Comprehensive antibody and cytokine profiling in hospitalized COVID-19 patients in relation to clinical outcomes in a large Belgian cohort.

The immune response in patients with Coronavirus Disease 2019 (COVID-19) is highly variable and is linked to disease severity and mortality. However, antibody and cytokine responses in the early disease stage and their association with disease course and outcome are still not completely understood. In this large, multi-centre cohort study, blood samples of 434 Belgian COVID-19 hospitalized patients with different disease severities (ranging from asymptomatic/mild to critically ill) from the first wave of the COVID-19 pandemic were obtained. Baseline antibody and cytokine responses were characterized and associations with several clinical outcome parameters were determined. Anti-spike immunoglobulin (Ig)G and IgM levels were elevated in patients with a more severe disease course. This increased baseline antibody response however was associated with decreased odds for hospital mortality. Levels of the pro-inflammatory cytokines IL-6, IP-10 and IL-8, the anti-inflammatory cytokine IL-10 and the antiviral cytokines IFN-α, IFN-ß and IFN-λ1 were increased with disease severity. Remarkably, we found significantly lower levels of IFN-λ2,3 in critically ill patients compared to patients of the moderate and severe disease category. Finally, levels of IL-8, IL-6, IP-10, IL-10, IFN-α, IFN-ß, IFN-γ and IFN-λ1 at baseline were positively associated with mortality, whereas higher IFN-λ2,3 levels were negatively associated with mortality.

The effect of spinal versus general anaesthesia on perioperative muscle weakness in patients having bilateral total hip arthroplasty: a single center randomized clinical trial.

BACKGROUND: Perioperative neuro-endocrine stress response may contribute to acquired muscle weakness. Regional anaesthesia has been reported to improve the outcome of patients having total hip arthroplasty. In this study, it was hypothesized that spinal anaesthesia (SA) decreases the perioperative neuro-endocrine stress response and perioperatively acquired muscle weakness (PAMW), as compared to general anaesthesia (GA). METHODS: Fifty subjects undergoing bilateral total hip arthroplasty (THA) were randomly allocated to receive a standardized SA (n = 25) or GA (n = 25). Handgrip strength was assessed preoperatively, on the first postoperative day (primary endpoint) and on day 7 and 28. Respiratory muscle strength was measured by maximal inspiratory pressure (MIP). Stress response was assessed by measuring levels of Adrenocorticotropic hormone (ACTH), cortisol and interleukin-6 (IL-6). RESULTS: Handgrip strength postoperatively (day 1) decreased by 5.4 ± 15.9% in the SA group, versus 15.2 ± 11.7% in the GA group (p = 0.02). The handgrip strength returned to baseline at day 7 and did not differ between groups at day 28. MIP increased postoperatively in patients randomized to SA by 11.7 ± 48.3%, whereas it decreased in GA by 12.2 ± 19.9% (p = 0.04). On day 7, MIP increased in both groups, but more in the SA (49.0 ± 47.8%) than in the GA group (14.2 ± 32.1%) (p = 0.006). Postoperatively, the levels of ACTH, cortisol and IL-6 increased in the GA, but not in the SA group (p < 0.004). CONCLUSION: In patients having bilateral THA, SA preserved the postoperative respiratory and peripheral muscle strength and attenuated the neuro-endocrine and inflammatory responses. TRIAL REGISTRATION: clinicaltrials.gov NCT03600454.

Long-Term Outcome in Patients With Spinal Cord Stimulation for Failed Back Surgery Syndrome: A 20-Year Audit of a Single Center.

STUDY DESIGN: This is a retrospective, observational study. INTRODUCTION: Spinal cord stimulation (SCS) has found its application in chronic pain treatment, with failed back surgery syndrome (FBSS) as one of the most important indications. However, to date, little is known about the long-term effectiveness of the treatment. The aim of this study is to analyze retrospectively the long-term outcomes of SCS treatment in a single multidisciplinary pain center on predominant radicular pain, using devices of a single manufacturer. MATERIALS AND METHODS: Patient data on overall patient satisfaction, pain intensity, and adverse events were retrospectively collected in our clinical practice between January 1998 and January 2018, for 191 patients who received a permanent SCS implant. Secondary health measures included the influence of opioid and nicotine use on pain reduction after therapy. RESULTS: The trial-to-implant ratio was 93.6%. At a mean follow-up of 10.6 years, 78.5% of the patients were satisfied with the treatment outcome, with a significant pain reduction of an average three points on a Numeric Rating Scale. Opioid and nicotine usage did not have a significant link with the pain reduction one year after the treatment. Furthermore, devices had an average battery lifespan of 8.4 years. A total of 248 revisions were recorded. A total of 24 patients (11.7%) acquired an infection; 7 of 204 patients had an infection during the trial period, 2 of 191 patients had an infection in the first postoperative year, and 15 of 191 patients had an infection after the first year. The average time to infection, if not in the first year, was 10.1 years. CONCLUSIONS: A successful long-term outcome regarding pain relief in patients with predominant radicular pain due to FBSS is established with SCS therapy.

A comparative study of patient satisfaction about anesthesia with dexmedetomidine for ambulatory dental surgery.

OBJECTIVE: Intranasal administration of dexmedetomidine for monitored anesthesia care (MAC) appears to be an effective, safe, and appropriate alternative to general anesthesia (GA) for ambulatory dental surgery. Based on the available evidence we evaluated a new MAC protocol with intranasal dexmedetomidine as the primary choice. To assess a difference in patient satisfaction and anesthesia-related discomfort between GA and MAC in ambulatory dental surgery, a study was conducted among patients undergoing various dental procedures. Patient satisfaction and anesthesia-related discomfort were assessed on the first postoperative day using the Bauer patient satisfaction questionnaire. RESULTS: Although the differences were small, patients in the MAC group were overall more satisfied with the general care compared to the GA group (p < 0.02). Patients in the MAC group reported more postoperative drowsiness compared to the GA group (p < 0.05), but less postoperative hoarseness and sore throat (p = 0.005 and p < 0.001, respectively). Moreover, postoperative thirst was more common in the GA group (p = 0.002). In conclusion, the differences in patient satisfaction and anesthesia-related discomfort between GA and MAC in this implementation study were small but appeared to favor MAC with intranasal dexmedetomidine over GA as anesthesia method during dental ambulatory surgery.

Better COVID-19 Intensive Care Unit survival in females, independent of age, disease severity, comorbidities, and treatment.

Although male Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) patients have higher Intensive Care Unit (ICU) admission rates and a worse disease course, a comprehensive analysis of female and male ICU survival and underlying factors such as comorbidities, risk factors, and/or anti-infection/inflammatory therapy administration is currently lacking. Therefore, we investigated the association between sex and ICU survival, adjusting for these and other variables. In this multicenter observational cohort study, all patients with SARS-CoV-2 pneumonia admitted to seven ICUs in one region across Belgium, The Netherlands, and Germany, and requiring vital organ support during the first pandemic wave were included. With a random intercept for a center, mixed-effects logistic regression was used to investigate the association between sex and ICU survival. Models were adjusted for age, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, comorbidities, and anti-infection/inflammatory therapy. Interaction terms were added to investigate effect modifications by sex with country and sex with obesity. A total of 551 patients (29% were females) were included. Mean age was 65.4 ± 11.2 years. Females were more often obese and smoked less frequently than males (p-value 0.001 and 0.042, respectively). APACHE II scores of females and males were comparable. Overall, ICU mortality was 12% lower in females than males (27% vs 39% respectively, p-value < 0.01) with an odds ratio (OR) of 0.62 (95%CI 0.39-0.96, p-value 0.032) after adjustment for age and APACHE II score, 0.63 (95%CI 0.40-0.99, p-value 0.044) after additional adjustment for comorbidities, and 0.63 (95%CI 0.39-0.99, p-value 0.047) after adjustment for anti-infection/inflammatory therapy. No effect modifications by sex with country and sex with obesity were found (p-values for interaction > 0.23 and 0.84, respectively). ICU survival in female SARS-CoV-2 patients was higher than in male patients, independent of age, disease severity, smoking, obesity, comorbidities, anti-infection/inflammatory therapy, and country. Sex-specific biological mechanisms may play a role, emphasizing the need to address diversity, such as more sex-specific prediction, prognostic, and therapeutic approach strategies.

Salvage Lobectomy to Treat Necrotizing SARS-CoV-2 Pneumonia Complicated by a Bronchopleural Fistula.

We report a case of necrotizing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia complicated by a bronchopleural fistula and treated by decortication and salvage lobectomy. Owing to the unknown characteristics of the underlying SARS-CoV-2 infection, treatment of the abscess and bronchopleural fistula was delayed. This may have resulted in further deterioration of the patient, with ensuing multiple organ dysfunction. Complications of SARS-CoV-2 pneumonia, such as a bacterial abscess and a bronchopleural fistula, should be treated as if the patient were not infected with SARS-CoV-2.

Association between postoperative delirium and postoperative cerebral oxygen desaturation in older patients after cardiac surgery.

BACKGROUND: Near-infrared spectroscopy non-invasively measures regional cerebral oxygen saturation. Intraoperative cerebral desaturations have been associated with worse neurological outcomes. We investigated whether perioperative cerebral desaturations are associated with postoperative delirium in older patients after cardiac surgery. METHODS: Patients aged 70 yr and older scheduled for on-pump cardiac surgery were included between 2015 and 2017 in a single-centre, prospective, observational study. Baseline cerebral oxygen saturation was measured 1 day before surgery. Throughout surgery and after ICU admission, cerebral oxygen saturation was monitored continuously up to 72 h after operation. The presence of delirium was assessed using the confusion assessment method for the ICU. Association with delirium was evaluated with unadjusted analyses and multivariable logistic regression. RESULTS: Ninety-six of 103 patients were included, and 29 (30%) became delirious. Intraoperative cerebral oxygen saturation was not significantly associated with postoperative delirium. The lowest postoperative cerebral oxygen saturation was lower in patients who became delirious (P=0.001). The absolute and relative postoperative cerebral oxygen saturation decreases were more marked in patients with delirium (13 [6]% and 19 [9]%, respectively) compared with patients without delirium (9 [4]% and 14 [5]%; P=0.002 and P=0.001, respectively). These differences in cerebral oxygen saturation were no longer present after excluding cerebral oxygen saturation values after patients became delirious. Older age, previous stroke, higher EuroSCORE II, lower preoperative Mini-Mental Status Examination, and more substantial absolute postoperative cerebral oxygen saturation decreases were independently associated with postoperative delirium incidence. CONCLUSIONS: Postoperative delirium in older patients undergoing cardiac surgery is associated with absolute decreases in postoperative cerebral oxygen saturation. These differences appear most detectable after the onset of delirium. CLINICAL TRIAL REGISTRATION: NCT02532530.

Hepatic PPARα is critical in the metabolic adaptation to sepsis.

BACKGROUND & AIMS: Although the role of inflammation to combat infection is known, the contribution of metabolic changes in response to sepsis is poorly understood. Sepsis induces the release of lipid mediators, many of which activate nuclear receptors such as the peroxisome proliferator-activated receptor (PPAR)α, which controls both lipid metabolism and inflammation. We aimed to elucidate the previously unknown role of hepatic PPARα in the response to sepsis. METHODS: Sepsis was induced by intraperitoneal injection of Escherichia coli in different models of cell-specific Ppara-deficiency and their controls. The systemic and hepatic metabolic response was analyzed using biochemical, transcriptomic and functional assays. PPARα expression was analyzed in livers from elective surgery and critically ill patients and correlated with hepatic gene expression and blood parameters. RESULTS: Both whole body and non-hematopoietic Ppara-deficiency in mice decreased survival upon bacterial infection. Livers of septic Ppara-deficient mice displayed an impaired metabolic shift from glucose to lipid utilization resulting in more severe hypoglycemia, impaired induction of hyperketonemia and increased steatosis due to lower expression of genes involved in fatty acid catabolism and ketogenesis. Hepatocyte-specific deletion of PPARα impaired the metabolic response to sepsis and was sufficient to decrease survival upon bacterial infection. Hepatic PPARA expression was lower in critically ill patients and correlated positively with expression of lipid metabolism genes, but not with systemic inflammatory markers. CONCLUSION: During sepsis, Ppara-deficiency in hepatocytes is deleterious as it impairs the adaptive metabolic shift from glucose to FA utilization. Metabolic control by PPARα in hepatocytes plays a key role in the host defense against infection. LAY SUMMARY: As the main cause of death in critically ill patients, sepsis remains a major health issue lacking efficacious therapies. While current clinical literature suggests an important role for inflammation, metabolic aspects of sepsis have mostly been overlooked. Here, we show that mice with an impaired metabolic response, due to deficiency of the nuclear receptor PPARα in the liver, exhibit enhanced mortality upon bacterial infection despite a similar inflammatory response, suggesting that metabolic interventions may be a viable strategy for improving sepsis outcomes.

Effect of Bupivacaine Liposome Injectable Suspension on Sensory Blockade and Analgesia for Dupuytren Contracture Release.

Purpose: To study the efficacy of bupivacaine liposome injectable suspension in prolonging sensory blocks of the median and ulnar nerves for subjects with Dupuytren contracture release by collagenase injection. We hypothesized that combining liposome bupivacaine and bupivacaine hydrochloride would extend the duration of blocks without added complications. Methods: We randomized 32 subjects scheduled for Dupuytren contracture release with collagenase Clostridium histolyticum injections to receive forearm blocks of the median and ulnar nerves with a mixture of 5 mL liposome bupivacaine 1.33% plus 2.5 mL bupivacaine hydrochloride 0.5% per nerve (n = 16) or 7.5 mL bupivacaine hydrochloride 0.5% alone per nerve (n = 16). Sensory block and analgesia were assessed through the first posttreatment week. Results: Sensory block was nearly 4 times longer in subjects who received the liposome bupivacaine mixture compared with subjects who received bupivacaine hydrochloride alone. Most subjects (13 of 16) who received the liposome bupivacaine mixture had adequate analgesia for finger manipulation to rupture the cords, whereas most subjects (15 of 16) who received bupivacaine hydrochloride alone required additional anesthesia. Subjects in the liposome mixture group reported lower pain scores through the first 3 days after treatment. There were no serious side effects. Conclusions: Addition of liposome bupivacaine to forearm blocks for Dupuytren contracture release prolonged sensory block and improved pain scores without increasing side effects or impairing hand function. Supplemental lidocaine injections for the painful phases of Dupuytren contracture release with collagenase C histolyticum injections were not required by most subjects who received liposome bupivacaine. Type of study/level of evidence: Therapeutic I.

Plasma N-glycome composition associates with chronic low back pain.

BACKGROUND: Low back pain (LBP) is the symptom of a group of syndromes with heterogeneous underlying mechanisms and molecular pathologies, making treatment selection and patient prognosis very challenging. Moreover, symptoms and prognosis of LBP are influenced by age, gender, occupation, habits, and psychological factors. LBP may be characterized by an underlying inflammatory process. Previous studies indicated a connection between inflammatory response and total plasma N-glycosylation. We wanted to identify potential changes in total plasma N-glycosylation pattern connected with chronic low back pain (CLBP), which could give an insight into the pathogenic mechanisms of the disease. METHODS: Plasma samples of 1128 CLBP patients and 760 healthy controls were collected in clinical centers in Italy, Belgium and Croatia and used for N-glycosylation profiling by hydrophilic interaction ultra-performance liquid chromatography (HILIC-UPLC) after N-glycans release, fluorescent labeling and clean-up. Observed N-glycosylation profiles have been compared with a cohort of 126 patients with acute inflammation that underwent abdominal surgery. RESULTS: We have found a statistically significant increase in the relative amount of high-branched (tri-antennary and tetra-antennary) N-glycan structures on CLBP patients' plasma glycoproteins compared to healthy controls. Furthermore, relative amounts of disialylated and trisialylated glycan structures were increased, while high-mannose and glycans containing bisecting N-acetylglucosamine decreased in CLBP. CONCLUSIONS: Observed changes in CLBP on the plasma N-glycome level are consistent with N-glycosylation changes usually seen in chronic inflammation. GENERAL SIGNIFICANCE: To our knowledge, this is a first large clinical study on CLBP patients and plasma N-glycome providing a new glycomics perspective on potential disease pathology.

Addition of Liposome Bupivacaine to Bupivacaine HCl Versus Bupivacaine HCl Alone for Interscalene Brachial Plexus Block in Patients Having Major Shoulder Surgery.

BACKGROUND AND OBJECTIVES: We examined whether liposome bupivacaine (Exparel) given in the interscalene brachial plexus block lowers pain in the setting of multimodal postoperative pain management for major shoulder surgery. METHODS: Fifty-two adult patients were randomized to receive either 5 mL of 0.25% bupivacaine HCl immediately followed by 10 mL of liposome bupivacaine 133 mg (n = 26) or 15 mL of 0.25% standard bupivacaine alone (n = 26) in interscalene brachial plexus block. The primary outcome (worst pain in the first postoperative week) was assessed by the Modified Brief Pain Inventory short form. Secondary outcomes were overall satisfaction with analgesia (OBAS), functionality of the surgical arm, sleep duration, time to first opioid (tramadol) request and opioid consumption (mEq), sensory-motor block characteristics, and the occurrence of adverse effects. RESULTS: Worst pain was lower in patients given liposome bupivacaine added to standard bupivacaine than in patients given standard bupivacaine alone (generalized estimating equation [GEE] estimated marginal mean values, 3.6 ± 0.3 vs 5.3 ± 0.4 points on the Numeric Rating Scale, respectively, although the effect was modest, 1.6 ± 0.5; 95% confidence interval, 0.8-2.5). Total OBAS scores indicated greater satisfaction (GEE estimated marginal mean values, 1.8 ± 0.3 vs 3.3 ± 0.4 on total OBAS, respectively, with modest effect, difference, 1.4 ± 0.5; 95% confidence interval, 0.5-2.4). There were no differences in any of the other secondary outcomes. CONCLUSIONS: Liposome bupivacaine added to standard bupivacaine may lower pain and enhance patient's satisfaction in the first postoperative week even in the setting of multimodal analgesia for major shoulder surgery.This study was registered with clinicaltrials.gov (NCT02554357) on July 11, 2015, by Principal Investigator Catherine Vandepitte, MD.

Neurocognitive Development After Pediatric Heart Surgery.

OBJECTIVES: Children with congenital heart disease (CHD) often have neurocognitive deficits, sometimes with a detrimental impact on daily and school functioning. These deficits may increase through childhood. In this study, we investigated whether children with CHD, who underwent heart surgery as infants, show more neurocognitive deficits, especially in the executive functions, as they get older, compared with healthy controls. METHODS: In this longitudinal follow-up study, 107 children with CHD and 77 healthy control children underwent extensive neurocognitive testing at 4 years of age. Ninety-three percent of the children (100 patients with CHDs and 72 controls) underwent a second neurocognitive testing 3 years later. Intelligence, visual-motor integration (VMI), alertness, motor coordination, executive functions, and psychosocial functioning were assessed. RESULTS: IQ scores were consistently lower in the CHD group (P < .001); however, the difference of 11.7 IQ points between both groups at follow-up 1 decreased to 7 IQ points at follow-up 2 (P = .003). Inhibition reaction time had improved in both study groups at follow-up 2 (P < .001) and did not differ between both groups from follow-up 1 to follow-up 2 (P = .849). Deficits in VMI, alertness, motor coordination, and psychosocial functioning also did not worsen for patients with CHDs at follow-up 2, compared with healthy controls. CONCLUSIONS: Children with CHD, who underwent heart surgery as infants, do not show an increase of neurocognitive deficits between the ages of 4 and 7 years, compared with healthy controls. Patients with CHDs keep deficits in intelligence, VMI, and psychosocial functioning, but seem to partially grow out of their deficits.

Performance of strip-based glucose meters and cassette-based blood gas analyzer for monitoring glucose levels in a surgical intensive care setting.

BACKGROUND: We verified the analytical performance of strip-based handheld glucose meters (GM) for prescription use, in a comparative split-sample protocol using blood gas samples from a surgical intensive care unit (ICU). METHODS: Freestyle Precision Pro (Abbott), StatStrip Connectivity Meter (Nova), ACCU-CHEK Inform II (Roche) were evaluated for recovery/linearity, imprecision/repeatability. The GMs and the ABL90 (Radiometer) blood gas analyzer (BGA) were tested for relative accuracy vs. the comparator hexokinase glucose-6-phosphate-dehydrogenase (HK/G6PDH) assay on a Cobas c702 analyzer (Roche). RESULTS: Recovery of spiked glucose was linear up to 19.3 mmol/L (347 mg/dL) with a slope of 0.91-0.94 for all GMs. Repeatability estimated by pooling duplicate measurements on samples below (n=9), in (n=51) or above (n=80) the 4.2-5.9 mM (74-106 mg/dL) range were for Freestyle Precision Pro: 4.2%, 4.0%, 3.6%; StatStrip Connectivity Meter: 4.0%, 4.3%, 4.5%; and ACCU-CHEK Inform II: 1.4%, 2.5%, 3.5%. GMs were in agreement with the comparator method. The BGA outperformed the GMs, with a MARD of 3.9% compared to 6.5%, 5.8% and 4.4% for the FreeStyle, StatStrip and ACCU-CHEK, respectively. Zero % of the BGA results deviated more than the FDA 10% criterion as compared to 9.4%, 3.7% and 2.2% for the FreeStyle, StatStrip and ACCU-CHEK, respectively. For all GMs, icodextrin did not interfere. Variation in the putative influence factors hematocrit and O2 tension could not explain observed differences with the comparator method. CONCLUSIONS: GMs quantified blood glucose in whole blood at about the 10% total error criterion, proposed by the FDA for prescription use.

Neurocognition after paediatric heart surgery: a systematic review and meta-analysis.

UNLABELLED: Children with congenital heart disease (CHD) often experience difficulties in academic and daily functioning, which have been associated with intelligence and neurocognitive skills, including executive functions (EFs), attention and memory. We report the neurocognitive data of children with CHD who were included in the Leuven glucose control trial (LGC trial). Through a systematic review and meta-analysis, we aimed to find which neurocognitive functions are most consistently and prominently affected. 365 children with CHD and 216 healthy control children underwent extensive neurocognitive testing in the LGC trial. A comprehensive search of electronic databases PubMed, EMBASE and Cochrane was conducted for studies measuring intelligence, EFs, attention and memory in children who underwent heart surgery for CHD. Standardised mean differences (SMDs) between the CHD group and a healthy control group were calculated for these neurocognitive functions. LGC trial data were included in the meta-analysis. Twelve studies with a healthy control group were included in the meta-analysis, involving 647 patients with CHD and 633 controls. The CHD group (median age 7.35 years at testing) had worse scores than healthy control children, for all investigated neurocognitive functions. A medium SMD was found for intelligence (SMD=-0.53 (95% CI -0.68 to -0.38), p<0.00001). Alertness, an attentional function, was also consistently poorer in the CHD group. Memory was less affected, while EF had a medium SMD with large heterogeneity. Children with CHD risk displayed lower performance on intelligence and alertness assessment, which may contribute to difficulties in daily life and school. Heterogeneity in neurocognitive assessment and small sizes in most studies limit the interpretation. TRIAL REGISTRATION NUMBER: clinicaltrials.gov Identifier NCT00214916.

Amino acid concentrations in critically ill children following cardiac surgery*.

OBJECTIVE: Guidelines for administering amino acids to critically ill children are largely based on uncontrolled observational studies and expert opinion, without support from rigorous outcome studies. Also, data on circulating amino acid concentrations during critical illness are scarce. We thoroughly studied the time profiles of circulating amino acid concentrations in critically ill children who received standard nutritional care according to international guidelines. DESIGN: This is a subanalysis of pediatric critically ill patients included in a large (n = 700) randomized controlled study on intensive insulin therapy. SETTING: The study was conducted at a university hospital PICU. PATIENTS: We studied 100 patients in PICU for at least 3 days following cardiac surgery. INTERVENTIONS: Patients were assigned to intensive insulin therapy targeting normal-for-age fasting blood glucose concentrations or insulin infusion only to prevent excessive hyperglycemia. MEASUREMENTS AND MAIN RESULTS: Plasma amino acid concentrations were measured at admission, day 3, and day 7 in PICU. At admission, the concentrations of most amino acids were comparable to those reported for healthy children. Total amino acid concentrations remained stable during ICU stay, but individual amino acids showed different time profiles with eight of them showing an increase and five a decrease. Nonsurviving children had higher total amino acid concentrations and individual amino acids compared with survivors at admission and/or during ICU stay. Intensive insulin therapy lowered the concentrations of total amino acids and several individual amino acids. Neonates showed somewhat different amino acid profiles with rather increased concentrations from baseline with time in ICU for total amino acids and several individual amino acids as compared with older infants and children. CONCLUSIONS: Circulating amino acid concentrations in critically ill children after cardiac surgery differ according to survival status, blood glucose control with intensive insulin therapy, and age.

Effect of tolerating macronutrient deficit on the development of intensive-care unit acquired weakness: a subanalysis of the EPaNIC trial.

BACKGROUND: Patients who are critically ill can develop so-called intensive-care unit acquired weakness, which delays rehabilitation. Reduced muscle mass, quality, or both might have a role. The Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients (EPaNIC) trial (registered with ClinicalTrials.gov, number NCT00512122) showed that tolerating macronutrient deficit for 1 week in intensive-care units (late parenteral nutrition [PN]) accelerated recovery compared with early PN. The role of weakness was unclear. Our aim was to assess whether late PN and early PN differentially affect muscle weakness and autophagic quality control of myofibres. METHODS: In this prospectively planned subanalysis of the EPaNIC trial, weakness (MRC sum score) was assessed in 600 awake, cooperative patients. Skeletal muscle biopsies, harvested from 122 patients 8 days after randomisation and from 20 matched healthy controls, were studied for autophagy and atrophy. We determined the significance of differences with Mann-Whitney U, Median, Kruskal-Wallis, or χ(2) (exact) tests, as appropriate. FINDINGS: With late PN, 105 (34%) of 305 patients had weakness on first assessment (median day 9 post-randomisation) compared with 127 (43%) of 295 patients given early PN (absolute difference -9%, 95% CI -16 to -1; p=0·030). Weakness recovered faster with late PN than with early PN (p=0·021). Myofibre cross-sectional area was less and density was lower in critically ill patients than in healthy controls, similarly with early PN and late PN. The LC3 (microtubule-associated protein light chain 3) II to LC3I ratio, related to autophagosome formation, was higher in patients given late PN than early PN (p=0·026), reaching values almost double those in the healthy control group (p=0·0016), and coinciding with less ubiquitin staining (p=0·019). A higher LC3II to LC3I ratio was independently associated with less weakness (p=0·047). Expression of mRNA encoding contractile myofibrillary proteins was lower and E3-ligase expression higher in muscle biopsies from patients than in control participants (p≤0·0006), but was unaffected by nutrition. INTERPRETATION: Tolerating a substantial macronutrient deficit early during critical illness did not affect muscle wasting, but allowed more efficient activation of autophagic quality control of myofibres and reduced weakness. FUNDING: UZ Leuven, Research Foundation-Flanders, the Flemish Government, and the European Research Council.

Critical illness evokes elevated circulating bile acids related to altered hepatic transporter and nuclear receptor expression.

UNLABELLED: Hyperbilirubinemia is common during critical illness and is associated with adverse outcome. Whether hyperbilirubinemia reflects intensive care unit (ICU) cholestasis is unclear. Therefore, the aim of this study was to analyze hyperbilirubinemia in conjunction with serum bile acids (BAs) and the key steps in BA synthesis, transport, and regulation by nuclear receptors (NRs). Serum BA and bilirubin levels were determined in 130 ICU and 20 control patients. In liver biopsies messenger RNA (mRNA) expression of BA synthesis enzymes, BA transporters, and NRs was assessed. In a subset (40 ICU / 10 controls) immunohistochemical staining of the transporters and receptors together with a histological evaluation of cholestasis was performed. BA levels were much more elevated than bilirubin in ICU patients. Conjugated cholic acid (CA) and chenodeoxycholic acid (CDCA) were elevated, with an increased CA/CDCA ratio. Unconjugated BA did not differ between controls and patients. Despite elevated serum BA levels, CYP7A1 protein, the rate-limiting enzyme in BA synthesis, was not lowered in ICU patients. Also, protein expression of the apical bile salt export pump (BSEP) was decreased, whereas multidrug resistance-associated protein (MRP) 3 was strongly increased at the basolateral side. This reversal of BA transport toward the sinusoidal blood compartment is in line with the increased serum conjugated BA levels. Immunostaining showed marked down-regulation of nuclear farnesoid X receptor, retinoid X receptor alpha, constitutive androstane receptor, and pregnane X receptor nuclear protein levels. CONCLUSION: Failure to inhibit BA synthesis, up-regulate canalicular BA export, and localize pivotal NR in the hepatocytic nuclei may indicate dysfunctional feedback regulation by increased BA levels. Alternatively, critical illness may result in maintained BA synthesis (CYP7A1), reversal of normal BA transport (BSEP/MRP3), and inhibition of the BA sensor (FXR/RXRα) to increase serum BA levels.

Tight glycemic control protects the myocardium and reduces inflammation in neonatal heart surgery.

BACKGROUND: Neonatal cardiac surgery evokes hyperglycemia and a systemic inflammatory response. Hyperglycemia is associated with intensified inflammation and adverse outcome in critically ill children and in pediatric cardiac surgery. Recently we demonstrated that tight glycemic control (TGC) reduced morbidity and mortality of critically ill children. Experimental data suggest that insulin protects the myocardium in the setting of ischemia-reperfusion injury, but this benefit could be blunted by coinciding hyperglycemia. We hypothesized that insulin-titrated TGC, initiated prior to myocardial ischemia and reperfusion, protects the myocardium and attenuates the inflammatory response after neonatal cardiac surgery. METHODS: This is a prospective randomized study at a university hospital. Fourteen neonates were randomized to intraoperative and postoperative conventional insulin therapy or TGC. Study endpoints were effects on myocardial damage and function; inflammation, endothelial activation, and clinical outcome parameters. RESULTS: Tight glycemic control significantly reduced circulating levels of cardiac troponin-I (p = 0.009), heart fatty acid-binding protein (p = 0.01), B-type natriuretic peptide (p = 0.002), and the need for vasoactive support (p = 0.008). The TGC suppressed the rise of the proinflammatory cytokines interleukin-6 (p = 0.02) and interleukin-8 (p = 0.05), and reduced the postoperative increase in C-reactive protein (p = 0.04). Myocardial concentrations of Akt, endothelial nitric-oxide synthase, and their phosphorylated forms were not different between groups. CONCLUSIONS: In neonates undergoing cardiac surgery, intraoperative and postoperative TGC protects the myocardium and reduces the inflammatory response. This appears not to be mediated by an early, direct insulin signaling effect, but may rather be due to independent effects of preventing hyperglycemia during reperfusion.

The impact of resuscitated fecal peritonitis on the expression of the hepatic bile salt transporters in a porcine model.

Sepsis is often associated with cholestatic liver dysfunction caused by changes in the expression profile of hepatic bile salt transporters. However, in rodent endotoxin models, the role of ischemic hepatitis caused by liver hypoperfusion cannot be delineated. We hypothesized that hepatocytes change their expression pattern of bile salt transporters during early severe sepsis despite adequate resuscitation. Fifteen anesthetized and instrumented pigs were randomized to either fecal peritonitis (n = 8) or control (n = 7). Resuscitation was performed by hydroxyethyl starch and norepinephrine infusion. Hemodynamic parameters and markers of cholestatic and ischemic hepatic dysfunction were recorded. At baseline and after 21 h, messenger RNA (mRNA) and protein expression of bile salt transporters was determined by quantitative real-time polymerase chain reaction and immunohistochemistry, respectively, on in vivo liver biopsies. All resuscitated septic pigs developed a normotensive hyperdynamic circulation with increased portal flow. After 21 h of peritonitis, no signs of biochemical or histological cholestasis were present. Na-taurocholate cotransporting polypeptide and bile salt export pump mRNA were downregulated by 83% (P = 0.001) and 67% (P = 0.001), respectively, in comparison with controls, whereas multidrug resistance-associated protein 4 (MRP4) mRNA was upregulated by 85% (P = 0.02). Bile salt export pump and MRP2 staining were downregulated in septic pigs. During early porcine fluid-resuscitated sepsis, hepatic basolateral influx (Na-taurocholate cotransporting polypeptide) and canalicular efflux (bile salt export pump) of bile salts were downregulated without hemodynamic signs of hepatic hypoperfusion or biochemical signs of cholestasis. In parallel, the basolateral escape transport (MRP4) was markedly upregulated, possibly as an early adaptive response to counteract hepatocellular accumulation of toxic bile acids.

Changes within the GH/IGF-I/IGFBP axis in critical illness.

Interest in the somatotropic axis, with its complex network of interactions, during critical illness started only a few decades ago. The distinguished neuroendocrine features of prolonged critically ill patients were not differentiated from those during the acute phase until the 1990s. This incomplete understanding of the somatotropic axis has contributed to some disastrous results. Aiming to stimulate the somatotropic axis without a proper preceding neuroendocrine diagnosis should be held obsolete, because recent data indicate that the patient with the best anabolic parameters may not necessarily be the most favored to survive the ICU stay. Moreover, the fascinating link between regulators of carbohydrate metabolism, such as insulin and insulin-like growth factor 1, and the somatotropic axis may lead to future therapeutic possibilities.