Chemosaturation with percutaneous hepatic perfusion is effective in patients with ocular melanoma and cholangiocarcinoma.

BACKGROUND: Chemosaturation with percutaneous hepatic perfusion (CS-PHP; Hepatic CHEMOSAT® Delivery System; Delcath Systems Inc, USA) is a novel interventional procedure, which delivers high doses of melphalan directly to the liver in patients with liver tumors while limiting systemic toxicity through hemofiltration of the hepatic venous blood. We have previously shown promising efficacy for patients with ocular melanoma (OM) and cholangiocarcinoma (CCA) within our single-center and multi-center experiences. The aim of this study was to analyze the safety and efficacy of CS-PHP after 141 treatments at Hannover Medical School, Germany. METHODS: Overall response rates (ORR) were assessed according to Response Evaluation Criteria In Solid Tumors (RECIST1.1). Median Overall survival (mOS), median progression-free survival (mPFS), and median hepatic PFS (mhPFS) were analyzed using the Kaplan-Meier estimation. RESULTS: Overall, 60 patients were treated with CS-PHP in the salvage setting from October 2014 until January 2019 at Hannover Medical School with a total of 141 procedures. Half of the patients were patients with hepatic metastases of ocular melanoma (OM) (n = 30), 14 patients had CCA (23.3%), 6 patients had hepatocellular carcinoma (10%), and 10 patients were treated for other secondary liver malignancies (16.7%). In total, ORR and disease stabilization rate were 33.3% and 70.3% (n = 25), respectively. ORR was highest for patients with OM (42.3%), followed by patients with CCA (30.8%). Independent response-associated factors were normal levels of lactate dehydrogenase (odds ratio (OR) 13.7; p = 0.015) and diagnosis with OM (OR 9.3; p = 0.028). Overall, mOS was 9 months, mPFS was 4 months, and mhPFS was 5 months. Patients with OM had the longest mOS, mPFS, and mhPFS with 12, 6, and 6 months, respectively. Adverse events included most frequently significant, but transient, hematologic toxicities (80% of grade 3/4 thrombopenia), less frequently hepatic injury up to liver failure (3.3%) and cardiovascular events including two cases of ischemic insults (5%). CONCLUSION: Salvage treatment with CS-PHP is safe and effective particularly in patients OM and CCA. Careful attention should be paid to possible, serious hepatic, and cardiovascular complications.

Expectations, training and evaluation of intensive care staff to an interprofessional simulation course in Germany - Development of a relevant training concept.

Objective: Increasingly, intensive care units (ICU) are operated by teams of physicians and nurses with specialist training in anaesthesia and intensive care. The aims of our study were to evaluate any prior experience, expectations and the requisites for interprofessional ICU simulation-based training (SBT), and to evaluate a newly designed training course incorporating these findings. Methods: The study was laid out as a cross-sectional study and is projected in three steps. First, questionnaires were sent out to ICU nurses and physicians from 15 different hospitals in a greater metropolitan area (> million citizens). Based upon this survey a one-day ICU simulator course designed for 12 participants (6 nurses and 6 physicians) was developed, with evaluation data from four subsequent courses being analysed. Results: In the survey 40% of nurses and 57% of the physicians had had prior exposure to SBT. Various course formats were explored with respect to duration, day of the week, and group composition. After completing the course, the majority deemed a full working day in interprofessional setting to be most appropriate (p<0.001). The scenarios were considered relevant and had a positive impact on communication, workflow and coping with stress. Conclusion: Currently SBT is not a mainstream tool used by German ICU teams for further education, and this lack of familiarity must be taken into consideration when preparing SBT courses for them. We developed a nontechnical skills training course for ICU teams which was undertaken in the setting of simulated clinical scenarios (pertinent to their work environment). The participants found the course's content to be relevant for their daily work, rated the course's impact on their workplace practices as being good and advocated for longer training sessions.

Low anaesthetic waste gas concentrations in postanaesthesia care unit: A prospective observational study.

BACKGROUND: Volatile anaesthetics are a potential hazard during occupational exposure, pregnancy or in individuals with existing disposition to malignant hyperthermia. Anaesthetic waste gas concentration in postanaesthesia care units (PACU) has rarely been investigated. OBJECTIVE(S): The current study aims to assess concentrations of volatile anaesthetics in relation to room size, number of patients and ventilator settings in different PACUs. DESIGN: A prospective observational study. SETTING: Two different PACUs of the Hannover Medical School (Hannover, Germany) were evaluated in this study. The rooms differed in dimensions, patient numbers and room ventilation settings. PATIENTS: During the observation period, sevoflurane anaesthesia was performed in 65 of 140 patients monitored in postanaesthesia unit one and in 42 of 70 patients monitored in postanaesthesia unit two. MAIN OUTCOME MEASURES: Absolute trace gas room concentrations of sevoflurane measured with a compact, closed gas loop high-resolution ion mobility spectrometer. RESULTS: Traces of sevoflurane could be detected in 805 out of 970 samples. Maximum concentrations were 0.96 ±â€Š0.20 ppm in postanaesthesia unit one, 0.82 ±â€Š0.07 ppm in postanaesthesia unit two. Median concentration was 0.12 (0.34) ppm in postanaesthesia unit one and 0.11 (0.28) ppm in postanaesthesia unit two. CONCLUSION: Low trace amounts of sevoflurane were detected in both PACUs equipped with controlled air exchange systems. Occupational exposure limits were not exceeded.

Compatibility of common IV drugs with 6% hydroxyethyl starch 130/0.42 and 4% gelatin.

BACKGROUND: Acetate-containing colloid infusion solutions are recommended to recover normovolemia during pediatric anesthesia. Until now, no studies investigating the compatibility with common anesthetic drugs were available. AIMS: This in vitro study was conducted to reveal possible incompatibilities between common anesthetic drugs and the acetate-containing colloid infusion solutions 6% hydroxyethyl starch and 4% gelatin with normal saline as control. METHODS: The colloid infusion solutions were mixed 1:1 with 29 common intravenous drugs in concentrations used in daily clinical practice. Macroscopically visible changes as well as electrical conductivity, pH, and turbidimetric light diffusion at 405 nm were measured immediately after mixing and subsequently 30 and 60 minutes later. All experiments were conducted in triplicate. RESULTS: Fifty-nine of the 87 colloid infusion-drug mixtures showed no significant changes in pH, electrical conductivity, turbidimetrically detectable light diffusion, or macroscopic appearance after mixing with hydroxyethyl starch, gelatin, and NaCl 0.9%. Fifteen mixtures showed equivocal reactions, and 13 mixtures showed incompatibility reactions. CONCLUSION: Most of the tested drugs did not show observable incompatibility reactions. However, some common drugs are highly incompatible with colloid infusion solutions: gelatin (cefazolin, diazepam, midazolam, phenytoin, vancomycin), hydroxyethyl starch (diazepam, midazolam, phenytoin, thiopental), and NaCl 0.9% (diazepam, ketamine (S), phenytoin, thiopental). These combinations should be avoided in clinical practice in case there are fewer intravenous lines available than needed.

A systematic decision-making process on the need for updating clinical practice guidelines proved to be feasible in a pilot study.

OBJECTIVES: The objective of this study was to test and evaluate a new decision-making process on the need for updating within the update of a German clinical practice guideline (CPG). STUDY DESIGN AND SETTING: The pilot study comprised (1) limited searches in Pubmed to identify new potentially relevant evidence, (2) an online survey among the members of the CPG group to assess the need for update, and (3) a consensus conference for determination and prioritization of guideline sections with a high need for update. Subsequently, we conducted a second online survey to evaluate the procedure. RESULTS: The searches resulted in 902 abstracts that were graded as new potentially relevant evidence. Twenty five of 39 members of the CPG group (64%) participated in the online survey. Seventy six percent of those took part in the second online survey. The evaluation study found on average a grade of support of the procedure regarding the determination of the need for update of 3.65 (standard deviation: 0.76) on a likert scale with 1 = "no support" to 5 = "very strong support." CONCLUSION: The conducted procedure presents a systematic approach for assessing whether and to what extent a CPG requires updating and enables setting priorities for which particular guideline section to update within a CPG.

Safety and efficacy of chemosaturation in patients with primary and secondary liver tumors.

BACKGROUND: Chemosaturation with percutaneous hepatic perfusion (CS-PHP; hepatic CHEMOSAT® delivery system; Delcath Systems Inc, USA) is a novel medical device, which delivers high doses of melphalan directly to the liver in patients with primary and secondary liver tumors while limiting systemic toxicity through hemofiltration of the hepatic venous blood. The aim of this study was to analyze the safety and efficacy of the second-generation CS-PHP after 54 treatments at Hannover Medical School, Germany. METHODS: Overall response rates (ORR) were assessed according to response evaluation criteria in solid tumors (RECIST1.1). Overall survival (OS), progression-free survival (PFS), and hepatic PFS (hPFS) were analyzed using the Kaplan-Meier estimation. RESULTS: 29 patients were treated with CS-PHP as last-line therapy up to five sessions. 19 patients had unresectable hepatic metastases from solid tumors [ocular melanoma (OM) n = 11; colorectal carcinoma n = 2; pancreatic adenocarcinoma n = 2; periampular carcinoma n = 2; breast and endometrial cancer each n = 1] and 10 patients were diagnosed with hepatocellular or cholangiocarcinoma (HCC/CCA). ORR was 19.2%. Patients with OM had the highest ORR (33.3%). Similar to patients with OM, patients with hepatobiliary tumors had durable disease stabilization (40%). Median OS, PFS, and hPFS were 261, 117, and 135 days, respectively. Tumor volume negatively correlated with OS. Complications and toxicities included thrombocytopenia, cardiovascular events, ulcerous bleeding, and edema. CONCLUSION: Second-generation CS-PHP seems to be effective and tolerable. Patient selection based on tumor volume and entity is of importance. Particularly, patients with OM and hepatobiliary tumors represent promising candidates for CS-PHP.

Effects of Different Anesthetics on Pain Processing in an Experimental Human Pain Model.

OBJECTIVE: After surgical procedures, anesthesia itself may affect pain perception. Particularly, there is increasing evidence that opioids not only have analgesic effects but also provoke pronociceptive changes, that is, opioid-induced hyperalgesia. We investigated the effect of different anesthetic regimens on pain processing in volunteers using a transdermal electrical pain model. In this model, stimulation of epidermal nerve fibers representing mainly peptidergic C-nociceptors leads to secondary hyperalgesia and habituation to the stimulus. METHODS: Forty-eight healthy volunteers underwent conditioning noxious stimulation (CS) over 5 days. On day 2, the volunteers were randomized into 4 groups: control group (no anesthesia) and 3 groups receiving anesthesia before CS in anesthetic doses: propofol (P), propofol/remifentanil (PR), and propofol/remifentanil/S-ketamine (PRK). Quantitative sensory testing was performed on days 1 through 5 and on day 22. RESULTS: In every group, CS was associated with short- and long-term habituation to the electrical stimulus. Repetitive CS resulted in unmodified short-term sensitization with stable areas of hyperalgesia. Although the PR group showed a trend toward increased areas of hyperalgesia on day 2, no significant differences were detectable between the groups. In contrast, anesthesia resulted in decreased intensity of the electrically evoked pain on day 2. Finally, the mechanical pain threshold before CS on day 5 was increased in all groups and remained elevated 3 weeks after the first CS, consistent with a long-term antinociceptive effect after CS. CONCLUSIONS: The results suggest a short-term analgesic effect of general anesthesia. Furthermore, the conditioning stimulation over several days induced differential modulation of pro- and antinociceptive systems.

[Part-time concepts in anaesthesia -example of a department of anaesthesiology at a university hospital in Germany]. / Teilzeitmodelle in der Anästhesie - Beispiel einer Anästhesieabteilung eines deutschen Universitätsklinikums.

Part-time work concepts are requested for different reasons from an increasing number of employees. Despite this fact there are no systematic part-time work concepts published in the German literature, especially for physicians working in hospitals. This article describes background and circumstances of a part-time work concept which was established two years ago in a department of anaesthesiology at a university hospital in Germany. This concept considers needs of young families as well as older employees. We are convinced that a transparent part-time work concept is a good argument for job-seeking physicians when deciding for an employer. The benefit for the already employed colleagues has at least the same value.

[Helsinki Declaration on Patient Safety in Anaesthesiology--part 9: Recommendations for clinical airway management organisation]. / Deklaration von Helsinki zur Patientensicherheit in der Anästhesiologie - Teil 9: Empfehlungen zur Organisation des klinischen Atemwegsmanagements.

In the Helsinki Declaration terms and conditions are demanded to control problems in airway management in perioperative care situations. A differentiated airway management can reduce morbidity and mortality. This includes staff- and structure-adjusted standard operating procedures (SOP), which take into account different patient groups, situations of treatment and current guidelines. Along with these SOPs continuing education, sytematic screening of patients and the use of algorithms and checklists are recommended. In this regard paediatric care requires special consideration. Furthermore the fibreoptic as the gold standard for the difficult airway as well as surgical airway management are essential and must be available at all times, whereas videolaryngoscopy takes on increasing evidence as an additional technique.

The distinct effects of lipid emulsions used for "lipid resuscitation" on gating and bupivacaine-induced inhibition of the cardiac sodium channel Nav1.5.

BACKGROUND: Systemic administration of lipid emulsions is an established treatment for local anesthetic intoxication. However, it is unclear by which mechanisms lipids achieve this function. The high cardiac toxicity of the lipophilic local anesthetic bupivacaine probably results from a long-lasting inhibition of the cardiac Na channel Nav1.5. In this study, we sought to determine whether lipid emulsions functionally interact with Nav1.5 or counteract inhibition by bupivacaine. METHODS: Human embryonic kidney cells expressing human Nav1.5 were investigated by whole-cell patch clamp. The effects of Intralipid® and Lipofundin® were explored on functional properties and on bupivacaine-induced inhibition. RESULTS: Intralipid and Lipofundin did not affect the voltage dependency of activation, but induced a small hyperpolarizing shift of the steady-state fast inactivation and impaired the recovery from fast inactivation. Lipofundin, but not Intralipid, induced a concentration-dependent but voltage-independent tonic block (42% ± 4% by 3% Lipofundin). The half-maximal inhibitory concentration (IC50) values for tonic block by bupivacaine (50 ± 4 µM) were significantly increased when lipids were coapplied (5% Intralipid: 196 ± 22 µM and 5% Lipofundin: 103 ± 8 µM). Use-dependent block by bupivacaine at 10 Hz was also reduced by both lipid emulsions. Moreover, the recovery of inactivated channels from bupivacaine-induced block was faster in the presence of lipids. CONCLUSIONS: Our data indicate that lipid emulsions reduce rather than increase availability of Nav1.5. However, both Intralipid and Lipofundin partly relieve Nav1.5 from block by bupivacaine. These effects are likely to involve not only a direct interaction of lipids with Nav1.5 but also the ability of lipid emulsions to absorb bupivacaine and thus reduce its effective concentration.

The molecular basis for species-specific activation of human TRPA1 protein by protons involves poorly conserved residues within transmembrane domains 5 and 6.

The surveillance of acid-base homeostasis is concerted by diverse mechanisms, including an activation of sensory afferents. Proton-evoked activation of rodent sensory neurons is mainly mediated by the capsaicin receptor TRPV1 and acid-sensing ion channels. In this study, we demonstrate that extracellular acidosis activates and sensitizes the human irritant receptor TRPA1 (hTRPA1). Proton-evoked membrane currents and calcium influx through hTRPA1 occurred at physiological acidic pH values, were concentration-dependent, and were blocked by the selective TRPA1 antagonist HC030031. Both rodent and rhesus monkey TRPA1 failed to respond to extracellular acidosis, and protons even inhibited rodent TRPA1. Accordingly, mouse dorsal root ganglion neurons lacking TRPV1 only responded to protons when hTRPA1 was expressed heterologously. This species-specific activation of hTRPA1 by protons was reversed in both mouse and rhesus monkey TRPA1 by exchange of distinct residues within transmembrane domains 5 and 6. Furthermore, protons seem to interact with an extracellular interaction site to gate TRPA1 and not via a modification of intracellular N-terminal cysteines known as important interaction sites for electrophilic TRPA1 agonists. Our data suggest that hTRPA1 acts as a sensor for extracellular acidosis in human sensory neurons and should thus be taken into account as a yet unrecognized transduction molecule for proton-evoked pain and inflammation. The species specificity of this property is unique among known endogenous TRPA1 agonists, possibly indicating that evolutionary pressure enforced TRPA1 to inherit the role as an acid sensor in human sensory neurons.