C. J. J. Avezaat

Brain oxygen tension in severe head injury.

OBJECTIVE Ensuring adequate cerebral oxygenation and perfusion is of fundamental importance in the treatment of patients with acute cerebral disorders. Online continuous monitoring of brain oxygenation is possible with a parenchymal microelectrode that measures local brain oxygen tension. The ultimate question is whether therapeutic approaches can be targeted on the basis of such monitoring. Before this question can be addressed, the technique requires validation in the clinical setting. The frequency of occurrence of low values and its relation to outcome need to be established. METHODS One hundred one comatose head-injured patients (Glasgow Coma Scale score < or = 8) were studied. Local brain oxygen tension probes were inserted in an undamaged part of the frontal region. Patients were treated in conformance with the European Brain Injury Consortium guidelines. Outcome at 6 months was determined by Glasgow Outcome Scale score. RESULTS Early brain tissue hypoxia was frequently observed, despite aggressive treatment for intracranial pressure and cerebral perfusion pressure. Values lower than 15 mm Hg, for a duration longer than 30 minutes, were observed in 57 patients. Values lower than 10 mm Hg in 42 patients, and lower than 5 mm Hg in 22 patients, were observed during the first 24 hours. Depth and duration of tissue hypoxia were related to outcome and proved to be an independent predictor of unfavorable outcome and death. CONCLUSION Monitoring the partial oxygen pressure of local brain tissue is a safe and reliable method for regulating cerebral oxygenation. Because brain tissue hypoxia occurs frequently and is significantly related to poor outcome, future efforts should be aimed at the treatment of brain tissue hypoxia. The effects of such brain hypoxia-targeted treatment need to be established in a multicenter study.

Continuous monitoring of partial pressure of brain tissue oxygen in patients with severe head injury

ISCHEMIA IS ONE of the major factors causing secondary brain damage after severe head injury. We have investigated the value of continuous partial pressure of brain tissue oxygen (P br O2) monitoring as a parameter for cerebral oxygenation in 22 patients with severe head injury(Glasgow Coma Scale score, <=8). Jugular bulb oxygenation, intracranial pressure, and cerebral perfusion pressure were simultaneously recorded. O 2 and CO 2 reactivity tests were performed daily to evaluate oxygen autoregulatory mechanisms. P br O2 monitoring was started an average of 7.0 hours after trauma with a mean duration of 74.3 hours. No complications were seen, and the calibration of the catheters after measurement showed a zero drift of 1.2 ± 0.8 mm Hg and a sensitivity drift of 9.7 ± 5.3%. In 86% of the patients, P br O2 was<20 mm Hg in the acute phase. Mean P br O2 significantly increased during the first 24 hours after injury. Two distinct patterns of change of Pbr O2 over time were noted. The first pattern was characterized by normal stable levels after 24 hours, and the second was characterized by transiently elevated levels of P br O2 during the second and third days. P br O2 values <=5 mm Hg within 24 hours after trauma negatively correlated with outcome. O 2 reactivity was significantly lower in patients with good outcomes. CO 2 reactivity showed no constant pattern of change over time and was not correlated with outcome. Increased hyperventilation was shown to decrease P br O2 in some patients. Accurate detection of the moment of cerebral death was possible on the basis of the P br O2 measurements. The correlation between P br O2 and other parameters, such as intracranial pressure and cerebral perfusion pressure, was weak. We conclude that Pbr O2 monitoring is a safe and clinically applicable method in patients with severe head injury. The early occurrence of ischemia after head injury can be monitored on a continuous basis. Deficiency of oxygen autoregulatory mechanisms can be demonstrated, and their occurrence is inversely related to outcome. For practical clinical use, the method seemed to be superior to jugular oximetry.Ischemia is one of the major factors causing secondary brain damage after severe head injury. We have investigated the value of continuous partial pressure of brain tissue oxygen (PbrO2) monitoring as a parameter for cerebral oxygenation in 22 patients with severe head injury (Glasgow Coma Scale score, < or = 8). Jugular bulb oxygenation, intracranial pressure, and cerebral perfusion pressure were simultaneously recorded. O2 and CO2 reactivity tests were performed daily to evaluate oxygen autoregulatory mechanisms. PbrO2 monitoring was started an average of 7.0 hours after trauma with a mean duration of 74.3 hours. No complications were seen, and the calibration of the catheters after measurement showed a zero drift of 1.2 +/- 0.8 mm Hg and a sensitivity drift of 9.7 +/- 5.3%. In 86% of patients, PbrO2 was < 20 mm Hg in the acute phase. Mean PbrO2 significantly increased during the first 24 hours after injury. Two distinct patterns of change of PbrO2 over time were noted. The first pattern was characterized by normal stable levels after 24 hours, and the second was characterized by transiently elevated levels of PbrO2 during the second and third days. PbrO2 values < or = 5 mm Hg within 24 hours after trauma negatively correlated with outcome. O2 reactivity was significantly lower in patients with good outcomes. CO2 reactivity showed no constant pattern of change over time and was not correlated with outcome. Increased hyperventilation was shown to decrease PbrO2 in some patients. Accurate detection of the moment of cerebral death was possible on the basis of the PbrO2 measurements. The correlation between PbrO2 and other parameters, such as intracranial pressure and cerebral perfusion pressure, was weak. We conclude that PbrO2 monitoring is a safe and clinically applicable method in patients with severe head injury. The early occurrence of ischemia after head injury can be monitored on a continuous basis. Deficiency of oxygen autoregulatory mechanisms can be demonstrated, and their occurrence is inversely related to outcome. For practical clinical use, the method seemed to be superior to jugular oximetry.

Cerebrospinal fluid pulse pressure and intracranial volume-pressure relationships.

In six anaesthetised and ventilated dogs the CSF pulse pressure was compared with the volume-pressure response (VPR) during continuous inflation of an extradural balloon. Both pulse pressure and VPR increased linearly with the ventricular fluid pressure (VFP) up to a mean VFP of 60 mmHg. At this pressure a breakpoint occurred above which the CSF pulse pressure showed a steeper linear increase, while the VPR remained constant. It is suggested that the breakpoint is related to failure of autoregulation, and that in non-autoregulating patients the CSF pulse pressure is a better parameter of the clinical state than the VPR.

Risk factors for infections related to external ventricular drainage

SummaryBackground. External ventricular drainage (EVD) is frequently used in neurosurgery for cerebrospinal fluid (CSF) drainage in patients with raised intracranial pressure. The major complication of this procedure is an EVD-related infection, i.e., meningitis or ventriculitis. The purpose of the present retrospective single centre study is to assess the possible causes of these infections.Patients and methods. Two hundred and twenty-eight patients were included in the period from January 1993 until April 2005. Patient and disease demographics, as well as EVD data, and the occurrence of infection were reviewed, compared, and included in a risk-analysis study.Results. The population’s mean age was 56 ± 15 years and the sexes were equally distributed. Most frequently, the indication for EVD was hydrocephalus due to intraventricular haemorrhage (48.2%). An infection was documented in 23.2% of all patients. Duration of EVD drainage appeared to be a risk factor for infection (>11 days: OR 4.1; 95% CI 1.8–9.2, p = 0.001). CSF sampling frequency was also a significant risk-factor (no sampling: OR 0.2, 95% CI 0.2–0.5, p = 0.003).Conclusions. We found a relatively high percentage of EVD-related infections. After multivariate analysis there appears to be a relation with duration of drainage and frequent CSF sampling. As a result, a new EVD protocol is proposed in our institution that we believe will decrease the number of EVD-related infections to a minimum.

Safety and efficacy of frameless and frame-based intracranial biopsy techniques

SummaryBackground. Frameless stereotaxy or neuronavigation has evolved into a feasible technology to acquire intracaranial biopsies with good accuracy and little mortality. However, few studies have evaluated the diagnostic yield, morbidity, and mortality of this technique as compared to the established standard of frame-based stereotactic brain biopsy. We report our experience of a large number of procedures performed with one or other technique. Patients and methods. We retrospectively assessed 465 consecutive biopsies done over a ten-year time span; Data from 391 biopsies (227 frame-based and 164 frameless) were available for analysis. Patient demographics, peri-operative characteristics, and histological diagnosis were reviewed and then information was analysed to identify factors associated with the biopsy not yielding a diagnosis and of it being followed by death. Results. On average, nine tissue samples were taken with either stereotaxy technique. Overall, the biopsy led to a diagnosis on 89.4% of occasions. No differences were found between the two biopsy procedures. In a multiple regression analysis, it was found that left-sided lesions were less likely to result in a non-diagnostic tissue sample (p = 0.023), and cerebellar lesions showed a high risk of negative histology (p = 0.006). Postoperative complications were seen after 12.1% of biopsies, including 15 symptomatic haemorrhages (3.8%). There was not a difference between the rates of complication after either a frame-based or a frameless biopsy. Overall, peri-operative complications (p = 0.030) and deep-seated lesions (p = 0.060) increased the risk of biopsy-related death. Symptomatic haemorrhages resulting in death (1.5% of all biopsies) were more frequently seen after biopsy of a fronto-temporally located lesion (p = 0.007) and in patients with a histologically confirmed lymphoma (p = 0.039). Conclusions. The diagnostic yield, complication rates, and biopsy-related mortality did not differ between a frameless biopsy technique and the established frame-based technique. The site of the lesion and the occurrence of a peri-operative complication were associated with the likelihood of failure to achieve a diagnosis and with death after biopsy. We believe that using intraoperative frozen section or cytologic smear histology is essential during a stereotactic biopsy in order to increase the diagnostic yield and to limit the number of biopsy specimens that need to be taken.

CO2 reactivity and brain oxygen pressure monitoring in severe head injury.

ObjectiveTo investigate the effect of hyperventilation on cerebral oxygenation after severe head injury. DesignA prospective, observational study. SettingNeurointensive care unit at a university hospital. PatientsA total of 90 patients with severe head injury (Glasgow Coma Scale score ≤8), in whom continuous monitoring of brain tissue oxygen pressure (Pbro2) was performed as a measure of cerebral oxygenation. InterventionsArterial Pco2 was decreased each day over a 5-day period for 15 mins by increasing minute volume on the ventilator setting to 20% above baseline. Arterial blood gas analysis was performed before and after changing ventilator settings. Multimodality monitoring, including Pbro2, was performed in all patients. Absolute and relative Pbro2/Paco2 reactivity was calculated. Outcome at 6 months was evaluated according to the Glasgow Outcome Scale. Measurements and Main Results:Effective hyperventilation, defined by a decrease of Paco2 ≥2 torr (0.27 kPa), was obtained in 218 (84%) of 272 tests performed. Baseline Paco2 averaged 32.3 ± 4.5 torr (4.31 ± 0.60 kPa). Average reduction in Paco2 was 3.8 ± 1.7 torr (0.51 ± 0.23 kPa). Pbro2 decreased by 2.8 ± 3.7 torr (0.37 ± 0.49 kPa;p < .001) from a baseline value of 26.5 ± 11.6 torr (3.53 ± 1.55 kPa). Pbro2/Paco2 reactivity was low on day 1 (0.8 ± 2.3 torr [0.11 ± 0.31 kPa]), increasing on subsequent days to 6.1 ± 4.4 torr (0.81 ± 0.59 kPa) on day 5. Pbro2/Paco2 reactivity on days 1 and 2 was not related to outcome. In later phases in patients with unfavorable outcome, relative reactivity was increased more markedly, reaching statistical significance on day 5. ConclusionsIncreased hyperventilation causes a significant reduction in Pbro2, providing further evidence for possible increased risk of secondary ischemic damage during hyperventilation. The low Pbro2/Paco2 reactivity on day 1 indicates the decreased responsiveness of cerebral microvascular vessels to Paco2 changes, caused by generalized vascular narrowing. The increasing Pbro2/Paco2 reactivity from days 2 to 5 suggests that the risk of compromising cerebral oxygenation by hyperventilation may increase over time.

Treatment of relapsed malignant glioma with an adenoviral vector containing the herpes simplex thymidine kinase gene followed by ganciclovir.

Between November 1998 and December 2001, we treated 14 patients with advanced recurrent high-grade gliomas with a total dose of 4.6 x 10(8), 4.6 x 10(9), 4.6 x 10(10), or 4.6 x 10(11) viral particles (VP) of a replication-incompetent adenoviral vector harboring the herpes simplex virus thymidine kinase gene driven by the adenoviral major late promoter (IG.Ad.MLPI.TK), followed by ganciclovir (GCV) treatment. The VP-to-infectious-unit ratio was 40. The vector was administered by 50 intraoperative wound-bed injections of 0.2 ml each (total volume 10 ml). The studys primary objective was to determine the safety of this treatment and establish the maximum tolerated dose (MTD). Injection of all doses of IG.Ad.MLPI.TK followed by GCV was safely tolerated and MTD was not reached. All patients had recurrence or progression of the tumor 1-24 months (median 3.5 months) after gene therapy. The overall median survival was 4 months. Four patients survived longer than 1 year following gene therapy. One patient is still alive, with histologically confirmed progression of the tumor, 29 months after treatment. Ten patients died within 8 months of treatment, all from progression of the tumor. In 5 patients residual and measurable tumor was visible on the direct (<48 h) postoperative MRI. No objective radiological response was documented on subsequent MRI. None of the patients came to autopsy. In conclusion, the administration of 4.6 x 10(11) VP of IG.Ad.MLPI.TK by 50 injections into the wound bed following resection of recurrent malignant glioma, followed by GCV treatment, was well tolerated.

Cytogenetic, Molecular Genetic and Pathological Analyses in 126 Meningiomas

Abstract. In a series of 126 meningiomas, tumor and patient charactersitics were investigated and statistically analyzed. A combined cytogenetic and molecular genetic approach was used to study chromosomal abnormalities and loss of markers on chromosome 22q. This apprach was successfully applied to 93 meningiomas. In 66 cases, complete or partial loss of chromosome 22 was observed and in at least 12 of them this chromosome was involved in structural aberrations. In addition to chromosome 22 changes, chromosomes 1, 6, 11, 13, 14, 18, 19, X, and Y were also frequently involved in structural and numerical aberrations. Statistical analysis revealed a significant association between the number of choromosomal abnormalities and tumor grade. Complex karyotypes predominated in the group of grade II/III meningiomas. Furthermore, other variables showed statistically (or marginally statistically) significant differences. Meningiomas from the convexity were more ofthen grade II/III, displayed predominantly (partial) loss of chromosome 22 and had complex karyotypes more often. These fetures were frequently found in meningiomas from males. Base meningiomas, on the other hand, occurred more often in females; they were usually grade I, showed loss of (parts of) chromosome 22 less often and displayed fewer additional chromosomal abnormalities.

Brain tissue oxygen response in severe traumatic brain injury.

Summary¶Objective. To investigate clinical relevance and prognostic value of brain tissue oxygen response (TOR: response of brain tissue pO2 to changes in arterial pO2) in traumatic brain injury (TBI). Patients and methods. In a prospective cohort study TOR was investigated in 41 patients with severe TBI (Glasgow Coma Score ≤8) in whom continuous monitoring of brain tissue oxygen pressure (PbrO2) was performed.TOR was investigated each day over a five day period for 15 minutes by increasing FiO2 on the ventilator setting. FiO2 was increased directly from baseline to 1.0 for a period of 15 minutes under stable conditions (145 tests). In 34 patients the effect of decreasing PaCO2 was evaluated on TOR by performing the same test after increasing inspiratory minute volume on the ventilator setting to 20% above baseline. Arterial blood gas analysis was performed before and after changing ventilator settings. Multimodality monitoring, including PbrO2 was performed in all patients. Outcome at six months was evaluated according to the Glasgow Outcome Scale. For statistical analysis the Mann-whitney U-test was used for ordinally distributed variables, and the Chi-square test for categorical variables. Predictive value of TOR was analyzed in a multivariable model. Results. 145 tests were available for analysis. Baseline PbrO2 varied from 4.0 to 50 mmHg at PaO2 values of 73–237 mmHg. At FiO2 settings of 1.0, PbrO2 varied from 9.1–200 mmHg and PaO2 from 196–499 mmHg. Three distinct patterns of response were noted: response type A is characterized by a sharp increase in PbrO2, reaching a plateau within several minutes; type B by the absence of a plateau, and type C by a short plateau phase followed by a subsequent further increase in PbrO2. Patterns characterized by a stable plateau (type A), considered indicative of intact regulatory mechanisms, were seen more frequently from 48 hours after injury on. If present within the first 24 hours after injury such a response was related to more favorable outcome (p = 0.06). Mean TOR of all tests was 0.73 ± 0.59 with an median TOR of 0.58. Patients with an unfavourable outcome had a higher TOR (1.03 ± 0.60) during the first 24 hours, compared to patients with a favorable outcome (0.61 ± 0.51; p = 0.02). Multiple logistic regression analysis supported the independent predictive value of tissue oxygen response for unfavorable outcome (odds ratio 4.8). During increased hyperventilation, mean TOR decreased substantially from 0.75 ± 0.54 to 0.65 ± 0.45 (p = 0.06; Wilcoxon test). Within the first 24 hours after injury a decrease in TOR following hyperventilation was significantly related to poorer outcome (p = 0.01). Conclusions. Evaluation of TOR affords insight in (disturbances in) oxygen regulation after traumatic brain injury, is of prognostic value and may aid in identifying patients at (increased) risk for ischemia.

Identification of relevant prognostic histopathologic features in 69 intracranial ependymomas, excluding myxopapillary ependymomas and subependymomas

The results of attempts to identify histopathologic parameters that contribute to the clinical outcome of patients with ependymomas have been controversial. This may be due to the relative rareness of ependymomas. Furthermore, in many investigations, myxopapillary ependymomas and subependymomas were included and may have confounded results, because those tumors should be considered clinicopathologic entities distinct from the other ependymomas.