Dipyrone (metamizole) is a widely used non-opioid analgesic. Its use is restricted due to the risk of side effects such as liver toxicity. We report the case of a patient who accidentally received an oral dose of 12.5 g (132 mg/kg) dipyrone. The patient was monitored for the next 62 days and remained asymptomatic, showing no signs of gastrointestinal, hepatic, or other toxicity. Dipyrone was not detectable in the plasma, while the plasma concentrations of its active metabolites 4-methylaminoantipyrine and 4-aminoantipyrine were elevated. The pharmacokinetics were best described by nonlinear one-compartment models with Michaelis–Menten elimination. The terminal half-life of both metabolites was 2.9 h. These results demonstrate the rapid absorption of dipyrone and the extremely short window for effective gastric decontamination. Due to its specific pharmacokinetic profile, the high systemic exposure to active dipyrone metabolites did not result in acute organ toxicity in this case. Therefore, intensive medical monitoring may not always be mandatory after dipyrone overdose in otherwise clinically stable patients, although agranulocytosis remains as idiosyncratic long-term risk.

Although beta-lactam antibiotics are widely used in intensive care, rare but potentially fatal anaphylactic reactions can occur due to cross-reactions between penicillins and cephalosporins. We report the case of a 68-year-old man who suffered perioperative cardiac arrest following the administration of cefuroxime. During the postoperative period, the patient received ampicillin/sulbactam without any signs of hypersensitivity. Following a switch to piperacillin/tazobactam prior to a procedure, the patient suddenly developed cardiovascular arrest and died. The autopsy revealed no macroscopic cause of death, but immunohistochemistry showed mast cell degranulation ("starry sky pattern") in the tissue, suggesting anaphylaxis. We present the clinical and histopathological findings of a case with severe allergic reactions to both cefuroxime and piperacillin/tazobactam, as a result of either cross-reaction or isolated sensitization to both antibiotics. This case report highlights the potential risks of cross-reactivity between beta-lactam antibiotics and the importance of autopsy in ambiguous cases. Clinicians should be aware of cross-reactivity or cosensitization to multiple beta-lactams in patients with a beta-lactam allergy and consider non-beta-lactam alternatives in high-risk cases.

Dipyrone (metamizole) is widely used as a nonopioid analgesic in perioperative and intensive care settings; however, its administration may be associated with severe adverse effects. In this study, we describe an analytical assay for the quantification of the active metabolites 4-methylaminoantipyrine (4-MAA) and 4-aminoantipyrine (4-AA) in human plasma using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). In addition, the protein-unbound fractions of both metabolites were determined by ultrafiltration. Chromatographic separation was performed on a UPLC system using gradient elution, followed by MS/MS detection with an electrospray ionization source. The limits of detection for both metabolites were 100 ng/mL. Across the investigated concentration range (100-10,000 ng/mL), the relative error (%RE) ranged from -6.3% to +3.5%. Intra-day and inter-assay variability were below 10%. Method validation was conducted in accordance with the 2018 FDA Bioanalytical Method Validation Guidance, and all evaluated parameters met the required criteria for analytical accuracy and precision. The developed assay is suitable for monitoring dipyrone metabolites and may support the prevention of potential overdosing during prolonged analgesic therapy or in intensive care settings.

Bleeding and thromboembolic events (BTE) increase the mortality of COVID-19 acute respiratory distress syndrome (ARDS) treated with extracorporeal membrane oxygenation (ECMO). The current analysis aimed to assess frequency and determinants of BTE according to their location and severity in a retrospective analysis of the German ECMO COVID-19 registry. Logistic regression was applied to identify factors influencing ICU survival as well as variables associated with risks of BTE. In total, 708 of 945 patients (75%) suffered from BTE. Overall, 1,348 events were registered, including 406 (30%) major bleeding and 258 (19%) major thromboembolic events. Most common major bleeding locations were intracranial (n = 133, 10%) and pulmonary bleeding (n = 116, 9%). In-ICU survival was 35, 46% without BTE and 22% with major bleeding (p < 0.05). In summary, major bleeding was a core outcome-determinant of COVID-19 ECMO mortality with intracranial major bleeding as the most devastating complication (OR: 5.3; CI: 2.9-9.9; p < 0.001). Neither major thromboembolism nor minor BTE impacted ICU-mortality. Potentially modifiable factors associated with major bleeding included prolonged duration of ECMO >14 days (OR: 2.9; CI 1.8-4.7; p < 0.001) and platelet counts <100.000/μL ≥ 72 h (OR: 2.0; CI 1.1-3.6; p = 0.018). Hence, prevention, early recognition and treatment of major bleedings are key to increase the survival of COVID-19 ECMO. In this regard, our data indicate that the implementation of early weaning strategies to minimize duration of ECMO therapy and prevention of prolonged thrombocytopenia with platelet counts <100.000/μl ≥ 72 h could decrease the risk of devastating bleeds and could ameliorate survival. Clinical trial registration:Registered in the German Clinical Trials Register (study ID: DRKS00022964), retrospectively registered, September 7th 2020, https://drks.de/DRKS00022964.

The long-term stability of drug concentrations in human plasma samples, when stored under normal laboratory conditions over several years, is important for research purposes and clinical re-evaluation, and forensic toxicology. Fifty human plasma samples from a former clinical trial were re-analyzed after storage at -20 degrees C for 11 years. Plasma samples were extracted using solid-phase extraction. Isotope labeled sufentanil-D5 was used as internal standard. Sufentanil plasma concentrations were determined by ultra-performance liquid chromatography with gradient elution, followed by tandem mass spectrometry with electrospray ionization. The linear dynamic range was 25-2500 pg/mL, the limit of detection was 10 pg/mL, and the lower limit of quantifcation was 25 pg/mL. Intra- and inter-assay error did not exceed 6%. The deviation of the measured sufentanil plasma concentrations between the re-analysis and the frst analysis was -63 +/- 14% (mean +/- SD). Therefore, sufentanil concentrations in human plasma were not stable in samples frozen at -20 degrees C over 11 years.

Background/Objectives: Descending necrotising mediastinitis (DNM) is a severe, life-threatening infection that originates from the oropharyngeal or odontogenic regions and spreads to the mediastinum. It poses significant challenges due to its rapid progression and high morbidity. Methods: This monocentric, retrospective study analysed the records of 22 patients treated for DNM between 2008 and 2022. Diagnosis relied on characteristic clinical, radiological, and intraoperative findings linking oropharyngeal or cervical infections to mediastinitis. Contrast-enhanced computed tomography (CT) was used in all cases for diagnosis. Data collected included demographics, comorbidities, surgical interventions, time from diagnosis to surgery, re-operations, and complications. Microbiological analyses targeted aerobic and anaerobic pathogens. Results: The study included 22 patients (mean age 60 ± 9 years, 59% male) with DNM. The primary sources of infection were oropharyngeal (77%) and odontogenic (23%). Hypertension (86%), diabetes (68%), and cardiac arrhythmias (59%) were common comorbidities. Thoracotomy with mediastinal drainage and debridement was performed in 95% of patients, while 45% underwent cervicotomy and 82% required tracheostomy. The median intensive care unit (ICU) and hospital stays were 21 and 30 days, respectively. Delayed surgery (>24 h) significantly prolonged hospital stays (median: 62 vs. 28 days, p = 0.05). Re-operations were required in 82% of patients, with longer ICU stays observed in this group (median: 25 vs. 7 days, p = 0.003). Sepsis occurred in 55% and was associated with a higher tracheostomy rate (100% vs. 60%, p = 0.029). The mortality rate was 9%. Conclusions: Early recognition and prompt aggressive surgical intervention are paramount in managing DNM to mitigate complications and improve survival.

The intravenous anesthetic propofol is frequently used for the induction and maintenance of general anesthesia. Propofol has, however, a potential for abuse, and it has been involved in suicide deaths particularly among medical personnel. The long-term stability of propofol concentrations in human plasma samples when stored under normal laboratory conditions over several years might be important for forensic toxicology. The present study investigated the long-term stability of propofol after storage at -20°C for eight years. For this purpose, 67 plasma samples from five patients, who had undergone a former clinical trial, were re-analyzed. Plasma samples were extracted using protein precipitation. Propofol plasma concentrations were determined by ultra-performance liquid chromatography (UPLC) with gradient elution, followed by tandem mass spectrometry with electrospray ionization. Deuterium-labeled propofol was used as an internal standard. The assay was linear in the range of 50-10,000 ng/mL with a limit of detection of 0.5 ng/mL and a lower limit of quantification of 50 ng/mL, respectively. Accuracy and precision were high with intra- and interassay errors within ±5%. The median relative deviation between the measurements in 2023 and 2015 was -7.0% (interquartile range: -19.7% and 5.3%). Therefore, propofol concentrations in human plasma can be considered relatively stable in samples frozen at -20°C over eight years, and plasma samples stored under these conditions might be used for forensic purposes. Trial Registration: ClinicalTrials.gov identifier: NCT02199067.

During the COVID 19 pandemic, advanced age, scoring systems, and a shortage of ICU beds were used as cut-offs for ICU admission. This case report describes the epicrisis of an elderly patient who was almost mistakenly not treated in an ICU.

Streptococcal toxic shock syndrome is a severe, invasive and life-threatening infection associated with a high risk of rapid multiorgan failure. It is associated with high morbidity and mortality. Streptococcal toxic shock syndrome is very commonly caused by group A- Streptococcus pyogenes , ß-haemolytic streptococcus, a typical human-specific gram-positive bacterial pathogen. We present here the case report of a 54-year-old man with a rapidly progressive streptococcal toxic shock syndrome due to necrotising fasciitis of the left lower limb and describe the successful treatment through close interdisciplinary care.

OBJECTIVES:To compare the efficacy, safety, and side effects of hydromorphone and morphine administered as patient-controlled analgesia (PCA) for postoperative pain therapy after cardiac surgery with median sternotomy.DESIGN:A retrospective analysis of data from 2 prospective, single-blinded, randomized trials.SETTING:A single-center intensive care unit at a university hospital.PARTICIPANTS:Forty-one adult patients undergoing cardiac surgery with median sternotomy.INTERVENTIONS:Postoperative pain therapy at the intensive care unit was performed by PCA with intravenously administered bolus doses of 0.2 mg of hydromorphone (n = 21) or 2 mg of morphine (n = 20).MEASUREMENTS AND MAIN RESULTS:Pain at rest and under deep inspiration regularly was assessed using the 11-point numerical rating scale (NRS). Blood pressure, heart rate, cardiac output, oxygen saturation, and respiratory rate were monitored, and adverse events were registered. The median (range) NRS rating at rest was 1.5 (0-5) after hydromorphone and 0.5 (0-5) after morphine, respectively (p = 0.41). The median NRS rating under deep inspiration was 3 (0-6) after hydromorphone and 4 (0-7) after morphine, respectively (p = 0.074). The dose ratio of morphine to hydromorphone during PCA was 5.7 (95% confidence interval: 2.9-7.6). Hemodynamics and respiration were stable and did not differ significantly. Postoperative nausea and vomiting were the most frequent adverse events, which were observed in 29% of the patients after hydromorphone and in 35% after morphine, respectively (p = 0.74).CONCLUSIONS:There were no significant differences in analgesic efficacy and safety between hydromorphone and morphine when used for postoperative pain therapy with PCA after cardiac surgery with median sternotomy.

The long-term stability of drugs under normal laboratory storage conditions (−20°C) for years is important for research purposes, clinical re-evaluation, and also for forensic toxicology. To evaluate the stability of the analgesic opioid hydromorphone, 44 human frozen plasma samples of a former clinical trial were reanalyzed after at least three years. Blood samples were disposed using solid-phase extraction with an additional substitution of stable isotope labelled hydromorphone as an internal standard. Hydromorphone concentrations were determined by ultra-performance liquid chromatography (UPLC) with gradient elution, followed by tandem mass spectrometry with electrospray ionization. Calibration curves demonstrated linearity of the assay in the concentration range of 0.3–20 ng/mL hydromorphone. The limit of detection of the hydromorphone plasma concentration was 0.001 ng/mL, and the lower limit of quantification was 0.3 ng/mL. Intra- and interassay errors did not exceed 16%. The percentage deviation of the measured hydromorphone plasma concentrations between the reanalysis and the first analysis was −1.07% ± 14.8% (mean ± SD). These results demonstrate that hydromorphone concentration in human plasma was stable when the samples were frozen at −20°C over three years. This finding is of value for re-evaluations or delayed analyses for research purposes and in pharmacokinetic studies, such as in forensic medicine.

Abstract Background Severe COVID-19 induced acute respiratory distress syndrome (ARDS) often requires extracorporeal membrane oxygenation (ECMO). Recent German health insurance data revealed low ICU survival rates. Patient characteristics and experience of the ECMO center may determine intensive care unit (ICU) survival. The current study aimed to identify factors affecting ICU survival of COVID-19 ECMO patients. Methods 673 COVID-19 ARDS ECMO patients treated in 26 centers between January 1st 2020 and March 22nd 2021 were included. Data on clinical characteristics, adjunct therapies, complications, and outcome were documented. Block wise logistic regression analysis was applied to identify variables associated with ICU-survival. Results Most patients were between 50 and 70 years of age. PaO2/FiO2 ratio prior to ECMO was 72 mmHg (IQR: 58–99). ICU survival was 31.4%. Survival was significantly lower during the 2nd wave of the COVID-19 pandemic. A subgroup of 284 (42%) patients fulfilling modified EOLIA criteria had a higher survival (38%) (p = 0.0014, OR 0.64 (CI 0.41–0.99)). Survival differed between low, intermediate, and high-volume centers with 20%, 30%, and 38%, respectively (p = 0.0024). Treatment in high volume centers resulted in an odds ratio of 0.55 (CI 0.28–1.02) compared to low volume centers. Additional factors associated with survival were younger age, shorter time between intubation and ECMO initiation, BMI > 35 (compared to < 25), absence of renal replacement therapy or major bleeding/thromboembolic events. Conclusions Structural and patient-related factors, including age, comorbidities and ECMO case volume, determined the survival of COVID-19 ECMO. These factors combined with a more liberal ECMO indication during the 2nd wave may explain the reasonably overall low survival rate. Careful selection of patients and treatment in high volume ECMO centers was associated with higher odds of ICU survival. Trial registration Registered in the German Clinical Trials Register (study ID: DRKS00022964, retrospectively registered, September 7th 2020, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00022964. Graphical abstract

BACKGROUND Remifentanil is an effective drug in peri-operative pain therapy, but it can also induce and aggravate hyperalgesia. Supplemental administration of N2O may help to reduce remifentanil-induced hyperalgesia. OBJECTIVE To evaluate the effect of 35 and 50% N2O on hyperalgesia and pain after remifentanil infusion. DESIGN Single site, phase 1, double-blind, placebo-controlled, randomised crossover study. SETTING University Hospital, Germany from January 2012 to April 2012. PARTICIPANTS Twenty-one healthy male volunteers. INTERVENTIONS Transcutaneous electrical stimulation induced spontaneous acute pain and stable areas of hyperalgesia. Each volunteer underwent the following four sessions in a randomised order: 50 to 50% N-2-O-2 and intravenous (i.v.) 0.9% saline infusion (placebo); 50 to 50% N-2-O-2 and i.v. remifentanil infusion at 0.1 mu g kg(-1) min(-1) (remifentanil); 35 to 15 to 50% N2O-N-2-O-2 and i.v. remifentanil infusion at 0.1 mu g kg(-1) min(-1) (tested drug) and 50 to 50% N2O-O-2 and i.v. remifentanil infusion at 0.1 mu g kg(-1) min(-1) (gas active control). Gas mixtures were inhaled for 60 min; i.v. drugs were administered for 30 min. MAIN OUTCOME MEASURES Areas of pin-prick hyperalgesia, areas of touch-evoked allodynia and pain intensity on a visual analogue scale were assessed repeatedly for 160 min. RESULTS Data from 20 volunteers were analysed. There were significant treatment and treatment-by-time effects regarding areas of hyperalgesia (P < 0.001). After the treatment period, the area of hyperalgesia was significantly reduced (P < 0.001) in the tested drug and in the gas active control (30.6 +/- 9.25 and 24.4 +/- 7.3 cm(2), respectively) compared with remifentanil (51.0 +/- 17.0 cm(2)). There was also a significant difference between the gas active control and the tested drug sessions (P < 0.001). For the area of allodynia and pain rating, results were consistent with the results for hyperalgesia. CONCLUSIONS Administration of 35% N2O significantly reduced hyperalgesia, allodynia and pain intensity induced after remifentanil. It might therefore be suitable in peri-operative pain relief characterised by hyperalgesia and allodynia, such as postoperative pain, and may help to reduce opioid demand.

BACKGROUND Remifentanil is an effective drug in peri-operative pain therapy, but it can also induce and aggravate hyperalgesia. Supplemental administration of N2O may help to reduce remifentanil-induced hyperalgesia. OBJECTIVE To evaluate the effect of 35 and 50% N2O on hyperalgesia and pain after remifentanil infusion. DESIGN Single site, phase 1, double-blind, placebo-controlled, randomised crossover study. SETTING University Hospital, Germany from January 2012 to April 2012. PARTICIPANTS Twenty-one healthy male volunteers. INTERVENTIONS Transcutaneous electrical stimulation induced spontaneous acute pain and stable areas of hyperalgesia. Each volunteer underwent the following four sessions in a randomised order: 50 to 50% N2-O2 and intravenous (i.v.) 0.9% saline infusion (placebo); 50 to 50% N2-O2 and i.v. remifentanil infusion at 0.1 μg kg−1 min−1 (remifentanil); 35 to 15 to 50% N2O-N2-O2 and i.v. remifentanil infusion at 0.1 μg kg−1 min−1 (tested drug) and 50 to 50% N2O-O2 and i.v. remifentanil infusion at 0.1 μg kg−1 min−1 (gas active control). Gas mixtures were inhaled for 60 min; i.v. drugs were administered for 30 min. MAIN OUTCOME MEASURES Areas of pin-prick hyperalgesia, areas of touch-evoked allodynia and pain intensity on a visual analogue scale were assessed repeatedly for 160 min. RESULTS Data from 20 volunteers were analysed. There were significant treatment and treatment-by-time effects regarding areas of hyperalgesia (P < 0.001). After the treatment period, the area of hyperalgesia was significantly reduced (P < 0.001) in the tested drug and in the gas active control (30.6 ± 9.25 and 24.4 ± 7.3 cm2, respectively) compared with remifentanil (51.0 ± 17.0 cm2). There was also a significant difference between the gas active control and the tested drug sessions (P < 0.001). For the area of allodynia and pain rating, results were consistent with the results for hyperalgesia. CONCLUSIONS Administration of 35% N2O significantly reduced hyperalgesia, allodynia and pain intensity induced after remifentanil. It might therefore be suitable in peri-operative pain relief characterised by hyperalgesia and allodynia, such as postoperative pain, and may help to reduce opioid demand. TRIAL REGISTRATION EudraCT-No.: 2011-000966-37.

BACKGROUND:Coronavirus induced disease 2019 (COVID-19) can be complicated by severe organ damage leading to dysfunction of the lungs and other organs. The processes that trigger organ damage in COVID-19 are incompletely understood. METHODS:Samples were donated from hospitalized patients. Sera, plasma, and autopsy-derived tissue sections were examined employing flow cytometry, enzyme-linked immunosorbent assays, and immunohistochemistry. PATIENT FINDINGS:Here, we show that severe COVID-19 is characterized by a highly pronounced formation of neutrophil extracellular traps (NETs) inside the micro-vessels. Intravascular aggregation of NETs leads to rapid occlusion of the affected vessels, disturbed microcirculation, and organ damage. In severe COVID-19, neutrophil granulocytes are strongly activated and adopt a so-called low-density phenotype, prone to spontaneously form NETs. In accordance, markers indicating NET turnover are consistently increased in COVID-19 and linked to disease severity. Histopathology of the lungs and other organs from COVID-19 patients showed congestions of numerous micro-vessels by aggregated NETs associated with endothelial damage. INTERPRETATION:These data suggest that organ dysfunction in severe COVID-19 is associated with excessive NET formation and vascular damage. FUNDING:Deutsche Forschungsgemeinschaft (DFG), EU, Volkswagen-Stiftung.

BACKGROUND The challenge of managing acute postoperative pain is the well tolerated and effective administration of analgesics with a minimum of side effects. The standard therapeutic approach is patient-controlled analgesia (PCA) with systemic opioids. To overcome problems of oscillating opioid concentrations, we studied patient-controlled analgesia by target-controlled infusion (TCI-PCA) as an alternative. OBJECTIVE To compare efficacy, safety and side effects of standard PCA with TCI-PCA for postoperative pain therapy with hydromorphone. DESIGN Single-blinded, randomised trial. SETTING University Hospital, Germany from December 2013 to April 2015. PARTICIPANTS Fifty adults undergoing cardiac surgery. INTERVENTIONS Postoperative pain therapy on the ICU was managed with intravenous (i.v.) hydromorphone and patients randomised to TCI-PCA with target plasma concentrations between 0.8 and 10 ng ml−1, or PCA with bolus doses of 0.2 mg. Pain was regularly assessed using the 11-point numerical rating scale (NRS). Blood pressure, heart rate, oxygen saturation and cardiac output were continuously monitored, and adverse events were registered throughout the study. MAIN OUTCOME MEASURES NRS pain ratings, hydromorphone doses, haemodynamic effects and side effects. RESULTS NRS pain ratings, total doses of hydromorphone and haemodynamic data did not differ significantly between TCI-PCA and PCA. The number of bolus doses during PCA was significantly higher than the number of target increases during TCI-PCA (P = 0.006). The number of negative requests was also significantly higher during PCA than during TCI-PCA (P = 0.02). The respiratory rate on the first postoperative morning was 25 ± 6 min−1 during TCI-PCA, compared with 19 ± 4 min−1 during PCA (P = 0.022). Nausea occurred in 30% after TCI-PCA and 24% after PCA (P = 0.46). CONCLUSION TCI-PCA was effective and well tolerated in acute postoperative pain management after cardiac surgery. Further studies are needed to evaluate this approach in clinical practice. TRIAL REGISTRATION EudraCT Number: 2013-002875-16, and ClinicalTrials.gov Identifier: NCT02035709.

BACKGROUND:The effects of environmental changes on the somato-sensory system during long-distance air ambulance flights need to be further investigated. Changes in nociceptive capacity are conceivable in light of previous studies performed under related environmental settings. We used standardized somato-sensory testing to investigate nociception in healthy volunteers during air-ambulance flights.METHODS:Twenty-five healthy individuals were submitted to a test compilation analogous to the quantitative sensory testing battery-performed during actual air-ambulance flights. Measurements were paired around the major changes of external factors during take-off/climb and descent/landing. Bland-Altman-Plots were calculated to identify possible systemic effects.RESULTS:Bland-Altman-analyses suggest that the thresholds of stimulus detection and pain as well as above-threshold pain along critical waypoints of travel are not subject to systemic effects but instead demonstrate random variations.CONCLUSIONS:We provide a novel description of a real-life experimental setup and demonstrate the general feasibility of performing somato-sensory testing during ambulance flights. No systematic effects on the nociception of healthy individuals were apparent from our data. Our findings open up the possibility of future investigations into potential effects of ambulance flights on patients suffering acute or chronic pain.

Objective: Evaluate the accuracy and trending ability of the fourth-generation FloTrac/EV1000 (Edwards Lifesciences, Irvine, CA) system in patients with severe aortic valve stenosis by comparing FloTrac/EV1000-derived cardiac output (CCO-FT) with continuous thermodilution pulmonary artery catheter (CCO-PAC) measurements before and after surgical valve replacement. Design: Prospective clinical study. Setting: Anesthesia for cardiac surgery, operating room, single-center university hospital. Participants: Twenty-five patients were included. After exclusion, 20 patients undergoing elective aortic valve replacement were analyzed. Interventions: After induction of general anesthesia, CCO-FT and CCO-PAC values were recorded every 30 seconds before and after aortic valve replacement with a bioprosthesis under cardiopulmonary bypass (CPB). Measurements and Main Results: Data were analyzed separately from skin incision to last suture and before and after CPB. Regression analyses, Bland-Altman analyses, and trending analyses (4-quadrant plot, polar plot) were performed. The percentage errors of the FloTrac/EV1000 were 69.7% and 59.3% before and after CPB, respectively. The concordance rates (CRs) and angular CRs of the FloTrac/EV1000 were 50.9% and 57.1%, and 48.7% and 61.9% before and after CPB, respectively. Conclusion: This study revealed a low level of agreement and poor trending ability of the FloTrac/EV1000 system compared to continuous thermodilution pulmonary artery catheter in patients with severe aortic stenosis. Although there was a slight improvement after surgical valve replacement and CPB, the results were not within acceptable limits to replace CCO-PAC in this patient population. (C) 2018 Elsevier Inc. All rights reserved.

For the quantification of propofol total and unbound drug concentrations a sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated. To separate unbound propofol an ultrafiltration step before sample preparation was performed. Both the ultrafiltrate and plasma samples were extracted with solid-phase extraction and substituted with deuterated propofol as an internal standard. Separation was performed by gradient elution using UPLC-like system and analyzed by MS/MS consisting of an electrospray ionization source. To detect low and high concentration levels of propofol two calibration curves were identified and showed linearity within the range of 1-50 ng/ml and 50-20000 ng/ml. The lower limit of quantification was 1 ng/ml. Intra- and interassay precision and accuracy did not exceed +/- 15%. The method was applied to a clinical study during intensive care treatment of patients after coronary artery bypass grafting. (C) 2016 Elsevier B.V. All rights reserved.

BackgroundOpioids are known to relieve pain, and also aggravate pre-existing hyperalgesia. In animal studies, the N-methyl-d-aspartate-receptor antagonist nitrous oxide (N2O) was able to prevent hyperalgesia. The present study evaluated the effect of N2O on hyperalgesia after remifentanil infusion in healthy volunteers.MethodsTwenty-one healthy volunteers were enrolled in this placebo-controlled cross-over study. Transcutaneous electrical stimulation at high current densities induced spontaneous acute pain and stable areas of hyperalgesia. Each volunteer underwent the following four sessions: (1) 50-50% N-2-O-2 and i.v. saline; (2) 50-50% N-2-O-2 and i.v. remifentanil 0.1g/kg/min; (3) 50-50% N2O-O-2 and i.v. saline; (4) 50-50% N2O-O-2 and i.v. remifentanil 0.1g/kg/min. Inhaled gas mixtures lasted for 60min, i.v. drug administration for 30min. Visual analogue scale pain intensity, areas of pinprick hyperalgesia and touch-evoked allodynia were assessed repeatedly for 160min.ResultsData of 19 volunteers were analysed. There were significant time and treatment effects regarding areas of hyperalgesia and allodynia (p<0.02). The area of hyperalgesia was significantly reduced in the N2O+remifentanil session compared to the remifentanil session (35.8822.37 vs. 43.5518.48cm(2), p=0.004). The area of allodynia was significantly reduced in the N2O+remifentanil session compared to the remifentanil session (29.95 +/- 16.15 vs. 34.80 +/- 15.35cm(2), p=0.008). The pain intensity was significantly reduced in the N2O+remifentanil session compared to the remifentanil session (37.96 +/- 12.78 vs. 42.15 +/- 13.34mm, p<0.0001).ConclusionsNitrous oxide significantly reduced hyperalgesia, allodynia and pain intensity aggravated after remifentanil administration in a human volunteer model.What does this study add?This study brings the evidence that N2O reduces the remifentanil aggravated secondary hyperalgesia in human volunteers exposed to a well-known model of electrical pain. N2O was able to oppose the hyperalgesia, the allodynia and the pain intensity consecutive to remifentanil use in this specific pain model.