Reporting of method comparison studies: a review of advice, an assessment of current practice, and specific suggestions for future reports.

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.

Translational toxicological research: investigating and preventing acute lung injury in organophosphorus insecticide poisoning.

Poisoning through ingestion of organophosphorus (OP) insecticide is a leading cause of suicide globally. Severe poisoning with OP compounds creates an unconscious, paralysed patient with respiratory failure. These symptoms make pulmonary aspiration of stomach contents highly likely, potentially causing an acute lung injury. To explore this hypothesis, we created a Gottingen minipig pulmonary aspiration model (n=26) to investigate the mechanism and severity of lung injury created through pulmonary instillation of 0.5 mL/kg mixtures of porcine gastric juice (GJ), OP and/or its solvent. Early results show that aspiration of OP and GJ causes pulmonary neutrophil sequestration, alveolar haemorrhage and interstitial oedema, with disruption of the alveolar-capillary membrane. Further measurements will include quantitative CT imaging, histopathology scoring, acute lung injury biomarkers and respiratory function. In order to test the validity of the minipig model, a pilot study in Sri Lanka has been devised to observe signs of lung injury in human patients who have ingested OP insecticide with or without clinical evidence of pulmonary aspiration. Lung injury will be assessed with PaO2/FIO2 ratios and physiological dead space measurement. Blood, bronchoalveolar lavage and urine will be taken at 24 and 48 h after poisoning and at 3-4 h in surgical control patients to measure acute lung injury biomarkers. An unpublished toxicology study from Sri Lanka, 2011-2012, showed that over 40% of unconscious poisoned patients with a GCS <9 were not intubated for ambulance transfer between rural and district hospitals. Delay in intubation leads to aspiration pneumonitis and pneumonia in 38%-45% of unconscious poisoned patients. We hypothesise that non-drug assisted placement of supraglottic airways may be a good tool for use in unconscious poisoned patients requiring transfer from small rural hospitals in Asia. They could confer better airway protection than no airway intervention and reduce both morbidity and mortality.

Characterization of breathing patterns during patient-controlled opioid analgesia.

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.

Direct measurement of nitrous oxide kinetics.

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 T(1/2) 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 T(1/2) 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.

Ventilatory responses after major surgery and high dependency care.

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.

A conceptual model for changes in finger photoplethysmograph signals caused by hand posture and isothermic regulation.

Objective. To observe changes in baseline position and pulsatile light absorbance (photoplethysmograph, PPG) in the finger-tip, by raising the hand above the horizontal plane in recumbent subjects. We applied current knowledge of the circulation to the finger-tip, particularly arteriovenous anastomoses (AVAs), and the physiology of the venous circulation.Approach.We studied healthy young volunteers in a quiet thermoneutral environment. A finger plethysmograph on the non-dominant hand recorded transmission of red and infra-red light, with observations expressed as absorbance to allow comparisons within and between subjects. Breathing movements were recorded unobtrusively to assess any effect on absorbance and the pulse amplitude of the signals. All body movements were passive: the study arm was elevated in a trough to about 40° above the horizontal plane. The following conditions were studied, each for 15 min, using the last 10 min for analysis: recumbent, study arm elevated, study arm horizontal, and both legs elevated by 40°.Main results. We found a substantial time-related effect, and considerable variation between subjects. Arm elevation reduced red light absorbance and increased the range of amplitudes of the PPG waveform: only in subjects with large absorbances, did waveform amplitude increase. Spontaneous, thermoregulatory decreases in absorbance were large and associated with decreases in waveform amplitude.Significance. Finger-tip vessels distend with blood and light absorbance increases when AVAs open. The vessels pulsate more strongly when the hand is raised: venous collapse allows the vessels to become more compliant. The postcapillary circulation is likely to be an important source of pulsation.

Effects of airway occlusion on breathing muscle electromyogram signals, during isoflurane anaesthesia, with and without the effects of fentanyl and hypercapnia.

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 CO(2). 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.

Validation of a new non-invasive automatic monitor of respiratory rate for postoperative subjects.

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.

Potent heme-degrading action of antimony and antimony-containing parasiticidal agents.

The ability of antimony and antimony-containing parasiticidal agents to enhance the rate of heme degradation in liver and kidney was investigated. Trivalent antimony was shown to be an extremely potent inducer of heme oxygenase, the initial and rate-limiting enzyme in heme degradation, in both organs, whereas the pentavalent form was a weak inducer of this enzyme. The ability of antimony to induce heme oxygenase was dose-dependent, independent of the salt used, and not a result of a direct activation of the enzyme in vitro. Concomitant with heme oxygenase induction by antimony, microsomal heme and cytochrome P-450 contents decreased, the cyto-chrome P-450-dependent mixed function oxidase system was impaired, and delta-ami-nolevulinate synthase (ALAS), the rate-limiting enzyme of heme synthesis, underwent the sequential changes-initial inhibition followed by rebound induction-usually associated with the administration of transition elements such as cobalt. Antimony induction of heme oxygenase however, unlike the enzyme induction elicited by cobalt, was not prevented either by cysteine administered orally or as a cysteine metal complex, or by simultaneous zinc administration. Desferoxamine also did not block heme oxygenase induction by antimony, but this chelator did prevent the rebound increase in ALAS activity associated with antimony or cobalt treatment. Antimony-containing parasiticidal drugs were also potent inducers of heme oxygenase in liver and kidney. The heme degradative action of these drugs may be related in part to the jaundice commonly associated with the prolonged therapeutic use of these agents. The heme-oxygenase-inducing action of antimony-containing parasiticidal drugs is a newly defined biological property of these compounds. The relation between the parasiticidal and the heme-oxygenase-inducing actions of such drugs is unknown. However, certain parasites contain hemoproteins or require heme compounds during their life cycle. It may therefore be useful to explore the possibility that the heme-degrading and the parasiticidal actions of certain metals or metal-containing therapeutic agents are in some way related.

Suppression of hyperbilirubinemia in the rat neonate by chromium-protoporphyrin. Interactions of metalloporphyrins with microsomal heme oxygenase of human spleen.

The synthetic metalloporphyrin, Cr-protoporphyrin, as a potent competitive inhibitor of heme oxygenase activity in rat spleen, liver, and kidney. When administered to neonatal animals in a single dose immediately after birth, Cr-protoporphyrin suppresses postnatal hyperbilirubinemia and produces a marked and sustained lowering of heme oxidation activity in liver, spleen, and kidney. The metalloporphyrin also potently inhibited the rate of heme degradation to bile pigment in human spleen.

Proof that Sn-protoporphyrin inhibits the enzymatic catabolism of heme in vivo. Suppression of 14CO generation from radiolabeled endogenous and exogenous heme sources.

Sn-protoporphyrin (SnPP) suppresses generation of 14CO from hepatic heme labeled with delta-aminolevulinic acid (5-[14C]ALA) or from infused [14C]hemin in rats. SnPP administered 1 h before administration of 5-[14C]ALA virtually abolished the peak output of 14CO occurring 2-3 h after injection of this heme precursor, and during the succeeding 12 h reduced 14CO excretion by approximately 61% compared with controls. When [14C]hemin was infused, SnPP diminished 14CO excretion by approximately 50%. These findings, derived from experiments using radiolabeled endogenous and exogenous heme sources, establish conclusively that the synthetic metalloporphyrin SnPP inhibits the oxidative degradation of heme in the intact animal.

Long-term administration of massive doses of Sn-protoporphyrin in anemic mutant mice (sphha/sphha).

The effects of long-term administration of very large doses of Sn-protoporphyrin on hematological indices, histological changes, plasma bilirubin levels, tissue heme oxygenase activity, and activities of heme biosynthetic enzymes, were examined in genetically anemic mutant mice with hemolytic anemia (sphha/sphha). Long-term weekly treatment with Sn-protoporphyrin (100 mumol/kg body weight for 32 wk) did not alter hematological indices, histological findings, or enzyme activities related to heme biosynthesis, even though it resulted in sustained decreases in microsomal heme oxygenase activity in the liver, kidney, and spleen, and a prolonged decrease in plasma bilirubin concentration. Inhibition of heme oxygenase did not alter the level of cytochrome P-450 in the liver and the kidney. The results indicate that long-term treatment with massive doses of Sn-protoporphyrin suppresses bilirubin formation but does not produce significant histopathological changes or appreciably interfere with heme synthesis, in this strain of genetically anemic mice. These findings provide further support for the idea that suppression of heme degradation to bile pigment by the inhibition of heme oxygenase may prove useful to the prevention of severe hyperbilirubinemia in humans.

Sn-protoporphyrin blocks the increase in serum bilirubin levels that develops postnatally in homozygous Gunn rats.

Administration of Sn-protoporphyrin to Gunn rats that are characterized by a genetically determined absence of UDP-glucuronyl transferase activity for bilirubin, 24-30 h after birth, prevented the marked increase in serum bilirubin concentration that occurs in these animals in the postnatal period. A second administration of Sn-protoporphyrin at day 6 maintained serum bilirubin levels in the neonates at the initial level for an additional 6 d. In contrast, in untreated Gunn neonates, serum bilirubin levels increased substantially as expected during the immediate 2-wk period after birth. Studies in adult Gunn rats demonstrated that Sn-protoporphyrin administration diminished biliary bilirubin output, decreased tissue heme oxygenase activity, and did not alter hepatic cytochrome P450 levels. These findings raise the possibility that Sn-protoporphyrin may prove clinically useful in maintaining low levels of serum bilirubin in congenitally jaundiced individuals, such as patients with the Crigler-Najjar syndrome.

Do simple ventilation and gas exchange measurements predict early successful weaning from respiratory support in unselected general intensive care patients?

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.

Passage of pathogenic microorganisms through breathing system filters used in anaesthesia and intensive care.

SUMMARY: Invasive ventilation poses a risk of respiratory infection that can be drug-resistant. One means of reducing transmission of infection is the use of a breathing system filter. Filters are intended to be used with dry gas. Current international standards do not require that filters prevent bacterial transfer when wet. It is not known whether microorganisms pass through wet filters, but theory predicts that this might occur. We tested six filters from three different manufacturers. We passed a suspension of microorganisms through the filters using the least pressure necessary, and incubated a sample of the filtrate on blood agar. All the filters tested allowed free passage of both Candida albicans and coagulase-negative staphylococci. The median (IQR [range]) pressure required for fluid to flow across the filter varied greatly between different filter types (20 (0-48 [0-138]) cmH(2)O). We conclude that even large microorganisms pass across moist breathing system filters in conditions that are found in clinical practice.

Chemoprevention of neonatal jaundice: potency of tin-protoporphyrin in an animal model.

The substantial increases of hepatic, splenic, and renal heme oxygenase levels that occur shortly after birth in neonatal rats were prevented by a single administration of tin-protoporphyrin (10 micromoles per kilogram of body weight). With this treatment serum bilirubin levels declined within 24 hours to near-normal adult levels and remained low throughout the postnatal period. Zinc-protoporphyrin at doses up to 50-fold greater than the effective dose of tin-protoporphyrin did not prevent the immediate increases in tissue heme oxygenase activities and in serum bilirubin levels that occur postnatally. Studies in vitro with microsomal heme oxygenase in human spleen indicate that tin-protoporphyrin is a potent competitive inhibitor of the oxidation of heme to bile pigment in this tissue.