Hyperbaric oxygen for carbon monoxide poisoning : a systematic review and critical analysis of the evidence

Poisoning with carbon monoxide (CO) is an important cause of unintentional and intentional injury worldwide. Hyperbaric oxygen (HBO) enhances CO elimination and has been postulated to reduce the incidence of neurological sequelae. These observations have led some clinicians to use HBO for selected patients with CO poisoning, although there is considerable variability in clinical practice. This article assesses the effectiveness of HBO compared with normobaric oxygen (NBO) for the prevention of neurological sequelae in patients with acute CO poisoning. The following databases were searched: MEDLINE (1966 to present), EMBASE (1980 to present), and the Controlled Trials Register of the Cochrane Collaboration, supplemented by a manual review of bibliographies of identified articles and discussion with recognised content experts. All randomised controlled trials involving people acutely poisoned with CO, regardless of severity, were examined. The primary analysis included all trials from which data could be extracted. Sensitivity analysis examined trials with better validity (defined using the validated instrument of Jadad) and those enrolling more severely poisoned patients. Two reviewers independently extracted from each trial, including information on the number of randomised patients, types of participants, the dose and duration of the intervention, and the prevalence of neurological sequelae at follow-up. A pooled odds ratio (OR) for the presence of neurological symptoms at 1-month follow-up was calculated using a random effects model. Bayesian models were also investigated to illustrate the degree of certainty about clinical effectiveness. Eight randomised controlled trials were identified. Two had no evaluable data and were excluded. The remaining trials were of varying quality and two have been published only as abstracts. The severity of CO poisoning varied among trials. At 1-month follow-up after treatment, sequelae possibly related to CO poisoning were present in 242 of 761 patients (36.1%) treated with NBO, compared with 259 of 718 patients (31.8%) treated with HBO. Restricting the analysis to the trials with the highest quality scores or those that enrolled all patients regardless of severity did not change the lack of statistical significance in the outcome of the pooled analysis. We found empiric evidence of multiple biases that operated to inflate the benefit of HBO in two positive trials. In contrast, the interpretation of negative trials was hampered by low rates of follow-up, unusual interventions for control patients and inclusion of less severely poisoned patients. Collectively, these limitations may have led negative trials to overlook a real and substantial benefit of HBO (type II error). There is conflicting evidence regarding the efficacy of HBO treatment for patients with CO poisoning. Methodological shortcomings are evident in all published trials, with empiric evidence of bias in some, particularly those that suggest a benefit of HBO. Bayesian analysis further illustrates the uncertainty about a meaningful clinical benefit. Consequently, firm guidelines regarding the use of HBO for patients with CO poisoning cannot be established. Further research is needed to better define the role of HBO, if any, in the treatment of CO poisoning. Such research should not exclude patients with severe poisoning, have a primary outcome that is clinically meaningful and have oversight from an independent data monitoring and ethics committee.     

Reduction in functional potency of the neurotoxin domoic acid in the presence of cadmium and zinc ions

The tricarboxylic neurotoxin domoic acid (DA) binds trace metals such as iron and copper. In vitro brain slice recording (area CA1 of rat hippocampal slices) was used to assess changes in DA potency in the presence of cadmium and zinc. Cadmium or zinc alone had little or no effect on CA1 responses. DA alone produced hyperexcitability and, with prolonged administration, a robust suppression of CA1 responses. Coadministration of DA with either 2 or 4μM Cd(2+) produced significant reductions in the potency of DA; less striking effects were seen in the presence of 4μM Zn(2+). These findings suggest that interactions of Cd(2+) and Zn(2+) with DA result in the formation of trace metal-neurotoxin complexes which are either unavailable for binding to ionotropic glutamate receptors, or bind without producing full agonist activity.     

Five years of ankle fractures grouped by stability

Categories of displaced and undisplaced stable ankle fracture are well recognised. We report on a further group of ankle fractures which are undisplaced at presentation, but do not fulfil criteria for stable injuries, and therefore, may be at risk of displacement. The Blackburn Foot and Ankle Service operates evidence-based guidelines for ankle fractures, introduced in 1998. These were prospectively applied to 306 skeletally mature patients (308 fractures) following classification of the ankle fracture based upon clinical examination and radiography (mortise and lateral views). One hundred and forty-eight (48.4%) of fractures were stable, including 63 male and 85 women, median age 53 years (14-92). Eighty-eight (28.8%) of fractures were undisplaced but potentially unstable based on criteria, including 53 men and 35 women, median age 42 years (14-93). Seventy (22.9%) of fractures were displaced, including 41 men and 29 women, median age 44 years (16-94). Undisplaced, unstable fractures were treated mostly in below-knee casts with immediate weight-bearing and follow-up radiography. Two fractures in this group subsequently displaced requiring fixation according to AO principles. The risk of displacement in potentially unstable fractures is 2.3%. The unstable fracture groups, whether displaced or not, were similar in age/sex profile.     

Para-aortic lymph node radiation in advanced cervical cancer

From 1970 until December, 1977, 36 patients with advanced carcinoma of the uterine cervix and with iliac or para-aortic nodes interpreted as un-equivocally positive on lymphangiography have received radiation therapy (4500–5000 rad) to the para-aortic area at the Department of Therapeutic Radiology at Tufts-New England Medical Center Hospital. Of 29 patients who received para-aortic area irradiation as part of their initial treatment, local control was achieved in 18 patients (62%). Of these, 11 patients are currently alive with no evidence of disease (NED); two died without evidence of tumor. The remaining 16 patients died of their tumor (11 with locally uncontrolled tumor and five with distant metastasis). Of seven patients in whom the para-aortic area was treated because of retroperitoneal nodal recurrence, only two are alive without disease and the rest succumbed to their tumor. Overall, four patients developed major complications requiring surgical intervention. Detailed results and our current pre-treatment evaluation policy including lymphangiography, percutaneous needle biopsy and selective extra-peritoneal lymph node biopsy will be discussed.     

Massage therapy for symptom control: outcome study at a major cancer center

Massage is increasingly applied to relieve symptoms in patients with cancer. This practice is supported by evidence from small randomized trials. No study has examined massage therapy outcome in a large group of patients. At Memorial Sloan-Kettering Cancer Center, patients report symptom severity pre- and post-massage therapy using 0-10 rating scales of pain, fatigue, stress/anxiety, nausea, depression and "other." Changes in symptom scores and the modifying effects of patient status (in- or outpatient) and type of massage were analyzed. Over a three-year period, 1,290 patients were treated. Symptom scores were reduced by approximately 50%, even for patients reporting high baseline scores. Outpatients improved about 10% more than inpatients. Benefits persisted, with outpatients experiencing no return toward baseline scores throughout the duration of 48-hour follow-up. These data indicate that massage therapy is associated with substantive improvement in cancer patients' symptom scores.     

Phase II study of temozolomide without radiotherapy in newly diagnosed glioblastoma multiforme in an elderly populations

BACKGROUND: Currently, the survival of patients age > 70 years with glioblastoma multiforme (GBM) ranges from 4 months to 6 months, although radiotherapy and/or chemotherapy may prolong survival in certain subgroups. Temozolomide is an oral chemotherapeutic agent with efficacy against malignant gliomas and a favorable safety profile. This open-label, single-center, Phase II study was designed to evaluate the efficacy and safety of temozolomide as first-line chemotherapy and exclusive treatment in elderly patients with newly diagnosed GBM. METHODS: Chemotherapy-na?ve patients (age > 70 years) were treated with temozolomide at a dose of 150-200 mg/m(2) per day for 5 consecutive days of a 28-day cycle until they developed disease progression. No radiation therapy was administered. The primary endpoint was median overall survival (OS); secondary endpoints included progression-free survival (PFS) and toxicity. RESULTS: Thirty-two patients (median age, 75 years; median Karnofsky performance status, 70) experienced a median OS of 6.4 months and a median PFS of 5.0 months. Of 29 patients who were assessed for response, 9 patients (31%) achieved a partial response, 12 patients (41%) maintained stable disease, and 8 patients (28%) developed progressive disease. Adverse events primarily were mild, with NCI CTC Grade 3-4 thrombocytopenia and neutropenia reported to occur in 6% and 9% of patients, respectively. No neurotoxicity was observed. Treatment delays and dose reductions occurred in 13% and 14% of cycles, respectively. CONCLUSIONS: Temozolomide represents a safe, easily administered, and effective therapeutic approach for elderly patients with newly diagnosed GBM.     

Acupuncture for postchemotherapy fatigue: a phase II study.

PURPOSE: To determine whether improvement in postchemotherapy fatigue following acupuncture treatment is substantial enough to warrant a controlled trial. PATIENTS AND METHODS: We accrued patients at Memorial Sloan-Kettering Cancer Center who had completed cytotoxic chemotherapy but experienced persisting fatigue. Patients with severe anemia, clinical depression, or Karnofsky performance status score less than 70 were excluded. Thirty-seven patients were registered in two cohorts; 31 provided follow-up data. Patients received acupuncture either twice per week for 4 weeks (25 patients) or once per week for 6 weeks (12 patients). The primary end point was change in score on the Brief Fatigue Inventory between baseline and 2 weeks after the final treatment. A baseline Brief Fatigue Inventory score of four or greater was an eligibility requirement for the trial. RESULTS: Patients had completed cytotoxic chemotherapy an average of more than 2 years previously. Baseline fatigue scores were high, with approximately half of the sample scoring in the "severe" range. Mean improvement following acupuncture was 31.1% (95% CI, 20.6% to 41.5%), meeting our prespecified criterion for declaring acupuncture worthy of further study. Increasing age was associated with poorer response and failure to complete the study. There was no important difference in improvement following once-weekly and twice-weekly treatments. CONCLUSION: Acupuncture is worthy of further study in the treatment of postchemotherapy fatigue.     

On the regulation of NMDA receptors by nitric oxide

Nitric oxide (NO) is generated in central synapses on activation of N-methyl-D-aspartate (NMDA) receptors and exerts physiological effects by changing cGMP levels. NO has frequently also been claimed to engage a different mechanism, namely the covalent modification of thiol residues (S-nitrosation), and thereby exert a negative feedback on NMDA receptors. Tests of this hypothesis were conducted by recording NMDA receptor-mediated synaptic potentials in the CA1 area of rat hippocampal slices. Manipulations designed to increase or decrease endogenous NO levels had no effect. Addition of exogenous NO using a NONOate donor in concentrations up to 30-fold higher than those needed to evoke maximal cGMP accumulation also had no effect. Nevertheless, in agreement with previous findings, photolysis of a caged NO derivative with UV light led to an enduring block of synaptic NMDA receptors. To address these contradictory results, NMDA receptor-mediated currents were recorded from HEK-293 cells transfected with NR1 and NR2A subunits. As found in slices, photolysis of caged NO inhibited the currents whereas perfusion of NO (up to 5 microM) was ineffective. However, when NO was supplied at a concentration found to be effective when released photolytically (5 microM) and the cells simultaneously exposed to the UV light used for photolysis, NMDA receptor-mediated currents were inhibited. This effect was not observed at more physiological NO concentrations (10 nM range). The results indicate that neither endogenous NO nor exogenous NO in supra-physiological concentration inhibits synaptic NMDA receptors; the combination of high NO concentration and UV light can give an artifactual result.