. Using immunocytochemistry, the authors investigated the induction of the 70-kD heat shock protein, HSP70, a sensitive marker for cellular stress or injury in the brain, 1 and 5 days following endovascular SAH. The authors also used the conventional histological techniques of cresyl violet and hematoxylin and eosin staining to investigate cellular damage 1 and 5 days after the endovascular SAH. One day following the SAH, HSP70 was induced in all six animals examined in multiple anatomical regions, including the basal forebrain, thalamus, neocortex, striatum, and hippocampus. This HSP70 induction was observed in multiple vascular distributions bilaterally. Immunostaining with HSP70 occurred primarily in neurons but also was observed in glia and endothelium. Five days after the SAH, a similar but more intense pattern of HSP70 immunostaining was observed in all eight animals examined. Specifically, HSP70 immunoreactivity was observed in at least one region of the hippocampus more often at 5 days (six of eight animals) than at 1 day (one of six animals, p < 0.05, one-tailed Fisher's exact test). No HSP70 immunostaining was observed in control animals at 1 day or at 5 days. Conventional histology demonstrated foci of ischemic neuronal damage and cellular necrosis; however, HSP70 immunocytochemistry detailed cellular injury far better than conventional histology in all animals tested at both 1 day and 5 days. Our results demonstrate that HSP70 is induced in multiple regions and cell types 1 day and 5 days following endovascular SAH. Because ischemia is a known inducer of stress genes, the authors propose that acute and delayed ischemia are the processes responsible for the induction of HSP70 that was observed at 1 day and 5 days, respectively. Investigation of HSP70 induction following endovascular SAH may also serve as the basis for a new, inexpensive animal model to assess potential therapeutic interventions.