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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.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.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. Patients60 years of age at the time of aSAH had more self-assessed problems, including pain/headache (p .01), than patients60 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.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.

The prevalence and importance of cardiac dysfunction in critically ill patients with COVID-19 in Sweden is not yet established. The aim of the study was to assess the prevalence of cardiac dysfunction and elevated pulmonary artery pressure (PAP), and its influence on mortality in patients with COVID-19 in intensive care in Sweden.This was a multicentre observational study performed in five intensive care units (ICUs) in Sweden. Patients admitted to participating ICU with COVID-19 were examined with echocardiography within 72 h from admission and again after 4 to 7 days. Cardiac dysfunction was defined as left ventricular (LV) dysfunction (ejection fraction50% and/or regional hypokinesia) or right ventricular (RV) dysfunction (defined as TAPSE17 mm or visually assessed moderate/severe RV dysfunction).We included 132 patients, of whom 127 (96%) were intubated. Cardiac dysfunction was found in 42 (32%) patients. Most patients had cardiac dysfunction at the first assessment (n = 35) while a few developed cardiac dysfunction later (n = 7) and some changed type of dysfunction (n = 3). LV dysfunction was found in 21 and RV dysfunction in 19 patients, while 5 patients had combined dysfunction. Elevated PAP was found in 34 patients (26%) and was more common in patients with RV dysfunction. RV dysfunction and elevated PAP were independently associated with an increased risk of death (OR 3.98, p = .013 and OR 3.88, p = .007, respectively).Cardiac dysfunction occurs commonly in critically ill patients with COVID-19 in Sweden. RV dysfunction and elevated PAP are associated with an increased risk of death.

Protocolised REDUction of non-resuscitation fluids versus usual care in SEptic shock patients (REDUSE) - a statistical analysis plan for a multicentre feasibility trial The objective of this trial is to assess the feasibility of a trial comparing a protocolised reduction in administration of non-resuscitation fluids to usual care in patients with septic shock. Here, we describe the statistical analysis plan for this feasibility trial.

IntroductionAdministration of large volumes of fluids is associated with poor outcome in septic shock. Recent data suggest that non-resuscitation fluids are the major source of fluids in the intensive care unit (ICU) patients suffering from septic shock. The present trial is designed to test the hypothesis that a protocol targeting this source of fluids can reduce fluid administration compared with usual care.Methods and analysisThe design will be a multicentre, randomised, feasibility trial. Adult patients admitted to ICUs with septic shock will be randomised within 12 hours of admission to receive non-resuscitation fluids either according to a restrictive protocol or to receive usual care. The healthcare providers involved in the care of participants will not be blinded. The participants, outcome assessors at the 6-month follow-up and statisticians will be blinded. Primary outcome will be litres of fluids administered within 3 days of randomisation. Secondary outcomes will be proportion of randomised participants with outcome data on all-cause mortality; days alive and free of mechanical ventilation within 90 days of inclusion; any acute kidney injury and ischaemic events in the ICU (cerebral, cardiac, intestinal or limb ischaemia); proportion of surviving randomised patients who were assessed by European Quality of Life 5-Dimensions 5-Level questionnaire and Montreal Cognitive Assessment; proportion of all eligible patients who were randomised and proportion of participants experiencing at least one protocol violation.Ethics and disseminationEthics approval has been obtained in Sweden. Results of the primary and secondary outcomes will be submitted for publication in a peer-reviewed journal.Trial registration numberNCT05249088.

IntroductionPre-eclampsia, a multisystem disorder in pregnancy, is one of the most common causes of maternal morbidity and mortality worldwide. However, we lack methods for objective assessment of organ function in pre-eclampsia and predictors of organ impairment during and after pre-eclampsia. The women’s and their partners’ experiences of pre-eclampsia have not been studied in detail. To phenotype different subtypes of the disorder is of importance for prediction, prevention, surveillance, treatment and follow-up of pre-eclampsia.The aim of this study is to set up a multicentre database and biobank for pre-eclampsia in order to contribute to a safer and more individualised treatment and care.Methods and analysisThis is a multicentre cohort study. Prospectively recruited pregnant women ≥18 years, diagnosed with pre-eclampsia presenting at Sahlgrenska University Hospital, Uppsala University Hospital and at Södra Älvsborgs Hospital, Sweden, as well as normotensive controls are eligible for participation. At inclusion and at 1-year follow-up, the participants donate biosamples that are stored in a biobank and they are also asked to participate in various organ-specific evaluations. In addition, questionnaires and interviews regarding the women’s and partner’s experiences are distributed at follow-up.Ethics and disseminationBy creating a database and biobank, we will provide the means to explore the disorder in a broader sense and allow clinical and laboratory discoveries that can be translated to clinical trials aiming at improved care of women with pre-eclampsia. Further, to evaluate experiences and the psychological impact of being affected by pre-eclampsia can improve the care of pregnant women and their partners. In case of incidental pathological findings during examinations performed, they will be handled in accordance with clinical routine. Data are stored in a secure online database. Biobank samples are identified through the women’s personal identification number and pseudonymised after identification in the biobank before analysis.This study was approved by the regional ethical review board in Gothenburg on 28 December 2018 (approval number 955-18) and by the Swedish Ethical Review Authority on 27 February 2019 (approval number 2019-00309).Results from the study will be published in international peer-reviewed journals.Trial registration numberISRCTN13060768

Aims Left ventricular (LV) dysfunction can be triggered by non‐cardiac disease, such as sepsis, hypoxia, major haemorrhage, or severe stress (Takotsubo syndrome), but its clinical importance is not established. In this study, we evaluate the incidence and impact on mortality of LV dysfunction associated with critical illness. Methods and results In this single‐centre, observational study, consecutive patients underwent an echocardiographic examination within 24 h of intensive care unit (ICU) admission. LV systolic dysfunction was defined as an ejection fraction (EF)

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.

Background Takotsubo syndrome (TS) is an acute cardiac syndrome characterized by regional myocardial akinesia that is not caused by coronary artery occlusion. Exogenous as well as endogenous excess catecholamines can induce TS. The aim of this study was to explore the effects of pharmacological cardio-simulative and cardio-depressing drugs on the development of isoprenaline-induced takotsubo-like cardiac dysfunction, a rat model of TS. Methods We randomized 295 rats into twelve groups. The animals were randomized to pre-treatment with either a low or high dose of metoprolol, propranolol, ICI 118551 (beta2-receptor antagonists), milrinone (phosphodiesterase inhibitor), levosimendan or saline (control) before induction of TS with isoprenaline. In one additional group, high dose of milrinone was administered alone. We measured invasively blood pressure and heart rate over a period of 90 min. Cardiac function and morphology were evaluated with high-resolution echocardiography. Results Milrinone alone induced apical ballooning similar to isoprenaline. Pretreatment with propranolol and metoprolol but not with ICI 118551 attenuated takotsubo-like akinesia in a dose-dependent manner. Pretreatment with metoprolol decreased mortality. Pretreatment with levosimendan resulted in higher incidence of apical ballooning while pretreatment with milrinone did not change the degree of akinesia. Conclusion The phosphodiesterase inhibitor milrinone induces takotsubo-like dysfunction in the absence of exogenous catecholamines. This finding challenges the concept that high levels of circulating catecholamines or excessive stimulation of adrenergic receptors are necessary for the development of takotsubo syndrome. Our study provides experimental evidence for the concept of avoidance of inotropes and that selective beta1-blockade may be beneficial in the treatment of TS-patients.

Aims Takotsubo syndrome (TTS) is an acute potentially reversible cardiac syndrome characterized by variable regional myocardial akinesia that cannot be attributed to a culprit coronary artery occlusion. TTS is an important differential diagnosis of acute heart failure where brain natriuretic peptides are elevated. Sacubitril/valsartan is a novel and effective pharmacological agent for the treatment of patients with heart failure. Our aim was to explore whether treatment with sacubitril/valsartan could prevent isoprenaline‐induced takotsubo‐like phenotype in rats. Methods and results A total number of 186 Sprague–Dawley male rats were randomized to receive pretreatment with water (CONTROL, n = 62), valsartan (VAL, n = 62), or sacubitril/valsartan (SAC/VAL, n = 62) before receiving isoprenaline for induction of TTS. We recorded heart rate and blood pressure invasively. Cardiac morphology and function were evaluated by high‐resolution echocardiography 90 min after the administration of isoprenaline. We documented the survival rate at the time of echocardiography. Compared with the CONTROL group, the SAC/VAL group had less pronounced TTS‐like cardiac dysfunction and lower mortality rate, while the VAL group did not differ. Heart rate and blood pressure were not significantly different between the groups. Analysis of cardiac lipids was performed with mass spectrometry. The VAL and SAC/VAL groups had significantly higher levels of lysophosphatidylcholine (LPC), in particular LPC 18:1 and LPC 16:0. Conclusions Pretreatment with sacubitril/valsartan but not with valsartan reduces mortality and attenuates isoprenaline‐induced apical akinesia in the TTS‐like model in rats. Sacubitril/valsartan could be a potential treatment option in patients with TTS in humans.

Introduction: The importance of cardiac dysfunction in critically ill patients with COVID-19 is not well studied. The aim of the study was to assess the incidence, clinical risk factors, and prognosis of cardiac dysfunction in critical illness caused by COVID-19, and to evaluate if cardiac biomarkers can detect this condition.Methods: This was a multicentre observational study performed in five intensive care units (ICUs) in Sweden. Patients admitted to participating ICU with COVID-19 were examined with echocardiography within 72 hours from admission to the ICU and again after four to seven days. Cardiac biomarkers and clinical data were collected at the time of echocardiography. Cardiac dysfunction was defined as either left ventricular (LV) dysfunction (having an ejection fraction < 50% and/or regional hypokinesia) or right ventricular (RV) dysfunction (having a tricuspid annular plane systolic excursion (TAPSE) < 17mm or a moderate/severe RV dysfunction assessed visually).Results: We included 132 patients of whom 94 (71%) were included prospectively. The vast majority were intubated (n=127). At the time of admission to ICU, 35 (27%) patients had cardiac dysfunction and 7 patients (5%) had cardiac dysfunction detected later in the ICU-period. LV dysfunction was found in 18 patients and RV dysfunction in 17 patients, 7 patients had both RV and LV dysfunction. Noradrenaline > 0.20µg/kg/min was the only clinical variable associated with a higher risk of cardiac dysfunction. RV dysfunction was associated with an increased risk of death in a risk-adjusted model (OR 3.98, p = 0.013). Troponin and N-terminal pro b-type natriuretic peptide (NTproBNP) had moderate values in detecting cardiac dysfunction (AUC 0.729 and AUC 0.744, respectively). A combination of troponin < 1.44 times the upper reference limit and NTproBNP < 857ng/L had 85% probability of excluding cardiac dysfunction.Conclusions: Cardiac dysfunction is common in critically ill patients with COVID-19. Although not easily detected with clinical variables, cardiac biomarkers might be helpful. RV dysfunction is associated with an increased risk of death, these patients might benefit from further investigation or treatments. Trial registration: Registered on 24 Aug 2020 at Clinicaltrials.gov; registration number NCT04524234.

Background Cerebral injury is a common cause of maternal mortality due to preeclampsia and is challenging to predict and diagnose. In addition, there are associations between previous preeclampsia and stroke, dementia and epilepsy later in life. The cerebral biomarkers S100B, neuron specific enolase, (NSE), tau protein and neurofilament light chain (NfL) have proven useful as predictors and diagnostic tools in other neurological disorders. This case-control study sought to determine whether cerebral biomarkers were increased in cerebrospinal fluid (CSF) as a marker of cerebral origin and potential cerebral injury in preeclampsia and if concentrations in CSF correlated to concentrations in plasma. Methods CSF and blood at delivery from 15 women with preeclampsia and 15 women with normal pregnancies were analysed for the cerebral biomarkers S100B, NSE, tau protein and NfL by Simoa and ELISA based methods. MRI brain was performed after delivery and for women with preeclampsia also at six months postpartum. Results Women with preeclampsia demonstrated increased CSF- and plasma concentrations of NfL and these concentrations correlated to each other. CSF concentrations of NSE and tau were decreased in preeclampsia and there were no differences in plasma concentrations of NSE and tau between groups. For S100B, serum concentrations in preeclampsia were increased but there was no difference in CSF concentrations of S100B between women with preeclampsia and normal pregnancy. Conclusion NfL emerges as a promising circulating cerebral biomarker in preeclampsia and increased CSF concentrations point to a neuroaxonal injury in preeclampsia, even in the absence of clinically evident neurological complications.

Background Patients in the intensive care unit (ICU) are increasingly being transferred between ICUs due to a shortage of ICU beds, although this practice is potentially harmful. However, in tertiary units, the transfer of patients who are not in need of highly specialized care is often necessary. The aim of this study was to assess the association between a 90-day mortality and inter-hospital transfer due to a shortage of ICU beds in a tertiary centre. Methods Data were retrieved from the local ICU database from December 2011 to September 2019. The primary analysis was a risk-adjusted logistic regression model. Secondary analyses comprised case/control (transfer/non-transfer) matching. Results A total of 573 patients were transferred due to a shortage of ICU beds, and 8106 patients were not transferred. Crude 90-day mortality was higher in patients transferred due to a shortage of beds (189 patients (33%) vs 2188 patients (27%), p = 0.002). In the primary, risk-adjusted analysis, the risk of death at 90 days was similar between the groups (odds ratio 0.923, 95% confidence interval 0.75–1.14, p = 0.461). In the secondary analyses, a 90-day mortality was similar in transferred and non-transferred patients matched according to SAPS 3-score, age, days in the ICU and ICU diagnosis (p = 0.407); SOFA score on the day of discharge, ICU diagnosis and age (p = 0.634); or in a propensity score model (p = 0.229). Conclusion Mortality at 90 days in critically ill patients treated in a tertiary centre was not affected by transfer to another intensive care units due to a shortage of beds. We found this conclusion to be valid under the assumption that patients are carefully selected and that the transports are safely performed.

Background First-line treatment of high-risk pulmonary embolism with persistent hypotension and/or signs of shock is intravenous thrombolysis. However, if thrombolysis is contraindicated due to risk of serious bleeding, or if it yields insufficient effect, surgical thrombectomy or catheter-directed intervention (CDI) plus anticoagulation is recommended. The aim of this study was to assess the outcomes of the CDI modality introduced in a tertiary referral centre in 2013. Methods Retrospective comparison between patients treated with CDI plus anticoagulation (n = 22) and patients treated with anticoagulation only (n = 23) as used before the CDI technique was available. The main outcomes of interest were 90-day survival and reduction of right to left ventricle diameter (RV/LV) ratio, using the Fischer's exact test and a mixed model, respectively, for statistical analysis. Results Ninety-day survival was 59% after CDI and 61% after anticoagulation only; P = .903. The rate of RV/LV ratio reduction was 0.4 units higher per 24 hours in the CDI group (median 2.1 pre-treatment), than in the anticoagulation only group (median 1.3 pre-treatment); P = .007. Conclusion In patients with high-risk pulmonary embolism, 90-day survival was similar after treatment with CDI plus anticoagulation compared to anticoagulation only. The mean reduction in RV/LV ratio was larger in the CDI group. Our results support the use of CDI in selected patients, respecting the limitations and potential side effects of each technical device used.

Background Postoperative neurocognitive decline is a frequent complication in adult patients undergoing major surgery with increased risk for morbidity and mortality. The mechanisms behind cognitive decline after anaesthesia and surgery are not known. We studied the association between CSF and blood biomarkers of neuronal injury or brain amyloidosis and long-term changes in neurocognitive function. Methods In patients undergoing major orthopaedic surgery (knee or hip replacement), blood and CSF samples were obtained before surgery and then at 4, 8, 24, 32, and 48 h after skin incision through an indwelling spinal catheter. CSF and blood concentrations of total tau (T-tau), neurofilament light, neurone-specific enolase and amyloid β (Aβ1-42) were measured. Neurocognitive function was assessed using the International Study of Postoperative Cognitive Dysfunction (ISPOCD) test battery 1–2 weeks before surgery, at discharge from the hospital (2–5 days after surgery), and at 3 months after surgery. Results CSF and blood concentrations of T-tau, neurone-specific enolase, and Aβ1-42 increased after surgery. A similar increase in serum neurofilament light was seen with no overall changes in CSF concentrations. There were no differences between patients having a poor or good late postoperative neurocognitive outcome with respect to these biomarkers of neuronal injury and Aβ1-42. Conclusions The findings of the present explorative study showed that major orthopaedic surgery causes a release of CSF markers of neural injury and brain amyloidosis, suggesting neuronal damage or stress. We were unable to detect an association between the magnitude of biomarker changes and long-term postoperative neurocognitive dysfunction.

Objective: Long-term cognitive decline is an adverse outcome after major surgery associated with increased risk for mortality and morbidity. We studied the cerebrospinal fluid (CSF) and serum biochemical inflammatory response to a standardized orthopedic surgical procedure and the possible association with long-term changes in cognitive function. We hypothesized that the CSF inflammatory response pattern after surgery would differ in patients having long-term cognitive decline defined as a composite cognitive z score of ≥1.0 compared to patients without long-term cognitive decline at 3 months postsurgery. Methods: Serum and CSF biomarkers of inflammation and blood–brain barrier (BBB) integrity were measured preoperatively and up to 48 hours postoperatively, and cognitive function was assessed preoperatively and at 2 to 5 days and 3 months postoperatively. Results: Surgery was associated with a pronounced increase in inflammatory biomarkers in both CSF and blood throughout the 48-hour study period. A principal component (PC) analysis was performed on 52 inflammatory biomarkers. The 2 first PC (PC1 and PC2) construct outcome variables on CSF biomarkers were significantly associated with long-term cognitive decline at 3 months, but none of the PC construct serum variables showed a significant association with long-term cognitive decline at 3 months. Patients both with and patients without long-term cognitive decline showed early transient increases of the astroglial biomarkers S-100B and glial fibrillary acidic protein in CSF, and in BBB permeability (CSF/serum albumin ratio). Interpretation: Surgery rapidly triggers a temporal neuroinflammatory response closely associated with long-term cognitive outcome postsurgery. The findings of this explorative study require validation in a larger surgical patient cohort. Ann Neurol 2020;87:370–382.

BACKGROUND Acute kidney injury (AKI) is a common complication with a major impact on morbidity and mortality after cardiac surgery with cardiopulmonary bypass (CPB). The aim of the present study was to perform a detailed analysis on the release of the tubular injury biomarker N-acetyl-b-D-glucosaminidase (NAG) during and early after CPB and to describe independent predictors of maximal tubular injury. We hypothesized that renal tubular injury occurs early after the onset of CPB. METHODS In this prospective observational study, we included 61 patients undergoing open cardiac surgery with an expected CPB duration exceeding 60 min. The urinary NAG levels were measured at 30 min intervals during CPB, as well as early (30 min) after CPB and post-operatively. Independent predictors of tubular injury were identified using an Interquantile multivariate regression model. RESULTS Already 30 min after the onset of CPB, NAG excretion was significantly increased (P

Introduction Takotsubo syndrome (TS) is an acute cardiac condition that is often triggered by critical illness but that has rarely been studied in the intensive care unit (ICU) setting. The aim of this study was to (i) estimate the incidence of TS in a hemodynamically unstable ICU-population; (ii) identify predictors of TS in this population; (iii) study the impact of TS on prognosis and course of hospitalization. Methods Medical records from all patients admitted to our general ICU from 2012 to 2015 were analyzed. TS was defined as having transient regional wall motion abnormalities (RWMA) with a typical pattern not attributable to a history of coronary artery disease or acute coronary syndromes. Results Out of 6470 patients admitted to the ICU, echocardiography due to hemodynamic instability was performed in 1051 patients; 467 had LV dysfunction and 59 fulfilled TS criteria. Patients with TS had higher SAPS 3 scores on admission than patients with normal LV function. Septic shock, cardiac arrest, cerebral mass lesion, female sex and low pH were independently associated with TS on admission. Patients with TS needed more ICU resources measured by higher NEMS scores and longer ICU-stay. Crude mortality was higher in TS patients (32%) vs the ICU-population (20%, P = 0.020), but there were no differences in a SAPS 3 adjusted analysis. Conclusion TS was not an uncommon cause of LV dysfunction in hemodynamically unstable ICU-patients. Furthermore, TS was associated with a more complex disease. TS is a complication to take in consideration in the critically ill.

Background In enhanced recovery protocols (ERP), a restrictive fluid regimen is proposed. Patients who undergo major surgery have an increased risk of post-operative acute kidney injury (AKI). This combination may pose difficulties when ERP is used for patients undergoing major surgery. The aim of this study was to evaluate whether patients undergoing pancreatic surgery and treated with a restrictive fluid regimen are at greater risk of post-operative AKI. Furthermore, if there was an increased risk of AKI, we aimed to identify its cause. Methods We reviewed the medical records of patients who underwent pancreatic surgery during 2014 (preERP, n = 58) and 2015 (ERP, n = 65). Fluid balance, the administration of cyclooxygenase-2 inhibitors, creatinine levels and mean arterial pressure were recorded. The Kidney Disease: Improving Global Outcomes criteria were used to define AKI. Results The incidence of AKI was higher in the ERP group than in the PreERP group (12.5% vs. 1.8%, respectively, P = 0.035). The increased incidence of AKI could not be explained by differences in comorbidities, age, pre-operative creatinine or perioperative hypotension. Administration of coxibs was higher in the ERP group and was associated with increased incidence of post-operative AKI (P = 0.018). The combination of coxibs and restrictive fluid regimen seems particularly harmful. Conclusion Pancreatic surgery with a restrictive fluid regimen carries an increased risk of post-operative AKI if patients are also treated with cyclooxygenase-2 inhibitors. It is therefore suggested that in protocols including a restrictive fluid regimen for open pancreatic surgery, the use of cyclooxygenase-2 inhibitors should be avoided.

BACKGROUND Takotsubo syndrome (TS) is an acute cardiac condition, often triggered by critical illness, for which no specific treatment exists. Previously, we showed that isoflurane can prevent experimental TS. The aim of this study was to evaluate the potential treatment effects of isoflurane. Our primary hypothesis was that early treatment with isoflurane attenuates left ventricular akinesia in experimental TS. METHOD In propofol-sedated animals, TS was induced by an intraperitoneal bolus of isoprenaline (50 mg/kg). Animals were randomized to one of six groups (n = 15 in each group), and 1% isoflurane was administered for 90 min in all groups. Isoflurane treatment was started at 0, 10, 30 (early treatment) or 120 (late treatment) minutes after isoprenaline injection. One additional late treatment group received isoflurane 0.5% for 180 min. A control group did not receive isoflurane. Left ventricular (LV) echocardiographic examination was performed at 90 min and 48 h after isoprenaline. Mortality was assessed at 48 h. RESULTS Median degree of LV akinesia at 90 min was 24% in the control group and 0% in the early treatment groups (P < 0.001). Stroke volume, cardiac output and LV ejection fraction were higher in the early treatment groups vs. controls (P < 0.01). Mortality was lower in the early treatment groups (24%) vs. controls (86%) (P < 0.001). Mortality did not differ between the late treatment groups and controls. CONCLUSION Early treatment with isoflurane attenuates the LV akinesia and improves survival in experimental TS. Isoflurane sedation in patients at risk of developing Takotsubo syndrome could be a subject for future studies.

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.

Aims Takotsubo syndrome (TS) is an acute cardiac syndrome characterized by regional myocardial akinesia that cannot be attributed to a culprit lesion in coronary arteries. Cardiac overstimulation by catecholamines in the setting of stress is implicated in the pathogenesis of TS. While catecholamine‐induced alterations in cardiac contractility have been studied as part of the causal pathway in TS, the importance of catecholamine‐mediated tachycardia has not been studied. Our aim was to explore whether the reduction in heart rate, either by pharmacological suppression of the sinoatrial node with ivabradine or by surgical induction of third‐degree atrioventricular block, prevents isoprenaline‐induced TS‐like akinesia in an experimental animal model. Methods and results We used 142 female Sprague–Dawley rats in two separate protocols. The TS‐like phenotype was induced by an intraperitoneal bolus dose of isoprenaline (ISO) 50 mg/kg. In the first protocol, we randomized 54 rats to ivabradine 10 min before ISO (IVAB1), ivabradine 10 min after ISO (IVAB2), or saline 10 min before ISO (CONTROL). In the second protocol, we randomized 88 rats to surgically induced complete heart block (CHB) or sham operation (CTRL) 10 min before the administration of ISO. All drugs were administered intraperitoneally. We recorded heart rate and blood pressure invasively in the right carotid artery. Cardiac morphology and function were evaluated by high‐resolution echocardiography (VisualSonics 770 VEVO, Toronto, Ontario, Canada) 90 min after ISO injection. IVAB1 and IVAB2 rats had significantly lower heart rate and less pronounced TS‐like cardiac dysfunction than CONTROL. CHB rats had a lower (54%) heart rate, and no animal developed left ventricular akinesia. In the first protocol, the CONTROL group had a median degree of akinesia of 10.2 [inter‐quartile range (IQR) 0.0–18.6]. The IVAB1 group showed a median of akinesia of 0% (IQR 0.0–0.0, P

New onset of left ventricular (LV) dysfunction in organ donors is frequent and considered as a contraindication for utilization of the heart. However, such dysfunction might be caused by sympathetic stress and could be transient (Takotsubo syndrome). In this study, we assessed the incidence, pattern, and predictors of LV dysfunction in potential heart donors and evaluated its influence on recipient outcomes.Donor records of consecutive organ donors in western Sweden between 2006 and 2016 were reviewed. Recipients of transplanted donor hearts were identified in the Scandiatransplant database.Of 641 potential heart donors who underwent echocardiographic assessment, LV dysfunction (ejection fraction50% and/or regional hypokinesia) was found in 155 donors (24%). Regional hypokinesia was seen in 113 donors of whom 46 had a Takotsubo-like circumferential hypokinetic pattern. Independent donor variables associated with LV dysfunction were a younger age, cardiac arrest as a contributing factor to death, need for inotropic support, and a shorter time from admission to declaration of brain death. A total of 338 (54%) donor hearts were transplanted, of which 45 (14%) had LV dysfunction. LV dysfunction was a major determinant of not transplanting the heart (P .001). After transplantation, LV function normalized in the recipients. Neither short-term outcomes nor the composite end point of death or retransplantation over time differed between recipients of donor hearts with versus without LV dysfunction (P = .587).LV dysfunction is common among potential heart donors. These hearts were safely transplanted in this study. The use of these hearts might significantly increase transplantation rates.

Background Takotsubo syndrome (TS) is an acute cardiac condition with a substantial mortality for which no specific treatment is available. We have previously shown that isoflurane attenuates the development of left ventricular (LV) dysfunction in an experimental TS-model. We compared the effects of equi-anaesthetic doses of isoflurane, propofol and ketamine+midazolam on haemodynamics, global and regional LV systolic function and the activation of intracellular metabolic pathways in experimental TS. We hypothesized that cardioprotection in experimental TS is specific for isoflurane. Methods Forty-five rats were randomized to isoflurane (0.6 MAC, n = 15), propofol (bolus 200 mg/kg+360 mg/kg/h, n = 15) or ketamine (100 mg/kg)+midazolam (10 mg/kg, n = 15) anaesthesia. Arterial pressure, heart rate and body temperature were continuously measured and arterial blood gas analysis was performed intermittently. TS was induced by intraperitoneal injection of isoprenaline, 50 mg/kg. LV echocardiography was performed 90 min after isoprenaline injection. Apical cardiac tissue was analysed by global discovery proteomics and pathway analysis. Results Isoprenaline-induced changes in arterial blood pressure, heart rate or body temperature did not differ between groups. LV ejection fraction was higher and extent of LV akinesia was lower with isoflurane, when compared with the propofol and the ketamine+midazolam groups. In this TS-model, the proteomic analysis revealed an up-regulation of pathways involved in inflammation, coagulation, endocytosis and lipid metabolism. This up-regulation was clearly attenuated with isoflurane compared to propofol. Conclusion In an experimental model of TS, isoflurane, but not propofol, exerts a cardioprotective effect. The proteomic analysis suggests that inflammation might be involved in pathogenesis of TS.

Introduction: Takotsubo syndrome (TS) is an increasingly recognized acute heart failure syndrome which is self-limiting in most cases but can result in life-threatening complications. TS is difficult to distinguish from acute myocardial infarction (AMI) early in the disease course and currently lacks evidence-based treatment recommendations. Areas covered: Based on the available literature this systematic review discusses the clinical management of patients with TS during (i) the diagnostic workup; (ii) acutely after establishing the TS diagnosis; and (iii) after recovery of cardiac function. Expert commentary: Since TS is self-limiting in most cases it is recommended to refrain from unnecessary treatment (the do no harm principle) when managing patients with TS. The management of patients with TS should focus on careful monitoring of ECG and hemodynamics, and on preventing and treating complications. Because catecholamine-mediated inotropic overstimulation is implicated in the pathogenesis of TS, and because inotropic drugs have been associated with worse outcomes for patients with TS, we recommend the treating physician to avoid these drugs. Instead, mechanical assist devices should be considered early for patients with TS who develop cardiogenic shock with signs of end-organ hypo-perfusion.

Background Cardiac complications frequently occur after subarachnoid hemorrhage (SAH) and are associated with an increased risk of neurological complications and poor outcomes. The aim of this study was to evaluate the impact of acute cardiac complications after SAH on long-term mortality and cardiovascular events. Methods All patients admitted to our Neuro intensive care unit with verified SAH from January 2010 to April 2015, and electrocardiogram, echocardiogram, and troponin T or NTproBNP data obtained within 72 h of admission were included in the study. Mortality data were obtained from the Swedish population register. Data regarding cause of death and hospitalization for cardiovascular events were obtained from the Swedish Board of Health and Welfare. Results A total of 455 patients were included in the study analysis. There were 102 deaths during the study period. Cardiac troponin release (HR 1.08, CI 1.02–1.15 per 100 ng/l, p = 0.019), NTproBNP (HR 1.05, CI 1.01–1.09 per 1000 ng/l, p = 0.018), and ST-T abnormalities (HR 1.53, CI 1.02–2.29, p = 0.040) were independently associated with an increased risk of death. However, these associations were significant only during the first 3 months after the hemorrhage. Cardiac events were observed in 25 patients, and cerebrovascular events were observed in 62 patients during the study period. ST-T abnormalities were independently associated with an increased risk of cardiac events (HR 5.52, CI 2.07–14.7, p

BACKGROUND AND PURPOSE In the new era of endovascular treatment for acute ischemic stroke, one of the main predictors of good neurological outcome is a short time interval from stroke onset to recanalization of the occluded vessel. In this study, we examined the effect of on-hour vs off-hour admittance on the time intervals from stroke onset to recanalization in patients with acute ischemic stroke (AIS) undergoing endovascular treatment (EVT). METHODS One-hundred-ninety-eight patients receiving EVT for anterior AIS between 2007 and 2016 were included. Time of day and weekday for stroke admittance were recorded as well as several time intervals. Age, sex, co-morbidities, admission National Institutes of Health Stroke Scale (NIHSS), intraprocedural blood pressure, blood glucose, modified Thrombolysis in Cerebral Ischemia score (mTICI) and neurological outcome at 3 months, measured as modified Rankin Scale (mRS), were registered. On-hour was defined as 8 am-4 pm weekdays, and off-hour as weekdays outside these hours and weekends. RESULTS The time interval from CT (computed tomography) to recanalization was longer during off-hours, while no difference was seen in the time interval from stroke onset to CT. No statistically significant difference was seen in neurological outcome between the on- and off-hour groups in a univariate analysis. CONCLUSIONS Stroke admittance during off-hours is associated with longer time interval from CT examination to vessel recanalization. The study highlights the need of logistic improvement and probably more resources off-hour in order to deliver an effective stroke care around the clock.

BACKGROUND Myocardial injury with regional wall motion abnormalities (RWMA) is common in subarachnoid haemorrhage (SAH). We hypothesized that the diagnostic performance of left ventricular (LV) global and regional longitudinal strain (GLS and RLS, respectively), assessed with speckle tracking echocardiography is superior to standard echocardiography for the detection of myocardial injury in SAH. METHODS Seventy-one unselected patients with verified SAH were included. Echocardiography was performed within 48 hours after admission. hsTnT was followed daily up to 3 days post-admission. RWMA, LV ejection fraction (LVEF), GLS and RLS were analysed by two experienced echocardiographists, blinded to the information on plasma hsTnT. A reduced GLS was defined as >-15%. Two cut-off levels were used for the definition of RLS, ie when segmental strain was >-15% (liberal) or >-11% (conservative) in ≥2 adjacent segments. Myocardial injury was defined as a peak hsTnT ≥90 ng/L. RESULTS The incidence of myocardial injury was 25%. The hsTnT (median, 25% and 75% percentile) in patients with (a) reduced LV ejection fraction (LVEF

Background: Isocapnic hyperventilation (IHV) shortens recovery time after inhalation anaesthesia by increasing ventilation while maintaining a normal airway carbon dioxide (CO2)-level. One way of performing IHV is to infuse CO2 to the inspiratory limb of a breathing circuit during mechanical hyperventilation (HV). In a prospective randomized study, we compared this IHV technique to a standard emergence procedure (control). Methods: Thirty-one adult ASA I-III patients undergoing long-duration (>3 hours) sevoflurane anaesthesia for major head and neck surgery were included and randomized to IHV-treatment (n = 16) or control (n = 15). IHV was performed at minute ventilation 13.6 ± 4.3 L/min and CO2 delivery, dosed according to a nomogram tested in a pilot study. Time to extubation and eye-opening was recorded. Inspired (FICO2) and expired (FETCO2) CO2 and arterial CO2 levels (PaCO2) were monitored. Cognition was tested preoperatively and at 20, 40 and 60 minutes after surgery. Results: Time from turning off the vapourizer to extubation was 13.7 ± 2.5 minutes in the IHV group and 27.4 ± 6.5 minutes in controls (P

Background Stress-induced cardiomyopathy (SIC) is a common syndrome with substantial morbidity and mortality. SIC is common in intensive care units' patients. No therapeutic intervention for SIC has been evaluated in randomized clinical trial so far. Our aim was to investigate whether isoflurane is cardioprotective in an experimental SIC model. Methods We induced SIC-like cardiac dysfunction in rats with intraperitoneal injection of isoprenaline (50mg/kg) and performed this study in two parts. First, we pre-treated rats with isoflurane (1.5%, n=12), pentobarbital (50mg/kg, n=12) and ketamine (80mg/kg, n=12) and compared to controls (n=12). We used glyburide, an ATP-dependent potassium channel blocker (n=6), to test whether isoflurane-protection is mediated through K ATPm . In a second set of experiments, we treated rats with two different doses of isoflurane i.e. 0.75% (n=12) and 1.5% (n=12) before induction of SIC and compared to controls. We assessed left ventricular function and morphology in all rats by transthoracic echocardiography. We also measured peak body temperature, blood gases, acid–base homeostasis, blood pressure and heart rate. Results The extent of apical akinesia was lowest and cardiac function was best in the isoflurane treated rats. The protective effects were not attenuated by glibenclamide. Higher dose of isoflurane was more cardioprotective than the lower dose. This was persistent after the adjustment for changes in hemodynamics and blood biochemistry induced by anesthesia. Conclusions Isoflurane prevented SIC-like cardiac dysfunction in rats. This protection was not mediated via K ATPm . Our study provides an experimental foundation for future clinical trials in SIC.

Without a heart transplant, 20% of patients with end-stage heartfailure will die within 6 months. If the patient receives a new heart,however, the estimated median survival time exceeds 10 years [1].Unfortunately, because of the paucity of donors who meet the criteriafortransplantation[2,3],heartsareavailableforonlyasmallpercentageof recipients with refractory heart failure who are eligible for hearttransplantation. Current guidelines stipulate that donor hearts shouldnot have wall motion abnormalities and that ejection fraction shouldbe over 40% [4].Takotsubo syndrome is an acute condition with characteristicreversible regional wall motion abnormalities and decreased ejectionfraction. Takotsubo frequently affects patients with severe somaticdisease [5] and is common in patients with cerebral lesions, includingsubarachnoid hemorrhage [5]. The current guidelines do not mentionwhether patients with brain death and takotsubo could be consideredas organ donors.The process of brain death elicits significant somatic stress and acatecholamine surge [6] Increasing evidence suggests that takotsubosyndrome is caused by direct catecholamine toxicity in predisposedpatients and is therefore probably common in patients with braindeath. Here we present a case in which a heart was successfullytransplanted from a donor with wall motion abnormalities due totakotsubo syndrome.

Background Post-operative pain is common and often severe after open abdominal hysterectomy, and analgesic consumption high. This study assessed the efficacy of local infiltration analgesia (LIA) injected systematically into different tissues during surgery compared with saline on post-operative pain and analgesia. Methods Fifty-nine patients were randomized to Group LIA (n = 29) consisting of 156 ml of a mixture of 0.2% ropivacaine + 30 mg ketorolac + 0.5 mg (5 ml) adrenaline, where the drugs were injected systematically in the operating site, around the proximal vagina, the ligaments, in the fascia and subcutaneously, or to saline and intravenous ketorolac, Group C (Control, n = 28), in a double-blind study. Post-operative pain, analgesic consumption, side-effects, and home discharge were analysed. Results Median dose of rescue morphine given 0–24 h after surgery was significantly lower in group LIA (18 mg, IQR 5–25 mg) compared with group C (27 mg, IQR 15–43 mg, P = 0.028). Median time to first analgesic injection was significantly longer in group LIA (40 min, IQR 20–60 min) compared with group C (20 min, IQR 12–30 min, P = 0.009). NRS score was lower in the group LIA compared with group C in the direct post-operative period (0–2 h). No differences were found in post-operative side-effects or home discharge between the groups. Discussion Systematically injected local infiltration analgesia for pain management was superior to saline in the primary endpoint, resulting in significantly lower rescue morphine requirements during 0–24 h, longer time to first analgesic request and lower early post-operative pain intensity.