Decreased pain sensitivity and alterations of cerebrospinal fluid and plasma inflammatory mediators after total hip arthroplasty in patients with disabling osteoarthritis.

BACKGROUND: Proinflammatory mechanisms are implicated in pain states. Recent research indicates that patients with osteoarthritis (OA) with signs of central sensitization exhibit elevated cerebrospinal fluid (CSF) levels of interferon gamma-induced protein 10 (IP-10), Fms-related tyrosine kinase 1 (Flt-1), and monocyte chemoattractant protein 1 (MCP-1). METHODS: The current prospective cohort study, including 15 patients with OA, primarily aimed to evaluate associations among alterations in CSF IP-10, Flt-1, MCP-1, and pain sensitization following total hip arthroplasty (THA). Participants provided CSF and blood samples for analysis of 10 proinflammatory mediators, and underwent detailed clinical examination and quantitative sensory testing, immediately preoperative and 18 months after surgery. RESULTS: Neurophysiological measures of pain showed markedly reduced pain sensitivity long-term postoperative. Increases in remote site pressure pain detection thresholds (PPDTs) and decreased temporal summation indicated partial resolution of previous central sensitization. Compared to preoperative, CSF concentrations of IP-10 were increased (p = 0.041), whereas neither Flt-1 (p = 0.112) nor MCP-1 levels changed (p = 0.650). Compared to preoperative, plasma concentrations of IP-10 were increased (p = 0.006), whereas interleukin (IL)-8 was decreased (p = 0.023). Subjects who exhibited increases in arm PPDTs above median showed greater increases in CSF IP-10 compared to those with PPDT increases below median (p = 0.028). Analyses of plasma IP-10 and IL-8 indicated higher levels of peripheral inflammation were linked to decreased pressure pain thresholds (unadjusted ß = -0.79, p = 0.006, and ß = -118.1, p = 0.014, respectively). CONCLUSIONS: THA leads to long-term decreases in pain sensitivity, indicative of resolution of sensitization processes. Changes in CSF and plasma levels of IP-10, and plasma IL-8, may be associated with altered pain phenotype.

Morbidity and mortality in critically ill patients with invasive group A streptococcus infection: an observational study.

BACKGROUND: Group A streptococci (GAS) are known to cause serious invasive infections, but little is known about outcomes when patients with these infections are admitted to intensive care. We wanted to describe critically ill patients with severe sepsis or septic shock due to invasive GAS (iGAS) and compare them with other patients with severe sepsis or septic shock. METHODS: Adult patients admitted to a general intensive care unit (ICU) in Sweden (2007-2019) were screened for severe sepsis or septic shock according to Sepsis 2 definition. Individuals with iGAS infection were identified. The outcome variables were mortality, days alive and free of vasopressors and invasive mechanical ventilation, maximum acute kidney injury score for creatinine, use of continuous renal replacement therapy and maximum Sequential Organ Failure Assessment score during the ICU stay. Age, Simplified Acute Physiology Score (SAPS 3) and iGAS were used as independent, explanatory variables in regression analysis. Cox regression was used for survival analyses. RESULTS: iGAS was identified in 53 of 1021 (5.2%) patients. Patients with iGAS presented a lower median SAPS 3 score (62 [56-72]) vs 71 [61-81]), p <  0.001), had a higher frequency of cardiovascular cause of admission to the ICU (38 [72%] vs 145 [15%], p <  0.001) and had a higher median creatinine score (173 [100-311] vs 133 [86-208] µmol/L, p <  0.019). Of the GAS isolates, 50% were serotyped emm1/T1 and this group showed signs of more pronounced circulatory and renal failure than patients with non-emm1/T1 (p = 0.036 and p = 0.007, respectively). After correction for severity of illness (SAPS 3) and age, iGAS infection was associated with lower mortality risk (95% confidence interval (CI) of hazard ratio (HR) 0.204-0.746, p <  0.001). Morbidity analyses demonstrated that iGAS patients were more likely to develop renal failure. CONCLUSION: Critically ill patients with iGAS infection had a lower mortality risk but a higher degree of renal failure compared to similarly ill sepsis patients. emm1/T1 was found to be the most dominant serotype, and patients with emm1/T1 demonstrated more circulatory and renal failure than patients with other serotypes of iGAS.

Commercial albumin solution enhances endotoxin-induced vasoplegia and inflammation.

BACKGROUND: The Gram-negative bacterium Escherichia coli, commonly involved in severe sepsis and septic shock, shed endotoxin that upon detection by the host triggers an inflammatory cascade. Efficiency of albumin solutions to restore hypovolemia during sepsis has been debated. To aid identification of subgroups of sepsis patients that may respond positively or negatively to treatment with albumin we investigated if preparations of albumin for medical use could affect endotoxin-induced inflammatory response. METHODS: Isolated human omental arteries obtained during surgery were incubated with endotoxin in the presence or absence of albumin solution. Isolated human monocytes were incubated with endotoxin in the presence or absence of five different commercially available albumin solutions. Vascular contractile response to noradrenaline and release of interleukin (IL)-1ß, IL-6, IL-8, IL-10, and tumor necrosis factor (TNF)-α were measured. RESULTS: Incubation with albumin together with endotoxin decreased median maximum contraction and increased release of IL-6 and IL-8 from the arteries compared to incubation with endotoxin alone. All albumin solutions except one significantly increased endotoxin-induced TNF-α release from monocytes. IL-6 and IL-10 were also increased and no concentration dependency of TNF-α release was observed above 2 mg mL-1 . Incubation with albumin alone did not affect contraction or release of cytokines while no potentially endotoxin-enhancing contaminant could be identified. CONCLUSION: We have shown that albumin solution in combination with endotoxin cause vasoplegia in human omental arteries, paralleled by an inflammatory response. This finding could explain the variable efficiency of albumin solutions for sepsis treatment.

Analysis of Endotoxin Adsorption in Two Swedish Patients with Septic Shock.

BACKGROUND: Lipopolysaccharide (endotoxin) from the outer Gram-negative bacterial wall can induce a harmful immunologic response, involving hemodynamic deprivation, and is one important motor driving the septic cascade. The positively charged poly-imine ethylene layer on the oXiris membrane is capable of adsorbing negatively charged endotoxin molecules and removing them from the blood compartment. Endotoxin is detrimental and should be removed from blood. SUMMARY: The adsorbable endotoxin fraction in blood arises from a tight balance between seeding from an infectious focus and removal by an overwhelmed immune system. The net sum of remaining endotoxin in blood is available for an adsorption process in the oXiris filter. Endotoxin data from 2 patients with severe Gram-negative septic shock and endotoxemia in this case series, speaks for a considerable share of the adsorption of the oXiris filter in the endotoxin net removal over time. Key Messages: Analysis of combined in vitro and in vivo data speaks for an effect of the oXiris filter in lowering endotoxin.

Ventilation with increased apparatus dead space vs positive end-expiratory pressure: effects on gas exchange and circulation during anesthesia in a randomized clinical study.

Atelectasis formation can be reduced by positive end-expiratory pressure (PEEP), but resulting increases in intrathoracic pressure could affect circulation. We have earlier demonstrated that increased tidal volumes with larger apparatus dead space improves oxygenation and sevoflurane uptake. In the present study, we hypothesize that isocapnic ventilation with increased tidal volumes increases oxygen and sevoflurane uptake similar to ventilation with PEEP, but with less impact on cardiac output. Thirty patients, with ASA physical status 1 or 2, scheduled for elective open colon surgery were randomly assigned to be ventilated with either PEEP at 10 cm H20 (PEEP, 15 patients) or increased tidal volumes achieved with larger apparatus dead space but with zero end-expiratory pressure (DS group, 15 patients). Oxygen tension and arterial sevoflurane concentration were significantly higher in the DS group (P < .05). Cardiac output decreased significantly less in the DS group compared with the PEEP group (5% and 33%, respectively; P < .05). Consequently, isocapnic ventilation with increased tidal volumes using apparatus dead space increased oxygen and sevoflurane tensions in arterial blood and preserved cardiac output better than did PEEP.

Apparent dead space with the anesthetic conserving device, AnaConDa®: a clinical and laboratory investigation.

BACKGROUND: The anesthetic conserving device (ACD) reduces consumption of volatile anesthetic drug by a conserving medium adsorbing exhaled drug during expiration and releasing it during inspiration. Elevated arterial CO2 tension (PaCO2) has been observed in patients using the ACD, despite tidal volume increase to compensate for larger apparatus dead space. In a test lung using room temperature dry gas, this was shown to be due to adsorption of CO2 in the ACD during expiration and release of CO2 during the following inspiration. The effect in the test lung was higher than in patients. We tested the hypothesis that a lesser dead space effect in patients is due to higher temperature and/or moisture attenuating rebreathing of CO2. METHODS: The lungs of 6 postoperative cardiac surgery patients were ventilated using a conventional heat and moisture exchanger (HME) or an ACD. The ACD was studied with a test lung at varying temperatures and moistures. Infrared spectrometry was used to measure apparent dead space by the single-breath test for CO2 as well as rebreathing of CO2. RESULTS: In patients, the median apparent dead space was 136 mL (95% confidence interval [CI,] 120-167) larger using the ACD compared with an HME (after correction for difference in internal volume 100 and 50 mL, respectively). Median rebreathing of CO2 using the ACD was 53% (range 48-58) of exhaled CO2 compared with 29% (range 27-32) with an HME. The median difference in CO2 rebreathing was 23% (95% CI, 18-27). In the test lung apparent dead space using ACD was unaffected by body temperature but decreased from 360 to 260 mL when moisture was added. This decreased rebreathing of CO2 from 62% to 48%. CONCLUSIONS: The use of an ACD increases apparent dead space to a greater extent than can be explained by its internal volume. This is caused by adsorption of CO2 in the ACD during expiration and release of CO2 during inspiration. Rebreathing of CO2 was attenuated by moisture. The dead space effect of the ACD could be clinically relevant in acute respiratory distress syndrome and other diseases associated with ventilation difficulties, but investigations with larger sample sizes would be needed to determine the clinical importance.

Analysis of acid-base disorders in an ICU cohort using a computer script.

BACKGROUND/AIMS: Acid-base status is important for understanding pathophysiology, making a diagnosis, planning effective treatment and monitoring progress of critically ill patients. Manual calculations are cumbersome, easily result in wrong conclusions. We wanted to develop an automated assessment of acid-base status. METHODS: A simplified adaptive MATLAB script processing all available theory to date was created, evaluated and used on blood gas analyses drawn immediately after admission to ICU. The script was compared to golden standard, calculating manually by two experienced ICU physicians. RESULTS: Results from the script correlated completely with detailed manual calculations of randomly chosen 100 blood gas results and it was able to deliver complex data on cohort level with advanced graphics. The initial blood gas analyses from 8875 admissions constituted the cohort, of which 4111 (46.3%) were normal. Respiratory acidosis was the primary disturbance in 2753 (31.0%) and metabolic acidosis in 464 (5.2%). Respiratory alkalosis was the primary disturbance in 1501 (17.0%) and metabolic alkalosis in 46 (0.5%). Of the disturbances 74.7% were mixed with two and 2.1% with three simultaneous disturbances. Acidoses were less compensated compared to alkaloses. CONCLUSIONS: Acid-base theories are developed on ideal models and not on critical care patients, they require inputs that might not be available, and therefore, estimations are needed. In our cohort, it was difficult to develop a working script based on Stewart, whereas Boston/Copenhagen worked better. Acidoses were more common and more deviated compared to alkaloses.

Central nervous system monoaminergic activity in hip osteoarthritis patients with disabling pain: associations with pain severity and central sensitization.

INTRODUCTION: Monoaminergic activity modulates nociceptive transmission in the central nervous system (CNS). Although pain is the most disabling symptom of osteoarthritis (OA), limited knowledge exists regarding the CNS mechanisms that amplify pain and drive sensitization processes in humans. OBJECTIVES: The main objective of this study was to evaluate associations between cerebrospinal fluid (CSF) monoamine metabolites, pain severity, and central sensitization in patients with OA undergoing total hip arthroplasty (THA). METHODS: Patients with OA (n = 52) and pain-free controls (n = 30) provided CSF samples for measurement of serotonin (5-hydroxyindoleacetic acid [5-HIAA]), noradrenaline (3-methoxy-4-hydroxyphenylglycol [HMPG]), and dopamine (homovanillic acid [HVA]) monoamine metabolites. Patients with OA completed longitudinal evaluation of pain using clinical measures and quantitative sensory testing. RESULTS: Patients with OA had higher HMPG levels when compared with controls (P = 0.036). Within patients with OA undergoing THA, higher 5-HIAA and HVA levels were consistently associated with higher preoperative pain severity. Higher concentrations of 5-HIAA and HVA were also associated with lower conditioned pain modulation levels, whereas higher HMPG levels were linked to more efficient conditioned pain modulation. Patients with higher levels of CSF HVA exhibited increased pressure pain sensitivity (arm pressure pain detection threshold < 250 kPa vs ≥ 250 kPa, P = 0.042). Higher preoperative levels of CSF 5-HIAA predicted poorer pain control 6 months postoperatively (brief pain inventory pain severity; adjusted ß = 0.010, 95% CI 0.001-0.019). CONCLUSIONS: In OA patients with disabling pain, higher CSF levels of serotonin and dopamine metabolites are associated with increased pain severity and central sensitization. Increased noradrenergic activity may be associated with more efficient pain inhibitory capacity.

Screening of the ryanodine 1 gene for malignant hyperthermia causative mutations by high resolution melt curve analysis.

BACKGROUND: A diagnosis of malignant hyperthermia (MH) can be determined by performing an in vitro (muscle) contracture test (IVCT) or by identifying a known MH causative mutation in the ryanodine receptor 1 gene (RYR1). Genetic diagnosis has an advantage over IVCT because it is less invasive. Direct sequencing of the very large RYR1 coding region (15.117 bases) is a laborious and expensive task. In this study, we applied the High Resolution Melting (HRM) curve analysis as a tool to screen the entire coding region of the gene. METHODS: Genomic DNA was extracted from peripheral blood samples in a cohort of 16 MH-susceptible patients diagnosed by the IVCT. The total coding region of RYR1 was divided and amplified by polymerase chain reaction in 131 DNA fragments and the melting profiles were compared with those of control samples. HRM curves were evaluated by Rotor-Gene Q software and visual inspection. Fragments showing aberrant melting profiles were sequenced to identify the underlying sequence variation. RESULTS: A subset of 520 of 2520 DNA fragments (21%) showed significantly aberrant melting profiles. Upon sequencing, 131 known polymorphisms and 17 known or suspected mutations were found in 13 of 16 MH-susceptible patients (81%). Thus, the workload of sequencing was reduced by 79%. CONCLUSION: HRM curve analysis is a sensitive and cost-effective tool for the identification of nucleotide sequence variants in complex genes such as the RYR1 gene.

Increased apparatus dead space and tidal volume increase blood concentrations of oxygen and sevoflurane in overweight patients: a randomised controlled clinical study.

BACKGROUND AND OBJECTIVE: General anaesthesia impairs respiratory function in overweight patients. We wanted to determine whether increased tidal volume (V(T)), with unchanged end-tidal carbon dioxide partial pressure (P(ET)CO2), affects blood concentrations of oxygen and sevoflurane in overweight patients. METHODS: The present study is a prospective, randomised, clinical study. American Society of Anesthesiologists physical status I and II patients with BMI over 25 scheduled for elective surgery of the lower abdomen were randomly assigned to one of two groups with 10 patients in each. One group was ventilated with normal V(T) (NV(T)) and one group with increased V(T) (IV(T)) achieved by increasing inspired plateau pressure 0.04 cmH2O kg⁻¹ above initial plateau pressure. Extra apparatus dead space was added to maintain P(ET)CO2 at 4.5 kPa. Respiratory rate was set at 15 min⁻¹, and sevoflurane was delivered to the fresh gas by a vaporiser set at 3%. Arterial oxygenation, sevoflurane tensions (P(a)sevo, F(i)sevo, P(ET)sevo), paCO2, P(ET)CO2, V(t) and airway pressure were measured. RESULTS: The two groups of patients were similar with regard to sex, age, weight, height and BMI. Arterial oxygen tension (mean ± SD) was significantly higher in the IV(T) group (15 ± 4.3 vs. 10 ± 2.7 kPa after 60 min of anaesthesia, P < 0.05). Mean PETsevo did not differ between the groups, whereas arterial sevoflurane tension (mean ± SD) was significantly higher in the IVT group (1.74 ± 0.18 vs. 1.43 ± 0.19 kPa after 60 min of anaesthesia, P < 0.05). CONCLUSION: Ventilation with larger tidal volumes with isocapnia maintained with added apparatus dead space increases the tension of oxygen and sevoflurane in arterial blood in overweight patients.

Mathematical modelling of post-filter ionized calcium during citrate anticoagulated continuous renal replacement therapy.

BACKGROUND/AIMS: Post-filter ionized calcium (iCa) measured on a blood gas analyzer (BGA) during regional citrate anticoagulated continuous renal replacement therapy (CRRT) are needed to control the regime. This increases the workload and requires attention including interpretation of blood analyses. Two algorithms were developed to calculate the post-filter iCa instead. The first algorithm used measured systemic total calcium and the second used a selected set of values from an initial blood gas sample as input. METHODS: Calculated post-filter iCa values were compared to real blood gas analyses. 57 patients treated at the intensive care unit at Skåne University Hospital in Lund during 2010-2017 were included after applying inclusion and exclusion criteria. Clinical and machine parameters were collected from the electronic medical records. Non-quality checked data contained 1240 measurements and quality checked data contained 1034 measurements. RESULTS: The first algorithm using measured systemic total calcium resulted in slightly better precision and trueness with an average difference between the predicted and measured post-filter iCa concentration of 0.0185±0.0453 mmol/L for quality checked data, p<0.001. Neither algorithm could detect all instances requiring intervention. CONCLUSION: The algorithms were able to estimate in range postfilter iCa values with great trueness and precision. However, they had some difficulties to estimate out-of-range postfilter iCa values. More work is needed to improve the algorithms especially in their citrate-modelling.

Preoperative sleep quality and adverse pain outcomes after total hip arthroplasty.

BACKGROUND: Sleep disturbance is thought to aggravate acute postoperative pain. The influence of preoperative sleep problems on pain control in the long-term and development of chronic postsurgical pain is largely unknown. METHODS: This prospective, observational study aimed to examine the links between preoperative sleep disturbance (Pittsburgh Sleep Quality Index, PSQI) and pain severity (Brief Pain Inventory, BPI) 6 months postoperative (primary outcome), objective measures of pain and postoperative pain control variables (secondary outcomes). Patients (n = 52) with disabling osteoarthritis (OA) pain undergoing total hip arthroplasty (THA) were included. Quantitative sensory testing (QST) was performed preoperatively on the day of surgery to evaluate pain objectively. Clinical data, as well as measures of sleep quality and pain, were obtained preoperatively and longitudinally over a 6-month period. RESULTS: Preoperatively, sleep disturbance (i.e., PSQI score >5) occurred in 73.1% (n = 38) of THA patients, and pain severity was high (BPI pain severity 5.4 ± 1.3). Regression models, adjusting for relevant covariates, showed that preoperative PSQI score predicted pain severity 6 months postoperative (ß = 0.091 (95% CI 0.001-0.181), p = .048, R2  = 0.35). Poor sleep quality was associated with increased pressure pain sensitivity and impaired endogenous pain inhibitory capacity (R2 range 0.14-0.33, all p's < 0.04). Moreover, preoperative sleep disturbance predicted increased opioid treatment during the first 24 hr after surgery (unadjusted ß = 0.009 (95% CI 0.002-0.015) mg/kg, p = .007, R2  = 0.15). CONCLUSIONS: Preoperative sleep disturbance is prevalent in THA patients, is associated with objective measures of pain severity, and independently predicts immediate postoperative opioid treatment and poorer long-term pain control in patients who have undergone THA. SIGNIFICANCE: Poor sleep quality and impaired sleep continuity are associated with heightened pain sensitivity, but previous work has not evaluated whether preoperative sleep problems impact long-term postoperative pain outcomes. Here, we show that sleep difficulties prior to total hip arthroplasty adversely predict postoperative pain control 6 months after surgery. Given sleep difficulties robustly predict pain outcomes, targeting and improving sleep may have salutary effects on postoperative pain reports and management.

Functional properties of RYR1 mutations identified in Swedish patients with malignant hyperthermia and central core disease.

BACKGROUND: A diagnosis of malignant hyperthermia susceptibility by in vitro contraction testing can often only be performed at specialized laboratories far away from where patients live. Therefore, we have designed a protocol for genetic screening of the RYR1-cDNA and for functional testing of newly identified ryanodine receptor 1 (RYR1) gene variants in B lymphocytes isolated from peripheral blood samples drawn at local primary care centers. METHODS: B lymphocytes were isolated for the extraction of RYR1-mRNA and genomic DNA and for establishment of lymphoblastoid B cell lines in 5 patients carrying yet unclassified mutations in the RYR1. The B lymphoblastoid cell lines were used to study resting cytoplasmic calcium concentration, the peak calcium transient induced by the sarco(endo)plasmic reticulum Ca-ATPase inhibitor thapsigargin, and the dose-dependent calcium release induced by the ryanodine receptor agonist 4-chloro-m-cresol. RESULTS: It was possible to extract mRNA for cDNA synthesis and to create B lymphocyte clones from all samples. All B lymphoblastoid cell lines carrying RYR1 candidate mutations showed significantly increased resting cytoplasmic calcium levels as well as a shift to lower concentrations of 4-chloro-m-cresol inducing calcium release compared with controls. CONCLUSIONS: Peripheral blood samples are stable regarding RNA and DNA extraction and establishment of lymphoblastoid B cell lines after transportation at ambient temperature over large distances by ordinary mail. Functional tests on B cells harboring the newly identified amino acid substitutions indicate that they alter intracellular Ca2+ homeostasis and are most likely causative of malignant hyperthermia.

Acute reduction of cerebrospinal fluid volume prior to spinal anesthesia: implications for sensory block extent.

BACKGROUND: Multiple patient and clinical characteristics contribute to the variable outcome of spinal anesthesia (SPA). Acute reduction of cerebrospinal fluid (CSF) volume may alter the effect of SPA. The objective of the present study was to test if aspiration of 10 mL CSF immediately prior to SPA is associated with higher extent of sensory block. METHODS: Interventional cohort study. One hundred and two patients undergoing total hip arthroplasty (THA) were included. Fifty-one patients underwent sampling of 10 mL CSF prior to SPA (CSF aspiration group); 51 consecutive patients were used as controls. The primary outcome was the extent of sensory block to cold stimulus 20 minutes after injection of hyperbaric bupivacaine. Secondary outcome measures included duration of motor block and incidence of failed SPA. RESULTS: Acute reduction of CSF volume by 10 mL increased the extent of sensory anesthesia (mean thoracic level [T] 4.3±2.4 vs. 7.1±2.6, P<0.001). There were no significant between-group differences regarding motor block duration (P≥0.30) or failed SPA (three of 51 [CSF aspiration group] vs. one of 51 [control group], P=0.31). In a retrospective data analysis, 10 of 13 patients in the CSF aspiration group who had previously received SPA had a higher sensory block after 10 mL CSF aspiration compared to the previous SPA (T4.1 [range, 0-11] vs. T8.2 [4-10], P<0.01). CONCLUSIONS: Acute reduction of CSF volume by 10 mL prior to SPA leads to a higher thoracic level of sensory block.

Differential expression of cerebrospinal fluid neuroinflammatory mediators depending on osteoarthritis pain phenotype.

ABSTRACT: Neuroinflammation is implicated in the development and maintenance of persistent pain states, but there are limited data linking cerebrospinal fluid (CSF) inflammatory mediators with neurophysiological pain processes in humans. In a prospective observational study, CSF inflammatory mediators were compared between patients with osteoarthritis (OA) who were undergoing total hip arthroplasty due to disabling pain symptoms (n = 52) and pain-free comparison controls (n = 30). In OA patients only, detailed clinical examination and quantitative sensory testing were completed. Cerebrospinal fluid samples were analyzed for 10 proinflammatory mediators using Meso Scale Discovery platform. Compared to controls, OA patients had higher CSF levels of interleukin 8 (IL-8) (P = 0.002), intercellular adhesion molecule 1 (P = 0.007), and vascular cell adhesion molecule 1 (P = 0.006). Osteoarthritis patients with central sensitization possibly indicated by arm pressure pain detection threshold <250 kPa showed significantly higher CSF levels of Fms-related tyrosine kinase 1 (Flt-1) (P = 0.044) and interferon gamma-induced protein 10 (IP-10) (P = 0.024), as compared to subjects with PPDT above that threshold. In patients reporting pain numerical rating scale score ≥3/10 during peripheral venous cannulation, Flt-1 was elevated (P = 0.025), and in patients with punctate stimulus wind-up ratio ≥2, CSF monocyte chemoattractant protein 1 was higher (P = 0.011). Multiple logistic regression models showed that increased Flt-1 was associated with central sensitization, assessed by remote-site PPDT and peripheral venous cannulation pain, and monocyte chemoattractant protein-1 with temporal summation in the area of maximum pain. Multiple proinflammatory mediators measured in CSF are associated with persistent hip OA-related pain. Pain phenotype may be influenced by specific CSF neuroinflammatory profiles.

The Difficult Airway Trolley: A Narrative Review and Practical Guide.

Death and severe morbidity attributable to anesthesia are commonly associated with failed difficult airway management. When an airway emergency develops, immediate access to difficult airway equipment is critical for implementation of rescue strategies. Previously, national expert consensus guidelines have provided only limited guidance for the design and setup of a difficult airway trolley. The overarching aim of the current work was to create a dedicated difficult airway trolley (for patients>12 years old) for use in anesthesia theatres, intensive care units, and emergency departments. A systematic literature search was performed, using the PubMed, Embase, and Google Scholar search engines. Based on evidence presented in 11 national or international guidelines, and peer-reviewed journals, we present and outline a difficult airway trolley organized to accommodate sequential progression through a four-step difficult airway algorithm. The contents of the top four drawers correspond to specific steps in the airway algorithm (A = intubation, B = oxygenation via a supraglottic airway device, C = facemask ventilation, and D = emergency invasive airway access). Additionally, specialized airway equipment may be included in the fifth drawer of the proposed difficult airway trolley, thus enabling widespread use. A logically designed, guideline-based difficult airway trolley is a vital resource for any clinician involved in airway management and may aid the adherence to difficult airway algorithms during evolving airway emergencies. Future research examining the availability of rescue airway devices in various clinical settings, and simulation studies comparing different types of difficult airway trolleys, are encouraged.

Endotoxin and cytokine reducing properties of the oXiris membrane in patients with septic shock: A randomized crossover double-blind study.

BACKGROUND: Endotoxin induces an inflammatory response, with secondary release of cytokines, which can progress to shock and multiple organ failure. We explored whether continuous renal replacement therapy (CRRT) using a modified membrane (oXiris) capable of adsorption could reduce endotoxin and cytokine levels in septic patients. METHODS: Sixteen patients requiring CRRT for septic shock-associated acute renal failure and who had endotoxin levels >0.03 EU/ml were prospectively randomized in a crossover double-blind design to receive CRRT with an oXiris filter or with a standard filter. Endotoxin and cytokine levels were measured at baseline and 1, 3, 8, 16 and 24 hours after the start of CRRT. Norepinephrine infusion rate and blood lactate levels were monitored. RESULTS: During the first filter treatment period, endotoxin levels decreased in 7 of 9 (77.8%) oXiris filter patients, but in only 1 of 6 (16.7%) standard filter patients (P = 0.02). Levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-8 and interferon (IFN)γ decreased more with the oXiris filter than with the standard filter. Lactate concentration decreased with oXiris (-1.3[-2.2 to -1.1] mmol/l, P = 0.02), but not with the standard filter (+0.15[-0.95 to 0.6]). The norepinephrine infusion rate was reduced during oXiris CRRT, but not during standard filter CRRT. In the second filter treatment period, there was no significant reduction in endotoxin or cytokine levels in either group. CONCLUSIONS: CRRT with the oXiris filter seemed to allow effective removal of endotoxin and TNF-α, IL-6, IL-8 and IFNγ in patients with septic shock-associated acute renal failure. This may be associated with beneficial hemodynamic effects.

Streptococcal M1 protein induces hyporesponsiveness and cytokine release from human arteries in a fibrinogen-dependent manner: a translational study.

BACKGROUND: Streptococcus pyogenes is a Gram positive bacterial species commonly involved in sepsis. Invasive strains express virulence factors such as the M1 protein. M1 protein forms complexes with fibrinogen leading to a cytokine storm in plasma contributing to the development of septic shock and organ failure. In experimental animals M1 protein causes vascular nitric oxide production and hyporesponsiveness to pressors, but it is not known whether it affects the human vascular wall. METHODS: Human omental arteries obtained during surgery were incubated in vitro with M1 protein or lipopolysaccharide (LPS) as positive control, with or without plasma. After 48 h, contractile response to noradrenaline was measured, and levels of nitrite/nitrate and the cytokines interleukin (IL)-1ß, IL-6, IL-8, IL-10, and tumor necrosis factor (TNF)-α in the incubation medium were measured. A second set of arteries were incubated with or without main components of plasma (immunoglobulin G, albumin or fibrinogen), in the presence of M1 protein followed by cytokine measurement. RESULTS: Artery segments incubated with M1 protein and plasma contracted weaker in response to noradrenaline, and levels of IL-6 and IL-8 were significantly higher compared to after incubation with M1 protein alone. Incubation with M1 protein and fibrinogen resulted in elevated levels of IL-6 and IL-8, while incubation with M1 protein and albumin or immunoglobulin G did not affect the levels. Neither any of the other cytokines nor nitrite/nitrate was detected in the medium in any of the incubation conditions. CONCLUSIONS: The study shows that M1 protein of Streptococcus pyogenes has a direct effect on the human vascular wall in the presence of plasma, demonstrated both as a diminished contractile response to noradrenaline and increased cytokine production. The effect of plasma was attributed to fibrinogen. The findings suggest that M1 protein contributes to the development of septic shock through impairment of the contractility of the vascular wall.

Early depletion of contact system in patients with sepsis: a prospective matched control observational study.

Activation of the contact system generates bradykinin from high-molecular-weight kininogen and has been suggested to participate in the pathophysiology of sepsis. To test this, we prospectively measured bradykinin and high-molecular-weight kininogen levels in a cohort of sepsis patients requiring intensive care. From 29 patients meeting criteria for sepsis or septic shock according to Sepsis-3, blood was sampled within 24 h and on the fourth day following admittance to intensive care. Patients planned for neurosurgery served as matched controls. Sequential organ failure assessment score and 90-day mortality was registered. Bradykinin levels (median [interquartile range]) were lower in sepsis patients (79 [62-172] pg/ml) compared to controls (130 [86-255] pg/ml, p < 0.025) and did not correlate with mortality or severity of circulatory derangement. High-molecular-weight kininogen levels were lower in sepsis patients (1.6 [0.8-4.8] densitometry units) compared to controls (4.4 [2.9-7.7] densitometry units, p < 0.001), suggesting previous contact system activation. High-molecular-weight kininogen levels were lower in non-survivors than survivors (p = 0.003) and negatively correlated to severity of circulatory derangement. We conclude that a role for bradykinin in later stages of severe sepsis must be challenged. Low high-molecular-weight kininogen concentrations suggest that the decrease in bradykinin is due to substrate depletion.

Circulating syndecans during critical illness.

Circulating syndecans are proposed to be markers of glycocalyx degradation and previous investigations have found higher plasma levels of syndecan-1 among patients with different pathological conditions. We wanted to investigate if levels of other syndecans (-2,-3 and -4) are altered during critical illness and compare the levels to syndecan-1. In 137 consecutive intensive care unit (ICU) patients with sepsis, cardiac arrest, gastrointestinal bleeding, intoxication or trauma, plasma levels of syndecan-1, -2, -3 and -4 were measured using ELISA. Syndecan-1 and syndecan-3 levels were similar among the different ICU patient groups but higher than controls. No differences in plasma levels of syndecan-2 or syndecan-4 were found neither among the different ICU patient groups nor compared to controls. All syndecans showed an association with mortality and the levels of syndecan-1 and -3 and correlated with each other. The results indicate that syndecan release is triggered by the physiological stress of critical illness in general and involves several subtypes such as syndecan-1 and syndecan-3.