Repeated buffered acidic saline infusion in the human masseter muscle as a putative experimental pain model.

This study investigated if repeated buffered acidic saline infusions into the masseter muscles induced muscle pain and mechanical sensitization. Fourteen healthy men participated in this double-blind, randomized, and placebo-controlled study. Two repeated infusions (day 1 and 3) were given in the masseter muscles with either a buffered acidic saline solution (pH 5.2) or an isotonic saline solution (pH 6) as control. After 10 days of wash-out, the experiment was repeated with the other substance. Pressure pain thresholds (PPT), pain intensity, maximum unassisted mouth opening (MUO), and pain drawings were assessed before, directly following, and after each infusion at 5, 15, and 30 min and on day 4 and 7. Fatigue and pain intensity were assessed after a one-minute chewing test 30 min after infusions and day 4 and 7. Acidic saline induced higher pain intensity than control day 3 up to 5 min after infusions, but did not affect PPT. The chewing test did not evoke higher fatigue during chewing or MUO or after acidic saline infusion compared to control. Repeated acidic saline infusions in the masseter muscles induced a short-lasting muscle pain without mechanical hyperalgesia or functional pain. Hence, this model might not be superior to already existing experimental muscle pain models.

Determination of loss of consciousness: a comparison of clinical assessment, bispectral index and electroencephalogram: An observational study.

BACKGROUND: Computer-processed algorithms of encephalographic signals are widely used to assess the depth of anaesthesia. However, data indicate that the bispectral index (BIS), a processed electroencephalography monitoring system, may not be reliable for assessing the depth of anaesthesia. OBJECTIVE: The aim of this study was to evaluate the ability of the BIS monitoring system to assess changes in the level of unconsciousness, specifically during the transition from consciousness to unconsciousness, in patients undergoing total intravenous anaesthesia with propofol. We compared BIS with the electroencephalogram (EEG), and clinical loss of consciousness (LOC) defined as loss of verbal commands and eyelash reflex. DESIGN: This was an observational cohort study. SETTING: University Hospital Linköping, University Hospital Örebro, Finspång Hospital and Kalmar Hospital, Sweden from October 2011 to April 2013. PATIENTS: A total of 35 ASA I patients aged 18 to 49 years were recruited. INTERVENTIONS: The patients underwent total intravenous anaesthesia with propofol and remifentanil for elective day-case surgery. Changes in clinical levels of consciousness were assessed by BIS and compared with assessment of stage 3 neurophysiological activity using the EEG. The plasma concentrations of propofol were measured at clinical LOC and 20 and 30 min after LOC. MAIN OUTCOME MEASURES: The primary outcome was measurement of BIS, EEG and clinical LOC. RESULTS: The median BIS value at clinical LOC was 38 (IQR 30 to 43), and the BIS values varied greatly between patients. There was no correlation between BIS values and EEG stages at clinical LOC (r = -0.1, P = 0.064). Propofol concentration reached a steady state within 20 min. CONCLUSION: There was no statistically significant correlation between BIS and EEG at clinical LOC. BIS monitoring may not be a reliable method for determining LOC. CLINICAL TRIALS REGISTRY: This trial was not registered because registration was not mandatory at the time of the trial.

N-terminal pro-B-type Natriuretic Peptides' Prognostic Utility Is Overestimated in Meta-analyses Using Study-specific Optimal Diagnostic Thresholds.

BACKGROUND: N-terminal fragment B-type natriuretic peptide (NT-proBNP) prognostic utility is commonly determined post hoc by identifying a single optimal discrimination threshold tailored to the individual study population. The authors aimed to determine how using these study-specific post hoc thresholds impacts meta-analysis results. METHODS: The authors conducted a systematic review of studies reporting the ability of preoperative NT-proBNP measurements to predict the composite outcome of all-cause mortality and nonfatal myocardial infarction at 30 days after noncardiac surgery. Individual patient-level data NT-proBNP thresholds were determined using two different methodologies. First, a single combined NT-proBNP threshold was determined for the entire cohort of patients, and a meta-analysis conducted using this single threshold. Second, study-specific thresholds were determined for each individual study, with meta-analysis being conducted using these study-specific thresholds. RESULTS: The authors obtained individual patient data from 14 studies (n = 2,196). Using a single NT-proBNP cohort threshold, the odds ratio (OR) associated with an increased NT-proBNP measurement was 3.43 (95% CI, 2.08 to 5.64). Using individual study-specific thresholds, the OR associated with an increased NT-proBNP measurement was 6.45 (95% CI, 3.98 to 10.46). In smaller studies (<100 patients) a single cohort threshold was associated with an OR of 5.4 (95% CI, 2.27 to 12.84) as compared with an OR of 14.38 (95% CI, 6.08 to 34.01) for study-specific thresholds. CONCLUSIONS: Post hoc identification of study-specific prognostic biomarker thresholds artificially maximizes biomarker predictive power, resulting in an amplification or overestimation during meta-analysis of these results. This effect is accentuated in small studies.

Strain echocardiography in septic shock - a comparison with systolic and diastolic function parameters, cardiac biomarkers and outcome.

INTRODUCTION: Myocardial dysfunction is a well-known complication in septic shock but its characteristics and frequency remains elusive. Here, we evaluate global longitudinal peak strain (GLPS) of the left ventricle as a diagnostic and prognostic tool in septic shock. METHODS: Fifty adult patients with septic shock admitted to a general intensive care unit were included. Transthoracic echocardiography was performed on the first day, and repeated during and after ICU stay. Laboratory and clinical data and data on outcome were collected daily from admission and up to 7 days, shorter in cases of death or ICU discharge. The correlation of GLPS to left ventricular systolic and diastolic function parameters, cardiac biomarkers and clinical data were compared using Spearman's correlation test and linear regression analysis, and the ability of GLPS to predict outcome was evaluated using a logistic regression model. RESULTS: On the day of admission, there was a strong correlation and co-linearity of GLPS to left ventricular ejection fraction (LVEF), mitral annular motion velocity (é) and to amino-terminal pro-brain natriuretic peptide (NT-proBNP) (Spearman's ρ -0.70, -0.53 and 0.54, and R(2) 0.49, 0.20 and 0.24, respectively). In LVEF and NT-proBNP there was a significant improvement during the study period (analysis of variance (ANOVA) with repeated measures, p = 0.05 and p < 0.001, respectively), but not in GLPS, which remained unchanged over time (p = 0.10). GLPS did not correlate to the improvement in clinical characteristics over time, did not differ significantly between survivors and non-survivors (-17.4 (-20.5-(-13.7)) vs. -14.7 (-19.0 - (-10.6)), p = 0.11), and could not predict mortality. CONCLUSIONS: GLPS is frequently reduced in septic shock patients, alone or in combination with reduced LVEF and/or é. It correlates with LVEF, é and NT-proBNP, and remains affected over time. GLPS may provide further understanding on the character of myocardial dysfunction in septic shock.

Variability in echocardiographic measurements of left ventricular function in septic shock patients.

BACKGROUND: Echocardiography is increasingly used for haemodynamic evaluation and titration of therapy in intensive care, warranting reliable and reproducible measurements. The aim of this study was to evaluate the observer dependence of echocardiographic findings of left ventricular (LV) diastolic and systolic dysfunction in patients with septic shock. METHODS: Echocardiograms performed in 47 adult patients admitted with septic shock to a general intensive care unit (ICU) were independently evaluated by one cardiologist and one intensivist for the following signs: decreased diastolic tissue velocity of the base of the LV septum (é), increased early mitral inflow (E) to é ratio (E/é), decreased LV ejection fraction (EF) and decreased LV global longitudinal peak strain (GLPS). Diastolic dysfunction was defined as é <8.0 cm/s and/or E/é ≥15 and systolic dysfunction as EF <50% and/or GLPS > -15%. Ten randomly selected examinations were re-analysed two months later. Pearson's r was used to test the correlation and Bland-Altman plots to assess the agreement between observers. Kappa statistics were used to test the consistency between readers and intraclass correlation coefficients (ICC) for inter- and intraobserver variability. RESULTS: In 44 patients (94%), image quality was sufficient for echocardiographic measurements. The agreement between observers was moderate (k = 0.60 for é, k = 0.50 for E/é and k = 0.60 for EF) to good (k = 0.71 for GLPS). Pearson's r was 0.76 for é, 0.85 for E/é, 0.78 for EF and 0.84 for GLPS (p < 0.001 for all four). The ICC between observers for é was very good (0.85; 95% confidence interval (CI) 0.73-0.92), good for E/é (0.70; 95% CI 0.45 - 0.84), very good for EF (0.87; 95% CI 0.77 - 0.93), excellent for GLPS (0.91; 95% CI 0.74 - 0.95), and very good for all measures repeated by one of the observers. On Bland-Altman analysis, the mean differences and 95% limits of agreement for é, E/é, EF and GLPS were -0.01 (0.04 - 0.07), 2.0 (-14.2 - 18.1), 0.86 (-16 - 14.3) and 0.04 (-5.04 - 5.12), respectively. CONCLUSIONS: Moderate observer-related differences in assessing LV dysfunction were seen. GLPS is the least user dependent and most reproducible echocardiographic measurement of LV function in septic shock.

Pharmacogenetics, plasma concentrations, clinical signs and EEG during propofol treatment.

A variety of techniques have been developed to monitor the depth of anaesthesia. Propofol's pharmacokinetics and response vary greatly, which might be explained by genetic polymorphisms. We investigated the impact of genetic variations on dosage, anaesthetic depth and recovery after total intravenous anaesthesia with propofol. A total of 101 patients were enrolled in the study. The plasma concentration of propofol during anaesthesia was measured using high-performance liquid chromatography. EEG was monitored during the surgical procedure as a measure of anaesthetic depth. Pyrosequencing was used to determine genetic polymorphisms in CYP2B6, CYP2C9, the UGTIA9-promotor and the GABRE gene. The correlation between genotype and to plasma concentration at the time of loss of consciousness (LOC), the total induction dose, the time to anaesthesia, eye opening and clearance were investigated. EEG monitoring showed that the majority of the patients had not reached a sufficient level of anaesthetic depth (subdelta) at the time of loss of consciousness despite a high induction dose of propofol. Patients with UGT1A9-331C/T had a higher propofol clearance than those without (p = 0.03) and required a higher induction dose (p = 0.03). The patients with UGT1A9-1818T/C required a longer time to LOC (p = 0.03). The patients with CYP2C9*2 had a higher concentration of propofol at the time of LOC (p = 0.02). The polymorphisms in the metabolizing enzymes and the receptor could not explain the large variation seen in the pharmacokinetics of propofol and the clinical response seen. At LOC, the patients showed a large difference in EEG pattern.

Amino-terminal pro-brain natriuretic peptide as a predictor of outcome in patients admitted to intensive care. A prospective observational study.

CONTEXT: Amino-terminal pro-brain-type natriuretic peptide is known to predict outcome in patients with heart failure, but its role in an intensive care setting is not yet fully established. OBJECTIVE: To assess the incidence of elevated amino-terminal pro-brain natriuretic peptide (NT-pro-BNP) on admission to intensive care and its relation to death in the ICU and within 30 days. DESIGN: Prospective, observational cohort study. SETTING: A mixed non-cardiothoracic tertiary ICU in Sweden. PATIENTS AND MAIN OUTCOME MEASURES: NT-pro-BNP was collected from 481 consecutive patients on admission to intensive care, in addition to data on patient characteristics and outcome. A receiver-operating characteristic curve was used to identify a discriminatory level of significance, a stepwise logistic regression analysis to correct for other clinical factors and a Kaplan-Meier analysis to assess survival. The correlation between Simplified Acute Physiology Score (SAPS) 3, Sequential Organ Failure Assessment score (SOFA) and NT-pro-BNP was analysed using Spearman's correlation test. Quartiles of NT-pro-BNP elevation were compared for baseline data and outcome using a logistic regression model. RESULTS: An NT-pro-BNP more than 1380 ng -l on admission was an independent predictor of death in the ICU and within 30 days [odds ratio (OR) 2.6; 95% confidence interval (CI), 1.5 to 4.4] and was present in 44% of patients. Thirty-three percent of patients with NT-pro-BNP more than 1380 ng -1, and 14.6% of patients below that threshold died within 30 days (log rank P=0.005). NT-pro-BNP correlated moderately with SAPS 3 and with SOFA on admission (Spearman's ρ 0.5552 and 0.5129, respectively). In quartiles of NT-pro-BNP elevation on admission, severity of illness and mortality increased significantly (30-day mortality 36.1%; OR 3.9; 95% CI, 2.0 to 7.3 in the quartile with the highest values, vs. 12.8% in the lowest quartile). CONCLUSION: We conclude that NT-pro-BNP is commonly elevated on admission to intensive care, that it increases with severity of illness and that it is an independent predictor of mortality.

The prognostic value of the Modified Early Warning Score in critically ill patients: a prospective, observational study.

CONTEXT: The Modified Early Warning Score is a validated assessment tool for detecting risk of deterioration in patients at risk on medical and surgical wards. OBJECTIVE: To assess the prognostic ability of the Modified Early Warning Score in predicting outcome after critical care. DESIGN: A prospective observational study. SETTING: A tertiary care general ICU. PATIENTS: Five hundred and eighteen patients aged at least 16 years admitted to the ICU at Linköping University Hospital were included. INTERVENTION: The Modified Early Warning Score was documented on arrival at the ICU and every hour for as long as the patient was breathing spontaneously, until discharge from the ICU. MAIN OUTCOME MEASURES: The primary endpoint was mortality in the ICU. Secondary endpoints were 30-day mortality, length of stay and readmission to the ICU. RESULTS: Patients with a Modified Early Warning Score of at least six had significantly higher mortality in the ICU than those with a Modified Early Warning Score <6 (24 vs. 3.4%, P < 0.001). A Modified Early Warning Score of at least six was an independent predictor of mortality in the ICU [odds ratio (OR) 5.5, 95% confidence interval (CI) 2.4-20.6]. The prognostic ability of the Modified Early Warning Score on admission to the ICU [area under the curve (AUC) 0.80, 95% CI 0.72-0.88] approached those of the Simplified Acute Physiology Score III (AUC 0.89, 95% CI 0.83-0.94) and the Sequential Organ Failure Assessment score on admission (AUC 0.91, 95% CI 0.86-0.97). A Modified Early Warning Score of at least six on admission was also an independent predictor of 30-day mortality (OR 4.3, 95% CI 2.3-8.1) and length of stay in the ICU (OR 2.3, 95% CI 1.4-3.8). In contrast, the Modified Early Warning Score on discharge from the ICU did not predict the need for readmission. CONCLUSION: This study shows that the Modified Early Warning Score is a useful predictor of mortality in the ICU, 30-day mortality and length of stay in the ICU.

Platelet function assessed by whole-blood aggregometry in patients undergoing non-cardiac surgery.

BACKGROUND: The risk/benefit of continuing low-dose acetylsalicylic acid (aspirin) for secondary prevention in the perioperative period is still debated. The primary aim of this study was to determine the effect of acetylsalicylic acid compared with placebo on platelet function in the perioperative period. METHODS: This is a subgroup analysis of a randomised, double-blind, placebo-controlled multicentre study. High-risk patients undergoing major non-cardiac surgery were randomised to 75 mg acetylsalicylic acid or placebo 7 days preoperatively, until the third postoperative day. In 36 patients, platelet function in response to arachidonic acid was assessed by whole-blood impedance aggregometry using a multiplate analyser 1 h before surgery, directly after surgery and 48 h postoperatively. RESULTS: The platelet function was significantly reduced in patients treated with acetylsalicylic acid compared with placebo in the preoperative period [200 aggregation units (AU) min (interquartile range [IQR] 133-261 AU min⁻¹) vs. 860 AU min (IQR 800-1010 AU min), P < 0.001] as well as postoperatively [198 AU min (IQR 138-270 AU min) vs. 605 AU min (IQR 434-836 AU min), P < 0.001]. The platelet response was significantly reduced postoperatively compared with preoperatively in patients receiving placebo [860 AU min (IQR 800-1010 AU min) vs. 605 AU min (IQR 434-861 AU min), P = 0.0009]. No significant differences were found between pre- and postoperative platelet function in patients on acetylsalicylic acid [200 AU min (IQR 133-261 AU min) vs. 198 AU min (133-270 AU min), P = 0.21]. CONCLUSION: Multiplate whole-blood impedance aggregometry demonstrates acetylsalicylic affect in preoperative as well as postoperative samples derived from patients undergoing non-cardiac surgery.