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Background Anaesthetic journals frequently publish studies comparing measurement methods. A common method of analysis is the Bland and Altman plot, which relates the difference between paired measurements to the mean of the pair. Previous reviews have shown that key data are often omitted from reports using this method of analysis, and the analysis of more complex data is frequently insufficient. Methods We identified articles by searching reports, and subsequent citations, considering use of the method. We assembled a list of frequent and important criteria from these articles. These key features were tested by assessing articles in the yr 2013 and 2014, in five anaesthetic journals: Anaesthesia, Anesthesiology, Anesthesia and Analgesia, The British Journal of Anaesthesia, and The Canadian Journal of Anaesthesia. Results We found 29 features suggested for reporting such studies. Eight of these were frequently found. We chose 13 key features. In the journal articles reviewed to test these features, three features were almost always reported: the data structure, a plot of the bias, and the limits of agreement of the differences. Often, features required for adequate interpretation of the studies were absent, notably an a priori decision of acceptable limits of agreement, and an estimate of the precision of the limits of agreement. Conclusions Bland and Altman analysis remains poorly reported. Our formal list of key criteria will assist authors in providing all the relevant features of a study. We explain errors that may be made in reporting, and suggest methods for analysis, including easily available software.

Bland and Altman have developed a measure called “limits of agreement” to assess correspondence of two methods of clinical measurement. In many circumstances, comparisons are made using several paired measurements in each individual subject. If such measurements are considered as statistically independent pairs, rather than as sets of measurements from separate individuals, limits of agreement will be too narrow. In addition, the confidence intervals for these limits will also be too narrow. Suitable software to compute valid limits of agreement and their confidence intervals is not readily available. Therefore, we set out to provide a freely available implementation accompanied by a formal description of the more advanced Bland–Altman comparison methods. We validate the implementation using simulated data, and demonstrate the effects caused by failing to take the presence of multiple paired measurements per individual properly into account. We propose a standard format of reporting that would improve analysis and interpretation of comparison studies.

Background Respiratory rate is an important measurement in patient care, but accurate measurement is often difficult. We have developed a simple non-invasive device to measure respiratory movements in clinical circumstances, with minimal interference with the patient. We investigated respiratory patterns in patients receiving postoperative morphine analgesia to assess the capacity of the device to detect abnormalities. Methods We studied subjects during self-administered opioid analgesia after major gynaecological surgery, and related the derived signals with a signal from a nasal cannula. Respiratory movement signals were transmitted wirelessly to a recorder from two encapsulated tri-axial accelerometer (RESpeck) sensors. We analysed the signals using two different sensor placements, each for 30 min. The nasal cannula signal was used to classify breathing patterns as obstructive or non-obstructed. Results We studied 20 patients for a mean duration of 49 min each. Breathing patterns were very variable, between and within patients. The median breathing rates ranged from 6.4 to 19.5 bpm. Breathing was partly obstructed in 10 patients, and six patients had repeated cycles of obstruction and transient recovery. In these patients, we found a consistent and statistically significant pattern of changes in chest wall movement, with increased abdominal and decreased rib cage movement during obstruction. In patients with slow respiratory rates, breath-to-breath times were highly variable. Conclusions In undisturbed subjects receiving patient-controlled morphine analgesia after surgery, abnormal breathing patterns are extremely common. Cyclical airway obstruction is frequent and associated with a typical pattern of changes in chest wall movement.

Key Points this final article in our series draws together some of the ideas we have addressed, and suggests important ingredients that make a paper palatable to the reviewer and the reader. #### Describe the methods. Imagine that you are starting an experiment, which involves a method that is

Opioids increase abdominal muscle activity during anaesthesia. We proposed that opioid activity during anaesthesia would change chest wall size and movement, and contribute to ventilation. Using an optical system to measure chest wall volume, we studied 10 patients during isoflurane anaesthesia, first under the influence of an opioid and then after reversal with naloxone. Measurements were made during quiet breathing and with carbon dioxide stimulation. Airway occlusion pressure was measured to assess inspiratory and expiratory muscle activity. Chest wall volume decreased with the onset of spontaneous breathing, and decreased further when breathing was stimulated by carbon dioxide. Reversal of opioid activity increased chest wall volume. Breathing movements were predominantly abdominal. Opioid action affected the timing and amplitude of breathing but the pattern of abdominal movement was not affected. Since opioids augment abdominal muscle action during expiration, the unchanged pattern of movement can be attributed to both diaphragm and abdominal activity displacing the abdominal wall reciprocally, in the inspiratory and expiratory phases of the respiratory cycle, respectively.

Background Using conscious subjects, measurement of the effects of low concentrations of anaesthetic agents can allow the dynamics of onset and offset of the agent to be measured and kinetic values estimated. However, the tests have to be rapid and preferably assess cerebral function. Methods We used a short version of the digit symbol substitution test (DSST) that allowed frequent measurement of the impairment caused by nitrous oxide. We compared 10 min of onset and offset of breathing 5% and 30% nitrous oxide in 30% oxygen, compared with 30% oxygen only. End-tidal nitrous oxide concentrations were used to predict the concentration in a central compartment, according to a range of T1/2 values chosen to be consistent with possible cerebral blood flow values. Results We studied 19 volunteers and estimated a mean response. Only 30% nitrous oxide decreased the DSST. When DSST scores were related to the values in the predicted central compartment, the best dose–effect relationship was found when the T1/2 was 37 s, consistent with a regional blood flow of about 120 ml 100 g−1 min−1. Conclusions The onset of nitrous oxide effect on DSST is rapid, consistent with the perfusion of metabolically active cerebral cortical tissues. The rate of onset is greater than previous measures based on a motor test which involved the function of subcortical structures in the central nervous system.

Scientists frequently want to answer the question ‘has this treatment had an effect?’ Most are unaware that the tests they usually use do not directly address this question. These tests usually pose a different question, based on the possibility that nothing has happened. The question becomes: ‘how probable are these data, if there were NO difference between the original populations from which the data have been randomly drawn?’ (In fact for most laboratory experiments, this supposition is patently false – the experiment has been conducted using a pre-ordained sample, possibly randomly divided into treatment and control groups, but certainly not randomly sampled.)

Background Expiratory muscle action is prominent during anaesthesia and can impair lung function. This activity is exaggerated by the use of opioids. Airway pressure during occlusion of expiration would be a valuable measure in the study of expiratory muscle activation. However, this would only be valid if the imposed occlusion did not itself alter muscle activation. This possibility can be checked by directly assessing muscle activity by electromyography; varying arterial carbon dioxide tensions and opioid action should be considered. Methods We studied seven spontaneously breathing patients, anaesthetized with nitrous oxide and isoflurane, in four conditions: during an infusion of fentanyl and after naloxone, breathing normally and with breathing stimulated with CO2. We compared diaphragm and external oblique abdominal electromyogram (EMG) signals during normal and occluded breaths. We also measured chest wall volume and compared airway occlusion pressure, during inspiration and expiration, with the EMG results. Results Inspiratory occlusion increased the duration of inspiration during hypercapnia by 20%, but not the rate of electrical activation of the diaphragm, indicating that occlusion does not cause a reflex increase in diaphragm contraction. In contrast, expiratory occlusion did not affect either the duration of expiration or the electrical activity of the external oblique muscles. Conclusions In these conditions, except for a change in inspiratory duration, respiratory muscle activity is unaffected by airway occlusion. Airway occlusion will permit valid measures of muscle activity in inspiration and expiration and provide simple measurements of respiratory muscle function during anaesthesia.

Background Respiratory rate is an important measurement in patient care but frequently poorly assessed. We set out to develop a simple non-invasive device to reliably measure respiratory movements and estimate respiratory rate, in clinical circumstances. Methods Respiratory movement was detected with an encapsulated tri-axial accelerometer (Orient speck) and the data transmitted wirelessly to a computer for analysis. We studied subjects after gynaecological surgery who received opioid analgesia, and compared the derived signal with a signal from nasal cannula using directly matched breaths and within the same 5 min epoch. We analysed the signals for 5 min epochs over a 15 h recording period. Results For matched breath analysis, the instantaneous respiratory rates matched within 2 bpm on 86% of occasions. A similar match was found between epoch averages of the respiratory rate. The mean absolute difference between the respiratory rate measured by nasal cannula and Orient speck was 0.6 bpm. The Orient speck generated reliable measures of respiratory rate every 5 min in 95.4% of epochs. Conclusions The Orient speck provides a reliable measure of respiratory rate at frequent intervals in subjects receiving patient-controlled morphine analgesia after surgery.

Statisticians use words deliberately and specifically, but not necessarily in the way they are used colloquially. For example, in general parlance ‘statistics’ can mean numerical information, usually data. In contrast, one large statistics textbook defines the term ‘statistic’ to denote ‘a characteristic of a sample, such as the average score’, and the word ‘parameter’ to denote ‘a characteristic of a population’. However, for statisticians, statistics means more than just numerical information or a characteristic of a sample. Statistics is also a discipline. It is relevant to all areas of scientific enquiry, and spans study design, data collection, developing methods of analysis and analysing data, interpreting results, and making predictions. Other words that statisticians use carefully, and very particularly, form the cornerstones of statistical reasoning, words such as probability, significance, likelihood. Why does this matter? Well, it may well explain why non-statisticians struggle with the ideas and concepts used by statisticians. The reader is confused by the terminology, not the least because the statistician uses familiar words in different ways, a jargon similar to other professional vocabularies.

• Samples are often compared by first proposing that they could have come from the same population • Two random samples from the same population are unlikely to be the same • Although not exactly the same, is it probable that two samples have been drawn from the same population? • If the probability they came from the same population is small, then the original proposal is not supported • If it is improbable that the difference between the mean values of the two samples could be zero, this is poor support for the proposal that the samples have come from the same source • A ‘confidence interval’ is the range of values that could contain the true value • Small samples are often imprecise, so a difference between samples may be concealed • Precision is also affected by the variability in a population: this could swamp the ‘signal’ difference • Significant does not mean important, only unlikely to have happened by chance

Objective To compare recovery from sedation using remifentanil and propofol with our standard regimen of morphine and midazolam for closed reduction in shoulder dislocation in an ED. Methods We randomised 40 patients for closed shoulder reduction to receive either remifentanil and propofol (R&P) (20 patients) or morphine and midazolam (M&M) (20 patients). A suitably trained ED doctor gave the sedation. R&P patients received oxygen from a tight-fitting facemask and Mapleson C circuit to prevent hypocapnia and thus reduce the risk of apnoea. Shoulder reduction was performed by another doctor with an ED nurse also present. We noted recovery times, pain and sedation scores, operative conditions, additional medication and adverse events. Results All patients given remifentanil and propofol had recovered within 30 min in contrast to the morphine and midazolam group where 17 of 20 patients had recovered after 60 min, the remainder requiring a total of 90 min. Median recovery times were 15 min (95% CI 15 to 20) for the remifentanil and propofol group, and 45 min (95% CI 29 to 48) for the morphine and midazolam group. Reduction conditions and scores for pain/distress did not differ between the groups. Seven patients required additional sedation (four R&P, three M&M) to enable shoulder reduction. Five patients (three R&P, two M&M) had received analgesia prior to the procedure from the ambulance service (one R&P, one M&M) and ED (two R&P). Two patients given morphine and midazolam required flumazenil to counter oversedation. Conclusions Remifentanil and propofol reduces patient recovery time and provides equivalent operating conditions compared with morphine and midazolam for the reduction of anterior glenohumeral dislocation.

Background and objective In patients after surgery, we observed large-amplitude low-frequency changes in digital plethysmograph measurements when DC coupling of the signal was used. We set out to assess factors that might contribute to these events and in particular to test the possibility that low-frequency signals could be used to assess respiratory disturbances. Methods We recorded values in 23 patients who had undergone gynaecological surgery. We measured nasal flow, abdominal pressure (by urinary catheter), venous pressure in the hand, and DC-coupled optical transmission plethysmography. Signals were replayed and analysed to assess the incidence of specific patterns of events. Results Most patients received morphine for postoperative analgesia. Respiratory irregularity and expiratory muscle action were very frequent. Increases in abdominal pressure during expiration caused increases in venous pressure and pulsation. In 12 out of 23 patients, a characteristic response consistent with vasoconstriction was noted after increases in breath size, and, in seven patients, very-low-frequency (0.2–0.7 Hz) oscillations of finger volume were present that appeared unrelated to respiratory events. Patients who did not receive morphine had very different plethysmograph patterns, with significantly smaller pulse amplitude. Conclusion Low-frequency changes in finger volume can be simply obtained and provide considerable information about peripheral circulatory dynamics. Diverse patterns can be recognized, but the range of responses suggests that current techniques cannot be used alone to assess cardiorespiratory status. However, a combination of plethysmography with respiratory measurements shows characteristic events.

Background The predominant effect of opioids on respiratory pattern during anaesthesia is an increase in the duration of expiration (an effect on ‘timing’), but there may also be changes in tidal volume (an effect on ‘drive’). Timing and drive are controlled by separate neuronal systems, but are infrequently considered individually. The effects of opioids on breathing are not well characterized clinically because changes in carbon dioxide and anaesthetic levels usually occur at the same time, and can obscure the effects of the opioid. Methods To study these effects in isolation, we established stable mild hypercapnia in female patients breathing spontaneously during sevoflurane anaesthesia, and then gave fentanyl 0.5 μg kg−1 i.v. End-tidal carbon dioxide and sevoflurane concentrations were maintained constant, and the changes in timing of inspiration, expiration and tidal volume were measured. Results The duration of inspiration increased by 30%, and the duration of expiration increased by 95%. Tidal volume increased in proportion to inspiratory duration, and the pattern of flow during the breath was recognizably changed, with a reduction in the rate of increase of flow at the onset of inspiration. Conclusions Small doses of opioid given when anaesthesia and carbon dioxide are stable affect respiratory timing predominantly, but in addition changes in the pattern of motor output can be detected.

In normal subjects, alcohol increases handwriting size, but the mechanism is not understood. Here we show that the alcohol effect on handwriting can be explained by a selective impairment of kinaesthetic perception. Thirty volunteers (15 male, aged 18-29 years) took part in an open study. They were tested before and after a drink containing vodka intended to produce a blood alcohol concentration of about 80mg/100ml. Tests included kinaesthetic distance estimation, in which volunteers worked with preferred hand and arm behind a screen which hid their movements; visual distance estimation; and measures of handwriting and drawing. Blood alcohol concentration at 55min, based on breathalyser measurements, was 76.7mg/100ml (SD 9.8). When asked to move the hand and mark a distance of 10cm from a starting point, distances estimates increased by 7-10% ( p 0.01). Similar increases were seen for writing words and drawing characters. Signatures were increased in height but not in length. Distances estimated visually were increased much less, by 3-4% ( p 0.05). Tests of psychomotor performance indicated the expected effects of ethanol. These results suggest that ethanol affects writing size by reducing kinaesthetically perceived distances.

Objective. To compare measurements of thyroid and adrenal function between survivors and non-survivors in critical illness. Design and setting. Prospective, observational study at the medical/surgical intensive care unit (ICU) at Royal Infirmary of Edinburgh, Scotland. Patients. 163 patients admitted to the intensive care unit over a 4-month period. Interventions. We took blood samples within 1 h of ICU admission, and at 08:00 hours on the subsequent 2 days of ICU admission. We measured serum total (TT4) and free (fT4) thyroxine, total (TT3) and free (fT3) tri-iodothyronine, thyrotropin (TSH) and plasma cortisol concentrations. Measurements and results. TT3 and TT4 concentrations were significantly less in non-survivors than in survivors on admission and on day 1 but not on day 2. Cortisol concentrations were higher in non-survivors on admission and on day 1 but not on day 2. TSH, fT3 and fT4 concentrations did not differ significantly between survivors and non-survivors at any time. Only TT4 and cortisol were independent predictors of outcome. Prediction of outcome from the admission sample values was not better than using APACHE II scoring. Conclusions. Thyroid hormone and cortisol concentrations differ between survivors and non-survivors on admission to intensive care, but the values overlap. These differences do not allow accurate prediction of outcome from critical illness.

Background After major surgery, analgesia with opioids can cause obstructive apnea and intermittent hypoxemia, probably from loss of upper airway control. Since this resembles the obstructive sleep apnea syndrome, we tested the possibility that nasal continuous positive airway pressure (nCPAP) would reduce episodes of reduced oxygen saturation and sleep disruption. Because oxygen therapy is frequent after surgery, we also assessed the effect of oxygen on sleep disruption. Methods We recruited 48 patients about to have major abdominal surgery. We present data for 34 patients: 27 who received patient-controlled intravenous morphine and 7 who received epidural opioid. Treatment was randomized to either nCPAP or conventional therapy with an oxygen mask. Alternate periods of administration of air and 35% oxygen were used in both groups. If the oxygen saturation as measured by pulse oximetry was consistently Results The median proportion of time awake was 65% (45-79%) among control patients and 74% (55-87%) among those undergoing nCPAP. Oxygen administration did not affect the sleep pattern. The median frequency of arousals per hour of sleep was very similar in each group: during air breathing from nCPAP, 125 (76-187), and during air breathing by mask, 116 (84-187). Oxygen therapy had no effect. Oxygenation and hypoxemic events were not improved by nCPAP. Oxygen therapy improved oxygenation and reduced but did not eliminate episodes of desaturation. Conclusions Nasal CPAP does not improve sleep and oxygenation or reduce hypoxemic events in the first night after major abdominal surgery.

Background\ud Inappropriate prescribing of intravenous (IV) fluid, particularly 0.9% sodium chloride, causes post-operative complications. Fluid prescription is often left to junior medical staff and is frequently poorly managed. One reason for poor intravenous fluid prescribing practices could be inadequate coverage of this topic in the textbooks that are used.\ud \ud Methods\ud We formulated a comprehensive set of topics, related to important common clinical situations involving IV fluid therapy, (routine fluid replacement, fluid loss, fluids overload) to assess the adequacy of textbooks in common use. We assessed 29 medical textbooks widely available to students in the UK, scoring the presence of information provided by each book on each of the topics. The scores indicated how fully the topics were considered: not at all, partly, and adequately. No attempt was made to judge the quality of the information, because there is no consensus on these topics.\ud \ud Results\ud The maximum score that a book could achieve was 52. Three of the topics we chose were not considered by any of the books. Discounting these topics as “too esoteric”, the maximum possible score became 46. One textbook gained a score of 45, but the general score was poor (median 11, quartiles 4, 21). In particular, coverage of routine postoperative management was inadequate.\ud \ud Conclusions\ud Textbooks for undergraduates cover the topic of intravenous therapy badly, which may partly explain the poor knowledge and performance of junior doctors in this important field. Systematic revision of current textbooks might improve knowledge and practice by junior doctors. Careful definition of the remit and content of textbooks should be applied more widely to ensure quality and “fitness for purpose”, and avoid omission of vital knowledge.

We studied the effect of tramadol on the ventilatory response to 7 min acute isocapnic hypoxia (SpO2 85.1 (SD 0.4)%) during steady mild hypercapnia (PE'CO2 0.7 kPa above normoxic baseline) in 14 healthy volunteers (seven male). The acute hypoxic response was measured before and 1 h after oral placebo or tramadol (100 mg). After tramadol, ventilation during mild hypercapnia (mean 11.28 litres min-1) was significantly less (P < 0.05) than during placebo baseline (13.93 litres min-1), tramadol baseline (14.63 litres min-1), or after placebo (14.95 litres min-1), confirming that tramadol has a small depressive effect on the hypercapnic ventilatory response. There was no significant difference in the hypoxic ventilation/SpO2 response (1 min-1 %-1) measured during the placebo baseline (0.99), placebo (1.18), tramadol baseline (0.78) or tramadol (0.68) runs. These data suggest that tramadol does not depress the hypoxic ventilatory response.

We studied healthy female patients, allocated randomly to three breathing regimens for induction of anaesthesia using sevoflurane and oxygen from a co-axial Mapleson D breathing system and a mask, to test the hypothesis that rebreathing reduces the incidence of apnoea associated with loss of consciousness. The non-rebreathing group received sevoflurane in oxygen 6 litre min-1 from the start, doubling in concentration from 0.5% to 8% every 3 breaths. The second group received oxygen 6 litre min-1 for 1 min before sevoflurane was introduced, and the third group received oxygen 3 litre min-1 for 1 min before sevoflurane. The incidence and duration of apnoea were assessed using pneumotachograph and impedance pneumograph recordings, and time to induction of anaesthesia (weight drop) was measured from the time the breathing sequence was started. There was no difference in these times, which were mean 121 (95% confidence values 91-160) s, 117 (69-201) s and 125 (76-192) s, respectively. There was a significant difference in the incidence of apnoea. No apnoea occurred during induction using oxygen 3 litre min-1. Apnoea occurred in five of 15 patients who did not receive oxygen before sevoflurane and in four of 13 who received oxygen 6 litre min-1 (P0.05). No patient showed a reduction in pulse oximeter saturation. We conclude that inhalation induction of anaesthesia can be performed reliably in approximately 3 min using sevoflurane in oxygen 3 litre min-1.

We have studied the ventilatory responses to acute isocapnic hypoxia (SpO2 78.8 (SD 1.4)% for 10 min) in 10 male volunteers given three different doses of oral domperidone: placebo, domperidone tablets 10 mg, 20 mg or 30 mg every 8 h for 48 h on separate days. Neither baseline ventilation nor the acute hypoxic ventilatory response was significantly different from placebo for any of the domperidone doses. However, hypoxic responses were either increased with increments of domperidone or subjects were not sensitive. We arbitrarily divided subjects into two groups according to their hypoxic response-plasma domperidone concentration relationship. Analysis of subjects (n = 5) who demonstrated at least a 2-litre min-1 increase in ventilation per 10 ng ml-1 increase in plasma domperidone concentration showed the greatest augmentation of hypoxic responses with the 20-mg dose (median 19.45 (range 13.37, 22.30) litre min-1) compared with placebo (median 8.21 (3.74, 9.47)) (P = 0.003). We were unable to predict which subjects would be sensitive to the effects of domperidone.

Background Airway obstruction after anesthesia may be caused or exaggerated by residual neuromuscular block, with loss of muscle support for collapsible upper airway structures. Methods Six male volunteers were studied before treatment, during stable partial neuromuscular block with vecuronium at a mean train-of-four (TOF) ratio of 50% (95% CI, 36-61%), and after reversal by neostigmine. Catheter-mounted transducers were placed in the pharynx and esophagus to estimate, respectively, the upper airway resistance, and the work of breathing (calculated as the time integral of the inspiratory pressure developed by the respiratory muscles, esophageal pressure time product) during quiet breathing, during breathing 5% carbon dioxide, and while breathing with an inspiratory resistor. Breathing with pressure at the airway opening held at pressures from -5 to 40 cm H2O were also tested to assess airway collapsibility. Results Although breathing through a resistor increased upper airway resistance from 1.2 (0.67, 1.72) cm H2O x l(-1) x s to 2.5 (1.32, 3.38) cm H2O x l(-1) x s, and carbon dioxide stimulation reduced resistance to 0.8 (0.46, 1.33) cm H2O x l(-1) x s, no effect of partial neuromuscular block (mean TOF ratio, 52%) on upper airway properties could be shown. Conclusions Neuromuscular block with a TOF ratio of 50% can be present yet clinically difficult to detect in patients recovering from anesthesia. This degree of block has no effect on airway patency in volunteers, even during challenge. Airway obstruction during recovery from anesthesia thus is more likely to be caused by residual effects of general anesthetic agents or centrally acting analgesics, either alone or perhaps in concert with residual neuromuscular block.

We have studied the ventilatory responses to transient hyperoxia in two groups of patients (n = 10) anaesthetized with isoflurane (0.3 MAC); patients were allocated randomly to receive either domperidone or placebo orally before anaesthesia. In each patient, five two-breath oxygen tests were averaged and minute ventilation (VEinst) or mean inspiratory flow rate (VT/TI) for each post-test breath was compared with the mean values for these variables during baseline ventilation. A decrease to less than the 95% confidence limits of mean baseline values was considered a definite response. According to this definition, transient hyperoxia decreased VEinst in nine of 10 patients in the placebo group and in all patients in the domperidone group. Similar changes occurred in VT/TI, with eight of 10 definite responses in the placebo group and 10 of 10 in the domperidone group. Compared with placebo, in the domperidone group there were larger changes in VEinst (0.30 vs 0.55 litre min-1 (P = 0.05) and VT/TI (8.5 vs 26.6 ml s-1 (P = 0.02)) from respective baselines. Peripheral chemoreceptors appeared to be active during isoflurane anaesthesia and domperidone pretreatment enhanced this activity by increasing respiratory drive.

After surgery, patients may receive little audiovisual stimulation and may sleep. Lack of audiovisual stimulation enhances the suppression of the hypoxic ventilatory response (HVR) by 0.1 minimum alveolar anesthetic concentration (MAC) isoflurane. Sleep also reduces the HVR and may thus increase the risk of hypoxia in patients at this time. We therefore measured the ventilatory response in volunteers to a sustained step hypoxic stimulus (mean arterial oxygen saturation [SaO2] 80% [SEM 0.3] for 20 min) in the presence of 0.1 MAC isoflurane, with subjects in the awake and asleep states. The behavioral states were studied in random order in nine male subjects. The combination of isoflurane and sleep significantly reduced (P < 0.05) normoxic ventilation (6.71 [0.39] vs 8.24 [0.29] L/min) and increased end-tidal PCO2 (PETCO2) (43.1 [0.5] vs 40.4 [0.8] mm Hg) compared with the awake state. However, ventilation was similar in the asleep and awake states during early (15.10 [1.35] vs 15.50 [1.61] L/min) and late (10.45 [0.97] vs 11.03 [0.99] L/min) hypoxia in the presence of isoflurane. Thus sleep did not reduce ventilation during hypoxia in the presence of isoflurane sedation. The increase in PETCO2 during sleep may have offset suppression of the HVR.

Department of Medicine, University of California, Los Angeles, Cardiovascular Research Laboratory at UCLA, Los Angeles, CA, USA, Department of Anaesthesia and Pain Medicine, University of Edinburgh, Royal Infirmary, Edinburgh, UK, and Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK Correspondence Dr Gordon B Drummond, Department of Anaesthesia and Pain Medicine, University of Edinburgh, Royal Infirmary, Edinburgh, 51 Little France Crescent, Edinburgh EH16 4HA, UK. E-mail: g.b.drummond@ed.ac.uk

Key Points our previous article in this series considered analysis of variance ([4][1]), which is applied to measurements made of samples from different groups. That approach considers the variation of the data, and specifically the variation between samples, which is related to the presence of

Background Disturbed breathing during sleep, with episodic upper airway obstruction, is frequent after major surgery. Ventilatory responses to hypercapnia and hypoxia during episodes of airway obstruction are difficult to investigate because the usual measure, that of ventilation, has been attenuated by the obstruction. We simulated the blood gas stimulus associated with obstruction to allow investigation of the responses. Methods To assess ventilatory responses, we studied 19 patients, mean age 59 (19–79), first at discharge from high dependency care after major abdominal surgery and then at surgical review, ∼6 weeks later. Exhaled gas was analysed and inspired gas adjusted to simulate changes that would occur during airway obstruction. Changes in ventilation were measured over the following 45–70 s. Studies were done from air breathing if possible, and also from an increased inspired oxygen concentration. Results During simulated obstruction, hypercapnia developed similarly in all the test conditions. Arterial oxygen saturation decreased significantly more rapidly when the test was started from air breathing. The mean ventilatory response was 5.8 litre min −2 starting from air breathing and 4.5 litre min −2 with oxygen breathing. The values 6 weeks later were 5.9 and 4.3 litre min −2 , respectively ( P =0.05, analysis of variance). There was no statistical difference between the responses starting from air and those on oxygen. Conclusions After major surgery, ventilatory responses to hypercapnia and hypoxaemia associated with airway obstruction are small and do not improve after 6 weeks. With air breathing, arterial oxygen desaturation during simulated rebreathing is substantial.

BACKGROUND Previous modeling of the kinetics of uptake and elimination of anesthetic drugs from the site of action has used measures derived from the electroencephalogram. Such measures lag the current brain activity because of the time needed to acquire a signal sample and derive the measure. With a direct measure of anesthetic activity, we could model brain uptake more exactly. METHODS In volunteers, using a double-blind single-session design, we made repeated measurements using a well-known psychomotor test, the 2 target tapping test, during the washin and washout of 30% nitrous oxide. We also assessed maximal drug effect with a test of cognitive function, the digit symbol substitution test. Concentration at the site of action was modeled from end-tidal measurements, using a simple exponential washin and washout function, with half-times between 0.5 and 3 minutes. Comparisons were made within subjects, using 0 and 5% nitrous oxide. RESULTS We studied 20 subjects. Nitrous oxide, at 30%, consistently reduced performance of the digit symbol substitution test. Tapping frequency was also reduced, but the effect was less consistent, and only 9 of 20 subjects showed a significant individual reduction in tapping frequency. In these subjects, the relationship between the modeled brain concentration and drug effect was better with a half-time set at 2 minutes, compared with 1.5 or 3 minutes. CONCLUSIONS Given in subanesthetic concentrations, nitrous oxide has rapid onset and offset, consistent with a half-time of 2 minutes. This value is less than the values expected from studies during anesthesia using processed electroencephalogram, but consistent with measures of blood flow to active cerebral tissue in conscious subjects. Studies of performance in conscious subjects may aid further studies of anesthetic kinetics.

Key Points • Although relatively robust to the following, ANOVA assumes • Normal distribution of residuals • Variation in each group is similar • ANOVA is sensitive to outliers, and transforms of the data may be necessary • ANOVA is a test of group differences: do at least two of the means differ from each other? • Two-way ANOVA tests a number of sources of variability • It is important to know which source of variation is of interest • Do the sources of variation interact? • Care is needed with repeated measures • There may be better tests, particularly if the factor can be expressed as a continuous variable.

Key Points most biological scientists conduct experiments to look for effects, and test the results statistically. We have already described Student's t test which is very commonly used. However, this test concentrates on a very limited question. We assume that there is no effect in the experiment

To determine the effects of induction agent and obesity on the change in functional residual capacity caused by induction of anaesthesia, we measured the change in end-expiratory respiratory volume (EERV) during induction of anaesthesia with either thiopentone or propofol. Female patients breathed via a face mask from a closed circle system connected to a water spirometer. The spirometer tracing was used to measure the decrease in EERV. The median decrease was 200 (95% confidence limits 90-280) ml after thiopentone and 285 (200-425) ml after propofol. The decrease in each group was significant (P0.01) but there was no difference between the two groups. The change in EERV, expressed as a proportion of the predicted functional residual capacity, was not related to obesity (estimated as the ratio of actual to predicted body weight).

Key points experimental data are analysed statistically to allow us to draw conclusions from a limited set of measurements. The hard fact is that we can never be certain that measurements from a sample will exactly reflect the properties of the entire group of possible candidates available to be

In clinical practice, the elements of the circulation that receive most attention are the heart and blood vessels, despite the fact that ‘the heart and vasculature exists for one fundamental purpose: the delivery of metabolic substrate to the cells of the organism’ (Levick, 1991). Attitudes to this ‘fundamental purpose’ vary. The book cited here assigns nearly 20% of its text to these processes, although another similar basic textbook devotes a mere 5%, and generally the emphasis in medical teaching is on the arterial side of the circulation. One of the reasons for this blind spot may be that scientists, and clinical scientists in particular, tend to study features that are accessible, where equipment and methods are available, and where interest already lies. Thus despite the common definition of shock as ‘where vital tissues are inadequately perfused’, consideration of the processes that govern exchange from the capillary to the cell, and interest in the regulation of the medium in which this exchange occurs, are remarkably limited in clinical science. The lymphatic tree that flows from the tissues is a challenge to our knowledge. Its function may in many respects mirror the better known vasculature: it has mechanical, hydraulic and regulatory systems that are vital to tissue life, and indeed there may be some very analogous control of blood and lymph vessels. Because of the impression that most intensive care considerations focus on the blood system, a Journal of Physiology symposium entitled ‘Physiology, pharmacology and pathology of tissue fluid exchange’ was held at the 31st International Symposium on Intensive Care and Emergency Medicine in Brussels, Belgium, on 22 March 2011, to encourage clinicians to lift their eyes from the bloodstream to the horizon of the tissues, and consider these vital processes in the interstitial space. Oedema is recognised as a marker and a consequence of disease, one of the cardinal signs of inflammation, and one of the classic signs of cardiac failure: but lymphatic processes continue (or fail) unseen. The contributions from the symposium published in this issue of The Journal aim to encourage consideration of the wider aspects of tissue fluid, and perhaps stimulate research and therapy in these topics. The structure and mechanical behaviour of the lymphatic channels is fascinatingly diverse. Negrini & Moriondo (2011) explain how lymphatic vessels and their surrounding tissues interact to provide a range of different characteristics, and sustain varying functions that contribute to the formation, modification, and transport of lymphatic fluids. In particular, their analysis illustrates how changes in tissue activity can impact on the drainage of tissue fluid, and may offer some additional therapeutic reasons for aiming to sustain respiratory muscle activity during critical illness. The factors that control lymphatic exchange have some interesting parallels with the better known capillaries. Huxley & Scallan (2011) have studied lymphatic exchange and transport processes. Their review considers the structures and forces that affect and regulate fluid and protein exchange, and emphasises how these can be very actively regulated. These regulatory factors include structure and activity of the vessels themselves, and responses to mediators that substantially affect circulatory dynamics, such as ANP and cytokines. These agents affect both mechanical activity and permeability, often in different ways. If we include the heterogeneity of the lymphatic vessels in this mix, then it's clear that this is, in health, a finely balanced medium where the potential for disruption by disease is considerable. It also may well be that some the agents currently used to manage the circulation could have substantial effects on lymphatic function. The review by Wiig (2011) extends these considerations to some pathological scenarios: vascular overload and sepsis. He emphasises the diversity of the composition of interstitial fluid, the different physicochemical features of the interstitial matrix, and the capacity of the gradients in composition to be altered by dynamic processes such as a change in filtration rate. Even a remarkably effective regulation of interstitial fluid, as found in the trachea, can be disrupted by fluid overload, as well as by other forms of damage such as neurogenic inflammation. Local paracrine factors are also highly important in tissue fluid formation, as he shows in considering experiments using the lymph circulation through the spleen. The spleen generates a large lymph flow and liberates not only formed elements but also soluble mediators such as cytokines. Sepsis magnifies these processes. Responses in these two tissues, spleen and trachea, differ substantially, showing that epithelial tissue has an important part to play in cytokine output. Overall, these reviews emphasise how vital it should be that we study what is important rather than what we can study easily. On this new horizon, we can only speculate what therapeutic targets may emerge, but the signs are that there may be many, and varied, approaches that may be taken in managing this vital medium, the interstitial fluid.

The Physiological and Pharmacological Societies in the UK have been aware for some time that statistical testing and data presentation in our journals can fall short of the high standards that we wish to maintain. Over recent years other medical and life science journals have made substantial efforts to address similar problems. For example, the BMJ set out to improve reporting in medical journals through a sustained campaign of education and guidance (Swinscow, 1983). Among basic life science journals, the American Physiological Society notably has tried to improve statistical reporting in its journals (Curran-Everett & Benos, 2004, 2007). A more recent initiative was a series of revealing ‘worked examples’, starting in 2007 (Lew, 2007). Our Societies recently endorsed the ARRIVE guidelines for reporting experiments involving animals (Drummond et al. 2010), which repeat the same advice on statistical reporting. Nevertheless, in many instances the quality of data presentation and statistical analysis can be poor, and this despite the widespread availability of books, articles, websites and easily used statistical packages. We feel that these messages, which are often a plea for simplicity, have not reached a critical mass of authors, and more needs to be done to raise reporting standards. To meet this need, we are publishing a series of short articles to provide clear non-technical guidance for authors on best practice in statistical testing and data presentation. Several other life science journals share our concerns and are also publishing the articles to broadcast the message as widely as possible. The articles will appear monthly over the next 15 months. Authorship of the series was a key question in early discussions. To get the project up and running we asked local authors to generate articles and get the project started. One of us, Gordon Drummond, Senior Statistics Editor for The Journal of Physiology, has had the help of a qualified medical statistician, Sarah Vowler (Cancer Research UK), in writing these articles. Others may become involved with future articles. We invite comment on the articles, as we are well aware that there is no single path, and valid differences of opinion should be considered. We recognise that in some fields, special means of data presentation and statistical treatment are required. We intend to address some of these fields and we would be happy to receive suggestions for topics. We may not explore these topics in depth, because the over-riding aim is to keep the articles simple to encourage easy reading and widespread application. The prime aim is to illustrate good practice and illuminate the perils and problems that often trap the unwary. The articles will be published under a non-exclusive licence to enable free re-use and duplicate publication in multiple journals. They will be published simultaneously in The Journal of Physiology, Experimental Physiology, The British Journal of Pharmacology, the American Physiological Society's Advances in Physiology Education, Clinical and Experimental Pharmacology and Physiology, and Microcirculation. We have adapted our Guidelines for Authors to reflect the advice given in the articles and will collate the articles in virtual collections as a resource for authors, students and teachers.

This short editorial is the first of a planned series to guide the handling of data from laboratory experiments. We hope that authors (and editors) may find this helpful in writing and assessing future journal articles. It's clear that data handling in science needs to be improved, if only from the number of attempts that have been made to rectify the problem. Books, articles and websites give copious words of advice, too numerous to cite. Many are indeed helpful, but others are often too dense and discouraging for the non-specialist. Often the advice is ‘too general in nature, too limited in scope, and too specialized in vocabulary to be useful to most authors and editors’ (Lang & Secic, 2010). On one occasion the American Physiological Society gave specific advice (Curran-Everett & Benos, 2004). When the guidelines were followed up, the results were found to be mixed, with some praise but also criticism and controversy, with little overall effect on the quality of publication (Curran-Everett & Benos, 2007). In general, encouraged by the slow but substantial change that has occurred in medical journals, there seems to be a mood to improve, although changes in basic science journals have been slow, if they have occurred at all. Comparison of basic science reports with clinical studies is not flattering (Watters & Goodman, 1999). We are well aware that advice alone has been ineffective. We could easily list a comprehensive set of guidelines, which would probably suffer a fate similar to those that have gone before. In contrast we hope that by keeping the articles in this series short and focused, they will offer advice that is digestible and palatable. They may even attract readers who find such topics difficult and unappealing when they are presented in larger portions. We shall try to avoid technical terms and complicated maths. Much advice starts with a suggestion that one should consult a statistician. Considering the time and cost of some experiments, this would often be prudent. Admittedly statisticians are a rare breed and can be hard to find. Often when the data are given to a statistician there is a problem with them that might have been avoided if the consultation had occurred at the start. Fisher once said: ‘To consult a statistician after an experiment is finished is often merely to ask him to conduct a post-mortem examination. He can perhaps say what the experiment died of’ (Fisher, 1938). In practice, it's likely that basic scientists do not know that they should seek advice beforehand, as they may not be sure what they will find, or they consider that what they will find will be easily described and analysed with a simple toolbox of tests. On occasion, physiological studies resemble a random walk through a series of ‘what ifs?’ and ‘how can we prove this mechanism?’ stages that may leave a statistician searching for a single testable hypothesis. When basic scientists do have data to analyse, they may think the exciting part of the study is done. They look around for an easy way to deal with their data, and often ask someone with possibly more experience but probably no more training what to do. The advice is often ‘well, this is what I did …’, almost designed to sustain the status quo and perhaps perpetuate error. A recent article repeated the often heard advice: ‘The choice of how to express the data is very important and should not be made solely on the basis of habit or convention. Always inspect the data in its raw form’ (Lew, 2007).

We investigated the incidence of AMS amongst a general population of trekkers on Mount Kilimanjaro, using the Lake Louise consensus scoring system (LLS). Additionally we examined the effect of prophylactic acetazolamide and different ascent profiles. Climbers on 3 different ascent itineraries were recruited. At 2743 m we recruited 177 participants (mean age 31, range [18-71]) who completed LLS together with an epidemiological questionnaire. At 4730 m participants (n=189, male=108, female=68, mean age 33, range [1871]) completed LLS, 136 of whom had been followed up from 2730 m. At 2743 m, 3% (5/177) of climbers were AMS positive, and 47% (89/189) of climbers from all itineraries were AMS positive at 4730 m. Of climbers attempting the Marangu itineraries, 33% (45/136) were taking acetazolamide. This group had a similar rate of AMS and no statistical difference in severity of LLS when compared with those not taking prophylactic drugs. We also did not demonstrate a difference between the incidence of AMS in climbers who did or did not take a rest day at 3700 m. However, there was a significant reduction in the incidence of AMS amongst pre-acclimatized subjects. Consistent with previous work, we found that the rate of AMS on Mount Kilimanjaro is high. Furthermore, at these fast ascent rates, there was no evidence of a protective effect of acetazolamide or a single rest day. There is a need to increase public awareness of the risks of altitude sickness and we advocate a pragmatic "golden rules" approach (http://www.altitude.org/altitude_sickness.php).

BACKGROUND: The value of respiratory variables as weaning predictors in the intensive care unit (ICU) is controversial. We evaluated the ability of tidal volume (Vt(exp)), respiratory rate (f), minute volume (MV(exp)), rapid shallow breathing index (f/Vt), inspired-expired oxygen concentration difference [(I-E)O(2)], and end-tidal carbon dioxide concentration (Pe'(co(2))) at the end of a weaning trial to predict early weaning outcomes. METHODS: Seventy-three patients who required >24 h of mechanical ventilation were studied. A controlled pressure support weaning trial was undertaken until 5 cm H(2)O continuous positive airway pressure or predefined criteria were reached. The ability of data from the last 5 min of the trial to predict whether a predefined endpoint indicating discontinuation of ventilator support within the next 24 h was evaluated. RESULTS: Pre-test probability for achieving the outcome was 44% in the cohort (n=32). Non-achievers were older, had higher APACHE II and organ failure scores before the trial, and higher baseline arterial H(+) concentrations. The Vt, MV, f, and f/Vt had no predictive power using a range of cut-off values or from receiver operating characteristic (ROC) analysis. The [I-E]O(2) and Pe'(co(2)) had weak discriminatory power [area under the ROC curve: [I-E]O(2) 0.64 (P=0.03); Pe'(co(2)) 0.63 (P=0.05)]. Using best cut-off values for [I-E]O(2) of 5.6% and Pe'(co(2)) of 5.1 kPa, positive and negative likelihood ratios were 2 and 0.5, respectively, which only changed the pre- to post-test probability by about 20%. CONCLUSIONS: In unselected ICU patients, respiratory variables predict early weaning from mechanical ventilation poorly.

Overdistension of lung tissue during mechanical ventilation causes cytokine release, which may be facilitated by the autonomic nervous system. We used mechanical ventilation to cause lung injury in rats, and studied how cervical section of the vagus nerve, or substance P (SP) antagonism, affected the injury. The effects of 40 or 25 cmH(2)O high airway pressure injurious ventilation (HV(40) and HV(25)) were studied and compared with low airway pressure ventilation (LV) and spontaneous breathing (controls). Lung mechanics, lung weight, gas exchange, lung myeloperoxidase activity, lung concentrations of interleukin (IL)-1 beta and IL-6, and amounts of lung SP were measured. Control rats were intact, others were bivagotomized, and in some animals we administered the neurokinin-1 (NK-1) receptor blocking agent SR140333. We first determined the durations of HV(40) and HV(25) that induced the same levels of lung injury and increased lung contents of IL-1 beta and IL-6. They were 90 min and 120 min, respectively. Both HV(40) and HV(25) increased lung SP, IL-1 beta and IL-6 levels, these effects being markedly reduced by NK-1 receptor blockade. Bivagotomy reduced to a lesser extent the HV(40)- and HV(25)-induced increases in SP but significantly reduced cytokine production. Neither vagotomy nor NK-1 receptor blockade prevented HV(40)-induced lung injury but, in the HV(25) group, they made it possible to maintain lung injury indices close to those measured in the LV group. This study suggests that both neuronal and extra-neuronal SP might be involved in ventilator-induced lung inflammation and injury. NK-1 receptor blockade could be a pharmacological tool to minimize some adverse effects of mechanical ventilation.

Background: Mobile phone (cellphone) technology makes it practicable to assess cognitivefunction in a natural setting. We assessed this method and compared impairment of performancedue to alcohol in everyday life with measurements made in the laboratory.Methods: Thirty-eight volunteers (20 male, aged 18–54 years) took part in the everyday study,completing assessments twice a day for 14 days following requests sent by text messages to themobile phone. Twenty-six of them (12 male, aged 19–54) took part in a subsequent two-periodcrossover lab study comparing alcohol with no alcohol (placebo).Results: Everyday entries with 5 or more units of alcohol consumed in the past 6 hours(inferred mean blood alcohol concentration 95 ml⁄100 ml) showed higher scores for errors in testsof attention and working memory compared with entries with no alcohol consumed that day.Response times were impaired for only 1 test, sustained attention to response. The laboratorycomparison of alcohol (mean blood alcohol concentration 124 mg⁄100 ml) with placebo showedimpairment to both reaction time and error scores for all tests. A similar degree of subjectivedrunkenness was reported in both settings.Conclusions: We found that mobile phones allowed practical research on cognitive perfor-mance in an everyday life setting. Alcohol impaired function in both laboratory and everyday lifesettings at relevant doses of alcohol.Key Words: Ethanol (Alcohol), Everyday Assessments, Mobile Phone (Cellphone), Neuro-psychological Assessment, Speed Accuracy Trade-Off.

Background Mixed venous partial pressure of carbon dioxide has often been estimated in anaesthesia, usually by rebreathing techniques. This assumes equilibrium between respired gas and mixed venous blood before significant recirculation can occur, and requires vigorous rebreathing and precise identification of equilibrium. Modern clinical sidestream capnometers do not measure gas composition as rapidly as the devices used in previous studies, and cannot measure end-tidal values adequately during vigorous rebreathing. In contrast, a single-staged exhalation provides a stable sample for more accurate measurement of gas composition, and clinical measurements then allow examination of the evidence that equilibration occurs before recirculation. Theoretically, this assumption is optimistic, although it forms the basis of a method for non-invasive measurement of cardiac output. We used measurements of staged exhalation to study the evidence for equilibrium more closely. Methods We studied 19 patients during general anaesthesia. The lungs were inflated with mixed exhaled gas. Stepwise expiration allowed exhaled gas to be analysed over ∼1 min. The rate of increase in exhaled carbon dioxide fraction was related to the duration of expiration. Results Carbon dioxide concentration continued to change throughout the study period. The lack of equilibrium of carbon dioxide concentration over this time supports simulation studies which predict recirculation from well-perfused body compartments within 20 s, and that the subsequent increase of carbon dioxide reflects the wash in of multiple body compartments. Conclusions This method allows adequate time for full response of sidestream analysers. Recirculation is an important early feature affecting breath-hold estimates of mixed venous carbon dioxide. Carbon dioxide accumulation during apnoea or rebreathing will have prompt effects on arterial carbon dioxide values and a constant mixed venous composition cannot be assumed when methods based on partial rebreathing are used over this time period.

Reporting of ethical matters in The Journal is very important. To advise and assist authors, particularly those who may be less familiar with the legislation in the UK, this article sets out the basic principles and methods that should be used and provides many key web sources of information. It addresses the structure of regulations, and introduces the concept of research governance. The UK law is summarized. Advice is given on the format and description of experiments, and common problems addressed. Aspects of human studies are addressed. Ethical considerations of publication such as authorship and originality, and problems such as plagiarism and fabrication are described. Updates will be published regularly.

Maintenance fluid therapy is a protean topic but is clinically often mismanaged. Our teaching of medical students led us to suspect that textbooks provide limited information about the topic, so we set out to verify this possibility by reviewing the content of books written in English that covered perioperative care.We reviewed publishers' lists of textbooks and found 22 suitable books. After compiling a standard list of questions on intravenous therapy, we read each book to find out to what extent it delivered the answers, and listed the information obtained.Only 13 books answered more than half of the questions. The information varied considerably. Suggested quantities of daily fluid, sodium and potassium requirements varied hugely.Information provided in standard textbooks to guide fluid prescription is scant and variable. This could be a cogent reason why junior doctors prescribe postoperative fluids badly: the information in textbooks is inadequate and varies from book to book. The reasons for the poor coverage are not clear. Perhaps other common topics that are often poorly managed are also badly addressed by standard books.

SummaryVentilatory control undergoes profound changes on ascent to high altitude. We hypothesized that the fall in citric acid cough threshold seen on ascent to altitude is mediated by changes in the central control of cough and would parallel changes in central ventilatory control assessed by the hypercapnic ventilatory response (HCVR). Twenty-five healthy volunteers underwent measurements of HCVR and citric acid sensitivity at sea level and during a 9 day sojourn at 5200m. None of the subjects had any evidence of respiratory infection. Citric acid cough threshold fell significantly on ascent to 5200m. The slope, S, of the HCVR increased significantly on ascent to 5200m and during the stay at altitude. There was no correlation between citric acid sensitivity and HCVR. We conclude that the change in citric acid cough threshold seen on exposure to hypobaric hypoxia is unlikely to be mediated by changes in the central control of cough. Sensitivity to citric acid may be due to early subclinical pulmonary edema stimulating airway sensory nerve endings.

Background In patients breathing spontaneously during anaesthesia, expiratory muscle activity can be a prominent feature. This activity is triggered or exaggerated by opioid administration, which causes a prompt increase in intra-abdominal pressure. The effect of this increased expiratory activity on end-expiratory lung volume is not described. Methods Nine patients having minor gynaecological procedures were studied during stable anaesthetic conditions, breathing sevoflurane (end tidal 2.6%) through a laryngeal mask airway, in a circle system. The spill valve was closed and the fresh gas flow was temporarily reduced to approximate the oxygen uptake. The volume of the reservoir bag was then measured by placing it in a hinged, wedge-shaped container. Fentanyl (0.5 µg kg−1 ideal body weight) was given after 1 min of stable recording, and the change in end-expiratory volume measured after 3 min. Results End-expiratory lung volume decreased in all patients by 160 (111) ml (mean, sd ) (P Conclusions During sevoflurane anaesthesia, fentanyl causes a rapid reduction in functional residual capacity. This is caused by increased activity of expiratory muscles and an increase in intra-abdominal pressure.

Anaesthetics which work by different mechanisms may have different patterns of effect. Measurement of these patterns thus may elucidate their mechanisms of action and allow therapeutic choices between the agents.We compared the effects of ethanol (approximately 80 mg per 100 ml), and different end-tidal concentrations of nitrous oxide (15% and 25%) and sevoflurane (0.3% and 0.5%) in volunteers. We measured speed and accuracy in psychomotor tests, reaction time and memory, touch and pain sensitivity to von Frey filaments, and subjective mood for a range of descriptors.All treatments caused the same degree of overall abnormal feelings, but sevoflurane caused more obtunding (subjective drowsiness, slow reaction times, and loss of memory function) and nitrous oxide was more analgesic. Ethanol caused a marked feeling of drunkenness, but little drowsiness or analgesia.In the same volunteer subjects, direct comparison of sub-anaesthetic doses of these agents showed a clear and characteristic pattern of effects. These support the possible mechanisms for these disparate agents and may help choose appropriate agents for specific desired anaesthetic outcomes such as sedation or analgesia.

Current textbooks in anaesthesia describe how gravity affects the regional distribution of ventilation and blood flow in the lung, in terms of vertical gradients of pleural pressure and pulmonary vascular pressures. This concept fails to explain some of the clinical features of disturbed lung function. Evidence now suggests that gravity has a less important role in the variation of regional distribution than structural features of the airways and blood vessels. We review more recent studies that used a variety of methods: external radioactive counters, measurements using inhaled and injected particles, and computer tomography scans. These give a higher spatial resolution of regional blood flow and ventilation. The matching between ventilation and blood flow in these small units of lung is considered; the effects of microgravity, increased gravity, and different postures are reviewed, and the application of these findings to conditions such as acute lung injury is discussed. Down to the scale of the acinus, there is considerable heterogeneity in the distribution of both ventilation and blood flow. However, the matching of blood flow with ventilation is well maintained and may result from a common pattern of asymmetric branching of the airways and blood vessels. Disruption of this pattern may explain impaired gas exchange after acute lung injury and explain how the prone position improves gas exchange.

Both hypoxia and hyperoxia have major effects on cardiovascular function. However, both states affect ventilation and many previous studies have not controlled CO2 tension. We investigated whether hemodynamic effects previously attributed to modified O2 tension were still apparent under isocapnic conditions. In eight healthy men, we studied blood pressure (BP), heart rate (HR), cardiac index (CI), systemic vascular resistance index (SVRI) and arterial stiffness (augmentation index, AI) during 1 h of hyperoxia (mean end-tidal O2 79.6 ± 2.0%) or hypoxia (pulse oximeter oxygen saturation 82.6 ± 0.3%). Hyperoxia increased SVRI (18.9 ± 1.9%; P < 0.001) and reduced HR (−10.3 ± 1.0%; P < 0.001), CI (−10.3 ± 1.7%; P < 0.001), and stroke index (SI) (−7.3 ± 1.3%; P < 0.001) but had no effect on AI, whereas hypoxia reduced SVRI (−15.2 ± 1.2%; P < 0.001) and AI (−10.7 ± 1.1%; P < 0.001) and increased HR (18.2 ± 1.2%; P < 0.001), CI (20.2 ± 1.8%; P < 0.001), and pulse pressure (13.2 ± 2.3%; P = 0.02). The effects of hyperoxia on CI and SVRI, but not the other hemodynamic effects, persisted for up to 1 h after restoration of air breathing. Although increased oxidative stress has been proposed as a cause of the cardiovascular response to altered oxygenation, we found no significant changes in venous antioxidant or 8-iso-prostaglandin F2α levels. We conclude that both hyperoxia and hypoxia, when present during isocapnia, cause similar changes in cardiovascular function to those described with poikilocapnic conditions.