Anti-aging factor, serum alpha-Klotho, as a marker of acute physiological stress, and a predictor of ICU mortality, in patients with septic shock.

PURPOSE: Genetic deletions decreasing serum alpha-Klotho (alpha-KL) have been associated with rapid aging, multi-organ failure and increased mortality in experimental sepsis. We hypothesized that lower alpha-KL obtained at the onset of septic shock correlates with higher mortality. MATERIALS AND METHODS: Prospective cohort of 104 adult patients with septic shock. Alpha-KL was measured via ELISA on serum collected on the day of enrollment (within 72h from the onset of shock). Relationship between alpha-KL and clinical outcome measures was evaluated in uni- and multi-variable models. RESULTS: Median (IQR) alpha-KL was 816 (1020.4) pg/mL and demonstrated a bimodal distribution with two distinct populations, Cohort A [n=97, median alpha-KL 789.3 (767.1)] and Cohort B [n=7, median alpha-KL 4365.1(1374.4), >1.5 IQR greater than Cohort A]. Within Cohort A, ICU non-survivors had significantly higher serum alpha-KL compared to survivors as well as significantly higher APACHE II and SOFA scores, rates of mechanical ventilation, and serum BUN, creatinine, calcium, phosphorus and lactate (all p≤0.05). Serum alpha-KL≥1005, the highest tertile, was an independent predictor of ICU mortality when controlling for co-variates (p=0.028, 95% CI 1.143-11.136). CONCLUSIONS: Elevated serum alpha-KL in patients with septic shock is independently associated with higher mortality. Further studies are needed to corroborate these findings.

The effect of ex vivo CDDO-Me activation on nuclear factor erythroid 2-related factor 2 pathway in white blood cells from patients with septic shock.

Nuclear factor erythroid 2-related factor 2 (NRF2) has been shown to protect against experimental sepsis in mice and lipopolysaccharide (LPS)-induced inflammation in ex vivo white blood cells from healthy subjects by upregulating cellular antioxidant genes. The objective of this study was to test the hypothesis that ex vivo methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate (CDDO-Me) activates NRF2-regulated antioxidant genes in white blood cells from patients with septic shock and protects against LPS-induced inflammation and reactive oxidative species production. Peripheral blood was collected from 18 patients with septic shock who were being treated in medical and surgical intensive care units. Real-time polymerase chain reaction was used to quantify the expression of NRF2 target genes (NQO1, HO-1, GCLM, and FTL) and IL-6 in peripheral blood mononuclear cells (PBMCs), monocytes, and neutrophils after CDDO-Me treatment alone or after subsequent LPS exposure. Superoxide anion (O2) was measured to assess the effect of CDDO-Me pretreatment on subsequent LPS exposure. Treatment with CDDO-Me increased the gene expression of NQO1 (P = 0.04) and decreased the expression of HO-1 (P = 0.03) in PBMCs from patients with septic shock. Purified monocytes exhibited significant increases in the expression of NQO1 (P = 0.01) and GCLM (P = 0.003) after CDDO-Me treatment. Levels of other NRF2 target genes (HO-1 and FTL) remained similar to those of vehicle-treated cells. Peripheral blood mononuclear cells showed a trend toward increased IL-6 gene expression after CDDO-Me treatment, whereas purified monocytes showed a trend toward decreased IL-6. There was no discernible trend in the IL-6 expression subsequent to LPS treatment in either vehicle-treated or CDDO-Me-treated PBMCs and monocytes. Treatment with CDDO-Me significantly increased O2 production in PBMCs (P = 0.04). Although CDDO-Me pretreatment significantly attenuated O2 production to subsequent LPS exposure (P = 0.03), the change was comparable to that observed in vehicle-treated PBMCs. Pretreatment with CDDO-Me followed by LPS exposure had no significant effect on O2 levels in purified monocytes. These data suggest that the NRF2 pathway is differentially responsive to CDDO-Me activation in peripheral blood cells from patients with septic shock and results in increased O2 production. The data may also suggest a suppressed NRF2 pathway in white blood cells from critically ill patients.

Preclinical evaluation of targeting the Nrf2 pathway by triterpenoids (CDDO-Im and CDDO-Me) for protection from LPS-induced inflammatory response and reactive oxygen species in human peripheral blood mononuclear cells and neutrophils.

Sepsis is characterized by an inappropriate host immune-inflammatory response and sustained oxidative damage. Nrf2, a bZIP oxidant-responsive transcription factor, regulates a battery of cytoprotective genes including antioxidants and maintains cellular redox homeostasis. Mouse studies have demonstrated a critical role of Nrf2 in improving survival during sepsis. This preclinical ex vivo study using neutrophils and peripheral blood mononuclear cells (PBMCs) as a surrogate cells evaluates the efficacy of CDDO-Im and CDDO-Me [imidazole and methyl ester derivative of 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO)] to activate the Nrf2 pathway and protect from lipopolysaccharide (LPS)-induced inflammatory response in humans. CDDO-Im treatment significantly induced Nrf2-dependent antioxidative genes (HO-1, GCLC, GCLM, and NQO1) in PBMCs isolated from six normal subjects. CDDO-Im increased nuclear accumulation of Nrf2 protein. Pretreatment of PBMC by CDDO-Im significantly attenuated LPS-induced cytokine expression. Similar increases in levels of antioxidant genes and suppression of LPS-induced cytokine expression was observed after CDDO-Me pretreatment. CDDO-Im also greatly inhibited LPS, fMLP, TNF-alpha, and TPA-induced ROS generation in neutrophils. In conclusion, these results demonstrate that activation of the Nrf2-dependent antioxidative pathway by CDDO-Im or CDDO-Me protects against the LPS-induced inflammatory response and suggest that they can be potential therapeutic candidates for intervening sepsis syndrome.

Perioperative coagulation management in a patient with afibrinogenemia undergoing liver transplantation.

Afibrinogenemia is a rare hereditary coagulation disorder characterized by a propensity toward bleeding. A 21-year-old Hispanic woman with afibrinogenemia developed ascites, a distended abdomen, an enlarged liver, scleral icterus, and umbilical vein and abdominal wall vein distension. Computed tomography (CT) scan showed occlusion of the hepatic veins and the infrahepatic vena cava consistent with Budd-Chiari syndrome. These developments led to her evaluation for, and placement on, the liver transplantation waiting list. The patient's unmeasurable international normalized ratio (INR) artifactually increased her Model for End-Stage Liver Disease (MELD) score to 40. Immediately before transplant surgery, an initial thrombelastogram (TEG) showed a flat line, indicating a complete lack of fibrin clot formation. Preoperatively, 20 units of cryoprecipitate were infused. The first intraoperative TEG demonstrated a tracing consistent with normal clot formation. Coagulation studies normalized with the newly functioning liver. The liver transplantation appears to have corrected the fibrinogen deficiency, presumably limiting the chance of recurrent Budd-Chiari syndrome. This case report discusses the essential role of fibrinogen in the coagulation cascade, as visualized by thrombelastography, and exposes the interplay between plasma fibrinogen and thrombin levels, which determine coagulation or fibrinolysis.

Do intensivists in ICU improve outcome?

Despite considerable investment of resources, there remains wide variation in organization of Intensive Care Units (ICUs). One key domain is the physician staffing. In particular, does staffing with physicians trained in critical care (intensivists) improve clinical outcomes? The rationale for improved outcome with intensivist staffing is that physicians who have the skills to treat critically ill patients, and who are immediately available to detect and treat problems, may prevent or attenuate morbidity and mortality. Intensivist staffing may also yield benefits through a leadership role at the intensive care unit organizational level. The improved sense of continuity and close attendance to patients may also bolster improved patient and family satisfaction. Intensivist-led or intensivist-staffed ICUs may also realize decreased resource use because these physicians may be better at reducing inappropriate admissions, preventing complications that prolong length of stay, and recognizing opportunities for prompt discharge.

Aceruloplasminemia: an inherited neurodegenerative disease with impairment of iron homeostasis.

In 1987, Miyajima et al. first characterized an autosomal recessive, adult-onset neurodegenerative disorder resembling Parkinson's disease associated with near-absent circulating serum ceruloplasmin levels. Coined "familial apoceruloplasmin deficiency", they described a patient with a presenting triad of diabetes mellitus, retinal degeneration, and neurodegeneration with blepharospasm. Neuropathological evaluation revealed abundant iron deposition in selected neurons of the basal ganglia and substantia nigra with associated neuronal dropout and spongioform degeneration without evidence of reactive gliosis. Subsequently, mutations in the ceruloplasmin gene have been determined to result in the excessive iron accumulation seen in the pancreas, retina, and brain. Elevated serum ferritin suggests a systemic iron overload syndrome, yet affected patients had low transferrin saturation and a mild anemia. This new disease, "aceruloplasminemia", reveals a role for ceruloplasmin as an essential ferroxidase critical for iron homeostasis. This multicopper oxidase promotes efficient iron efflux such that individuals lacking ceruloplasmin develop a presumed oxidative injury secondary to iron accumulation and significant neuronal damage. Aceruloplasminemic mice provide a valuable model to further study the mechanisms by which ceruloplasmin regulates iron trafficking and the role of iron in oxidative injury. Despite the dependence of ceruloplasmin on copper for its function, aceruloplasminemia represents an iron storage disease and not a defect in copper metabolism. However, recent evidence in Saccharomyces cerevisiae indicates that Fet3, the yeast homologue of ceruloplasmin, functions as an essential cuprous oxidase. Further investigation into the mechanisms by which ceruloplasmin regulates iron and copper homeostasis will provide valuable insight into the pathogenesis of metallo-mediated diseases and elucidate mechanisms for transition metal (copper, iron) neuropathology.

Transient paraplegia after stent grafting of a descending thoracic aortic aneurysm treated with cerebrospinal fluid drainage.

We present a case of descending thoracic aortic aneurysm repair using an endovascular stent graft, complicated by postoperative paraplegia, which was successfully treated by placing a spinal drain. The case highlights the importance of the concept of collateral flow to the spinal cord and of choosing an anesthetic technique that allows immediate postoperative evaluation of lower extremity neurologic function.

Carcinoid heart disease: a case report and literature review.

We report a patient who presented for elective exploratory laparotomy, and resection of a pelvic mass, which was thought to be ovarian carcinoma. Intraoperative transesophageal echocardiography demonstrated right-sided valvular heart lesions, which suggested the diagnosis of carcinoid syndrome before a pathologic confirmation was obtained. This article discusses the classical presentation and anesthetic management of patients with carcinoid syndrome and emphasizes the importance of proper preoperative diagnosis and careful planning if the incidence and severity of the symptoms that this condition can provoke are to be reduced.