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Objective: Evaluate the dose-response relationship between intraoperative fluid administration and postoperative outcomes in a large cohort of surgical patients. Background: Healthy humans may live in a state of fluid responsiveness without the need for fluid supplementation. Goal-directed protocols driven by such measures are limited in their ability to define the optimal fluid state during surgery. Methods: This analysis of data on file included 92,094 adult patients undergoing noncardiac surgery with endotracheal intubation between 2007 and 2014 at an academic tertiary care hospital and two affiliated community hospitals. The primary exposure variable was total intraoperative volume of crystalloid and colloid administered. The primary outcome was 30-day survival. Secondary outcomes were respiratory complications within three postoperative days (pulmonary edema, reintubation, pneumonia, or respiratory failure) and acute kidney injury. Exploratory outcomes were postoperative length of stay and total cost of care. Our models were adjusted for patient-, procedure-, and anesthesia-related factors. Results: A U-shaped association was observed between the volume of fluid administered intraoperatively and 30-day mortality, costs, and postoperative length of stay. Liberal fluid volumes (highest quintile of fluid administration practice) were significantly associated with respiratory complications whereas both liberal and restrictive (lowest quintile) volumes were significantly associated with acute kidney injury. Moderately restrictive volumes (second quintile) were consistently associated with optimal postoperative outcomes and were characterized by volumes approximately 40% less than traditional textbook estimates: infusion rates of approximately 6–7 mL/kg/hr or 1 L of fluid for a 3-hour case. Conclusions: Intraoperative fluid dosing at the liberal and restrictive margins of observed practice is associated with increased morbidity, mortality, cost, and length of stay. [ABSTRACT FROM AUTHOR]

: Patient monitoring on low acuity general hospital wards is currently based largely on intermittent observations and measurements of simple variables, such as blood pressure and temperature, by nursing staff. Often several hours can pass between such measurements and patient deterioration can go unnoticed. Moreover, the integration and interpretation of the information gleaned through these measurements remains highly dependent on clinical judgement. More intensive monitoring, which is commonly used in peri-operative and intensive care settings, is more likely to lead to the early identification of patients who are developing complications than is intermittent monitoring. Early identification can trigger appropriate management, thereby reducing the need for higher acuity care, reducing hospital lengths of stay and admission costs and even, at times, improving survival. However, this degree of monitoring has thus far been considered largely inappropriate for general hospital ward settings due to device costs and the need for staff expertise in data interpretation. In this review, we discuss some developing options to improve patient monitoring and thus detection of deterioration in low acuity general hospital wards. [ABSTRACT FROM AUTHOR]

Background: Perioperative and critically ill patients are often exposed to iron (in the form of parenteral-iron administration or blood transfusion) and inflammatory stimuli, but the effects of iron loading on the inflammatory response are unclear. Recent data suggest that mitochondrial reactive oxygen species have an important role in the innate immune response and that increased mitochondrial reactive oxygen species production is a result of dysfunctional mitochondria. We tested the hypothesis that increased intracellular iron potentiates lipopolysaccharide-induced inflammation by increasing mitochondrial reactive oxygen species levels.Methods: Murine macrophage cells were incubated with iron and then stimulated with lipopolysaccharide. C57BL/6 wild-type mice were intraperitoneally injected with iron and then with lipopolysaccharide. Markers of inflammation and mitochondrial superoxide production were examined. Mitochondrial homeostasis (the balance between mitochondrial biogenesis and destruction) was assessed, as were mitochondrial mass and the proportion of nonfunctional to total mitochondria.Results: Iron loading of mice and cells potentiated the inflammatory response to lipopolysaccharide. Iron loading increased mitochondrial superoxide production. Treatment with MitoTEMPO, a mitochondria-specific antioxidant, blunted the proinflammatory effects of iron loading. Iron loading increased mitochondrial mass in cells treated with lipopolysaccharide and increased the proportion of nonfunctional mitochondria. Iron loading also altered mitochondrial homeostasis to favor increased production of mitochondria.Conclusions: Acute iron loading potentiates the inflammatory response to lipopolysaccharide, at least in part by disrupting mitochondrial homeostasis and increasing the production of mitochondrial superoxide. Improved understanding of iron homeostasis in the context of acute inflammation may yield innovative therapeutic approaches in perioperative and critically ill patients. [ABSTRACT FROM AUTHOR]

Background: Cognitive strategies are a set of psychologic behaviors used to modulate one's perception or interpretation of a sensation or situation. Although the effectiveness of each cognitive strategy seems to differ between individuals, they are commonly used clinically to help patients with chronic pain cope with their condition. The neural basis of commonly used cognitive strategies is not well understood. Understanding the neural correlates that underlie these strategies will enhance understanding of the analgesic network of the brain and the cognitive modulation of pain.Methods: The current study examines patterns of brain activation during two common cognitive strategies, external focus of attention and reappraisal, in patients with chronic pain using functional magnetic resonance imaging.Results: Behavioral results revealed interindividual variability in the effectiveness of one strategy versus another in the patients. Functional magnetic resonance imaging revealed distinct patterns of activity when the two strategies were used. During external focus of attention, activity was observed mainly in cortical areas including the postcentral gyrus, inferior parietal lobule, middle occipital gyrus, and precentral gyrus. The use of reappraisal evoked activity in the thalamus and amygdala in addition to cortical regions. Only one area, the postcentral gyrus, was observed to be active during both strategies.Conclusions: The results of this study suggest that different cognitive behavioral strategies recruit different brain regions to perform the same task: pain modulation. [ABSTRACT FROM AUTHOR]

Background: Anaesthesia for awake craniotomy aims for an unconscious patient at the beginning and end of surgery but a rapidly awakening and responsive patient during the awake period. Therefore, an accurate pharmacokinetic/pharmacodynamic (PK/PD) model for propofol is required to tailor depth of anaesthesia.Objective: To compare the predictive performances of the Marsh and the Schnider PK/PD models during awake craniotomy.Design: A prospective observational study.Setting: Single university hospital from February 2009 to May 2010.Patients: Twelve patients undergoing elective awake craniotomy for resection of brain tumour or epileptogenic areas.Intervention: Arterial blood samples were drawn at intervals and the propofol plasma concentration was determined.Main Outcome Measures: The prediction error, bias [median prediction error (MDPE)] and inaccuracy [median absolute prediction error (MDAPE)] of the Marsh and the Schnider models were calculated. The secondary endpoint was the prediction probability PK, by which changes in the propofol effect-site concentration (as derived from simultaneous PK/PD modelling) predicted changes in anaesthetic depth (measured by the bispectral index).Results: The Marsh model was associated with a significantly (P = 0.05) higher inaccuracy (MDAPE 28.9 ± 12.0%) than the Schnider model (MDAPE 21.5 ± 7.7%) and tended to reach a higher bias (MDPE Marsh -11.7 ± 14.3%, MDPE Schnider -5.4 ± 20.7%, P = 0.09). MDAPE was outside of accepted limits in six (Marsh model) and two (Schnider model) of 12 patients. The prediction probability was comparable between the Marsh (PK 0.798 ± 0.056) and the Schnider model (PK 0.787 ± 0.055), but after adjusting the models to each individual patient, the Schnider model achieved significantly higher prediction probabilities (PK 0.807 ± 0.056, P = 0.05).Conclusion: When using the 'asleep-awake-asleep' anaesthetic technique during awake craniotomy, we advocate using the PK/PD model proposed by Schnider. Due to considerable interindividual variation, additional monitoring of anaesthetic depth is recommended.Trial Registration: ClinicalTrials.gov identifier: NCT 01128465. [ABSTRACT FROM AUTHOR]

Background: Evidence suggests that sleep deprivation associated with night-time working may adversely affect performance resulting in a reduction in the safety of surgery and anaesthesia.Objective: Our primary objective was to evaluate an association between nonelective night-time surgery and in-hospital mortality. We hypothesised that urgent surgery performed during the night was associated with higher in-hospital mortality and also an increase in the duration of hospital stay and the number of admissions to critical care.Design: A prospective cohort study. This is a secondary analysis of a large database related to perioperative care and outcome (European Surgical Outcome Study).Setting: Four hundred and ninety-eight hospitals in 28 European countries.Patients: Men and women older than 16 years who underwent nonelective, noncardiac surgery were included according to time of the procedure.Intervention: None.Main Outcome Measures: Primary outcome was in-hospital mortality; the secondary outcome was the duration of hospital stay and critical care admission.Results: Eleven thousand two hundred and ninety patients undergoing urgent surgery were included in the analysis with 636 in-hospital deaths (5.6%). Crude mortality odds ratios (ORs) increased sequentially from daytime [426 deaths (5.3%)] to evening [150 deaths (6.0%), OR 1.14; 95% confidence interval 0.94 to 1.38] to night-time [60 deaths (8.3%), OR 1.62; 95% confidence interval 1.22 to 2.14]. Following adjustment for confounding factors, surgery during the evening (OR 1.09; 95% confidence interval 0.91 to 1.31) and night (OR 1.20; 95% confidence interval 0.9 to 1.6) was not associated with an increased risk of postoperative death. Admittance rate to an ICU increased sequentially from daytime [891 (11.1%)], to evening [347 (13.8%)] to night time [149 (20.6%)].Conclusion: In patients undergoing nonelective urgent noncardiac surgery, in-hospital mortality was associated with well known risk factors related to patients and surgery, but we did not identify any relationship with the time of day at which the procedure was performed.Trial Registration: Clinicaltrials.gov identifier: NCT01203605. [ABSTRACT FROM AUTHOR]

Background: Postoperative respiratory failure (PRF) is the most frequent respiratory complication following surgery.Objective: The objective of this study was to build a clinically useful predictive model for the development of PRF.Design: A prospective observational study of a multicentre cohort.Setting: Sixty-three hospitals across Europe.Patients: Patients undergoing any surgical procedure under general or regional anaesthesia during 7-day recruitment periods.Main Outcome Measures: Development of PRF within 5 days of surgery. PRF was defined by a partial pressure of oxygen in arterial blood (PaO2) less than 8 kPa or new onset oxyhaemoglobin saturation measured by pulse oximetry (SpO2) less than 90% whilst breathing room air that required conventional oxygen therapy, noninvasive or invasive mechanical ventilation.Results: PRF developed in 224 patients (4.2% of the 5384 patients studied). In-hospital mortality [95% confidence interval (95% CI)] was higher in patients who developed PRF [10.3% (6.3 to 14.3) vs. 0.4% (0.2 to 0.6)]. Regression modelling identified a predictive PRF score that includes seven independent risk factors: low preoperative SpO2; at least one preoperative respiratory symptom; preoperative chronic liver disease; history of congestive heart failure; open intrathoracic or upper abdominal surgery; surgical procedure lasting at least 2 h; and emergency surgery. The area under the receiver operating characteristic curve (c-statistic) was 0.82 (95% CI 0.79 to 0.85) and the Hosmer-Lemeshow goodness-of-fit statistic was 7.08 (P = 0.253).Conclusion: A risk score based on seven objective, easily assessed factors was able to predict which patients would develop PRF. The score could potentially facilitate preoperative risk assessment and management and provide a basis for testing interventions to improve outcomes.The study was registered at ClinicalTrials.gov (identifier NCT01346709). [ABSTRACT FROM AUTHOR]

There is a need for large trials that test the clinical effectiveness of interventions in the field of perioperative medicine. Clinical outcome measures used in such trials must be robust, clearly defined and patient-relevant. Our objective was to develop standards for the use of clinical outcome measures to strengthen the methodological quality of perioperative medicine research. A literature search was conducted using PubMed and opinion leaders worldwide were invited to nominate papers that they believed the group should consider. The full texts of relevant articles were reviewed by the taskforce members and then discussed to reach a consensus on the required standards. The report was then circulated to opinion leaders for comment and review. This report describes definitions for 22 individual adverse events with a system of severity grading for each. In addition, four composite outcome measures were identified, which were designed to evaluate postoperative outcomes. The group also agreed on standards for four outcome measures for the evaluation of healthcare resource use and quality of life. Guidance for use of these outcome measures is provided, with particular emphasis on appropriate duration of follow-up. This report provides clearly defined and patient-relevant outcome measures for large clinical trials in perioperative medicine. These outcome measures may also be of use in clinical audit. This report is intended to complement and not replace other related work to improve assessment of clinical outcomes following specific surgical procedures. [ABSTRACT FROM AUTHOR]

Background: Visualisation of a central venous catheter (CVC) with ultrasound is restricted to the internal jugular vein (IJV). CVC tip position is confirmed by chest radiography, intracardiac ECG or transoesophageal/transthoracic echocardiography (TEE/TTE). Objective: We explored the feasibility, safety and accuracy of a right supraclavicular view for visualisation of the lower superior vena cava (SVC) and the right pulmonary artery (RPA) as an ultrasound landmark for real-time ultrasound-guided CVC tip positioning via the right IJV. Ultrasound was then compared with chest radiography. Design: An observational pilot study. Setting: Bonn, University Hospital, Germany. From July to October 2012. Patients: Fifty-one patients scheduled for elective surgery. Reasons for exclusion were emergency procedure, thrombosis or small IJV lumen and mechanical obstacle to guidewire advancement. Intervention: In 48 patients, CVC insertion via the right IJV and progress of the guidewire into the lower SVC were continuously guided by an ultrasound transducer in the right supraclavicular fossa. Main Outcome Measures: CVC tip position in lower SVC and tip-to-carina distance were assessed with chest radiography as a reference method and additionally with TEE in cardiothoracic patients. Insertion depth was compared with intracardiac ECG and body-height formula. Results: The guidewire tip was seen in the SVC of all patients. In four patients, the tip was not visible in proximity of the RPA. Chest radiography and TEE confirmed CVC tip position in the lower SVC (zone A). Bland-Altman analysis revealed an average of difference of 1.6 cm for ultrasound versus ECG (95% limit of agreement -2 to 5 cm) and an average of difference of 1 cm for ultrasound versus body-height formula (95% limit of agreement -2 to 4 cm). Conclusion: Ultrasound via a right supraclavicular view is a feasible, well tolerated and accurate approach and should be further explored. Chest radiography confirmed CVC position in the lower SVC. [ABSTRACT FROM AUTHOR]

VO2max is one of the most commonly used metrics in exercise physiology and related fields, and is typically measured through a graded exercise test. It is both the criterion measure of cardiorespiratory fitness and a predictor of endurance exercise performance. However, there is a lack of standardization in the reporting and measurement of VO2max. Differences in technology and measurement systems may affect results. Specifically, in a breath-by-breath measurement system, some form of data averaging or smoothing is used to calculate VO2max. We performed a brief examination of recent articles reporting VO2max data, and found that only 1 out of 20 articles stated the averaging methods used. PURPOSE: The purpose of this study was to compare four VO2max averaging methods, and to determine whether the method of averaging resulted in significantly different VO2max values. METHODS: VO2max data from a marathon training class at the University of Minnesota collected before and after training was analyzed. Participants were healthy college aged males and females (n=55). The following averaging methods were compared: unaveraged, mid 5-of-7, 8-breath mean, and 30-second rolling average. Pairwise comparisons were done to test for differences between averaging methods. RESULTS: Pre-training means and standard deviations of VO2max (in ml.kg-1.min-1) for the respective data averaging techniques were as follows: Mid 5-of-7 (47.54±7.66), 8-breath mean (46.95±7.65), 30-second rolling (44.66±7.31) and unaveraged (57.60±10.71). Post-training VO2max values for the respective data averaging techniques were: Mid 5-of-7 (50.90±8.15), 8- breath mean (50.40±7.995), 30-second rolling (48.57±7.993) and unaveraged (59.88±10.74). There were statistically significant differences between all averaging methods tested (P<0.05) in both pre- and post-training data. CONCLUSION: Studies reporting VO2max data should include the averaging method used in order to allow for interpretation and comparison between studies. [ABSTRACT FROM AUTHOR]

Intervention with riboflavin was recently shown to produce genotype-specific lowering of blood pressure (BP) in patients with premature cardiovascular disease homozygous for the 677C→T polymorphism (TT genotype) in the gene encoding the enzyme methylenetetrahydrofolate reductase (MTHFR). Whether this effect is confined to patients with high-risk cardiovascular disease is unknown. The aim of this randomized trial, therefore, was to investigate the responsiveness of BP to riboflavin supplementation in hypertensive individuals with the TT genotype but without overt cardiovascular disease. From an available sample of 1427 patients with hypertension, we identified 157 with the MTHFR 677TT genotype, 91 of whom agreed to participate in the trial. Participants were stratified by systolic BP and randomized to receive placebo or riboflavin (1.6 mg/d) for 16 weeks. At baseline, despite being prescribed multiple classes of antihypertensive drugs, >60% of participants with this genotype had failed to reach goal BP (≤140/90 mm Hg). A significant improvement in the biomarker status of riboflavin was observed in response to intervention (P<0.001). Correspondingly, an overall treatment effect of 5.6±2.6 mm Hg (P=0.033) in systolic BP was observed, with pre- and postintervention values of 141.8±2.9 and 137.1±3.0 mm Hg (treatment group) and 143.5±3.0 and 144.3±3.1 mm Hg (placebo group), whereas the treatment effect in diastolic BP was not significant (P=0.291). In conclusion, these results show that riboflavin supplementation targeted at hypertensive individuals with the MTHFR 677TT genotype can decrease BP more effectively than treatment with current antihypertensive drugs only and indicate the potential for a personalized approach to the management of hypertension in this genetically at-risk group. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: ISRCTN23620802. [ABSTRACT FROM AUTHOR]

Regional anaesthesia is commonly used for elective caesarean section. The aim of this study was to investigate whether there is a positive effect of either spinal or epidural anaesthesia on postoperative analgesic requirements and pain relief.~Background and Objective~Objective~The analgesic effect of either spinal or epidural induction of perispinal anaesthesia have been compared in 132 women (ASA I or II) scheduled for elective caesarean section, all having epidural catheterization for perioperative anaesthesia and postoperative analgesia. The patients were randomized into two groups. To achieve a sensory block height to the level of the sixth thoracic dermatome, the parturients received isobaric bupivacaine 0.5% and 5 microg sufentanil intrathecally or ropivacaine 0.75% and 10 microg sufentanil epidurally. For postoperative analgesia, all patients used patient-controlled epidural analgesia at identical settings [bolus of ropivacaine 0.133% (11-15 mg according to patient's height), lock-out time 1 h]. Intraoperative and postoperative pain was recorded using a visual analogue pain score as well as analgesic requirements over the first 24 h after surgery.~Methods~Methods~One hundred and twenty-five patients completed the study. There were no differences in patient-controlled epidural analgesic requirements between groups. During surgery, the pain score on a visual analogue scale was more intense with epidural anaesthesia than with spinal anaesthesia (P < 0.05). For the whole 24 h observation period, the area under the curve for pain was lower with spinal anaesthesia (P < 0.0005). At almost all postoperative time points, visual analogue scale scores at rest and during mobilization were lower with spinal anaesthesia (P < 0.05), which was accompanied by less motor blockade and lower frequency of adverse effects. More patients with epidural anaesthesia received supplemental analgesic medication.~Results~Results~In parturients undergoing elective caesarean section, postoperative use of epidural ropivacaine via patient-controlled epidural analgesia is similar after spinal and epidural anaesthesia. Spinal anaesthesia is, however, accompanied with less postoperative pain, use of additional analgesics and side-effects.~Conclusion~Conclusions [ABSTRACT FROM AUTHOR]

Background and objective: Proinflammatory cytokines as well as nitric oxide (NO) play a major role in mediating the response to lipopolysaccharide (LPS). The present study tested the hypothesis that LPS induces proinflammatory cytokines in the lung via the Toll-like receptor 4 (TLR4)/CD14 signalling cascade. Methods: Control mice and TLR4-deficient (TLR4-D) mice were used to test TLR4-mediated effects of LPS. Both strains received either Escherichia coli LPS (20 mg kg-1 intraperitoneal) or saline and their lungs were collected at different time points. Pulmonary nuclear factor κB (NFκB) activation was investigated with electromobility shift assay. mRNA expression of inflammatory mediators and their corresponding receptors were detected with Ribonuclease Protection Assay. Protein expression was detected by ELISA and western blotting. Inducible NO synthase (iNOS) expression was monitored by RT-PCR and iNOS activity by conversion of L-arginine to citrulline. Immune cells were sampled by bronchoalveolar lavage (BAL) and classified. Results: LPS application induced CD14-, but not TLR4 protein expression in control mice. Activation of pulmonary NFκB was observed within 60 min in control, but not in TLR4-D mice. Six hours of LPS administration induced a significant increase in pulmonary tumour necrosis factor α-, interleukin-1β- and interleukin-6 mRNA and protein expression in control mice compared to TLR4-D mice. Furthermore, LPS induced a significantly higher increase of the iNOS expression and catalytic activity in control mice than in TLR4-D mice. BAL revealed an increase in total cell count in all LPS treated mice. Conclusion: Our findings suggest that TLR4 plays a key role for regulating the expression of relevant cytokines within the lung during endotoxic shock. [ABSTRACT FROM AUTHOR]

Background and objective: µ-agonistic opioids cause concentration-dependent hypoventilation and increased irregularity of breathing. The aim was to quantify opioid-induced irregularity of breathing and to investigate its time-course during and after an opioid infusion, and its ability to predict the severity of respiratory depression. Methods: Twenty-three patients breathing spontaneously via a continuous positive airway pressure (CPAP) mask received an intravenous (i.v.) infusion of alfentanil (2.3 µg kg[sup -1] min[sup -1], 14 patients) or pirinitramide (piritramide) (17.9 µg kg[sup -1] min[sup -1], nine patients) until either a cumulative dose of 70 µg kg[sup -1] for alfentanil or 500 µg kg[sup -1] for pirinitramide had been achieved or the infusion had to be stopped for safety reasons. Tidal volumes (V[sub T]) and minute ventilation were measured with an anaesthesia workstation. For every 20 breaths, the quartile coefficient was calculated (Q[sub eff20]V[sub T]). Results: Both the decrease of minute volume and the increase of Q[sub eff20]V[sub T] during and after opioid infusion were highly significant (P < 0.001, ANOVA). Patients in which the alfentanil infusion had to be terminated prematurely had lower minute volumes (P = 0.002, t-test) and higher Q[sub eff20]V[sub T] (P = 0.034, t-test) than those who received the complete dose. Changes in the regularity of breathing measured as Q[sub eff20]V[sub T] parallel those of minute ventilation during and after opioid infusion. Conclusions: Opioids cause a more complicated disturbance of the control of respiration than a mere resetting to higher PCO[sub 2]. Furthermore, Q[sub eff20]V[sub T] appears to predict the severity of opioid-induced respiratory depression. [ABSTRACT FROM AUTHOR]

Background and objective: The common parameters of the electroencephalogram quantify a shift of its power spectrum towards lower frequencies with increasing anaesthetic drug concentrations (e.g. spectral-edge frequency 95). These adhoc parameters are not optimized for the content of information with regard to drug effect. Using semilinear canonical correlation, different frequency ranges (bins) of the power spectrum can be weighted for sensitivity to changes of drug concentration by multiplying their power with iteratively determined coefficients, yielding a new (canonical univariate) electroencephalographic parameter. Methods: Electroencephalographic data obtained during application of volatile anaesthetics were used: isoflurane (n = 6), desflurane (7), sevoflurane (7), desflurane during surgical stimulation (12). Volatile anaesthetic end-tidal concentrations varied between 0.5 and 1.6 minimum alveolar concentration (MAC). The canonical univariate parameter and spectral-edge frequency 95 were determined and their correlation with the volatile anaesthetic effect compartment concentration, obtained by simultaneous pharmacokinetic-pharmacodynamic modelling, were compared. Results: The canonical univariate parameter with individually optimized coefficients, but not with mean coefficients, was superior to the spectral-edge frequency 95 as a measure of anaesthetic drug effect. No significant differences of the coefficients were found between the three volatile anaesthetics or between the data with or without surgical stimulus. The coefficients for volatile anaesthetics were similar to the coefficients for opioids, but different from coefficients for propofol and midazolam. Conclusions: The canonical univariate parameter calculated with individually optimized coefficients, but not with mean coefficients, correlates more accurately and consistently with the effect site concentrations of volatile anaesthetics than with spectral-edge frequency 95. [ABSTRACT FROM AUTHOR]

Examines the effects of induction of anesthesia with sufentanil and positive-pressure ventilation on the intra- to extrathoracic volume distribution. Association of induction of general anesthesia with positive-pressure ventilation with a blood volume shift from intra- to extrathoracic compartments; Decrease of arterial pressure and hemodynamic instability associated with induction of anesthesia.