Impact of early surgery after aneurysmal subarachnoid haemorrhage.

OBJECTIVES: To investigate the effect of early aneurysm surgery (<72 h) on outcome in patients with subarachnoid haemorrhage (SAH). MATERIALS AND METHODS: We studied two consecutive series of patients with aneurysmal SAH [postponed surgery (PS) cohort, n = 118, 1989-1992: surgery was planned on day 12 and early surgery (ES) cohort, n = 85, 1996-1998: ES was performed only in patients with Glasgow Coma Scale (GCS) >13]. We used multivariable logistic regression analysis to assess outcome at 3 months. RESULTS: Favourable outcome (Glasgow Outcome Scale 4 or 5) was similar in both cohorts. Cerebral ischemia occurred significantly more often in the ES cohort. The occurrence of rebleeds was similar in both cohorts. External cerebrospinal fluid (CSF) drainage was performed more often in the ES cohort (51% vs 19%). Patients with cisternal sum score (CSS) of subarachnoid blood <15 on admission [adjusted odds ratio (OR) for favourable outcome: 6.4, 95% confidence interval (CI) 1.0-39.8] and patients with both CSS <15 and GCS > 12 on admission benefited from the strategy including ES (OR 10.5, 95% CI 1.1-99.4). CONCLUSIONS: Our results support the widely adopted practice of ES in good-grade SAH patients.

Risk factors for infections related to external ventricular drainage.

BACKGROUND: 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.

BACKGROUND: Frameless stereotaxy or neuronavigation has evolved into a feasible technology to acquire intracranial 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.

Human adenovirus type 35 vector for gene therapy of brain cancer: improved transduction and bypass of pre-existing anti-vector immunity in cancer patients.

Clinical trials in malignant glioma have demonstrated excellent safety of recombinant adenovirus type 5 (Ad5) but lack of convincing efficacy. The overall low expression levels of the Coxsackie and Adenovirus receptor and the presence of high anti-Ad5-neutralizing antibody (NAb) titers in the human population are considered detrimental for consistency of clinical results. To identify an adenoviral vector better suited to infect primary glioma cells, we tested a library of fiber-chimeric Ad5-based adenoviral vectors on 12 fresh human glioma cell suspensions. Significantly improved marker gene expression was obtained with several Ad5-chimeric vectors, predominantly vectors carrying fiber molecules derived from B-group viruses (Ad11, Ad16, Ad35 and Ad50). We next tested Ad35 sero prevalence in sera derived from 90 Dutch cancer patients including 30 glioma patients and investigated the transduction efficiency of this vector in glioma cell suspensions. Our results demonstrate that the sero prevalence and the titers of NAb against Ad35 are significantly lower than against Ad5. Also, recombinant Ad35 has significantly increased ability to transfer a gene to primary glioma cells compared to Ad5. We thus conclude that Ad35 represents an interesting candidate vector for gene therapy of malignant glioma.

The prognostic value of clinical characteristics and parameters of cerebrospinal fluid hydrodynamics in shunting for idiopathic normal pressure hydrocephalus.

BACKGROUND: It is difficult to predict which patients with symptoms and radiological signs of normal pressure hydrocephalus (NPH) will benefit from a shunting procedure and which patients will not. Risk of this procedure is also higher in patients with NPH than in the overall population of hydrocephalic patients. The aim of this study is to investigate which clinical characteristics, CT parameters and parameters of cerebrospinal fluid dynamics could predict improvement after shunting. METHODS: Eighty-three consecutive patients with symptoms and radiological signs of NPH were included in a prospective study. Parameters of the cerebrospinal fluid dynamics were measured by calculation of computerised data obtained by a constant-flow lumbar infusion test. Sixty-six patients considered candidates for surgery were treated with a medium-pressure Spitz-Holter valve; in seventeen patients a shunting procedure was not considered indicated. Clinical and radiological follow-up was performed for at least one year postoperatively. FINDINGS: The odds ratio, the sensitivity and specificity as well as the positive and negative predictive value of individual and combinations of measured parameters did not show a statistically significant relation to clinical improvement after shunting. CONCLUSIONS: We conclude that neither individual parameters nor combinations of measured parameters show any statistically significant relation to clinical improvement following shunting procedures in patients suspected of NPH. We suggest restricting the term normal pressure hydrocephalus to cases that improve after shunting and using the term normal pressure hydrocephalus syndrome for patients suspected of NPH and for patients not improving after implantation of a proven well-functioning shunt.

[High level of satisfaction among patients despite persistent symptoms in the mid-long-term following surgery for lumbosacral radicular syndrome]. / Na operatie wegens lumbosacraal radiculair syndroom bij meer dan de helft van de patiënten nog klachten op middellange termijn, maar wel grote tevredenheid.

OBJECTIVE: To determine the mid-long-term outcomes after surgery in patients with lumbosacral radicular syndrome (LRS) and to identify prognostic factors for persisting LRS symptoms. DESIGN: Descriptive retrospective and prospective. METHOD: A total of 250 consecutive patients operated on by 7 neurosurgeons in four hospitals between May and December 2001 were selected from medical records. They were asked to take part in a telephone questionnaire at 6 and 19 months after operation. They had all undergone discectomy for LRS at L4-L5 or L5-S1 and were aged from 18 to 65. RESULTS: Of the 250 patients, 163 participated in the study: 63% reported that they still had LRS-related symptoms 19 months after surgery. However, severe leg pain had decreased in 83% of the patients. In general the patients were satisfied with their treatment. Female gender and an age of 51-65 were prognostic factors for persistent LRS symptoms. CONCLUSION: More than half of the patients reported LRS symptoms 19 months after surgery.

Do neurosurgeons subscribe to the guideline lumbosacral radicular syndrome?

BACKGROUND: This study presents a survey of the opinion of neurosurgeons on the multidisciplinary clinical guideline 'lumbosacral radicular syndrome'. The aim was to describe to what extent neurosurgeons in the Netherlands endorse the content of this guideline. The guideline was issued in 1996 by the Netherlands Institute of Quality Health Care and this is the first attempt to evaluate the implementation of this guideline. METHODS: All active neurosurgeons (n=92) in the Netherlands were invited to complete a questionnaire investigating to what extent they agree with the 26 recommendations in the guideline 'lumbosacral radicular syndrome'. The results are represented in frequencies (%) in order to express the magnitude of their consent or dissent with the recommendations. RESULTS: Overall, 75% of the neurosurgeons responded and, of these, 94% agreed (at least partially) with the content of the guideline. Of the 26 recommendations in the guideline, seven were not fully endorsed by the neurosurgeons. Three of these seven recommendations may need revision based on newly published data. CONCLUSION: This survey shows that almost all neurosurgeons subscribed (at least partially) to the multidisciplinary LRS guideline. Therefore, one important aspect of the implementation process has been fulfilled, i.e. acceptance of the content of the guideline.

Brain tissue oxygen response in severe traumatic brain injury.

OBJECTIVE: To investigate clinical relevance and prognostic value of brain tissue oxygen response (TOR: response of brain tissue pO(2) to changes in arterial pO(2)) 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 < or =8) in whom continuous monitoring of brain tissue oxygen pressure (PbrO(2)) was performed.TOR was investigated each day over a five day period for 15 minutes by increasing FiO(2) on the ventilator setting. FiO(2) 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 PaCO(2) 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 PbrO(2) 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 PbrO(2) varied from 4.0 to 50 mmHg at PaO(2) values of 73-237 mmHg. At FiO(2) settings of 1.0, PbrO(2) varied from 9.1-200 mmHg and PaO(2) from 196-499 mmHg. Three distinct patterns of response were noted: response type A is characterized by a sharp increase in PbrO(2), 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 PbrO(2). 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.

Serial transcranial Doppler measurements in traumatic brain injury with special focus on the early posttraumatic period.

BACKGROUND: Cerebral ischemia is considered a key factor in the development of secondary damage after Traumatic Brain Injury (TBI). Studies on Cerebral Blood Flow (CBF) have documented decreased flow in over 50% of patients with TBI, studied in the acute phase. Transcranial Doppler (TCD) sonography is a non-invasive technique, permitting frequent or continuous measurements of blood flow velocity in the basal cerebral arteries. OBJECTIVES: To investigate the potential of TCD to detect decreased blood flow velocity in the early phase after TBI;To investigate whether flow velocity differs between hemispheres in patients with focal lesions versus those with more diffuse injuries;To investigate if decreased blood flow velocity is indicative of cerebral ischemia, as evidenced by measurements of brain tissue pO(2). METHODS: TCD examinations were performed in 57 patients with severe TBI (GCS

['Benign' meningioma]. / Een 'goedaardig' meningioom.

Meningioma was diagnosed in four women, aged 40, 24, 41 and almost 75 years, respectively. The first of these patients was treated with surgery, the second and third patients underwent surgery followed by conventional radiotherapy because of a tumour residue or dural tail, and the last patient was treated with stereotactic radiosurgery. They recovered well and were followed by means of regular outpatient check-ups. Twenty percent of all primary brain tumours are meningiomas, over 90% of which are benign. Nevertheless, a large hospital-based population study showed a 5-year survival rate of only 70%. Microsurgery is usually the treatment of first choice. However, in about 25% of cases, excision is incomplete and tumour growth almost always continues. Further surgery influences prognosis unfavourably. New sophisticated radiation techniques help to control tumour progression in about 80-90% of cases. This success, however, may be associated with new cranial nerve deficits or panhypopituitarism. Prospective, comparative studies are not available.

Treatment of malignant gliomas with a replicating adenoviral vector expressing herpes simplex virus-thymidine kinase.

We evaluated the interaction between oncolytic, replication-competent adenoviral vectors and the herpes simplex virus-1 thymidine kinase (HSV1-tk) gene/ganciclovir (GCV) suicide system for the treatment of malignant gliomas. We constructed a panel of replication-competent adenoviral vectors in which the luciferase (IG.Ad5E1(+). E3Luc) or HSV1-tk gene (IG.Ad5E1(+).E3TK) replace the M(r) 19,000 glycoprotein (gp19K) coding sequence in the E3 region. IG.Ad5E1. IG.Ad5.ClipLuc and IG.AdApt.TK are E1-deleted viruses that contain the luciferase or the HSV1-tk gene in the former E1 region driven by the human cytomegalovirus promoter. IG.Ad5. Sarcoma 1800HSA.E3Luc contains an irrelevant gene in the E1 region, whereas the gp19K coding sequence in the E3 region is replaced by the luciferase gene as in the replicating virus IG.Ad5E1(+).E3Luc. For in vitro experiments, we used a panel of human glioma cell lines (U87 MG, T98G, A172, LW5, and U251), a rat gliosarcoma cell line (9 L), and human lung (A549) and prostate carcinoma (P3) cell lines. In vitro, GCV sensitivity (10 microg/ml) was studied in U87 MG cells after infection at a multiplicity of infection of 1 and 10. A s.c. U87 MG glioma xenograft model was established in NIH-bg-nu-xid mice. Tumors of 100-150 mm(3) were treated with a single injection of adenovirus 10(9) IU suspended in 100 microl of PBS, and GCV 100 mg/kg was administered i.p. twice daily for 7 days. The cytopathic effect of all three replication-competent adenoviral vectors was similar to the cytopathic effect of wild-type adenovirus 5 on all human cell lines tested, indicating that deletion of the E3 gp19K sequences did not affect the oncolytic effect of the vectors. In vitro, luciferase expression was the same for both E1-deleted vectors (IG.Ad5.ClipLuc and IG.Ad5. Sarcoma 1800HSA.E3Luc), demonstrating the strength of the internal E3 promoter even in the absence of E1A. However, in vitro expression levels obtained with replication-competent IG.Ad5E1(+). E3Luc were 3 log higher (allowing infection with a 2-3-log lower multiplicity of infection) in the human cell lines. In U87 MG glioma cells, the oncolytic effect of replication-competent IG.Ad5E1(+).E3TK was significantly enhanced by the addition of GCV and greatly exceeded the cytotoxicity of replication-incompetent IG.AdApt.TK combined with GCV. In established s.c. U87 MG glioma xenografts, a single injection of IG.Ad5E1(+).E3TK resulted in a significant slowing of tumor growth and prolonged survival compared with injection of IG.AdApt.TK. Addition of GCV slowed tumor growth, further adding to survival. In conclusion, the oncolytic effect of replicating adenoviral vectors and HSV1-tk/GCV have potent antitumor effects in gliomas. When combined, these two approaches are complementary, resulting in a significantly improved treatment outcome. In addition, replication-competent adenoviral vectors missing the E3 gp19K coding sequences, have oncolytic efficacy comparable with wild type. In combination with high expression levels obtained with the natural E3 promoter, such vectors are promising new anticancer agents.

Analysis of hearing loss after shunt placement in patients with normal-pressure hydrocephalus.

OBJECT: Following shunt placement for treatment of normal-pressure hydrocephalus (NPH), several patients suffered hearing loss. The authors undertook a study to analyze this outcome. METHODS: Sixteen patients in whom NPH was diagnosed were treated by placement of a ventriculoperitoneal shunt. Their hearing was assessed pre- and postoperatively by using pure tone audiometry. Two thirds of the ears tested showed a postoperative hearing loss of more than 10 dB. Recovery of the hearing loss occurred 6 to 12 weeks after shunt placement in 75% of the ears examined. CONCLUSIONS: Although shunt insertion for treatment of NPH results in a decrease in hearing, most of the loss can be recovered.

Spatial variability of genomic aberrations in a large glioblastoma resection specimen.

In the present study, the distribution of genetic aberrations in a glioblastoma resection specimen of unusually large size (9x8x2 cm) was investigated using comparative genomic hybridization (CGH). CGH was performed on 20 samples taken from the specimen, and the genetic aberrations found were compared with the regional histology. The samples were histopathologically graded according to WHO criteria, and a division in high- and low-grade areas and infiltration rims was made. In high-grade areas, low-grade areas as well as infiltration rims, gains on 10p11.2-pter (14/20), 11q12-q22 (6/20) and losses on 4q13-qter (9/20), 10q22-qter (8/20), 11p14-pter (5/20), 13q12-qter (7/20) were revealed. Gains on 1q21-32 (2/4) and losses on 7p21-pter (3/4) were exclusively found in the high-grade areas. In the low-grade tumor samples and in the infiltration rim, gains on 16p11.2-pter (6/16), 17p11.2-pter (6/16), 17q11.2-qter (5/16), 20q11.2-q13 (3/16) and deletions on 5q31-qter (4/16) were detected. Gains on 7q21-qter (8/11) and 8q11.2-qter (6/11), and loss of chromosome 9 (4/11) and the Y-chromosome (4/11) were found in the high-grade and low-grade samples, not in the infiltration rims. The finding of a set of identical chromosomal aberrations throughout the resection specimen, most of which have been previously reported in gliomas, confirms a mechanism of clonal tumor proliferation operative in gliomas. The previously unreported genetic alterations which were predominantly traced in the tumor rims, might reflect either selection for properties related to infiltrating behavior, or genomic instability of subclones. The findings illustrate the importance of searching for high-grade genetic aberrations in low-grade tumor samples taken from cases in which sampling error is suspected.

Craniovascular selectivity of eletriptan and sumatriptan in human isolated blood vessels.

BACKGROUND: Eletriptan is a 5-HT(1B/1D) receptor agonist with proven efficacy in the acute treatment of migraine. OBJECTIVE: To assess the craniovascular selectivity of eletriptan and sumatriptan in blood vessels predictive of therapeutic efficacy (human middle meningeal artery) and adverse coronary side effects (human coronary artery and human saphenous vein). METHOD: The authors obtained coronary artery from organ donors (n = 9), middle meningeal artery from patients (n = 11) undergoing craniotomy, and saphenous vein from patients (n = 9) undergoing coronary bypass surgery. Concentration-response curves to eletriptan and sumatriptan were constructed to obtain measurements of efficacy (maximum contraction, E(max)) and potency (concentration eliciting 50% of E(max), EC(50)). The contraction that is likely to be induced at the maximal free plasma concentration (C(max)) was determined by calculating C(max)/EC(50) ratios and by interpolation of the concentration-response curves. RESULTS: Eletriptan and sumatriptan induced concentration-dependent contractions of meningeal artery, coronary artery, and saphenous vein. Eletriptan was less potent than sumatriptan in coronary artery, whereas both compounds had similar potency in meningeal artery and saphenous vein. However, the potency of eletriptan and sumatriptan was higher in meningeal artery than in coronary artery (86-fold for eletriptan and 30-fold for sumatriptan) or saphenous vein (66- and 25-fold). The efficacy of eletriptan and sumatriptan was similar within tissues. The predicted contraction by eletriptan (40 mg and 80 mg) and sumatriptan (100 mg) at free C(max) observed in clinical trials was similar in meningeal artery, whereas in coronary artery and saphenous vein it was lower for 40 mg eletriptan than for sumatriptan. CONCLUSIONS: At therapeutic concentrations both eletriptan and sumatriptan contract middle meningeal artery more than coronary artery. This suggests that in patients with healthy coronary arteries, they have a limited propensity to cause adverse coronary side effects. However, both drugs remain contraindicated in patients with coronary artery disease.

Pharmacological analysis of contractile effects of eletriptan and sumatriptan on human isolated blood vessels.

Eletriptan, a second-generation triptan with high affinity for 5-HT(1B/1D) receptors, is highly effective in migraine, with or without aura. We compared the effects of eletriptan and sumatriptan on the human isolated middle meningeal and coronary arteries and saphenous vein, used as models for therapeutic efficacy and potential side effects, and have investigated the role of 5-HT(1B/1D) receptors in contractions induced by these triptans. Concentration-response curves to eletriptan and sumatriptan were constructed in the absence or presence of a selective 5-HT(1B/1D) receptor antagonist, N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-methyl-4-(4-py rid yl) benzamide (GR125743). All three blood vessels constricted in response to eletriptan and sumatriptan, but the middle meningeal artery relaxed following the highest concentration (100 microM) of eletriptan. In the middle meningeal artery, GR125743 antagonised the contractions induced by both eletriptan (pEC(50): 7.34+/-0.13) and sumatriptan (pEC(50): 6.91+/-0.17) to a similar degree (pA(2): 8. 81+/-0.17 and 8.64+/-0.21, respectively). In the human coronary artery and saphenous vein, sumatriptan-induced contractions (pEC(50): 6.24+/-0.14 and 6.19+/-0.12, respectively) were also potently antagonised by GR125743 (pA(2): 8.18+/-0.27 and 8.34+/-0.12, respectively). The eletriptan-induced contractions of the human saphenous vein (pEC(50): 6.09+/-0.13) were antagonised less effectively by GR125743 (pK(B): 7.73+/-0.18), and those of the human coronary artery (pEC(50): 5.54+/-0.22) remained unaffected by GR125743 up to a concentration of 100 nM. These results suggest that (i) based on the differences in pEC(50) values, the cranioselectivity of eletriptan (63-fold) is higher than that of sumatriptan (5-fold) in coronary artery, (ii) the contractile effects of sumatriptan and eletriptan (lower concentrations) in the three blood vessels are mediated via the 5-HT(1B) receptor, and (iii) additional mechanisms seem to be involved in coronary artery and saphenous vein contractions and middle meningeal artery relaxation following high concentrations of eletriptan.

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

OBJECTIVE: To investigate the effect of hyperventilation on cerebral oxygenation after severe head injury. DESIGN: A prospective, observational study. SETTING: Neurointensive care unit at a university hospital. PATIENTS: A total of 90 patients with severe head injury (Glasgow Coma Scale score < or =8), in whom continuous monitoring of brain tissue oxygen pressure (PbrO2) was performed as a measure of cerebral oxygenation. INTERVENTIONS: Arterial 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 > or =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. CONCLUSIONS: Increased 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.

Intra-CSF administered recombinant adenovirus causes an immune response-mediated toxicity.

High doses of adenotk were injected into the cerebrospinal fluid of rats and nonhuman primates (Macaca mulatta). Vector administration was followed by ganciclovir administration for 14 days. Despite the absence of clinical symptoms, analysis of the cerebrospinal fluid (CSF) and histopathological examination of the central nervous system (CNS) of the monkeys (3 weeks after vector injection) were consistent with a viral meningitis. Immunohistochemical analysis of the inflammatory infiltrates in the monkeys revealed the presence of T and B lymphocytes, indicating a combined cellular and humoral immune response to the vector. This latter was supported by the finding of intrathecal anti-adenovirus antibody synthesis. Rats receiving high intrathecal adenotk doses showed a transient and dose-dependent clinical toxicity consisting of lethargy, hyperemic eyes and weight loss. Histopathological examination of the meninges showed a shift from polymorphonuclear infiltrates during the first post-injection days to clusters of mononuclear cells after 7 days. Acute toxicity is probably related to the early, innate immune response to the vector. In a separate experiment, high levels of IL-8 and IL-6, were measured during the first 2-3 post-injection days in the CSF of two monkeys which received intrathecal adenoLacZ. Therefore, these cytokines seem to play an important role in initiating the nonspecific immune response. In one monkey which received adenotk, recombinant adenovirus was cultured from serum samples obtained at the 7th post-injection day. At this time-point, no vector could be isolated from CSF samples. Based on these preclinical data, we recommend careful dose finding for clinical studies that aim to treat patients with leptomeningeal metastases.

Interobserver variability of cisternal blood on CT after aneurysmal subarachnoid hemorrhage.

Interobserver variability in the prediction of delayed cerebral ischemia by means of blood on CT was investigated in 159 patients with aneurysmal subarachnoid hemorrhage, admitted within 72 hours after the bleed. The authors found considerable interobserver variability in the assessment of the amount of blood in the individual cisterns. A high sum score was an independent predictor for delayed cerebral ischemia only for rater 1 (rater 1: hazard ratio, 3.26; 95% confidence interval [CI], 1.14 to 7.75; rater 2: hazard ratio, 1.72; 95% CI, 0.72 to 4.09). The authors conclude that interobserver variability limits the predictive power of the amount of blood on CT for the occurrence of cerebral ischemia.

Hydrostatic and hydrodynamic considerations in shunted normal pressure hydrocephalus.

Symptoms of overdrainage, a frequent complication following shunting procedures especially in patients with normal-pressure hydrocephalus (NPH), are presumed to be caused by siphoning: gravity-enhanced flow of cerebro spinal fluid (CSF) through shunts in upright position. A critical reappraisal of siphoning and overdrainage (OD) is presented considering the occurrence of subdural hygromas (SDH) encountered in a group of patients shunted for NPH. The patients participated in the multicentre Dutch NPH study: 101 NPH patients were randomised for treatment with shunts with low or medium-high working pressure. Treatment with shunts with low working pressure resulted in an increased incidence of SDH (iSDH). Current physiological concepts of overdrainage are discussed and criticised. A new theory is presented on the basis of general physiological considerations. The theoretical model proposed yields a revised explanation for the origin of extremely low ventricular pressure in the upright position found with overdrainage. The efficacy of siphoning-preventing shunts and subtemporal decompression is explored in the light of the proposed theory.

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.