General anesthesia in early childhood and possible association with autism: a population-based matched cohort study.

BACKGROUND: In experimental animal studies, exposure to general anesthesia in early childhood may results in changes in infant brain morphology and behavior, potentially leading to the development of autistic behaviors in the long-term. However, in clinical studies the role of exposure to general anesthesia in early childhood and the risk of autism is unknown. METHODS: This is a population-based cohort study including all children aged 0-5 years of age exposed to general anesthesia between 2001 and 2014 and a corresponding matched population without such an exposure. Propensity score calculation was based on 49 variables (including age of parents, malformations, APGAR Score, and family income, among others). Quasi-Poisson regression was used to estimate risk ratios (RRs) with 95% confidence intervals (CIs) for the association between exposure to general anesthesia and autism or autism spectrum disorder. RESULTS: In total, 401,750 children exposed to general anesthesia were compared with 1,187,796 unexposed individuals. Autism or autism spectrum disorder were more common in the children exposed to general anesthesia as compared to unexposed children (1.65% and 0.98%, respectively, P<0.01). There was a statistically significant higher risk of autism or autism spectrum disorder in children exposed to general anesthesia as compared to unexposed children also after propensity score adjustment (RR 1.62, 95% CI: 1.57-1.67). CONCLUSIONS: Exposure to general anesthesia in early childhood was associated with an increased risk of autism or autism spectrum disorder. Future studies are needed to asses if general anesthesia may cause autism or if the association is due to other factors.

The Contribution of Plasma Urea to Total Osmolality During Iatrogenic Fluid Reduction in Critically Ill Patients.

Hyperosmolality is common in critically ill patients during body fluid volume reduction. It is unknown whether this is only a result of decreased total body water or an active osmole-producing mechanism similar to that found in aestivating animals, where muscle degradation increases urea levels to preserve water. We hypothesized that fluid volume reduction in critically ill patients contributes to a shift from ionic to organic osmolytes similar to mechanisms of aestivation. We performed a post-hoc analysis on data from a multicenter observational study in adult intensive care unit (ICU) patients in the postresuscitative phase. Fluid, electrolyte, energy and nitrogen intake, fluid loss, estimated glomerular filtration rate (eGFR), and estimated plasma osmolality (eOSM) were registered. Contributions of osmolytes Na+, K+, urea, and glucose to eOSM expressed as proportions of eOSM were calculated. A total of 241 patients were included. eOSM increased (median change 7.4 mOsm/kg [IQR-1.9-18]) during the study. Sodium's and potassium's proportions of eOSM decreased (P < .05 and P < .01, respectively), whereas urea's proportion increased (P < .001). The urea's proportion of eOSM was higher in patients with negative vs. positive fluid balance. Urea's proportion of eOSM increased with eOSM (r = 0.63; adjusted for eGFR r = 0.80), but not nitrogen intake. In patients without furosemide and/or renal replacement therapy (n = 17), urea's proportion of eOSM and eOSM correlated strongly (r = 0.92). Urea's proportion of eOSM was higher in patients not surviving up to 90 d. In stabilized ICU patients, the contribution of urea to plasma osmolality increased during body water volume reduction, statistically independently of nitrogen administration and eGFR. The shift from ionic osmolytes to urea during body fluid volume reduction is similar to that seen in aestivating animals. ClinicalTrials.org Identifier: NCT03972475.

Lung-protective ventilation increases cerebral metabolism and non-inflammatory brain injury in porcine experimental sepsis.

BACKGROUND: Protective ventilation with lower tidal volumes reduces systemic and organ-specific inflammation. In sepsis-induced encephalopathy or acute brain injury the use of protective ventilation has not been widely investigated (experimentally or clinically). We hypothesized that protective ventilation would attenuate cerebral inflammation in a porcine endotoxemic sepsis model. The aim of the study was to study the effect of tidal volume on cerebral inflammatory response, cerebral metabolism and brain injury. Nine animals received protective mechanical ventilation with a tidal volume of 6 mL × kg-1 and nine animals were ventilated with a tidal volume of 10 mL × kg-1. During a 6-h experiment, the pigs received an endotoxin intravenous infusion of 0.25 µg × kg-1 × h-1. Systemic, superior sagittal sinus and jugular vein blood samples were analysed for inflammatory cytokines and S100B. Intracranial pressure, brain tissue oxygenation and brain microdialysis were sampled every hour. RESULTS: No differences in systemic or sagittal sinus levels of TNF-α or IL-6 were seen between the groups. The low tidal volume group had increased cerebral blood flow (p < 0.001) and cerebral oxygen delivery (p < 0.001), lower cerebral vascular resistance (p < 0.05), higher cerebral metabolic rate (p < 0.05) along with higher cerebral glucose consumption (p < 0.05) and lactate production (p < 0.05). Moreover, low tidal volume ventilation increased the levels of glutamate (p < 0.01), glycerol (p < 0.05) and showed a trend towards higher lactate to pyruvate ratio (p = 0.08) in cerebral microdialysate as well as higher levels of S-100B (p < 0.05) in jugular venous plasma compared with medium-high tidal volume ventilation. CONCLUSIONS: Contrary to the hypothesis, protective ventilation did not affect inflammatory cytokines. The low tidal volume group had increased cerebral blood flow, cerebral oxygen delivery and cerebral metabolism together with increased levels of markers of brain injury compared with medium-high tidal volume ventilation.

Hidden sources of fluids, sodium and potassium in stabilised Swedish ICU patients: A multicentre retrospective observational study.

BACKGROUND: Fluid overload in ICU patients is associated with increased morbidity and mortality. Although studies report on optimisation of resuscitation fluids given to ICU patients, increasing evidence suggests that maintenance fluids and fluids used to administer drugs are important sources of fluid overload. OBJECTIVES: We aimed to evaluate the volume of maintenance fluids and electrolytes on overall fluid balance and their relation to mortality in stabilised ICU patients. DESIGN: Multicentre retrospective observational study. SETTING: Six mixed surgical and medical ICUs in Sweden. PATIENTS: A total of 241 adult patients who spent at least 7 days in the ICU during 2018. MAIN OUTCOME MEASURES: The primary endpoint was the volume of maintenance, resuscitation and drug diluent fluids administered on days 3 to 7 in the ICU. Secondary endpoints were to compare dispensed amounts of maintenance fluids and electrolytes with predicted requirements. We also investigated the effects of administered fluids and electrolytes on patient outcomes. RESULTS: During ICU days 3 to 7, 56.4% of the total fluids given were maintenance fluids, nutritional fluids or both, 25.4% were drug fluids and 18.1% were resuscitation fluids. Patients received fluids 1.29 (95% confidence interval 1.07 to 1.56) times their estimated fluid needs. Despite this, 93% of the cohort was treated with diuretics or renal replacement therapy. Patients were given 2.17 (1.57 to 2.96) times their theoretical sodium needs and 1.22 (0.75 to 1.77) times their potassium needs. The median [IQR] volume of fluid loss during the 5-day study period was 3742 [3156 to 4479] ml day-1, with urine output the main source of fluid loss. Death at 90 days was not associated with fluid or electrolyte balance in this cohort. CONCLUSION: Maintenance and drug fluids far exceeded resuscitative fluids in ICU patients beyond the resuscitative phase. This excess fluid intake, in conjunction with high urinary output and treatment for fluid offload in almost all patients, suggests that a large volume of the maintenance fluids given was unnecessary. TRIAL REGISTRATION: ClinicalTrials.org NCT03972475.

The Patient's Gender Influencing the Accuracy of Diagnosis and Proposed Sepsis Treatment in Constructed Cases.

BACKGROUND: Male sex is an independent risk factor for sepsis development. In addition to immunological gender differences, women less often receive sepsis treatment once diagnosed. Gender differences have also been described in other medical conditions, such as acute coronary syndrome. AIM: To study whether the gender of patients influenced physicians' tendency to suspect sepsis and propose correct initial sepsis treatment in constructed cases. METHOD: Four cases were constructed to fulfil the sepsis-3 criteria as well as raise clinical suspicions of other common medical differential diagnoses. Two of the cases were drafted in two versions, only differing in the gender of the patient. The two versions were randomly distributed to all clinical physicians in a medical region in Sweden. The responding physicians were asked to state the three most important diagnoses and the three most important initial treatments for each case. If sepsis were among the stated diagnoses together with fluids and antibiotics, the case was considered as correctly identified and initially treated sepsis. RESULTS: 120 hospital physicians answered the cases. In the case the patient was a female, the respondents correctly identified and treated sepsis significantly more often than if the patient was of the male sex (Case 1: 12/58 vs 2/62, p < 0.01 and Case 2: 25/62 vs 13/58, p < 0.05). CONCLUSION: A low proportion of Swedish physicians identified and proposed treatment for sepsis in four constructed cases. In the case the patient strongly mimicked other diagnoses common in the male sex, the male cases were less often correctly identified and treated for sepsis.

Effects of surgery and propofol-remifentanil total intravenous anesthesia on cerebrospinal fluid biomarkers of inflammation, Alzheimer's disease, and neuronal injury in humans: a cohort study.

BACKGROUND: Surgery and anesthesia have been linked to postoperative cognitive disturbance and increased risk of Alzheimer's disease. It is not clear by which mechanisms this increased risk for cognitive disease is mediated. Further, amyloid ß production has been suggested to depend on the sleep-wake cycle and neuronal activity. The aim of the present study was to examine if cerebrospinal fluid (CSF) concentrations of a number of biomarkers for Alzheimer's disease-related processes, including amyloid ß, neuronal injury, and inflammation, changed over time during intravenous anesthesia in surgical patients. METHODS: We included patients scheduled for hysterectomy via laparotomy during general anesthesia with intravenous propofol and remifentanil. CSF samples were obtained before, during, and after surgery (5 h after induction) and tested for 27 biomarkers. Changes over time were tested with linear mixed effects models. RESULTS: A total of 22 patients, all females, were included. The mean age was 50 years (± 9 SD). The mean duration of the anesthesia was 145 min (± 40 SD). Interleukin (IL)-6, IL-8, monocyte chemoattractant protein 1, and vascular endothelial growth factor A increased over time. IL-15 and IL-7 decreased slightly over time. Macrophage inflammatory protein 1ß and placental growth factor also changed significantly. There were no significant effects on amyloid ß (Aß) or tau biomarkers. CONCLUSIONS: Surgery and general anesthesia with intravenous propofol and remifentanil induce, during and in the short term after the procedure, a neuroinflammatory response which is dominated by monocyte attractants, without biomarker signs of the effects on Alzheimer's disease pathology or neuronal injury.

Internal jugular dimensions and common carotid overlapping assessed in a cross-sectional study by ultrasonography at three neck levels in healthy volunteers.

BACKGROUND: Cannulation of the internal jugular vein may be associated with inadvertent puncture of the common carotid artery. Systematic use of ultrasound guidance has improved clinical success rates and reduced complications, but better knowledge of topographic relationships of the internal jugular vein and common carotid artery is desirable. This preclinical study was designed to determine by ultrasound technique relative topographic characteristics in humans of the internal jugular veins and common carotid arteries at different levels on both sides of the neck. METHODS: One hundred and twenty healthy volunteers were examined bilaterally by ultrasound at three neck levels with and without contralateral rotation of the head. Twelve digital pictures were recorded and used to determine venous diameters and extents of arteriovenous overlapping in each subject. RESULTS: Venous dimensions and arteriovenous overlapping were larger on the right side (p = 0.008) regardless of head rotation at all levels. There was more arteriovenous overlapping with than without rotation at right high- and mid-cervical levels (p<0.001). The only difference between right mid- and low-cervical levels was less arteriovenous overlapping at mid-cervical level without rotation (p = 0.017). The smallest venous dimensions and extent of arteriovenous overlapping were recorded at high-cervical level. CONCLUSIONS: Despite similar venous dimensions, less arteriovenous overlapping regardless of head rotation at mid-cervical level, together with the pleural proximity at low-cervical level, propose the internal jugular vein to be anatomically (other factors disregarded) favorable for vascular access on the right side, at mid-cervical level, close to the angle between the sternocleidomastoid muscle bellies, and with minimal rotation of the head.

Total-tau and neurofilament light in CSF reflect spinal cord ischaemia after endovascular aortic repair.

BACKGROUND: Repair of extensive aortic disease may be associated with spinal cord ischaemia (SCI). Here we test if levels of cerebrospinal fluid (CSF) biomarkers for neuronal injury are altered in patients with SCI after advanced endovascular repair in extensive aortic disease. METHODS: CSF was sampled for up to 48 h in ten patients undergoing endovascular aortic repair and analyzed for the axonal damage markers total-tau (T-tau) and neurofilament light (NFL). RESULTS: Six of ten patients developed SCI (clinically present within 3-6 h). CSF levels of NFL increased up to 37-fold in patients with, but were stable in patients without, SCI. CSF levels of T-tau also increased in patients with SCI, but with some overlap with patients without SCI. Levels of NFL and T-tau did not increase until after the appearance of clinical signs of neurological dysfunction (12-48 h after aortic repair). CONCLUSIONS: The CSF biomarkers NFL and T-tau both reflect development of SCI after endovascular aortic repair, but do not rise until after clinical signs of SCI appear. Future studies are desirable to further evaluate potential use of these biomarkers for assessment of the severity of SCI, and also to identify earlier biomarkers of SCI.

Parity influences the severity of ACPA-negative early rheumatoid arthritis: a cohort study based on the Swedish EIRA material.

BACKGROUND: In women with rheumatoid arthritis (RA) it has been observed that during pregnancy a majority of patients experience amelioration, but after delivery a relapse of the disease is common. However, there are few studies, with diverging results, addressing the effect of parity on the severity of RA over time. Our aim was to explore the impact of parity, with stratification for anti-citrullinated protein antibody (ACPA) status as well as for onset during reproductive age or not. METHODS: Female RA cases aged 18-70 years were recruited for the Epidemiological Investigation of Rheumatoid Arthritis (EIRA). Information on disease severity (the health assessment questionnaire (HAQ) and the disease activity score 28 (DAS28)) was retrieved from the Swedish Rheumatology Quality Register at inclusion and 3, 6, 12 and 24 months after diagnosis. Mixed models were used to compare mean DAS28 and HAQ scores over time in parous and nulliparous women. Mean differences at individual follow-up visits were compared using analysis of covariance. The odds of having DAS28 or HAQ above the median in parous verus nulliparous women were estimated in logistic regression models. RESULTS: A total of 1237 female cases (mean age 51 years, 65 % ACPA-positive) were included. ACPA-negative parous women, aged 18-44 years, had on average 1.17 units higher DAS28 (p < 0.001) and 0.43 units higher HAQ score (p < 0.001) compared to nulliparous women during the follow-up time, adjusted for age. In this subgroup, the average DAS28 and HAQ scores were significantly higher in parous women at all follow-up time points. Younger parous ACPA-negative women were significantly more likely to have DAS28 and HAQ values above the median compared to nulliparous women at all follow-up visits. No association between parity and severity of ACPA-positive disease was observed. CONCLUSIONS: Parity was a predictor of a more severe RA among ACPA-negative younger women, which might indicate that immunomodulatory changes during and after pregnancy affect RA severity, in particular for the ACPA-negative RA phenotype.

Inadvertent arterial catheterization complicating femoral venous access for haemodialysis.

OBJECTIVE: Large-bore catheters for temporary haemodialysis are often placed via the internal jugular or femoral vein, guided by external landmarks or ultrasound techniques. Inadvertent femoral artery catheterization may occur during attempted placement of the dialysis catheter in the femoral vein. MATERIAL AND METHODS: This investigation was carried out in Skåne University Hospital, Malmö, Sweden. Between 2008 and 2011, patients referred for consultation by a vascular specialist owing to inadvertent arterial catheterization after attempted placement of a dialysis catheter in the femoral vein were noted in a logbook and patients with iatrogenic arterial injuries undergoing vascular repair at Malmö-Lund Hospitals were identified through the Swedish vascular registry (Swedvasc). RESULTS: The five included patients had a dialysis catheter (11-13.5 Fr) inserted, without ultrasound guidance, into the femoral artery. One patient suffered from circulatory shock. Two cases were managed with external compression, while three cases required surgical repair. Two patients had postoperative wound infection in the groin. CONCLUSIONS: Femoral dialysis catheters should be inserted using ultrasound guidance. Large-bore catheters suspected of being in an inadvertent arterial position should be fixed securely before further diagnostic or interventional considerations. A management algorithm for inadvertently placed catheters in the femoral artery is proposed.

Depersonalization disorder may be related to glutamate receptor activation imbalance.

Low-dose ketamine administration mimics, both clinically and on gross neuroimaging, depersonalization disorder. The perceptual effects of ketamine may be due to secondary stimulation of glutamate release and lamotrigine, possibly by inhibited glutamate release, may reduce some of ketamine's so-called dissociative effects. However, lamotrigine does not seem to be useful in the treatment of depersonalization disorder. Glutamate release in prefrontal cortex is increased by subanaesthetic doses of ketamine, resulting in increased inhibition, possibly via intercalated GABAerg cells, of projections from amygdala, affecting structures critically involved in depersonalization. I speculate that, in depersonalization disorder, the increased glutamate activity in prefrontal cortex is due to intrinsic imbalance, resulting in long-term potentiation, at the postsynaptic glutamate receptors on the GABAerg interneurons while the same receptor abnormality at the synapses on the intercalated GABAerg cells of the amygdala result in long-term depression in the case of either normal or high glutamate release.

Extreme lactic acidosis type B associated with metformin treatment.

The elimination of metformin is exclusively through the kidneys and elevated plasma concentrations can cause lactic acidosis. We report a case of severe lactic acidosis (pH 6.60) occuring with ostensibly normal therapeutic doses of metformin in the setting of acute renal failure. Continuous veno-venous haemodiafiltration decreased plasma metformin concentrations from 266 lmol/L at presentation to 68 lmol/L, 21 h later. The patient improved rapidly.

Endovascular intervention for central venous cannulation in patients with vascular occlusion after previous catheterization.

OBJECTIVES: This study was designed to assess endovascular intervention for central venous cannulation in patients with vascular occlusion after previous catheterization. METHODS: Patients referred for endovascular management of central venous occlusion during a 42-month period were identified from a regional endovascular database, providing prospective information on techniques and clinical outcome. Corresponding patient records, angiograms, and radiographic reports were analyzed retrospectively. RESULTS: Sixteen patients aged 48 years (range 0.5-76), including 11 females, were included. All patients but 1 had had multiple central venous catheters with a median total indwelling time of 37 months. Eleven patients cannulated for hemodialysis had had significantly fewer individual catheters inserted compared with 5 patients cannulated for nutritional support (mean 3.6 vs. 10.2, p<0.001) before endovascular intervention. Preoperative imaging by magnetic resonance tomography (MRT) in 8 patients, computed tomography (CT) venography in 3, conventional angiography in 6, and/or ultrasonography in 8, verified 15 brachiocephalic, 13 internal jugular, 3 superior caval, and/or 3 subclavian venous occlusions. Patients were subjected to recanalization (n=2), recanalization and percutaneous transluminal angioplasty (n=5), or stenting for vena cava superior syndrome (n=1) prior to catheter insertion. The remaining 8 patients were cannulated by avoiding the occluded route. CONCLUSIONS: Central venous occlusion occurs particularly in patients under hemodialysis and with a history of multiple central venous catheterizations with large-diameter catheters and/or long total indwelling time periods. Patients with central venous occlusion verified by CT or MRT venography and need for central venous access should be referred for endovascular intervention.

Early surgical results after pneumonectomy for non-small cell lung cancer are not affected by preoperative radiotherapy and chemotherapy.

BACKGROUND: Higher operative risks after pneumonectomy for non-small cell lung cancer (NSCLC) have been reported after neoadjuvant chemotherapy or radiotherapy, or both. Patients who underwent pneumonectomy for NSCLC were evaluated for effect of neoadjuvant treatment on mortality and morbidity, especially bronchopleural fistula. METHODS: Between 1996 and 2003, 130 consecutive patients underwent pneumonectomy: 35 received preoperative radiotherapy and chemotherapy (the neoadjuvant group), and 95 patients did not (the first-surgery group). Operative mortality and postoperative complications were compared between the groups. RESULTS: Minor postoperative complications were comparable in both groups (p > 0.10). Five patients in the neoadjuvant group and 10 in the first-surgery group had serious complications (p = 0.55). Eight had bronchopleural fistulas (7 right and 1 left, p < 0.01); 3 were in the neoadjuvant group (p = 0.49). Three fistulas required reoperation. One patient in the first-surgery group died within 30 days postoperatively. Duration of symptoms (hazard ratio, 6.6; p = 0.01) and right-sided pneumonectomy (hazard ratio, 2.4; p = 0.05) were associated with an increased risk of bronchopleural fistula. Induction treatment, postoperative radiotherapy, or coverage of the bronchial stump did not increase the risk of bronchopleural fistulation. Survival at 1 and 5 years was comparable for the neoadjuvant and first-surgery groups: 74% and 46% vs 72% and 34%, respectively (p > 0.2). CONCLUSIONS: Pneumonectomy is a safe procedure with low operative mortality. Postoperative morbidity is significant, especially bronchopleural fistulas after right-sided pneumonectomy (11%). However, neither operative mortality nor morbidity appears to be directly associated with preoperative radiotherapy or chemotherapy.

Reoperations are common following VATS for spontaneous pneumothorax: study of risk factors.

OBJECTIVES: To identify risk factors for reoperation following surgery for spontaneous pneumothorax. MATERIALS AND METHODS: This is a retrospective clinical study conducted on 240 consecutive patients operated on for spontaneous pneumothorax in Lund University Hospital between January 1996 and December 2003. Patient information was gained from medical charts and operation reports. Logistic regression analysis was used to evaluate risk factors. Median follow-up was 54 months. RESULTS: Video-assisted thoracoscopic surgery (VATS) was used in 93% of the patients, where bullectomy with or without pleurodesis/pleurectomy was performed in most cases. Conversion to anterolateral thoracotomy was required in 6 cases (2.3%). Operative mortality (<30 days) was 0.8% (0% after VATS). Altogether 35 patients (13.7%) required a reoperation. Twenty patients were reoperated on within one month from surgery, most often due to prolonged air leakage (n=13, 5.1%) and bleeding (n=6, 2.3%). Fifteen patients (5.8%) were reoperated on because of recurrent pneumothorax, on average 17 months (range 1-39 months) after the primary operation. Significant independent risk factors for reoperation were; young age, operations performed for secondary pneumothorax due to emphysema and recurrent pneumothorax. The risk was also increased in patients where wedge resection was not performed. However, the type of pleurodesis or pleurectomy was not related to increased risk. CONCLUSIONS: A considerable number of patients require reoperation after VATS for pneumothorax. Most reoperations are due to prolonged air leakage or recurrent pneumothorax. The risk for reoperation is increased in younger patients, patients operated for recurrent or secondary pneumothorax, and in cases where pulmonary wedge resection is not performed.