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.

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.

Inflammasome activity is essential for one kidney/deoxycorticosterone acetate/salt-induced hypertension in mice.

BACKGROUND AND PURPOSE: Inflammasomes are multimeric complexes that facilitate caspase-1-mediated processing of the pro-inflammatory cytokines IL-1ß and IL-18. Clinical hypertension is associated with renal inflammation and elevated circulating levels of IL-1ß and IL-18. Therefore, we investigated whether hypertension in mice is associated with increased expression and/or activation of the inflammasome in the kidney, and if inhibition of inflammasome activity reduces BP, markers of renal inflammation and fibrosis. EXPERIMENTAL APPROACH: Wild-type and inflammasome-deficient ASC(-/-) mice were uninephrectomized and received deoxycorticosterone acetate and saline to drink (1K/DOCA/salt). Control mice were uninephrectomized but received a placebo pellet and water. BP was measured by tail cuff; renal expression of inflammasome subunits and inflammatory markers was measured by real-time PCR and immunoblotting; macrophage and collagen accumulation was assessed by immunohistochemistry. KEY RESULTS: 1K/DOCA/salt-induced hypertension in mice was associated with increased renal mRNA expression of inflammasome subunits NLRP3, ASC and pro-caspase-1, and the cytokine, pro-IL-1ß, as well as protein levels of active caspase-1 and mature IL-1ß. Following treatment with 1K/DOCA/salt, ASC(-/-) mice displayed blunted pressor responses and were also protected from increases in renal expression of IL-6, IL-17A, CCL2, ICAM-1 and VCAM-1, and accumulation of macrophages and collagen. Finally, treatment with a novel inflammasome inhibitor, MCC950, reversed hypertension in 1K/DOCA/salt-treated mice. CONCLUSIONS AND IMPLICATIONS: Renal inflammation, fibrosis and elevated BP induced by 1K/DOCA/salt treatment are dependent on inflammasome activity, highlighting the inflammasome/IL-1ß pathway as a potential therapeutic target in hypertension.

NOX1 deficiency in apolipoprotein E-knockout mice is associated with elevated plasma lipids and enhanced atherosclerosis.

Nicotinamide adenine dinucleotide phosphate oxidases (NOX) are enzymes that generate reactive oxygen species (ROS). NOX2 activity in the vascular wall is elevated in hypercholesterolemia, and contributes to oxidative stress and atherogenesis. Here we examined the role of another NOX isoform, NOX1, in atherogenesis in apolipoprotein E-knockout (APOE(-/-)) mice fed a Western diet for 14 weeks. Although NOX1 mRNA expression was unchanged in aortas from APOE(-/-) versus wild-type mice, expression of the NOX1-specific organizer, NOXO1, was diminished, consistent with an overall reduction in NOX1 activity in APOE(-/-) mice. To examine the impact of a further reduction in NOX1 activity, APOE(-/-) mice were crossed with NOX1(-/y) mice to generate NOX1(-/y)/APOE(-/-) double-knockouts. NOX1 deficiency in APOE(-/-) mice was associated with 30-50% higher plasma very-low-density lipoprotein (VLDL)/LDL and triglyceride levels (P < 0.01). Vascular ROS levels were also elevated by twofold in NOX1(-/y)/APOE(-/-) versus APOE(-/-) mice (P < 0.05), despite no changes in expression of other NOX subunits. Although en face analysis of the descending aorta revealed no differences in plaque area between NOX1(-/y)/APOE(-/-) and APOE(-/-) mice, intimal thickening in the aortic sinus was increased by 40% (P < 0.05) in the double-knockouts. Moreover, NOX1 deficiency was associated with a less stable plaque phenotype; aortic sinus lesions contained 60% less collagen (P < 0.01), 40% less smooth muscle (P < 0.01), and 2.5-fold higher levels of matrix metalloproteinase-9 (P < 0.001) than lesions in APOE(-/-) mice. Thus, these data, which suggest a protective role for NOX1 against hyperlipidemia and atherosclerosis in APOE(-/-) mice, highlight the complex and contrasting roles of different NOX isoforms (e.g., NOX2 versus NOX1) in vascular pathology.

IL-1ß and IL-18: inflammatory markers or mediators of hypertension?

Chronic inflammation in the kidneys and vascular wall is a major contributor to hypertension. However, the stimuli and cellular mechanisms responsible for such inflammatory responses remain poorly defined. Inflammasomes are crucial initiators of sterile inflammation in other diseases such as rheumatoid arthritis and gout. These pattern recognition receptors detect host-derived danger-associated molecular patterns (DAMPs), such as microcrystals and reactive oxygen species, and respond by inducing activation of caspase-1. Caspase-1 then processes the cytokines pro-IL-1ß and pro-IL-18 into their active forms thus triggering inflammation. While IL-1ß and IL-18 are known to be elevated in hypertensive patients, no studies have examined whether this occurs downstream of inflammasome activation or whether inhibition of inflammasome and/or IL-1ß/IL-18 signalling prevents hypertension. In this review, we will discuss some known actions of IL-1ß and IL-18 on leukocyte and vessel wall function that could potentially underlie a prohypertensive role for these cytokines. We will describe the major classes of inflammasome-activating DAMPs and present evidence that at least some of these are elevated in the setting of hypertension. Finally, we will provide information on drugs that are currently used to inhibit inflammasome/IL-1ß/IL-18 signalling and how these might ultimately be used as therapeutic agents for the clinical management of hypertension.

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.

Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke.

Multi-protein complexes called inflammasomes have recently been identified and shown to contribute to cell death in tissue injury. Intravenous immunoglobulin (IVIg) is an FDA-approved therapeutic modality used for various inflammatory diseases. The objective of this study is to investigate dynamic responses of the NLRP1 and NLRP3 inflammasomes in stroke and to determine whether the NLRP1 and NLRP3 inflammasomes can be targeted with IVIg for therapeutic intervention. Primary cortical neurons were subjected to glucose deprivation (GD), oxygen-glucose deprivation (OGD) or simulated ischemia-reperfusion (I/R). Ischemic stroke was induced in C57BL/6J mice by middle cerebral artery occlusion, followed by reperfusion. Neurological assessment was performed, brain tissue damage was quantified, and NLRP1 and NLRP3 inflammasome protein levels were evaluated. NLRP1 and NLRP3 inflammasome components were also analyzed in postmortem brain tissue samples from stroke patients. Ischemia-like conditions increased the levels of NLRP1 and NLRP3 inflammasome proteins, and IL-1ß and IL-18, in primary cortical neurons. Similarly, levels of NLRP1 and NLRP3 inflammasome proteins, IL-1ß and IL-18 were elevated in ipsilateral brain tissues of cerebral I/R mice and stroke patients. Caspase-1 inhibitor treatment protected cultured cortical neurons and brain cells in vivo in experimental stroke models. IVIg treatment protected neurons in experimental stroke models by a mechanism involving suppression of NLRP1 and NLRP3 inflammasome activity. Our findings provide evidence that the NLRP1 and NLRP3 inflammasomes have a major role in neuronal cell death and behavioral deficits in stroke. We also identified NLRP1 and NLRP3 inflammasome inhibition as a novel mechanism by which IVIg can protect brain cells against ischemic damage, suggesting a potential clinical benefit of therapeutic interventions that target inflammasome assembly and activity.

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.

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.