Serum Biomarkers of a Pro-Neuroinflammatory State May Define the Pre-Operative Risk for Postoperative Delirium in Spine Surgery.

Advances in spine surgery enable technically safe interventions in older patients with disabling spine disease, yet postoperative delirium (POD) poses a serious risk for postoperative recovery. This study investigates biomarkers of pro-neuroinflammatory states that may help objectively define the pre-operative risk for POD. This study enrolled patients aged ≥60 scheduled for elective spine surgery under general anesthesia. Biomarkers for a pro-neuroinflammatory state included S100 calcium-binding protein ß (S100ß), brain-derived neurotrophic factor (BDNF), Gasdermin D, and the soluble ectodomain of the triggering receptor expressed on myeloid cells 2 (sTREM2). Postoperative changes of Interleukin-6 (IL-6), Interleukin-1ß (IL-1ß), and C-reactive protein (CRP) were assessed as markers of systemic inflammation preoperatively, intraoperatively, and early postoperatively (up to 48 h). Patients with POD (n = 19, 75.7 ± 5.8 years) had higher pre-operative levels of sTREM2 (128.2 ± 69.4 pg/mL vs. 97.2 ± 52.0 pg/mL, p = 0.049) and Gasdermin D (2.9 ± 1.6 pg/mL vs. 2.1 ± 1.4 pg/mL, p = 0.29) than those without POD (n = 25, 75.6 ± 5.1 years). STREM2 was additionally a predictor for POD (OR = 1.01/(pg/mL) [1.00-1.03], p = 0.05), moderated by IL-6 (Wald-χ2 = 4.06, p = 0.04). Patients with POD additionally showed a significant increase in IL-6, IL-1ß, and S100ß levels on the first postoperative day. This study identified higher levels of sTREM2 and Gasdermin D as potential markers of a pro-neuroinflammatory state that predisposes to the development of POD. Future studies should confirm these results in a larger cohort and determine their potential as an objective biomarker to inform delirium prevention strategies.

Duration of Surgery and Intraoperative Blood Pressure Management Are Modifiable Risk Factors for Postoperative Neurocognitive Disorders After Spine Surgery: Results of the Prospective CONFESS Study.

STUDY DESIGN: Prospective quasi-experimental observational study. OBJECTIVE: The objective of this study was to evaluate whether duration of surgery is a modifiable risk factor for postoperative delirium (POD) after spine surgery and explore further modifiable risk factors. In addition, we sought to investigate the association between POD and postoperative cognitive dysfunction and persistent neurocognitive disorders. SUMMARY OF BACKGROUND DATA: Advances in spine surgery enable technically safe interventions in elderly patients with disabling spine disease. The occurrence of POD and delayed neurocognitive complications ( e.g. postoperative cognitive dysfunction/persistent neurocognitive disorder) remain a concern since these contribute to inferior functional outcomes and long-term care dependency after spine surgery. MATERIALS AND METHODS: This prospective single-center study recruited patients aged 60 years or above and scheduled for elective spine surgery between February 2018 and March 2020. Functional (Barthel Index, BI) and cognitive outcomes [Consortium to Establish a Registry for Alzheimer's Disease (CERAD) test battery; telephone Montréal Cognitive Assessment] were assessed at baseline, three (V3), and 12 months postoperatively. The primary hypothesis was that the duration of surgery predicts POD. Multivariable predictive models of POD included surgical and anesthesiological parameters. RESULTS: Twenty-two percent of patients developed POD (n=22/99). In a multivariable model, duration of surgery [OR adj =1.61/h (95% CI, 1.20-2.30)], age [OR adj =1.22/yr (95% CI, 1.10-1.36)], and baseline deviations of intraoperative systolic blood pressure [25th percentile: OR adj =0.94/mm Hg (95% CI, 0.89-0.99); 90th percentile: OR adj =1.07/mm Hg (95% CI, 1.01-1.14)] were significantly associated with POD. Postoperative cognitive scores generally improved (V3, ΔCERAD total z -score: 0.22±0.63). However, this positive group effect was counteracted by POD [beta: -0.87 (95% CI, -1.31 to 0.42)], older age [beta: -0.03/yr (95% CI, -0.05 to 0.01)], and lack of functional improvement [ΔBI; beta: -0.04/point (95% CI, -0.06 to 0.02)]. Cognitive scores at twelve months remained inferior in the POD group, adjusted for baseline cognition/age. CONCLUSIONS: This study identified distinct neurocognitive effects after spine surgery, which are influenced by perioperative risk factors. Potential cognitive benefits are counteracted by POD, rendering its prevention critical in an aging population.

Severe Neonatal Interstitial Lung Disease Caused by a Rare Surfactant Protein C Mutation.

Childhood interstitial lung disease (chILD) is a collective term for a group of rare lung disorders of heterogeneous origin. Surfactant dysfunction disorders are a cause of chILD with onset during the neonatal period and infancy. Clinical signs of tachypnea and hypoxemia are nonspecific and usually caused by common conditions like lower respiratory tract infections. We report on a full-term male newborn who was readmitted to the hospital at 7 days of age with marked tachypnea and poor feeding during the respiratory syncytial virus season. After exclusion of infection and other, more common congenital disorders, chILD was diagnosed using chest computed tomography and genetic analysis. A likely pathogenic heterozygous variant of SFTPC (c.163C>T, L55F) was detected by whole exome sequencing. The patient received supplemental oxygen and noninvasive respiratory support and was treated with intravenous methylprednisolone pulses and hydroxychloroquine. Despite the treatment, his respiratory situation deteriorated continuously, leading to several hospitalizations and continuous escalation of noninvasive ventilatory support. At 6 months of age, the patient was listed for lung transplant and transplanted successfully aged 7 months.

Mitochondrial Dysfunction in Intensive Care Unit-Acquired Weakness and Critical Illness Myopathy: A Narrative Review.

Mitochondria are key structures providing most of the energy needed to maintain homeostasis. They are the main source of adenosine triphosphate (ATP), participate in glucose, lipid and amino acid metabolism, store calcium and are integral components in various intracellular signaling cascades. However, due to their crucial role in cellular integrity, mitochondrial damage and dysregulation in the context of critical illness can severely impair organ function, leading to energetic crisis and organ failure. Skeletal muscle tissue is rich in mitochondria and, therefore, particularly vulnerable to mitochondrial dysfunction. Intensive care unit-acquired weakness (ICUAW) and critical illness myopathy (CIM) are phenomena of generalized weakness and atrophying skeletal muscle wasting, including preferential myosin breakdown in critical illness, which has also been linked to mitochondrial failure. Hence, imbalanced mitochondrial dynamics, dysregulation of the respiratory chain complexes, alterations in gene expression, disturbed signal transduction as well as impaired nutrient utilization have been proposed as underlying mechanisms. This narrative review aims to highlight the current known molecular mechanisms immanent in mitochondrial dysfunction of patients suffering from ICUAW and CIM, as well as to discuss possible implications for muscle phenotype, function and therapeutic approaches.

A novel ex vivo model for critical illness neuromyopathy using freshly resected human colon smooth muscle.

Patients suffering from critical illness are at risk to develop critical illness neuromyopathy (CINM). The underlying pathophysiology is complex and controversial. A central question is whether soluble serum factors are involved in the pathogenesis of CINM. In this study, smooth muscle preparations obtained from the colon of patients undergoing elective surgery were used to investigate the effects of serum from critically ill patients. At the time of blood draw, CINM was assessed by clinical rating and electrophysiology. Muscle strips were incubated with serum of healthy controls or patients in organ baths and isometric force was measured. Fifteen samples from healthy controls and 98 from patients were studied. Ratios of responses to electric field stimulation (EFS) before and after incubation were 118% for serum from controls and 51% and 62% with serum from critically ill patients obtained at day 3 and 10 of critical illness, respectively (p = 0.003, One-Way-ANOVA). Responses to carbachol and high-K+ were equal between these groups. Ratios of post/pre-EFS responses correlated with less severe CINM. These results support the existence of pathogenic, i.e. neurotoxic factors in the serum of critically ill patients. Using human colon smooth muscle as a bioassay may facilitate their future molecular identification.

Large Duodenal Hematoma Causing an Ileus after an Endoscopic Duodenal Biopsy in a 6-Year-Old Child: A Case Report.

Intramural duodenal hematoma (IDH) in children is a rare complication after esophagogastroduodenoscopy. It is commonly described in patients with additional disorders or risk factors, such as coagulopathy. We present a case of a previously healthy 6-year-old boy with a large obstructing intramural duodenal hematoma and concomitant pancreatitis after an elective esophagogastroduodenoscopy. The patient presented with typical symptoms of an IDH, such as abdominal pain and distension, nausea and vomiting. IDH was diagnosed using ultrasound and magnetic resonance imaging examination. Conservative management with gastric decompression using a nasogastric feeding tube, bowel rest, total parenteral nutrition and analgesia was performed. After three weeks, the patient was discharged from the hospital without any complaints. Interventional management of IDH in pediatric patients with a lack of response to conservative therapy or complicating IDH should be discussed in an interdisciplinary team.

Natriuretic Peptides as a Prognostic Marker for Delirium in Cardiac Surgery-A Pilot Study.

Background and Objectives: Delirium is a common and major complication subsequent to cardiac surgery. Despite scientific efforts, there are no parameters which reliably predict postoperative delirium. In delirium pathology, natriuretic peptides (NPs) interfere with the blood-brain barrier and thus promote delirium. Therefore, we aimed to assess whether NPs may predict postoperative delirium and long-term outcomes. Materials and Methods: To evaluate the predictive value of NPs for delirium we retrospectively analyzed data from a prospective, randomized study for serum levels of atrial natriuretic peptide (ANP) and the precursor of C-type natriuretic peptide (NT-proCNP) in patients undergoing coronary artery bypass grafting (CABG) with or without cardiopulmonary bypass (off-pump coronary bypass grafting; OPCAB). Delirium was assessed by a validated chart-based method. Long-term outcomes were assessed 10 years after surgery by a telephone interview. Results: The overall incidence of delirium in the total cohort was 48% regardless of the surgical approach (CABG vs. OPCAB). Serum ANP levels >64.6 pg/mL predicted delirium with a sensitivity (95% confidence interval) of 100% (75.3-100) and specificity of 42.9% (17.7-71.1). Serum NT-proCNP levels >1.7 pg/mL predicted delirium with a sensitivity (95% confidence interval) of 92.3% (64.0-99.8) and specificity of 42.9% (17.7-71.1). Both NPs could not predict postoperative survival or long-term cognitive decline. Conclusions: We found a positive correlation between delirium and preoperative plasma levels of ANP and NT-proCNP. A well-powered and prospective study might identify NPs as biomarkers indicating the risk of delirium and postoperative cognitive decline in patients at risk for postoperative delirium.

The synthetic LPS binding peptide 19-2.5 interferes with clotting and prevents degradation of high molecular weight kininogen in plasma.

Sepsis and septic shock are life-threatening conditions and remain an important medical problem, emphasizing the need to identify novel therapeutic approaches. Coagulation dysfunction, hypotension, disturbed microcirculation and multiorgan failure occur frequently. These severe conditions result from an overwhelming inflammatory response, induced by pathogen and damage associated molecular patterns (PAMPs and DAMPs) released into the bloodstream. In the present study, we demonstrated that the synthetic Lipopolysaccharid (LPS)-binding peptide 19-2.5 interferes with the activation of the coagulation and contact system. Moreover, binding of LPS to high molecular weight kininogen (HK), one of the major LPS carrier in blood, could be prevented by the peptide. Thus, peptide 19-2.5 might represent a promising target in the treatment of endotoxemia and sepsis, not only by its anti-inflammatory potential, but also by the anticoagulant effect, together with its ability to prevent degradation of HK.

A case series on the value of tau and neurofilament protein levels to predict and detect delirium in cardiac surgery patients.

BACKGROUND: Delirium following cardiac surgery is a relevant complication in the majority of elderly patients but its prediction is challenging. Cardiopulmonary bypass, essential for many interventions in cardiac surgery, is responsible for a severe inflammatory response leading to neuroinflammation and subsequent delirium. Neurofilament light protein (NfL) and tau protein (tau) are specific biomarkers to detect neuroaxonal injury as well as glial fibrillary acidic protein (GFAP), a marker of astrocytic activation. METHODS: We thought to examine the perioperative course of these markers in a case series of each three cardiac surgery patients under off-pump cardiac arterial bypass without evolving delirium (OPCAB-NDEL), patients with a procedure under cardio-pulmonary bypass (CPB) without delirium (CPB-NDEL) and delirium after a CPB procedure (CPB-DEL). Delirium was diagnosed by the Confusion Assessment Method for the ICU and chart reviews. RESULTS: We observed increased preoperative levels of tau in patients with later delirium, whereas values of NfL and GFAP did not differ. In the postoperative course, all biomarkers increased multi-fold. NfL levels sharply increased in patients with CPB reaching the highest levels in the CPB-DEL group. CONCLUSION: Tau and NfL might be of benefit to identify patients in cardiac surgery at risk for delirium and to detect patients with the postoperative emergence of delirium.

Muscular Ultrasound, Syndecan-1 and Procalcitonin Serum Levels to Assess Intensive Care Unit-Acquired Weakness.

BACKGROUND: Intensive care unit-acquired weakness (ICU-AW) is associated with poorer outcome of critically ill patients. Microcirculatory changes and altered vascular permeability of skeletal muscles might contribute to the pathogenesis of ICU-AW. Muscular ultrasound (MUS) displays increased muscle echogenicity, although its pathogenesis is uncertain. OBJECTIVE: We investigated the combined measurement of serum and ultrasound markers to assess ICU-AW and clinical patient outcome. METHODS: Fifteen patients and five healthy controls were longitudinally assessed for signs of ICU-AW at study days 3 and 10 using a muscle strength sum score. The definition of ICU-AW was based on decreased muscle strength assessed by the muscular research council-sum score. Ultrasound echogenicity of extremity muscles was assessed using a standardized protocol. Serum markers of inflammation and endothelial damage were measured. The 3-month outcome was assessed on the modified Rankin scale. RESULTS: ICU-AW was present in eight patients, and seven patients and the control subjects did not develop ICU-AW. The global muscle echogenicity score (GME) differed significantly between controls and patients (mean GME, 1.1 ± 0.06 vs. 2.3 ± 0.41; p = 0.001). Mean GME values significantly decreased in patients without ICU-AW from assessment 1 (2.30 ± 0.48) to assessment 2 (2.06 ± 0.45; p = 0.027), which was not observed in patients with ICU-AW. Serum levels of syndecan-1 at day 3 significantly correlated with higher GME values at day 10 (r = 0.63, p = 0.012). Furthermore, the patients' GME significantly correlated with mRS at day 100 (r = 0.67, p = 0.013). CONCLUSION: The combined use of muscular ultrasound and inflammatory biomarkers might be helpful to diagnose ICU-AW and to predict long-term outcome in critical illness.

Procalcitonin Impairs Liver Cell Viability and Function In Vitro: A Potential New Mechanism of Liver Dysfunction and Failure during Sepsis?

Purpose. Liver dysfunction and failure are severe complications of sepsis and result in poor outcome and increased mortality. The underlying pathologic mechanisms of hepatocyte dysfunction and necrosis during sepsis are only incompletely understood. Here, we investigated whether procalcitonin, a biomarker of sepsis, modulates liver cell function and viability. Materials and Methods. Employing a previously characterized and patented biosensor system evaluating hepatocyte toxicity in vitro, human hepatocellular carcinoma cells (HepG2/C3A) were exposed to 0.01-50 ng/mL procalcitonin for 2 × 72 h and evaluated for proliferation, necrosis, metabolic activity, cellular integrity, microalbumin synthesis, and detoxification capacity. Acetaminophen served as positive control. For further standardization, procalcitonin effects were confirmed in a cellular toxicology assay panel employing L929 fibroblasts. Data were analyzed using ANOVA/Tukey's test. Results. Already at concentrations as low as 0.25 ng/mL, procalcitonin induced HepG2/C3A necrosis (P < 0.05) and reduced metabolic activity, cellular integrity, synthesis, and detoxification capacity (all P < 0.001). Comparable effects were obtained employing L929 fibroblasts. Conclusion. We provide evidence for procalcitonin to directly impair function and viability of human hepatocytes and exert general cytotoxicity in vitro. Therapeutical targeting of procalcitonin could thus display a novel approach to reduce incidence of liver dysfunction and failure during sepsis and lower morbidity and mortality of septic patients.

Bioartificial Therapy of Sepsis: Changes of Norepinephrine-Dosage in Patients and Influence on Dynamic and Cell Based Liver Tests during Extracorporeal Treatments.

Purpose. Granulocyte transfusions have been used to treat immune cell dysfunction in sepsis. A granulocyte bioreactor for the extracorporeal treatment of sepsis was tested in a prospective clinical study focusing on the dosage of norepinephrine in patients and influence on dynamic and cell based liver tests during extracorporeal therapies. Methods and Patients. Ten patients with severe sepsis were treated twice within 72 h with the system containing granulocytes from healthy donors. Survival, physiologic parameters, extended hemodynamic measurement, and the indocyanine green plasma disappearance rate (PDR) were monitored. Plasma of patients before and after extracorporeal treatments were tested with a cell based biosensor for analysis of hepatotoxicity. Results. The observed mortality rate was 50% during stay in hospital. During the treatments, the norepinephrine-dosage could be significantly reduced while mean arterial pressure was stable. In the cell based analysis of hepatotoxicity, the viability and function of sensor-cells increased significantly during extracorporeal treatment in all patients and the PDR-values increased significantly between day 1 and day 7 only in survivors. Conclusion. The extracorporeal treatment with donor granulocytes showed promising effects on dosage of norepinephrine in patients, liver cell function, and viability in a cell based biosensor. Further studies with this approach are encouraged.