End-of-life decision-making in critically ill old patients with and without coronavirus disease 2019.

BACKGROUND: There are few studies on the differences in end-of-life decisions making in critically ill patients with and without coronavirus disease 2019 (COVID-19). This study aimed to investigate the independent factors that predicted the decision to withdraw or withhold life-sustaining treatments (LST) in critically ill patients and if these decisions were based on different variables for critically ill patients with COVID-19 compared to those for critically ill patients with other diagnoses in a Swedish intensive care unit. METHODS: This observational pilot study was performed at Sahlgrenska University Hospital, Gothenburg, Sweden. Patients ≥65 years were included from 1 March 2020 to 30 April 2021. The association between a decision to limit LST and a priori selected variables including sex, age, Simplified Acute Physiology Score 3 (SAPS 3), Clinical Frailty Scale ≥4, Charlson Comorbidity Index, Body Mass Index, living at home, invasive and non-invasive mechanical ventilation was assessed using a univariate and multivariable logistic regression model and presented as odds ratio with corresponding 95% confidence intervals. RESULTS: There were 394 patients included in this study, 131 in the non-COVID-19 group and 263 in the COVID-19 group. For the non-COVID-19 cohort, the univariate analysis demonstrated that age and SAPS 3 were significantly associated with the decision to withdraw or withhold life-sustaining treatments, and this association remained in the multivariable analysis, with odds ratios of 1.10 (1.03-1.19) p = .009 and 1.06 (1.03-1.10) p < .001, respectively. For the COVID-19 cohort, the univariate analysis indicated that age, SAPS 3, and Charlson comorbidity index were significantly associated with the decision to withdraw or withhold life-sustaining treatments. However, in multivariable analysis, only the Charlson comorbidity index remained independently associated with the decision to withdraw or withhold life-sustaining treatments, with an odds ratio of 1.26 (1.07-1.49), p = .006. CONCLUSION: Decisions to withdraw or withhold life-sustaining treatments were based on other variables for the critically ill COVID-19 cohort compared to those for the critically ill non-COVID-19 cohort. Further studies are warranted to forge a common path for ethical end-of-life decision-making in critically ill patients.

Navigating the complex dynamics of anesthesiologists' professional identity formation in the context of their specialty training program: a phenomenographic perspective.

BACKGROUND: A specialty training program is crucial for shaping future specialist doctors, imparting clinical knowledge and skills, and fostering a robust professional identity. This study investigates how anesthesiologists develop their professional identity while navigating unique challenges specific to their specialty. The formation of professional identity in anesthesiology significantly influences doctors' well-being, teamwork, and ultimately patient care, making it a crucial aspect of anesthesiology education. Utilizing a phenomenographic approach, the research explores the learners' personal experiences and perspectives of professional identity formation in their specialty training programs, providing valuable insights for enhancing future anesthetic educational programs. METHOD: The data for this phenomenographic study were collected through semi-structured interviews with anesthesiology trainees and specialists, guided by open-ended questions. The interviews were conducted at a Swedish university hospital, and participant selection used purposive sampling, providing rich and diverse data for analysis after 15 interviews. Iterative analysis followed the seven-step phenomenographic approach. The research team, comprising qualitative research and anesthesiology education experts, ensured result validity through regular review, discussion, and reflective practices. RESULTS: The study reveals three fundamental dimensions: 'Knowledge of Subject Matter,' 'Knowledge of Human Relations,' and 'Knowledge of Affect.' These dimensions offer insights into how anesthesiologists comprehend anesthesiology as a profession, navigate interactions with colleagues and patients, and interpret emotional experiences in anesthesiology practice - all crucial elements in the formation of professional identity. The findings could be synthesized and further described by three conceptions: The Outcome-Driven Learner, the Emerging Collaborator, and the Self-Directed Caregiver. CONCLUSION: The study uncovers differing learner understandings in the development of anesthesiologists' professional identity. Varying priorities, values, and role interpretations highlight the shortcomings of a generic, one-size-fits-all educational strategy. By acknowledging and integrating these nuanced learner perspectives, as elucidated in detail in this study, the future of anesthesia education can be improved. This will necessitate a holistic approach, intertwining both natural sciences and humanities studies, focus on tacit knowledge, and flexible teaching strategies, to guarantee thorough professional development, lifelong learning, and resilience.

Patterns and determinants of blood transfusion in intensive care in Sweden between 2010 and 2018: A nationwide, retrospective cohort study.

BACKGROUND: Intensive care unit (ICU) patients are transfused with blood products for a number of reasons, from massive ongoing hemorrhage, to mild anemia following blood sampling, combined with bone marrow depression due to critical illness. There's a paucity of data on transfusions in ICUs and most studies are based on audits or surveys. The aim of this study was to provide a complete picture of ICU-related transfusions in Sweden. METHODS: We conducted a register based retrospective cohort study with data on all adult patient admissions from 82 of 84 Swedish ICUs between 2010 and 2018, as recorded in the Swedish Intensive Care Register. Transfusions were obtained from the SCANDAT-3 database. Descriptive statistics were computed, characterizing transfused and nontransfused patients. The distribution of blood use comparing different ICUs was investigated by computing the observed proportion of ICU stays with a transfusion, as well as the expected proportion. RESULTS: In 330,938 ICU episodes analyzed, at least one transfusion was administered for 106,062 (32%). For both red-cell units and plasma, the fraction of patients who were transfused decreased during the study period from 31.3% in 2010 to 24.6% in 2018 for red-cells, and from 16.6% in 2010 to 9.4% in 2018 for plasma. After adjusting for a range of factors, substantial variation in transfusion frequency remained, especially for plasma units. CONCLUSION: Despite continuous decreases in utilization, transfusions remain common among Swedish ICU patients. There is considerable unexplained variation in transfusion rates. More research is needed to establish stronger critiera for when to transfuse ICU patients.

Machine learning analysis of heart rate variability to detect delayed cerebral ischemia in subarachnoid hemorrhage.

OBJECTIVES: Approximately 30% of patients with aneurysmal subarachnoid hemorrhage (aSAH) develop delayed cerebral ischemia (DCI). DCI is associated with increased mortality and persistent neurological deficits. This study aimed to analyze heart rate variability (HRV) data from patients with aSAH using machine learning to evaluate whether specific patterns could be found in patients developing DCI. MATERIAL & METHODS: This is an extended, in-depth analysis of all HRV data from a previous study wherein HRV data were collected prospectively from a cohort of 64 patients with aSAH admitted to Sahlgrenska University Hospital, Gothenburg, Sweden, from 2015 to 2016. The method used for analyzing HRV is based on several data processing steps combined with the random forest supervised machine learning algorithm. RESULTS: HRV data were available in 55 patients, but since data quality was significantly low in 19 patients, these were excluded. Twelve patients developed DCI. The machine learning process identified 71% of all DCI cases. However, the results also demonstrated a tendency to identify DCI in non-DCI patients, resulting in a specificity of 57%. CONCLUSIONS: These data suggest that machine learning applied to HRV data might help identify patients with DCI in the future; however, whereas the sensitivity in the present study was acceptable, the specificity was low. Possible confounders such as severity of illness and therapy may have affected the result. Future studies should focus on developing a robust method for detecting DCI using real-time HRV data and explore the limits of this technology in terms of its reliability and accuracy.

Long-term outcomes after aneurysmal subarachnoid hemorrhage: A prospective observational cohort study.

OBJECTIVES: The survival rates for patients affected by aneurysmal subarachnoid hemorrhage (aSAH) have increased in recent years; however, many patients continue to develop cognitive dysfunctions that affect their quality of life. The commonly used outcome measures often fail to identify these cognitive dysfunctions. This study aimed to evaluate the long-term outcomes at 1 and 3 years after aSAH to assess changes over time and relate outcomes to patient characteristics and events during the acute phase. MATERIALS AND METHODS: This prospective observational study included patients that experienced aSAH. Patients were assessed according to the extended Glasgow Outcome Scale, Life Satisfaction Questionnaire, Mayo-Portland Adaptability inventory-4, and Mental Fatigue scale. RESULTS: Patients were assessed after 1 year (n = 62) and 3 years (n = 54). At 3 years, the extended Glasgow Outcome Scale score improved in 15% and worsened in 12% of the patients. Mental fatigue was observed in 57% of the patients at 1 year. Patients <60 years of age at the time of aSAH had more self-assessed problems, including pain/headache (p < .01), than patients >60 years of age. Patients with delayed cerebral ischemia during the acute phase reported more dissatisfaction at 3 years, whereas no significant result was seen at 1 year. CONCLUSIONS: Cognitive dysfunction, especially mental fatigue, is common in patients with aSAH, which affects quality of life and recovery. Patient outcome is a dynamic process developing throughout years after aSAH, involving both improvement and deterioration. This study indicates the importance of longer follow-up periods with broad outcome assessments.

Association between inflammatory response and outcome after subarachnoid haemorrhage.

OBJECTIVES: Recent reports suggest an association between the inflammatory response after aneurysmal subarachnoid haemorrhage (aSAH) and patients' outcome. The primary aim of this study was to identify a potential association between the inflammatory response after aSAH and 1-year outcome. The secondary aim was to investigate whether the inflammatory response after aSAH could predict the development of delayed cerebral ischaemia (DCI). MATERIALS AND METHODS: This prospective observational pilot study included patients with an aSAH admitted to Sahlgrenska University Hospital, Gothenburg, Sweden, between May 2015 and October 2016. The patients were stratified according to the extended Glasgow Outcome Scale (GOSE) as having an unfavourable (score: 1-4) or favourable outcome (score: 5-8). Furthermore, patients were stratified depending on development of DCI or not. Patient data and blood samples were collected and analysed at admission and after 10 days. RESULTS: Elevated serum concentrations of inflammatory markers such as tumour necrosis factor-α and interleukin (IL)-6, IL-1Ra, C-reactive protein and intercellular adhesion molecule-1 were detected in patients with unfavourable outcome. When adjustments for Glasgow coma scale were made, only IL-1Ra remained significantly associated with poor outcome (p = 0.012). The inflammatory response after aSAH was not predictive of the development of DCI. CONCLUSION: Elevated serum concentrations of inflammatory markers were associated with poor neurological outcome 1-year after aSAH. However, inflammatory markers are affected by many clinical events, and when adjustments were made, only IL-1Ra remained significantly associated with poor outcome. The robustness of these results needs to be tested in a larger trial.

Long-term outcome after intensive care for COVID-19: differences between men and women-a nationwide cohort study.

BACKGROUND: Questions remain about long-term outcome for COVID-19 patients in general, and differences between men and women in particular given the fact that men seem to suffer a more dramatic course of the disease. We therefore analysed outcome beyond 90 days in ICU patients with COVID-19, with special focus on differences between men and women. METHODS: We identified all patient ≥ 18 years with COVID-19 admitted between March 6 and June 30, 2020, in the Swedish Intensive Care Registry. Patients were followed until death or study end-point October 22, 2020. Association with patient sex and mortality, in addition to clinical variables, was estimated using Cox regression. We also performed a logistic regression model estimating factors associated with 90-day mortality. RESULTS: In total, 2354 patients with COVID-19 were included. Four patients were still in the ICU at study end-point. Median follow-up time was 183 days. Mortality at 90-days was 26.9%, 23.4% in women and 28.2% in men. After 90 days until end of follow-up, only 11 deaths occurred. On multivariable Cox regression analysis, male sex (HR 1.28, 95% CI 1.06-1.54) remained significantly associated with mortality even after adjustments. Additionally, age, COPD/asthma, immune deficiency, malignancy, SAPS3 and admission month were associated with mortality. The logistic regression model of 90-day mortality showed almost identical results. CONCLUSIONS: In this nationwide study of ICU patients with COVID-19, men were at higher risk of poor long-term outcome compared to their female counterparts. The underlying mechanisms for these differences are not fully understood and warrant further studies.

Reasons for physician-related variability in end-of-life decision-making in intensive care.

BACKGROUND: There is increasing evidence that the individual physician is the main factor influencing variability in end-of-life decision-making in intensive care units. End-of-life decisions are complex and should be adapted to each patient. Physician-related variability is problematic as it may result in unequal assessments that affect patient outcomes. The primary aim of this study was to investigate factors contributing to physician-related variability in end-of-life decision-making. METHOD: This is a qualitative substudy of a previously conducted study. In-depth thematic analysis of semistructured interviews with 19 critical care specialists from five different Swedish intensive care units was performed. Interviews took place between 1 February 2017 and 31 May 2017. RESULTS: Factors influencing physician-related variability consisted of different assessment of patient preferences, as well as intensivists' personality and values. Personality was expressed mainly through pace and determination in the decision-making process. Personal prejudices appeared in decisions, but few respondents had personally witnessed this. Avoidance of criticism and conflicts as well as individual strategies for emotional coping were other factors that influenced physician-related variability. Many respondents feared criticism for making their assessments, and the challenging nature of end-of-life decision-making lead to avoidance as well as emotional stress. CONCLUSION: Variability in end-of-life decision-making is an important topic that needs further investigation. It is imperative that such variability be acknowledged and addressed in a more formal and transparent manner. The ethical issues faced by intensivists have recently been compounded by the devastating impact of the COVID-19 pandemic, demonstrating in profound terms the importance of the topic.

Intraperitoneal ropivacaine reduces time interval to initiation of chemotherapy after surgery for advanced ovarian cancer: randomised controlled double-blind pilot study.

BACKGROUND: Advanced-stage ovarian cancer has a poor prognosis; surgical resection with the intent to leave no residual tumour followed by adjuvant chemotherapy is the standard treatment. Local anaesthetics (LA) have anti-inflammatory and analgesic effects. We hypothesised that intraperitoneal LA (IPLA) would lead to improved postoperative recovery, better pain relief, and earlier start of chemotherapy. METHODS: This was a prospective, randomised, double-blind, placebo-controlled pilot study in 40 women undergoing open abdominal cytoreductive surgery. Patients were randomised to receive either intraperitoneal ropivacaine (Group IPLA) or saline (Group Placebo) perioperatively. Except for study drug, patients were treated similarly. Intraoperatively, ropivacaine 2 mg ml-1 or 0.9% saline was injected thrice intraperitoneally, and after operation via a catheter and analgesic pump into the peritoneal cavity for 72 h. Postoperative pain, time to recovery, home discharge, time to start of chemotherapy, and postoperative complications were recorded. RESULTS: No complications from LA administration were recorded. Pain intensity and rescue analgesic consumption were similar between groups. Time to initiation of chemotherapy was significantly shorter in Group IPLA (median 21 [inter-quartile range 21-29] vs 29 [inter-quartile range 21-40] days; P=0.021). Other parameters including time to home readiness, home discharge and incidence, and complexity of postoperative complications were similar between the groups. CONCLUSIONS: Intraperitoneal ropivacaine during and for 72 h after operation after cytoreductive surgery for ovarian cancer is safe and reduces the time interval to initiation of chemotherapy. Larger studies are warranted to confirm these initial findings. CLINICAL TRIAL REGISTRATION: NCT02256228.

Swedish intensivists' experiences and attitudes regarding end-of-life decisions.

BACKGROUND: To make end-of-life (EOL) decisions is a complex and challenging task for intensive care physicians and a substantial variability in this process has been previously reported. However, a deeper understanding of intensivists' experiences and attitudes regarding the decision-making process is still, to a large extent, lacking. The primary aim of this study was to address Swedish intensivists' experiences, beliefs and attitudes regarding decision-making pertaining to EOL decisions. Second, we aimed to identify underlying factors that may contribute to variability in the decision-making process. METHOD: This is a descriptive, qualitative study. Semi-structured interviews with nineteen intensivists from five different Swedish hospitals, with different ICU levels, were performed from 1 February 2017 to 31 May 2017. RESULTS: Intensivists strive to make end-of-life decisions that are well-grounded, based on sufficient information. Consensus with the patient, family and other physicians is important. Concurrently, decisions that are made with scarce information or uncertain medical prognosis, decisions made during on-call hours and without support from senior consultants cause concern for many intensivists. Underlying factors that contribute to the variability in decision-making are lack of continuity among senior intensivists, lack of needed support during on-call hours and disagreements with physicians from other specialties. There is also an individual variability primarily depending on the intensivist's personality. CONCLUSION: Swedish intensivists' wish to make end-of-life decisions based on sufficient information, medically certain prognosis and consensus with the patient, family, staff and other physicians. Swedish intensivists' experience a variability in end-of-life decisions, which is generally accepted and not questioned.

Cerebral ischemia detection using artificial intelligence (CIDAI)-A study protocol.

BACKGROUND: The onset of cerebral ischemia is difficult to predict in patients with altered consciousness using the methods available. We hypothesize that changes in Heart Rate Variability (HRV), Near-Infrared Spectroscopy (NIRS), and Electroencephalography (EEG) correlated with clinical data and processed by artificial intelligence (AI) can indicate the development of imminent cerebral ischemia and reperfusion, respectively. This study aimed to develop a method that enables detection of imminent cerebral ischemia in unconscious patients, noninvasively and with the support of AI. METHODS: This prospective observational study will include patients undergoing elective surgery for carotid endarterectomy and patients undergoing acute endovascular embolectomy for cerebral arterial embolism. HRV, NIRS, and EEG measurements and clinical information on patient status will be collected and processed using machine learning. The study will take place at Sahlgrenska University Hospital, Gothenburg, Sweden. Inclusion will start in September 2020, and patients will be included until a robust model can be constructed. By analyzing changes in HRV, EEG, and NIRS measurements in conjunction with cerebral ischemia or cerebral reperfusion, it should be possible to train artificial neural networks to detect patterns of impending cerebral ischemia. The analysis will be performed using machine learning with long short-term memory artificial neural networks combined with convolutional layers to identify patterns consistent with cerebral ischemia and reperfusion. DISCUSSION: Early signs of cerebral ischemia could be detected more rapidly by identifying patterns in integrated, continuously collected physiological data processed by AI. Clinicians could then be alerted, and appropriate actions could be taken to improve patient outcomes.

Heart rate variability monitoring for the detection of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.

BACKGROUND: Delayed cerebral ischemia (DCI) is a major cause of impaired outcome after aneurysmal subarachnoidal hemorrhage (aSAH). In this observational cohort study we investigated whether changes in heart rate variability (HRV) that precede DCI could be detected. METHODS: Sixty-four patients with aSAH were included. HRV data were collected for up to 10 days and analyzed offline. Correlation with clinical status and/or radiologic findings was investigated. A linear mixed model was used for the evaluation of HRV parameters over time in patients with and without DCI. Extended Glasgow outcome scale score was assessed after 1 year. RESULTS: In 55 patients HRV data could be analyzed. Fifteen patients developed DCI. No changes in HRV parameters were observed 24 hours before onset of DCI. Mean of the HRV parameters in the first 48 hours did not correlate with the development of DCI. Low/high frequency (LF/HF) ratio increased more in patients developing DCI (ß -0.07 (95% confidence interval, 0.12-0.01); P = .012). Lower STDRR (standard deviation of RR intervals), RMSSD (root mean square of the successive differences between adjacent RR intervals), and total power (P = .003, P = .007 and P = .004 respectively) in the first 48 hours were seen in patients who died within 1 year. CONCLUSION: Impaired HRV correlated with 1-year mortality and LF/HF ratio increased more in patients developing DCI. Even though DCI could not be detected by the intermittent analysis of HRV used in this study, continuous HRV monitoring may have potential in the detection of DCI after aSAH using different methods of analysis.

Does intraperitoneal ropivacaine reduce postoperative inflammation? A prospective, double-blind, placebo-controlled pilot study.

BACKGROUND: Postoperative inflammation is a common consequence of surgery and the ensuing stress response. Local anesthetics have anti-inflammatory properties. The primary aim of this study was to evaluate if LA administrated intraperitoneally perioperatively might inhibit expression of inflammatory cytokines. METHODS: This was a, randomized, double blind, placebo-controlled study (ClinicalTrial.gov reg no: NCT02256228) in patients undergoing surgery for ovarian cancer. Patients were randomized to receive: intraperitoneal ropivacaine (Group IPLA) or saline (Group P) perioperatively. Except for study drug, patients were treated similarly. At the end of surgery, a multi-port catheter was inserted intraperitoneally, and ropivacaine 2 mg/mL or 0.9% saline, 10 mL was injected intermittently every other hour during 72 hours postoperatively. Systemic expression of cytokines and plasma ropivacaine were determined before and 6, 24, and 48 hours after surgery. Stress response was measured by serum glucose, cortisol, and insulin. RESULTS: Forty patients were recruited, 20 in each group. There was no statistical significant difference in systemic cytokine between the groups at any time point. Serum cortisol was significantly lower in the IPLA group at 6 hours, median 103 nmol/L (IQR 53-250) compared to placebo, median 440 nmol/L (IQR 115-885), P = 0.023. Serum glucose and insulin were similar between the groups. Total and free serum concentrations of ropivacaine were well below toxic concentrations. CONCLUSION: In this small study, perioperative intraperitoneal ropivacaine did not reduce the systemic inflammatory response associated with major abdominal surgery. Total and free ropivacaine concentrations were below known toxic concentrations in humans.

Age, SAPS 3 and female sex are associated with decisions to withdraw or withhold intensive care.

BACKGROUND: Intensive care treat critically ill patients. When intensive care is not considered beneficial for the patient, decisions to withdraw or withhold treatments are made. We aimed to identify independent patient variables that increase the odds for receiving a decision to withdraw or withhold intensive care. METHODS: Registry study using data from the Swedish Intensive Care Registry (SIR) 2014-2016. Age, condition at admission, including co-morbidities (Simplified Acute Physiology Score version 3, SAPS 3), diagnosis, sex, and decisions on treatment limitations were extracted. Patient data were divided into a full care (FC) group, and a withhold or withdraw (WW) treatment group. RESULTS: Of all 97 095 cases, 47.1% were 61-80 years old, 41.9% were women and 58.1% men. 14 996 (15.4%) were allocated to the WW group and 82 149 (84.6%) to the FC group. The WW group, compared with the FC group, was older (P < 0.001), had higher SAPS 3 (P < 0.001) and were predominantly female (P < 0.001). Compared to patients 16-20 years old, patients >81 years old had 11 times higher odds of being allocated to the WW group. Higher SAPS 3 (continuous) increased the odds of being allocated to the WW group by odds ratio [OR] 1.085, (CI 1.084-1.087). Female sex increased the odds of being allocated to the WW group by 18% (1.18; CI 1.13- 1.23). CONCLUSION: Older age, higher SAPS 3 at admission and female sex were found to be independent variables that increased the odds to receive a decision to withdraw or withhold intensive care.

First mobilisation after abdominal and cardiothoracic surgery: when is it actually performed? A national, multicentre, cross-sectional study.

OBJECTIVES: Knowledge of clinical practice regarding mobilisation after surgery is lacking. This study therefore aimed to reveal current mobilisation routines after abdominal and cardiothoracic surgery and to identify factors associated with mobilisation within 6 hours postoperatively. DESIGN: A prospective observational national multicentre study. SETTING: 18 different hospitals in Sweden. PARTICIPANTS: 1492 adult patients undergoing abdominal and cardiothoracic surgery with duration of anaesthesia>2 hours. PRIMARY AND SECONDARY OUTCOMES: Primary outcome was time to first postoperative mobilisation. Secondary outcomes were the type and duration of the first mobilisation. Data were analysed using multivariate logistic regression and general structural equation modelling, and data are presented as ORs with 95% CIs. RESULTS: Among the included patients, 52% were mobilised to at least sitting on the edge of the bed within 6 hours, 70% within 12 hours and 96% within 24 hours. Besides sitting on the edge of the bed, 76% stood up by the bed and 22% were walking away from the bedside the first time they were mobilised. Patients undergoing major upper abdominal surgery required the longest time before mobilisation with an average time of 11 hours post surgery. Factors associated with increased likelihood of mobilisation within 6 hours of surgery were daytime arrival at the postoperative recovery unit (OR: 5.13, 95% CI: 2.16 to 12.18), anaesthesia <4 hours (OR: 1.68, 95% CI: 1.17 to 2.40) and American Society of Anaesthesiologists (ASA) classification 1-2, (OR: 1.63, 95% CI: 1.13 to 2.36). CONCLUSIONS: In total, 96% if the patients were mobilised within 24 hours after surgery and 52% within 6 hours. Daytime arrival at the postoperative recovery unit, low ASA classification and shorter duration of anaesthesia were associated with a shorter time to mobilisation. TRIAL REGISTRATION NUMBER: FoU, Forskning och Utveckling in VGR, Vastra Gotaland Region (Id:275357) and Clinical Trials (NCT04729634).

Ultralow concentrations of bupivacaine exert anti-inflammatory effects on inflammation-reactive astrocytes.

Bupivacaine is a widely used, local anesthetic agent that blocks voltage-gated Na(+) channels when used for neuro-axial blockades. Much lower concentrations of bupivacaine than in normal clinical use, < 10(-8)  m, evoked Ca(2+) transients in astrocytes from rat cerebral cortex, that were inositol trisphosphate receptor-dependent. We investigated whether bupivacaine exerts an influence on the Ca(2+) signaling and interleukin-1ß (IL-1ß) secretion in inflammation-reactive astrocytes when used at ultralow concentrations, < 10(-8)  m. Furthermore, we wanted to determine if bupivacaine interacts with the opioid-, 5-hydroxytryptamine- (5-HT) and glutamate-receptor systems. With respect to the µ-opioid- and 5-HT-receptor systems, bupivacaine restored the inflammation-reactive astrocytes to their normal non-inflammatory levels. With respect to the glutamate-receptor system, bupivacaine, in combination with an ultralow concentration of the µ-opioid receptor antagonist naloxone and µ-opioid receptor agonists, restored the inflammation-reactive astrocytes to their normal non-inflammatory levels. Ultralow concentrations of bupivacaine attenuated the inflammation-induced upregulation of IL-1ß secretion. The results indicate that bupivacaine interacts with the opioid-, 5-HT- and glutamate-receptor systems by affecting Ca(2+) signaling and IL-1ß release in inflammation-reactive astrocytes. These results suggest that bupivacaine may be used at ultralow concentrations as an anti-inflammatory drug, either alone or in combination with opioid agonists and ultralow concentrations of an opioid antagonist.

Development of and adherence to an ERAS® and prehabilitation protocol for patients undergoing pancreatic surgery: An observational study.

BACKGROUND AND OBJECTIVE: There are still gaps in knowledge concerning the adherence to different multimodal pathways in pancreatic surgery. The aim of this trial was to explore and evaluate an Enhanced Recovery After Surgery (ERAS®) and prehabilitation protocol in patients undergoing open pancreatic surgery. METHODS: Three groups of patients were included: two prospective series of 75 patients undergoing open pancreatic surgery following an ERAS® protocol with or without prehabilitation, and one group of 55 historical controls. Variables regarding adherence to, and effects of the protocols, were collected from the local database and the patients' hospital records. Patients' adherence to advice given pre-operatively was followed up using a study-specific questionnaire. RESULTS: The patients reported high adherence to remembered advice given. The health care professionals' adherence to the various parts of the concepts varied. ERAS® implementation resulted in more frequent gut motility stimulation (p < 0.001) and shorter duration of epidural anesthesia, site drains, and urinary catheter (p = 0.001). With prehabilitation, more patients were screened concerning nutritional status and prescribed preoperative training (p < 001). There was a significant change in weight before surgery, a shorter time to first flatus and a shorter length of stay after implementation of the concepts (p < 0.05). Complications were rare in all three groups and there were no significant differences between the groups. CONCLUSION: The implementation of an ERAS® and a prehabilitation protocol increased adherence to the protocols by both patients and healthcare professionals. An implementation of an ERAS® protocol with and without prehabilitation decreases length of stay and may decrease preoperative weight loss and time to bowel movement.

Naloxone and ouabain in ultralow concentrations restore Na+/K+-ATPase and cytoskeleton in lipopolysaccharide-treated astrocytes.

Astrocytes respond to inflammatory stimuli and may be important modulators of the inflammatory response in the nervous system. This study aimed first to assess how astrocytes in primary culture behave in response to inflammatory stimuli concerning intracellular Ca(2+) responses, expression of Toll-like receptor 4 (TLR4), Na(+)/K(+)-ATPase, actin filament organization, and expression of cytokines. In a cell culture model with lipopolysaccharide (LPS), astrocyte response was assessed first in the acute phase and then after incubation with LPS for 1-48 h. The concentration curve for LPS-stimulated Ca(2+) responses was bell-shaped, and the astrocytes expressed TLR4, which detects LPS and evokes intracellular Ca(2+) transients. After a long incubation with LPS, TLR4 was up-regulated, LPS-evoked Ca(2+) transients were expressed as oscillations, Na(+)/K(+)-ATPase was down-regulated, and the actin filaments were disorganized. Interleukin-1ß (IL-1ß) release was increased after 24 h in LPS. A second aim was to try to restore the LPS-induced changes in astrocytes with substances that may have dose-dependent anti-inflammatory properties. Naloxone and ouabain were tested separately in ultralow or high concentrations. Both substances evoked intracellular Ca(2+) transients for all of the concentrations from 10(-15) up to 10(-4) M. Neither substance blocked the TLR4-evoked Ca(2+) responses. Naloxone and ouabain prevented the LPS-induced down-regulation of Na(+)/K(+)-ATPase and restored the actin filaments. Ouabain, in addition, reduced the IL-1ß release from reactive astrocytes. Notably, ultralow concentrations (10(-12) M) of naloxone and ouabain showed these qualities. Ouabain seems to be more potent in these effects of the two tested substances.

A Challenging diagnosis that eventually results in a life-threatening condition: Addison's disease and adrenal crisis.

A young man endures many years with classic symptoms of Addison's disease due to difficulties in distinguishing this rare condition, whose features are non-specific and insidious in nature. With all facts on hand, the patient's notable history of psychiatric disorders, namely depression, anxiety and social isolation, as well as signs of extreme fatigue and syncope may well have been caused by a gradual onset of primary adrenal insufficiency. Long delays in diagnosis are not uncommon, as in this case where the actual condition was identified just in time when the patient presented with a life-threatening cardiovascular collapse.

Glial dysfunction and persistent neuropathic postsurgical pain.

BACKGROUND: Acute pain in response to injury is an important mechanism that serves to protect living beings from harm. However, persistent pain remaining long after the injury has healed serves no useful purpose and is a disabling condition. Persistent postsurgical pain, which is pain that lasts more than 3 months after surgery, affects 10-50% of patients undergoing elective surgery. Many of these patients are affected by neuropathic pain which is characterised as a pain caused by lesion or disease in the somatosensory nervous system. When established, this type of pain is difficult to treat and new approaches for prevention and treatment are needed. A possible contributing mechanism for the transition from acute physiological pain to persistent pain involves low-grade inflammation in the central nervous system (CNS), glial dysfunction and subsequently an imbalance in the neuron-glial interaction that causes enhanced and prolonged pain transmission. AIM: This topical review aims to highlight the contribution that inflammatory activated glial cell dysfunction may have for the development of persistent pain. METHOD: Relevant literature was searched for in PubMed. RESULTS: Immediately after an injury to a nerve ending in the periphery such as in surgery, the inflammatory cascade is activated and immunocompetent cells migrate to the site of injury. Macrophages infiltrate the injured nerve and cause an inflammatory reaction in the nerve cell. This reaction leads to microglia activation in the central nervous system and the release of pro-inflammatory cytokines that activate and alter astrocyte function. Once the astrocytes and microglia have become activated, they participate in the development, spread, and potentiation of low-grade neuroinflammation. The inflammatory activated glial cells exhibit cellular changes, and their communication to each other and to neurons is altered. This renders neurons more excitable and pain transmission is enhanced and prolonged. Astrocyte dysfunction can be experimentally restored using the combined actions of a µ-opioid receptor agonist, a µ-opioid receptor antagonist, and an anti-epileptic agent. To find these agents we searched the literature for substances with possible anti-inflammatory properties that are usually used for other purposes in medicine. Inflammatory induced glial cell dysfunction is restorable in vitro by a combination of endomorphine-1, ultralow doses of naloxone and levetiracetam. Restoring inflammatory-activated glial cells, thereby restoring astrocyte-neuron interaction has the potential to affect pain transmission in neurons. CONCLUSION: Surgery causes inflammation at the site of injury. Peripheral nerve injury can cause low-grade inflammation in the CNS known as neuroinflammation. Low-grade neuroinflammation can cause an imbalance in the glial-neuron interaction and communication. This renders neurons more excitable and pain transmission is enhanced and prolonged. Astrocytic dysfunction can be restored in vitro by a combination of endomorphin-1, ultralow doses of naloxone and levetiracetam. This restoration is essential for the interaction between astrocytes and neurons and hence also for modulation of synaptic pain transmission. IMPLICATIONS: Larger studies in clinical settings are needed before these findings can be applied in a clinical context. Potentially, by targeting inflammatory activated glial cells and not only neurons, a new arena for development of pharmacological agents for persistent pain is opened.