Critical Care

Septic shock is a major healthcare problem with a high mortality rate that might be caused by immunosuppression. Programmed cell death receptor-1 (PD-1) and programmed cell death receptor ligand-1 (PD-L1), which are co-inhibitory receptor molecules, participate in sepsis-induced immunosuppression. In this study, we investigated which PD-1-related molecules can be used to evaluate the risk stratification and prognosis of septic patients. Furthermore, we explored the prognostic significance of a combination of ideal predictors and conventional clinical risk parameters in septic shock patients. In total, 29 healthy controls, 59 septic patients, and 76 septic shock patients were enrolled in this study. Considering that the focus of the research was on the second phase of sepsis, blood samples were obtained at days 3–4 after the onset of systemic inflammatory response syndrome (SIRS). PD-1 and PD-L1 expression were measured on circulating CD4+ T cells, CD8+ T cells, and monocytes (PD-L1 only) by flow cytometry. Our results showed that only monocyte PD-L1 expression gradually increased, based on the increasing severity of disease (P < 0.001). Similarly, multivariate logistic regression analysis showed that only monocyte PD-L1 expression was an independent predictor of 28-day mortality in septic shock patients. Area under the receiver operating characteristic curve analysis of the combination of monocyte PD-L1 expression and conventional clinical risk parameters indicated a more significant prognostic ability than analysis of each parameter alone. Our study demonstrated that, among PD-1-related molecules, only monocyte PD-L1 expression after 3–4 days of sepsis was associated with risk stratification and mortality in septic patients. Furthermore, measurement of monocyte PD-L1 expression was a promising independent prognostic marker for septic shock patients.

A new randomised controlled trial suggested that plasma exchange hastened removal from the ventilator in mechanically ventilated children with Guillain-Barré syndrome compared with intravenous immunoglobulin. Two larger trials in adults showed the opposite result.

Critical illness is commonly complicated by hyperglycaemia caused by mediators of stress and inflammation. Severity of disease is the main risk factor for development of hyperglycaemia, but not all severely ill develop hyperglycemia and some do even in mild disease. We hypothesised that acute disease only exposes a latent disturbance of glucose metabolism which puts those patients at higher risk for developing diabetes. Medical patients with no history of impaired glucose metabolism or other endocrine disorder admitted to an intensive care unit between July 1998 and June 2004 were considered for inclusion. Glucose was measured at least two times a day, and patients were divided into the hyperglycaemia group (glucose ≥7.8 mmol/l) and normoglycaemia group. An oral glucose tolerance test was performed within six weeks after discharge to disclose patients with unknown diabetes or pre-diabetes who were excluded. Patients treated with corticosteroids and those terminally ill were also excluded from the follow-up which lasted for a minimum of five years with annual oral glucose tolerance tests. A five-year follow-up was completed for 398 patients in the normoglycaemia group, of which 14 (3.5%) developed type 2 diabetes. In the hyperglycaemia group 193 patients finished follow-up and 33 (17.1%) developed type 2 diabetes. The relative risk for type 2 diabetes during five years after the acute illness was 5.6 (95% confidence interval (CI) 3.1 to 10.2). Patients with hyperglycaemia during acute illness who are not diagnosed with diabetes before or during the hospitalization should be considered a population at increased risk for developing diabetes. They should, therefore, be followed-up, in order to be timely diagnosed and treated.

Delayed gastric emptying and feed intolerance occur frequently in the critically ill. In these patients, gastric motor responses to nutrients are disturbed. Peptide YY (PYY) slows gastric emptying. The aim of this study was to determine fasting and nutrient-stimulated plasma PYY concentrations and their relationship to cholecystokinin (CCK) in critically ill patients. Studies were performed in 19 unselected mechanically ventilated critically ill patients (12 males; 48 ± 7 years old) in a randomised, single-blind fashion. Subjects received a 60-minute duodenal infusion of Ensure® at either 1 or 2 kcal/minute. Blood samples were collected at baseline and at 20, 40, 60, and 180 minutes following commencement of the nutrient infusion for the measurement of plasma PYY and CCK concentrations (using radioimmunoassay). Patient data were compared to 24 healthy subjects (17 males; 43 ± 2 years old). Fasting PYY concentration was higher in patients (P < 0.05), particularly in those with feed intolerance (P < 0.05). Plasma PYY concentrations were higher in patients during nutrient infusion (area under the curve [AUC] at 1 kcal/minute: 2,265 ± 718 versus 1,125 ± 138 pmol/l.min, P < 0.05; at 2 kcal/minute: 2,276 ± 303 versus 1,378 ± 210 pmol/l.min, P = 0.01) compared to healthy subjects. The magnitude of PYY elevation was greater in patients during the 1 kcal/minute infusion (AUC: 441 ± 153 versus 186 ± 58 pmol/l.min, P < 0.05), but not the 2 kcal/minute infusion. Fasting and nutrient-stimulated plasma CCK concentrations were higher in patients (P < 0.05). There was a relationship between plasma PYY and CCK concentrations during fasting (r = 0.52, P < 0.05) and nutrient infusion (r = 0.98, P < 0.0001). In critical illness, both fasting and nutrient-stimulated plasma PYY concentrations are elevated, particularly in patients with feed intolerance, in conjunction with increased CCK concentrations.

Hypotension in septic patients results from hypovolemia, vasodilatation and hyporeactivity to vasoconstrictors, such as angiotensin II. The AT1 receptor-associated protein 1 (Arap1) is expressed in vascular smooth muscle cells and increases the surface expression of the AT1-receptor in vitro. We hypothesized that dysregulation of Arap1 may contribute to vascular hyporeactivity to angiotensin II during endotoxemia. Arap1-deficient mice were used to assess the role of Arap1 in sepsis-induced hypotension. The isolated perfused kidney was used as an in vitro model to determine the relevance of Arap1 for vascular resistance and sensitivity to angiotensin II. During endotoxemia, mean arterial blood pressure (MAP) decreased in both genotypes, with the time course of sepsis-induced hypotension being markedly accelerated in Arap1-/- compared to +/+ mice. However, baseline MAP was similar in Arap1-/- and wildtype mice (102 ± 2 vs.103 ± 2 mmHg; telemetry measurements; n = 10; P = 0.66). Following lipopolysaccharide (LPS) injections (3 mg/kg), Arap1 expression was successively down-regulated in the wildtype mice, reaching levels below 10% of baseline expression. The endotoxemia-related decline in Arap1 expression could be recapitulated in cultured mesangial cells by incubation with pro-inflammatory cytokines, such as tumor necrosis factor α and interferon γ. Plasma renin concentration was increased in Arap1-/- mice compared to wildtype mice (66 ± 6 vs. 41 ± 4 ng AngI/ml/h; n = 23; P = 0.001), presumably contributing to preserved MAP under baseline conditions. The sensitivity of the vasculature to angiotensin II was reduced in Arap1-/- compared to +/+ mice, as determined in the isolated perfused kidney. Our data suggest that down-regulation of Arap1 expression during sepsis contributes to the development of hypotension by causing reduced vascular sensitivity to angiotensin II.