Surgery in the treatment of malignant pleural mesothelioma: recruitment into trials should be the default position.

BACKGROUND: Europe is at the peak of an epidemic of malignant pleural mesothelioma and the burden of disease is likely to continue rising in the large areas of the world where asbestos remains unregulated. Patients with mesothelioma present with thoracic symptoms and radiological changes so respiratory physicians take a leading role in diagnosis and management. Belief that the modest survival times reported after radical surgery, whether alone or as part of multimodal therapy, are longer than they it would have been without surgery relies on data from highly selected, uncontrolled, retrospectively analysed case series. The only randomised study, the Mesothelioma and Radical Surgery (MARS) trial showed no benefit. A simple modelling study of registry patients, described here, shows that an impression of longer survival is eroded when patients who were never candidates for operation on grounds of histology, performance status and age are sequentially excluded from the model. CONCLUSION: Whenever the question arises `Might an operation help me?' there are two responses that can and should be given. The first is that there is doubt about whether there is any survival or symptomatic benefit from surgery but we know that there is harm. The second is that there are on-going studies, including two randomised trials, which patients should be informed about. The authors suggest that the default position for clinicians should be to encourage recruitment into these trials.

Alveolar PCO2 oscillations and ventilation at sea level and at high altitude.

This study examines the potential for a ventilatory drive, independent of mean PCO2, but depending instead on changes in PCO2 that occur during the respiratory cycle. This responsiveness is referred to here as "dynamic ventilatory sensitivity." The normal, spontaneous, respiratory oscillations in alveolar PCO2 have been modified with inspiratory pulses approximating alveolar PCO2 concentrations, both at sea level and at high altitude (5,000 m, 16,400 ft.). All tests were conducted with subjects exercising on a cycle ergometer at 60 W. The pulses last about half the inspiratory duration and are timed to arrive in the alveoli during early or late inspiration. Differences in ventilation, which then occur in the face of similar end-tidal PCO2 values, are taken to result from dynamic ventilatory sensitivity. Highly significant ventilatory responses (early pulse response greater than late) occurred in hypoxia and normoxia at sea level and after more than 4 days at 5,000 m. The response at high altitude was eliminated by normalizing PO2 and was reduced or eliminated with acetazolamide. No response was present soon after arrival (<4 days) at base camp, 5,000 m, on either of two high-altitude expeditions (BMEME, 1994, and Kanchenjunga, 1998). The largest responses at 5,000 m were obtained in subjects returning from very high altitude (7,100-8,848 m). The present study confirms and extends previous investigations that suggest that alveolar PCO2 oscillations provide a feedback signal for respiratory control, independent of changes in mean PCO2, suggesting that natural PCO2 oscillations drive breathing in exercise.

Breath-hold time during cold water immersion: effects of habituation with psychological training.

INTRODUCTION: The loss of the conscious control of respiration on whole body cold water immersion (CWI) can result in the aspiration of water and drowning. Repeated CWI reduces the respiratory drive evoked by CWI and should prolong breath-hold time on CWI (BHmax(CWI)). Psychological skills training (PST) can also increase BHmax(CWI) by improving the ability of individuals to consciously suppress the drive to breathe. This study tested the hypothesis that combining PST and repeated CWI would extend BHmax(CWI) beyond that seen following only repeated CWI. METHODS: There were 20 male subjects who completed two 2.5-min, head-out breath-hold CWI (BH1 and BH2) in water at 12 degrees C. Following BH1, subjects were matched on BHmax(CWI) and allocated to a habituation (HAB) group or a habituation plus PST group (H+PST). Between BH1 and BH2 both experimental groups undertook five 2.5-min CWI on separate days, during which they breathed freely. The H+PST also received psychological training to help tolerate cold and suppress the drive to breathe on immersion to extend BHmax(CWI). RESULTS: During BH1, mean BHmax(CWI) (+/- SD) in the HAB group was 22.00 (10.33) s and 22.38 (10.65) s in the H+PST. After the five free-breathing CWI, both groups had a longer BHmax(CWI) in BH2. The HAB group improved by 14.13 (20.21) s, an increase of 73%. H+PST improved by 26.86 (24.70) s, a 120% increase. No significant differences were identified between the groups. CONCLUSION: Habituation significantly increases BHmax on CWI, the addition of PST did not result in statistically significant improvements in BHmax(CWI), but may have practical significance.

The p300 as a marker of waning attention and error propensity.

Action errors can occur when routine responses are triggered inappropriately by familiar cues. Here, EEG was recorded as volunteers performed a "go/no-go" task of long duration that occasionally and unexpectedly required them to withhold a frequent, routine response. EEG components locked to the onset of relevant go trials were sorted according to whether participants erroneously responded to immediately subsequent no-go trials or correctly withheld their responses. Errors were associated with a significant relative reduction in the amplitude of the preceding P300, that is, a judgement could be made bout whether a response-inhibition error was likely before it had actually occurred. Furthermore, fluctuations in P300 amplitude across the task formed a reliable associate of individual error propensity, supporting its use as a marker of sustained control over action.

Breath-hold performance during cold water immersion: effects of psychological skills training.

INTRODUCTION: Accidental cold water immersion (CWI) is a significant cause of death, particularly in those who are immersed in rough water or forcibly submerged such as in a ditched and inverted helicopter. The marked reduction in maximal breath-hold time associated with CWI, part of the 'cold shock' response, significantly increases the risk of drowning. However, the response is highly variable between subjects. This experiment tested the hypothesis that part of this variability is due to psychological factors. METHODS: There were 32 subjects who completed 2 2.5-min, head-out immersions in 11 degrees C water, separated by 7 d. Between immersions, subjects were matched on initial maximum breath-hold time on immersion (BHwater) and allocated to either a psychological intervention group (PIG) or control group (CG). PIG (n=16) subjects each undertook a psychological skills intervention comprising 4 interlinked training sessions covering goal-setting, arousal regulation, mental imagery, and positive self-talk; CG (n=16) continued normal daily activity. RESULTS: Psychological intervention significantly increased BHwater on immersion in the PIG vs. the CG [mean (SD); CG BHwater immersion 1:24.01 (6.72) s; immersion 2: 21.34 (16.31) s; PIG: BHwater immersion 1: 24.66 (14.60) s; immersion 2: 44.25 (31.63) s]. The difference in maximum voluntary BHwater between immersion 1 and 2 in the PIG averaged 19.59 s, equating to an 80% increase following psychological intervention. CONCLUSION: Psychological influences may account for a significant amount of the variability in the respiratory responses during CWI, and may be a key factor in determining the chances of survival following accidental immersion.

Increased cerebral blood flow velocity in children with mild sleep-disordered breathing: a possible association with abnormal neuropsychological function.

OBJECTIVE: Sleep-disordered breathing describes a spectrum of upper airway obstruction in sleep from simple primary snoring, estimated to affect 10% of preschool children, to the syndrome of obstructive sleep apnea. Emerging evidence has challenged previous assumptions that primary snoring is benign. A recent report identified reduced attention and higher levels of social problems and anxiety/depressive symptoms in snoring children compared with controls. Uncertainty persists regarding clinical thresholds for medical or surgical intervention in sleep-disordered breathing, underlining the need to better understand the pathophysiology of this condition. Adults with sleep-disordered breathing have an increased risk of cerebrovascular disease independent of atherosclerotic risk factors. There has been little focus on cerebrovascular function in children with sleep-disordered breathing, although this would seem an important line of investigation, because studies have identified abnormalities of the systemic vasculature. Raised cerebral blood flow velocities on transcranial Doppler, compatible with raised blood flow and/or vascular narrowing, are associated with neuropsychological deficits in children with sickle cell disease, a condition in which sleep-disordered breathing is common. We hypothesized that there would be cerebral blood flow velocity differences in sleep-disordered breathing children without sickle cell disease that might contribute to the association with neuropsychological deficits. DESIGN: Thirty-one snoring children aged 3 to 7 years were recruited from adenotonsillectomy waiting lists, and 17 control children were identified through a local Sunday school or as siblings of cases. Children with craniofacial abnormalities, neuromuscular disorders, moderate or severe learning disabilities, chronic respiratory/cardiac conditions, or allergic rhinitis were excluded. Severity of sleep-disordered breathing in snoring children was categorized by attended polysomnography. Weight, height, and head circumference were measured in all of the children. BMI and occipitofrontal circumference z scores were computed. Resting systolic and diastolic blood pressure were obtained. Both sleep-disordered breathing children and the age- and BMI-similar controls were assessed using the Behavior Rating Inventory of Executive Function (BRIEF), Neuropsychological Test Battery for Children (NEPSY) visual attention and visuomotor integration, and IQ assessment (Wechsler Preschool and Primary Scale of Intelligence Version III). Transcranial Doppler was performed using a TL2-64b 2-MHz pulsed Doppler device between 2 pm and 7 pm in all of the patients and the majority of controls while awake. Time-averaged mean of the maximal cerebral blood flow velocities was measured in the left and right middle cerebral artery and the higher used for analysis. RESULTS: Twenty-one snoring children had an apnea/hypopnea index <5, consistent with mild sleep-disordered breathing below the conventional threshold for surgical intervention. Compared with 17 nonsnoring controls, these children had significantly raised middle cerebral artery blood flow velocities. There was no correlation between cerebral blood flow velocities and BMI or systolic or diastolic blood pressure indices. Exploratory analyses did not reveal any significant associations with apnea/hypopnea index, apnea index, hypopnea index, mean pulse oxygen saturation, lowest pulse oxygen saturation, accumulated time at pulse oxygen saturation <90%, or respiratory arousals when examined in separate bivariate correlations or in aggregate when entered simultaneously. Similarly, there was no significant association between cerebral blood flow velocities and parental estimation of child's exposure to sleep-disordered breathing. However, it is important to note that whereas the sleep-disordered breathing group did not exhibit significant hypoxia at the time of study, it was unclear to what extent this may have been a feature of their sleep-disordered breathing in the past. IQ measures were in the average range and comparable between groups. Measures of processing speed and visual attention were significantly lower in sleep-disordered breathing children compared with controls, although within the average range. There were similar group differences in parental-reported executive function behavior. Although there were no direct correlations, adjusting for cerebral blood flow velocities eliminated significant group differences between processing speed and visual attention and decreased the significance of differences in Behavior Rating Inventory of Executive Function scores, suggesting that cerebral hemodynamic factors contribute to the relationship between mild sleep-disordered breathing and these outcome measures. CONCLUSIONS: Cerebral blood flow velocities measured by noninvasive transcranial Doppler provide evidence for increased cerebral blood flow and/or vascular narrowing in childhood sleep-disordered breathing; the relationship with neuropsychological deficits requires further exploration. A number of physiologic changes might alter cerebral blood flow and/or vessel diameter and, therefore, affect cerebral blood flow velocities. We were able to explore potential confounding influences of obesity and hypertension, neither of which explained our findings. Second, although cerebral blood flow velocities increase with increasing partial pressure of carbon dioxide and hypoxia, it is unlikely that the observed differences could be accounted for by arterial blood gas tensions, because all of the children in the study were healthy, with no cardiorespiratory disease, other than sleep-disordered breathing in the snoring group. Although arterial partial pressure of oxygen and partial pressure of carbon dioxide were not monitored during cerebral blood flow velocity measurement, assessment was undertaken during the afternoon/early evening when the child was awake, and all of the sleep-disordered breathing children had normal resting oxyhemoglobin saturation at the outset of their subsequent sleep studies that day. Finally, there is an inverse linear relationship between cerebral blood flow and hematocrit in adults, and it is known that iron-deficient erythropoiesis is associated with chronic infection, such as recurrent tonsillitis, a clinical feature of many of the snoring children in the study. Preoperative full blood counts were not performed routinely in these children, and, therefore, it was not possible to exclude anemia as a cause of increased cerebral blood flow velocity in the sleep-disordered breathing group. However, hemoglobin levels were obtained in 4 children, 2 of whom had borderline low levels (10.9 and 10.2 g/dL). Although there was no apparent relationship with cerebral blood flow velocity in these children (cerebral blood flow velocity values of 131 and 130 cm/second compared with 130 and 137 cm/second in the 2 children with normal hemoglobin levels), this requires verification. It is of particular interest that our data suggest a relationship among snoring, increased cerebral blood flow velocities and indices of cognition (processing speed and visual attention) and perhaps behavioral (Behavior Rating Inventory of Executive Function) function. This finding is preliminary: a causal relationship is not established, and the physiologic mechanisms underlying such a relationship are not clear. Prospective studies that quantify cumulative exposure to the physiologic consequences of sleep-disordered breathing, such as hypoxia, would be informative.

Hypoxic adaptation during development: relation to pattern of neurological presentation and cognitive disability.

Children with acute hypoxic-ischaemic events (e.g. stroke) and chronic neurological conditions associated with hypoxia frequently present to paediatric neurologists. Failure to adapt to hypoxia may be a common pathophysiological pathway linking a number of other conditions of childhood with cognitive deficit. There is evidence that congenital cardiac disease, asthma and sleep disordered breathing, for example, are associated with cognitive deficit, but little is known about the mechanism and whether there is any structural change. This review describes what is known about how the brain reacts and adapts to hypoxia, focusing on epilepsy and sickle cell disease (SCD). We prospectively recorded overnight oxyhaemoglobin saturation (SpO2) in 18 children with intractable epilepsy, six of whom were currently or recently in minor status (MS). Children with MS were more likely to have an abnormal sleep study defined as either mean baseline SpO2 <94% or >4 dips of >4% in SpO2/hour (p = .04). In our series of prospectively followed patients with SCD who subsequently developed acute neurological symptoms and signs, mean overnight SpO2 was lower in those with cerebrovascular disease on magnetic resonance angiography (Mann-Whitney, p = .01). Acute, intermittent and chronic hypoxia may have detrimental effects on the brain, the clinical manifestations perhaps depending on rapidity of presentation and prior exposure.

Trials in sickle cell disease.

Children with sickle cell disease are at risk of developing neurologic complications, including stroke, transient ischemic attack, seizures, coma, and a progressive reduction in cognitive function. Transcranial Doppler ultrasound, magnetic resonance imaging, and overnight pulse oximetry appear to predict, making prevention an achievable goal so that there is now a focus on randomized controlled trials. The Stroke Prevention Trial in Sickle Cell Anemia (STOP) reported a reduction in the number of overt clinical strokes experienced by those children with critically high transcranial Doppler velocities (>200 centimeters per second) who were chronically transfused. Two additional Phase III studies and two pilot trials have been funded. STOP II focused on whether it is safe to discontinue blood in prophylactically transfused children when their velocities had remained normal for at least 30 months. The Silent Infarct Transfusion trial is designed to determine whether children with sickle cell anemia and silent cerebral infarcts, approximately 20% of the population, will have a decrease in the progressive neurologic complications after receiving regular blood transfusion therapy. Pilot safety and feasibility trials of low-dose aspirin and overnight respiratory support are also beginning. The collaboration provides an infrastructure for future clinical trials in this vulnerable group of children.

Respiratory responses to cold water immersion: neural pathways, interactions, and clinical consequences awake and asleep.

The ventilatory responses to immersion and changes in temperature are reviewed. A fall in skin temperature elicits a powerful cardiorespiratory response, termed "cold shock," comprising an initial gasp, hypertension, and hyperventilation despite a profound hypocapnia. The physiology and neural pathways of this are examined with data from original studies. The respiratory responses to skin cooling override both conscious and other autonomic respiratory controls and may act as a precursor to drowning. There is emerging evidence that the combination of the reestablishment of respiratory rhythm following apnea, hypoxemia, and coincident sympathetic nervous and cyclic vagal stimulation appears to be an arrhythmogenic trigger. The potential clinical implications of this during wakefulness and sleep are discussed in relation to sudden death during immersion, underwater birth, and sleep apnea. A drop in deep body temperature leads to a slowing of respiration, which is more profound than the reduced metabolic demand seen with hypothermia, leading to hypercapnia and hypoxia. The control of respiration is abnormal during hypothermia, and correction of the hypoxia by inhalation of oxygen may lead to a further depression of ventilation and even respiratory arrest. The immediate care of patients with hypothermia needs to take these factors into account to maximize the chances of a favorable outcome for the rescued casualty.

Physiologic impact of low-dose dopamine on renal function in the early post renal transplant period.

BACKGROUND: Low-dose dopamine (LDD) (< or =5.0 microg/kg/min) is often used in the early postrenal transplant period for its perceived improvements in renal function parameters. However, there is little published evidence to support its use. The aim of this study was to evaluate the effects of LDD on the physiologic parameters of the transplanted kidney. METHODS: With local ethics approval, 20 consecutive adult patients (age range, 27-74 years), who underwent cadaveric renal transplantation with cyclosporine immunosuppression, were randomized into two study groups, each with 10 patients. The study period was over 9 hrs on the first postoperative day. This 9-hr block was divided into three 3-hr periods. Patient group 1 received a dopamine infusion over the second 3-hr period only, and patient group 2 received a dopamine infusion over both the first and third 3-hr periods. During these periods, urine flow rate (UFR), effective renal plasma flow (ERPF), creatinine clearance (CC), and total urinary sodium excretion rate (tUNa) were measured. RESULTS: In both groups, there were significant (P<0.05, Wilcoxon rank sum test) increases in ERPF, UFR, CC, and tUNa during LDD infusion periods compared with periods of no LDD infusion. No changes in heart rate or mean arterial blood pressure were seen with LDD administration. CONCLUSIONS: LDD significantly increases ERPF, UFR, CC, and tUNa in the transplanted allograft kidney treated with cyclosporine immunosuppression in the early posttransplant period.

Enhancing the sensitivity of a sustained attention task to frontal damage: convergent clinical and functional imaging evidence.

Despite frequent reports of poor concentration following traumatic brain injury, studies have generally failed to find disproportionate time-on-task decrements using vigilance measures in this patient group. Using a rather different definition, neuropsychological and functional imaging research has however linked sustained attention performance to right prefrontal function--a region likely to be compromised by such injuries. These studies have emphasised more transitory lapses of attention during dull and ostensibly unchallenging activities. Here, an existing attention measure was modified to reduce its apparent difficulty or 'challenge'. Compared with the standard task, its capacity to discriminate traumatically head-injured participants from a control group was significantly enhanced. Unlike existing functional imaging studies, that have compared a sustained attention task with a no-task control, in study 2 we used positron emission tomography to contrast the two levels of the same task. Significantly increased blood flow in the dorsolateral region of the right prefrontal cortex was associated with the low challenge condition. While the results are discussed in terms of a frontal system involved in the voluntary maintenance of performance under conditions of low stimulation, alternative accounts in terms of strategy application are considered.

Coffee in the cornflakes: time-of-day as a modulator of executive response control.

Previous self-report based research has revealed a heightened propensity to slips-of-action in the early morning and at the end of the day. Here, we examined performance variability among healthy young adults as a function of time-of-day on a clinical task that is sensitive to absent-minded slips in brain-injured groups. We found significantly higher error rates at 1 pm and 7 pm compared with 1 am and 7 pm, and significant correlations between errors and two subjective sleepiness scales. No circadian modulation of the more routine aspects of the task was observed suggesting some specificity to the effect. Given evidence that the circadian cycle differentially affects different brain regions, and links between sleep deprivation and 'normal' dysexecutive behaviour, examining variation over the course of the day can prove a useful additional methodology in this area