c-Jun N-terminal kinase pathway activation in human and experimental cerebral contusion.

The c-Jun N-terminal kinase (JNK) pathway is involved in cell stress and apoptosis. We tested the hypothesis that this pathway plays a role in traumatic brain injury (TBI) by assessing JNK activation in human brain tissues and in brains of mice subjected to controlled cortical impact brain injury. We also assessed the effects of specific inhibition of the JNK pathway by the cell-permeable JNK inhibitor peptide, D-JNKI1, on neurobehavioral function and posttraumatic cell loss in mice. The inhibitor was administered intraperitoneally 10 minutes after injury. The JNK pathway showed robust activation both in human contusion specimens and in injured cortex and hippocampi of TBI-injured mice, 1, 4, and 48 hours after injury. D-JNKI1 treatment significantly improved motor performance at 48 hours and 7 days after injury and reduced the contusion volume compared with saline treatment; the numbers of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells were significantly decreased in the hippocampi of injured mice 48 hours after treatment. Thus, because the JNK pathway is activated after human and experimental TBI and the inhibitor peptide D-JNKI1 affords significant neuroprotection and amelioration of neurobehavioral deficits after experimental TBI, therapeutic targeting of the JNK activation pathway may hold promise for future clinical applications.

Refractory intracranial hypertension and "second-tier" therapies in traumatic brain injury.

OBJECTIVE: To quantify the occurrence of high intracranial pressure (HICP) refractory to conventional medical therapy after traumatic brain injury (TBI) and to describe the use of more aggressive therapies (profound hyperventilation, barbiturates, decompressive craniectomy). DESIGN: Prospective study of 407 consecutive TBI patients SETTING: Three neurosurgical intensive care units (ICU). MEASUREMENTS AND RESULTS: Intracranial pressure (ICP) was studied during the first week after TBI; 153 patients had at least 1 day of ICP>20 mmHg. Early surgery was necessary for 221 cases, and standard medical therapy [sedation, mannitol, cerebrospinal fluid (CSF) withdrawal, PaCO2 30-35 mmHg] was used in 135 patients. Reinforced treatment (PaCO2 25-29 mmHg, induced arterial hypertension, muscle relaxants) was used in 179 cases (44%), and second-tier therapies in 80 (20%). Surgical decompression and/or barbiturates were used in 28 of 407 cases (7%). Six-month outcome was recorded in 367 cases using the Glasgow outcome scale (GOS). The outcome was favorable (good recovery or moderate disability) in 195 cases (53%) and unfavorable (all the other categories) in 172 (47%). HICP was associated with worse outcome. Outcome for cases who had received second-tier therapies was significantly worse (43% favorable at 6 months, p=0.03). CONCLUSIONS: HICP is frequent and is associated with worse outcome. ICP was controlled by early surgery and first-tier therapies in the majority of cases. Profound hyperventilation, surgical decompression and barbiturates were used in various combinations in a minority of cases. The indications for surgical decompression and/or barbiturates seem restricted to less than 10% of severe TBI.

Intracranial pressure monitoring in intensive care: clinical advantages of a computerized system over manual recording.

INTRODUCTION: The presence of intracranial hypertension (HICP) after traumatic brain injury (TBI) affects patient outcome. Intracranial pressure (ICP) data from electronic monitoring equipment are usually calculated and recorded hourly in the clinical chart by trained nurses. Little is known, however, about how precisely this method reflects the real patterns of ICP after severe TBI. In this study, we compared hourly manual recording with a validated and continuous computerized reference standard. METHODS: Thirty randomly selected patients with severe TBI and HICP admitted to the neuroscience intensive care unit (Policlinico University Hospital, Milan, Italy) were retrospectively studied. A 24-hour interval with ICP monitoring was randomly selected for each patient. The manually recorded data available for analysis covered 672 hours corresponding to 36,492 digital data points. The two methods were evaluated using the correlation coefficient and the Bland and Altman method. We used the proportion test to analyze differences in the number of episodes of HICP (ICP > 20 mm Hg) detected with the two methods and the paired t test to analyze differences in the percentage of time of HICP. RESULTS: There was good agreement between the digitally collected ICP and the manual recordings of the end-hour values. Bland and Altman analysis confirmed a mean difference between the two methods of 0.05 mm Hg (standard deviation 3.66); 96% of data were within the limits of agreement (+7.37 and -7.28). The average percentages of time of ICP greater than 20 mm Hg were 39% calculated from the digital measurements and 34% from the manual observations. From the continuous digital recording, we identified 351 episodes of ICP greater than 20 mm Hg lasting at least five minutes and 287 similar episodes lasting at least ten minutes. Conversely, end-hour ICP of greater than 20 mm Hg was observed in only 204 cases using manual recording methods. CONCLUSION: Although manually recorded end-hour ICP accurately reflected the computerized end-hour and mean hour values, the important omission of a number of episodes of high ICP, some of long duration, results in a clinical picture that is not accurate or informative of the true pattern of unstable ICP in patients with TBI.

Oxygen and carbon dioxide in the cerebral circulation during progression to brain death.

BACKGROUND: The authors propose that for a moderate reduction of perfusion during progressive irreversible ischemia, oxygen extraction increases to maintain aerobic metabolism, and arteriojugular oxygen difference (AJDo2) increases. Because of reduced carbon dioxide washout, venoarterial difference in carbon dioxide tension (DPco2) increases, with no change in the DPco2/AJDo2 ratio. With further reduction of cerebral perfusion, the aerobic metabolism will begin to decrease, AJDo2 will decrease while DPco2 will continue to increase, and the ratio will increase. When brain infarction develops, the metabolism will be abated, no oxygen will be consumed, and no carbon dioxide will be produced. METHODS: The authors studied 12 patients with acute cerebral damage that evolved to brain death and collected intermittent arterial and jugular blood samples. RESULTS: Four patterns were observed: (1) AJDo2 of 4.1 +/- 0.7 vol%, DPco2 of 6.5 +/- 1.9 mmHg, and a ratio of 1.55 +/- 0.3 with cerebral perfusion pressure of 62.5 +/- 13.4 mmHg; (2) a coupled increase of AJDo2 (5.8 +/- 0.7 vol%) and DPco2 (10.1 +/- 1.0 mmHg) with no change in ratio (1.92 +/- 0.14) and cerebral perfusion pressure (57.9 +/- 5.8 mmHg); (3) AJDo2 of 4.7 +/- 0.4 vol% with an increase in DPco2 (11.8 +/- 1 mmHg) and correspondingly higher ratio (2.7 +/- 0.2); in this phase, cerebral perfusion pressure was 39.7 +/- 10.5 mmHg; (4) immediately before diagnosis of brain death (cerebral perfusion pressure, 17 +/- 10.4 mmHg), there was a decrease of AJDo2 (1.1 +/- 0.1 vol%) and of DPco2 (5.3 +/- 0.6 mmHg) with a further ratio increase (5.1 +/- 0.8). CONCLUSIONS: Until compensatory mechanisms are effective, AJDo2 and DPco2 remain coupled. However, when the brain's ability to compensate for reduced oxygen delivery is exceeded, the ratio of DPco2 to AJDo2 starts to increase.

Arterio-jugular difference of oxygen content and outcome after head injury.

This study investigated AJDO2 (arterio-jugular difference of oxygen content) in a large sample of severely head-injured patients to identify its pattern during the first days after injury and to describe the relationship of AJDO2 with acute neurological severity and with outcome 6 mo after trauma. In 229 comatose head-injured patients, we monitored intracranial pressure, cerebral perfusion pressure, and AJDO2. Outcome was defined 6 mo after injury. Jugular hemoglobin oxygen saturation (SjO2) averaged 68%. The mean AJDO2 was 4.24 vol% (SD, 1.3 vol%). There were 80 measurements (4.6%) with SjO2 <55% and 304 (17.6%) with saturation >75%. AJDO2 was higher than 8.7 vol% in 8 measurements (0.4%) and was lower than 3.9 vol% in 718 (42%) measurements. AJDO2 was higher during the first tests and decreased steadily over the next few days. Cases with a favorable outcome had a higher mean AJDO2 (4.3 vol%; SD, 0.3 vol%) than patients with severe disability or vegetative status (3.8 vol%; SD, 1.3 vol%) and patients who died (3.6 vol%; SD, 1 vol%). This difference was significant (P < 0.001). We conclude that low levels of AJDO2 are correlated with a poor prognosis, whereas normal or high levels of AJDO2 are predictive of better results.

Metabolic, neurochemical, and histologic responses to vibrissa motor cortex stimulation after traumatic brain injury.

During the prolonged metabolic depression after traumatic brain injury (TBI), neurons are less able to respond metabolically to peripheral stimulation. Because this decreased responsiveness has been attributed to circuit dysfunction, the present study examined the metabolic, neurochemical, and histologic responses to direct cortical stimulation after lateral fluid percussion injury (LFPI). This study addressed three specific hypotheses: that neurons, if activated after LFPI, will increase their utilization of glucose even during a period of posttraumatic metabolic depression; that this secondary activation results in an increase in the production of lactate and a depletion of extracellular glucose; and that because cells are known to be in a state of energy crisis after traumatic brain injury, additional energy demands resulting from activation can result in their death. The results indicate that stimulating to levels eliciting a vibrissa twitch resulted in an increase in the cerebral metabolic rate for glucose (CMR(glc); micromol.100 g(-1).min(-1)) of 34% to 61% in the sham-operated, 1-hour LFPI, and 7-day LFPI groups. However, in the 1-day LFPI group, stimulation induced a 161% increase in CMR(glc) and a 35% decrease in metabolic activation volume. Extracellular lactate concentrations during stimulation significantly increased from 23% in the sham-injured group to 55% to 63% in the 1-day and 7-day LFPI groups. Extracellular glucose concentrations during stimulation remained unchanged in the sham-injured and 7-day LFPI groups, but decreased 17% in the 1-day LFPI group. The extent of cortical degeneration around the stimulating electrode in the 1-day LFPI group nearly doubled when compared with controls. These results indicate that at 1 day after LFPI, the cortex can respond to stimulation with an increase in anaerobic glycolysis; however, this metabolic response to levels eliciting a vibrissa response via direct cortical stimulation appears to constitute a secondary injury in the TBI brain.

Increased hippocampal CA3 vulnerability to low-level kainic acid following lateral fluid percussion injury.

This study was designed to determine whether a secondary increase in neuronal activity induced by a low dose of kainic acid (KA), a glutamate analogue, exacerbates the anatomical damage in hippocampal regions following a mild lateral fluid percussion (LFP) brain injury. KA (9 mg/kg) was injected intraperitoneally in LFP-injured rats (n = 16) 1 h post-trauma. The neuronal loss in the CA3, CA4, and hilar regions at 7 days was quantified by two-dimensional cell counts. Hippocampal activation 15 min following KA injection was assessed by measuring local glucose metabolic rates (lCMR(glc)). Following LFP + KA, the ipsilateral side exhibited a 62.7%, 75.7%, and 52.1% decrease in the number of CA3, CA4 and hilar neurons, respectively, compared to naive rats (n = 3). These CA3 and CA4 neuronal counts were also significantly decreased compared to LFP + saline (n = 5) and sham + KA (n = 9) groups. The median Racine Score, used to rate the severity of behavioral seizures, was 4 in LFP + KA and 2 in sham + KA groups (p < 0.015), suggesting a reduction in seizure threshold following injury. lCMRglc in CA3 following LFP + KA was 121.8 +/- 2.0 (mean +/- SE) ipsilaterally and 71.5 +/- 5.4 contralaterally (p < 0.0012). No changes were found in the BBB permeability as measured by [(14)C]aminoisobutyric acid in CA3, CA4, and hilar regions. We conclude that the presence of low-level KA 1 h after LFP dramatically increases the extent of hippocampal activation and induces a striking loss of ipsilateral CA3 and CA4 pyramidal neurons. Neuronal excitation during a time of cellular vulnerability may trigger or amplify the cycle of secondary damage in functionally impaired, but potentially viable, tissue.

Pyrexia in head-injured patients admitted to intensive care.

OBJECTIVES: (a) To quantify the occurrence of pyrexia during the first week after head injury; (b) to elucidate the relationships between pyrexia and neurological severity, length of stay in the ICU, intracranial hypertension, and cerebral perfusion pressure (CPP); and (c) to describe the effects of antipyretic therapy on temperature, intracranial pressure (ICP) and CPP. DESIGN AND SETTING: Multicenter retrospective observational study in three ICUs in the Milan area. PATIENTS: 110 patients with traumatic brain injury. MEASUREMENTS AND RESULTS: Eighty patients suffered pyrexia, defined as an external temperature higher than 38 degrees C or internal temperature higher than 38.4 degrees C. Occurrence and duration of pyrexia were associated with the degree of neurological impairment and with prolonged ICU stay. In patients with normal perimesencephalic cisterns the episodes of increased ICP were more frequent in febrile cases. Various antipyretic therapies were used in 66 patients. Pharmacological treatment was slightly effective (mean temperature reduction 0.58+/-0.7 degrees C) but caused a significant drop in CPP (6.5+/-12.5 mmHg). CONCLUSIONS: Pyrexia is extremely frequent in the acute phase after head injury. Its incidence is higher in more severe cases and is correlated with a longer ICU stay. It may affect ICP, but its contribution is difficult to assess when other major causes of increased intracranial volume are present. Antipyretic therapy is poorly effective for controlling body temperature and may be deleterious for CPP.