Irineu Tadeu Velasco

Treatment of refractory hypovolaemic shock by 7.5% sodium chloride injections

Injections of hyperosmotic (7.5%) sodium chloride (100-400 ml) were given to 12 patients in terminal hypovolaemic shock who had not responded to vigorous volume replacement and corticosteroid and dopamine infusions. Hyperosmotic sodium chloride promptly reversed the shock in 11 of these patients. The immediate effects of the NaCl injections were a moderate rise in arterial pressure, the resumption of urine flow, and recovery of consciousness. These effects tended to persist for a few hours. The hyperosmotic infusion also reduced isosmotic fluid requirement by 90%.

CD16 promotes Escherichia coli sepsis through an FcR

Sepsis, a leading cause of death worldwide, involves proinflammatory responses and inefficient bacterial clearance. Phagocytic cells play a crucial part in the prevention of sepsis by clearing bacteria through host innate receptors. Here we show that the FcRγ adaptor, an immunoreceptor tyrosine-based activation motif (ITAM)-bearing signal transduction subunit of the Fc receptor family, has a deleterious effect on sepsis. FcRγ−/− mice show increased survival during peritonitis, owing to markedly increased E. coli phagocytosis and killing and to lower production of the proinflammatory cytokine tumor necrosis factor (TNF)-α. The FcRγ-associated receptor that inhibits E. coli phagocytosis is FcγRIII (also called CD16), and its absence protects mice from sepsis. FcγRIII binds E. coli, and this interaction induces FcRγ phosphorylation, recruitment of the tyrosine phosphatase SHP-1 and phosphatidylinositide-3 kinase (PI3K) dephosphorylation. Decreased PI3K activity inhibits E. coli phagocytosis and increases TNF-α production through Toll-like receptor 4. We identified the phagocytic receptor negatively regulated by FcRγ on macrophages as the class A scavenger receptor MARCO. E. coli-FcγRIII interaction induces the recruitment of SHP-1 to MARCO, thereby inhibiting E. coli phagocytosis. Thus, by binding FcγRIII, E. coli triggers an inhibitory FcRγ pathway that both impairs MARCO-mediated bacterial clearance and activates TNF-α secretion.

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OBJECTIVE To investigate the risk factors for delirium in the elderly during the post-operative period of coronary artery bypass graft surgery (CABG). METHODS A total of 220 inpatients submitted to CABG were evaluated prior to and after surgery. In order to investigate the possible risk factors, data were collected from pre- intra- and post-operative periods. INSTRUMENTS The patients were assessed using the Mini-mental State Examination and to the Geriatric Depression Scale. The diagnosis of delirium was determined according to DSM-IV criteria. RESULTS Delirium was detected in 74 (33.6%) patients. Increasing age, blood urea level, cardio-thoracic index, hypertension, smoking habits, blood replacement during bypass, atrial fibrillation (AF), pneumonia and blood balance in the post-operative period were the risk factors for delirium selected by the logistic regression analysis. No specific factor associated with the CABG (perfusion pressure, number of grafts) was correlated with an increased risk for delirium post-operatively. The length of stay was twice as long in the delirious group (p<0.001). CONCLUSIONS Delirium in the elderly after CABG is a multifactorial disorder. Nine factors taken together can identify patients at great risk for delirium. No specific factor associated with bypass procedure could be identified as a risk factor for delirium. The control of the risk factors should bring a decrease in delirium morbidity and mortality.

inhibitory pathway that prevents phagocytosis and facilitates inflammation

Objective:To reevaluate the clinical impact of external positive end-expiratory pressure (external-PEEP) application in patients with severe airway obstruction during controlled mechanical ventilation. The controversial occurrence of a paradoxic lung deflation promoted by PEEP was scrutinized. Design:External-PEEP was applied stepwise (2 cm H2O, 5-min steps) from zero-PEEP to 150% of intrinsic-PEEP in patients already submitted to ventilatory settings minimizing overinflation. Two commonly used frequencies during permissive hypercapnia (6 and 9/min), combined with two different tidal volumes (VT: 6 and 9 mL/kg), were tested. Setting:A hospital intensive care unit. Patients:Eight patients were enrolled after confirmation of an obstructive lung disease (inspiratory resistance, >20 cm H2O/L per sec) and the presence of intrinsic-PEEP (≥5 cm H2O) despite the use of very low minute ventilation. Interventions:All patients were continuously monitored for intra-arterial blood gas values, cardiac output, lung mechanics, and lung volume with plethysmography. Measurements and Main Results:Three different responses to external-PEEP were observed, which were independent of ventilatory settings. In the biphasic response, isovolume-expiratory flows and lung volumes remained constant during progressive PEEP steps until a threshold, beyond which overinflation ensued. In the classic overinflation response, any increment of external-PEEP caused a decrease in isovolume-expiratory flows, with evident overinflation. In the paradoxic response, a drop in functional residual capacity during external-PEEP application (when compared to zero-external-PEEP) was commonly accompanied by decreased plateau pressures and total-PEEP, with increased isovolume-expiratory flows. The paradoxic response was observed in five of the eight patients (three with asthma and two with chronic obstructive pulmonary disease) during at least one ventilator pattern. Conclusions:External-PEEP application may relieve overinflation in selected patients with airway obstruction during controlled mechanical ventilation. No a priori information about disease, mechanics, or ventilatory settings was predictive of the response. An empirical PEEP trial investigating plateau pressure response in these patients appears to be a reasonable strategy with minimal side effects.

Risk factors for delirium in the elderly after coronary artery bypass graft surgery

Objective: To describe the incidence, risk factors and clinical features (subtypes) of delirium during the postoperative period after hip fracture surgery in elderly patients. Design: Prospective study. Methods: Thirty-four consecutive patients (9 men and 25 women) were included in this study between June 16 to July 14, 2003. All patients underwent surgery for a fractured neck of femur and were pre- and postoperatively cared for at a combined geriatric/orthopedic ward. Assessment: The diagnosis of delirium was based on the criteria of the DSM-IV and the Confusion Assessment Method Scale. Subtypes of delirium were classified according to the criteria proposed by Lipowski: hyperactive-hyperalert (or agitated), hypoactive-hypoalert (somnolent) and mixed delirium. Results: Fifty-five percent (n = 19) of the 34 patients developed delirium after surgery. The development of delirium was associated with the medication midazolam taken perioperatively. Nine (47%) of the delirious patients had a hyperactive type of delirium; 5 (26%) developed a hypoactive delirium, and 5 (26%) had a mixed type. We did not find any association among subtypes of delirium and clinical features. Conclusions: Delirium is a common complication in the postoperative period of elderly patients treated for hip fractures. The use of midazolam in the perioperative period increased the risk of developing postoperative delirium. Thehyperactive type of delirium was the most common subtype of delirium.

Paradoxical responses to positive end-expiratory pressure in patients with airway obstruction during controlled ventilation

Refeeding syndrome encompasses fluid and electrolyte imbalances and metabolic, intestinal, and cardiorespiratory derangements associated with appreciable morbidity and mortality. Although refeeding syndrome has been well documented in concentration-camp subjects, and more recently during parenteral therapy of critically ill patients, little is known about the importance of refeeding syndrome during recovery from a hunger strike. Thus, we studied the response to a four-step dietary replenishment routine in eight hunger strikers who refused food for 43 d. In this retrospective, observational study, we assessed the safety and efficacy of the refeeding procedure and analyzed the clinical and nutritional course of the cohort during both starvation and refeeding, mainly on the basis of clinical as well as a few biochemical determinations. During starvation, average weight loss was about 18% and, with the exception of occasional oral vitamins and electrolytes, the subjects consumed only water. Available body-composition and biochemical profiles showed no clinically significant changes during starvation, but one-half of the group displayed spontaneous diarrhea at some time before refeeding. Stepwise nutritional replenishment lasted for 9 d, after which all patients tolerated a full, unrestricted diet. Only one episode of diarrhea occurred during this phase, and both clinical and biochemical indexes confirmed a favorable clinical course, without any manifestation of refeeding syndrome. In conclusion, we observed the following: 1) Hypophosphatemia and other micronutrient imbalances did not occur, nor was macronutrient intolerance detected. 2) Despite some episodes of diarrhea, nutritional replenishment was not associated with significant enteral dysfunction. 3) There was some fluid retention, but this was mild. 4) Acute-phase markers were abnormally elevated during the refeeding phase, without associated sepsis or inflammation.

Incidence, Clinical Features and Subtypes of Delirium in Elderly Patients Treated for Hip Fractures

Brain injury is responsible for significant morbidity and mortality in trauma patients, but controversy still exists over therapeutic management for these patients. The objective of this study was to analyze the effect of phototherapy with low intensity lasers on local and systemic immunomodulation following cryogenic brain injury. Laser phototherapy was applied (or not-controls) immediately after cryogenic brain injury performed in 51 adult male Wistar rats. The animals were irradiated twice (3 h interval), with continuous diode laser (gallium-aluminum-arsenide (GaAlAs), 780 nm, or indium-gallium-aluminum-phosphide (InGaAlP), 660 nm) in two points and contact mode, 40 mW, spot size 0.042 cm(2), 3 J/cm(2) and 5 J/cm(2) (3 s and 5 s, respectively). The experimental groups were: Control (non-irradiated), RL3 (visible red laser/ 3 J/cm(2)), RL5 (visible red laser/5 J/cm(2)), IRL3 (infrared laser/3 J/cm(2)), IRL5 (infrared laser/5 J/cm(2)). The production of interleukin-1IL-1beta (IL-1beta), interleukin6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor-alpha (TNF-alpha) was analyzed by enzyme immunoassay technique (ELISA) test in brain and blood samples. The IL-1beta concentration in brain of the control group was significantly reduced in 24 h (p<0.01). This reduction was also observed in the RL5 and IRL3 groups. The TNF-alpha and IL-6 concentrations increased significantly (p<0.01 and p<0.05, respectively) in the blood of all groups, except by the IRL3 group. The IL-6 levels in RL3 group were significantly smaller than in control group in both experimental times. IL-10 concentration was maintained stable in all groups in brain and blood. Under the conditions of this study, it is possible to conclude that the laser phototherapy can affect TNF-alpha, IL-1beta and IL-6 levels in the brain and in circulation in the first 24 h following cryogenic brain injury.

Refeeding procedures after 43 days of total fasting

Objectives: Severe acute pancreatitis (AP) is characterized by hemodynamic alterations and a systemic inflammatory response, leading to a high mortality rate. Treatment of hemorrhagic shock with hypertonic saline solutions significantly reduces mortality through an improvement in the hemodynamic conditions and possibly by an anti-inflammatory effect. Therefore, hypertonic solutions could be effective in AP. Methods: Wistar rats were divided in 4 groups: group C, control, without AP; group NT, AP, without treatment; group NS, treatment with normal saline solution (NaCl 0.9%) 1 hour after AP; group HTS, treatment with hypertonic saline solution (NaCl 7.5%) 1 hour after AP. AP was induced by injection of 2.5% sodium taurocholate into the pancreatic duct. Mean arterial blood pressure (MAP) and heart rate were recorded at 0 and 2, 4, 24, and 48 hours after AP. After induction of AP, animals were killed at 2, 12, 24, and 48 hours for serum amylase, interleukin (IL)-6, and IL-10 analysis, pancreatic tissue culture and histologic analysis, oxidation and phosphorylation of liver mitochondria, pulmonary myeloperoxidase activity (MPO), and mortality study. Results: In animals of groups NS and NT, a significant decrease of MAP was observed 48 hours after AP (NS: 91 ± 3 mm Hg; NT: 89 ± 3 mm Hg) compared with baseline (C: 105 ± 2 mm Hg) and to HTS group (HTS: 102 ± 2 mm Hg; P < 0.05). In animals of group NT, NS, and HTS, serum IL-6 and IL-10 levels were significantly higher at 2 hours after AP compared with the control group. However, IL-6 levels at 12 hours after AP and IL-10 levels at 2 and 12 hours after AP were significant lower in group HTS compared with NS and NT groups (P < 0.05). In group HTS, a decrease of pulmonary MPO activity and of pancreatic infection was observed 24 hours after AP compared with NT and NS groups (P < 0.05). A significant reduction on pancreatic acinar necrosis and mitochondrial dysfunction was observed after 48 hours of AP in animals of group HTS compared with groups NT and NS (P < 0.05). A significant reduction on mortality was observed in HTS (0/14) compared with NS (6/17; 35%) and NT (7/20; 35%). Conclusions: The administration of hypertonic saline solution in experimental AP attenuated hemodynamic alterations, decreased inflammatory cytokines, diminished systemic lesions and pancreatic acinar necrosis, prevented pancreatic infection, and reduced the mortality rate.

Effect of phototherapy with low intensity laser on local and systemic immunomodulation following focal brain damage in rat.

BACKGROUND Renal dysfunction is associated with increased mortality in patients with decompensated heart failure. However, interventions targeted to prevention in this setting have been disappointing. We investigated the effects of hypertonic saline solution (HSS) for prevention of renal dysfunction in decompensated heart failure. METHODS In a double-blind randomized trial, patients with decompensated heart failure were assigned to receive three-day course of 100mL HSS (NaCl 7.5%) twice daily or placebo. Primary end point was an increase in serum creatinine of 0.3mg/dL or more. Main secondary end point was change in biomarkers of renal function, including serum levels of creatinine, cystatin C, neutrophil gelatinase-associated lipocalin-NGAL and the urinary excretion of aquaporin 2 (AQP2), urea transporter (UT-A1), and sodium/hydrogen exchanger 3 (NHE3). RESULTS Twenty-two patients were assigned to HSS and 12 to placebo. Primary end point occurred in two (10%) patients in HSS group and six (50%) in placebo group (relative risk 0.3; 95% CI 0.09-0.98; P=0.01). Relative to baseline, serum creatinine and cystatin C levels were lower in HSS as compared to placebo (P=0.004 and 0.03, respectively). NGAL level was not statistically different between groups, however the urinary expression of AQP2, UT-A1 and NHE3 was significantly higher in HSS than in placebo. CONCLUSIONS HSS administration attenuated heart failure-induced kidney dysfunction as indicated by improvement in both glomerular and tubular defects, a finding with important clinical implications. HSS modulated the expression of tubular proteins involved in regulation of water and electrolyte homeostasis.

Local and systemic effects of hypertonic solution (NaCl 7.5%) in experimental acute pancreatitis.

Sepsis syndrome is caused by inappropriate immune activation due to bacteria and bacterial components released during infection. This syndrome is the leading cause of death in intensive care units. Specialized B-lymphocytes located in the peritoneal and pleural cavities are known as B-1 cells. These cells produce IgM and IL-10, both of which are potent regulators of cell-mediated immunity. It has been suggested that B-1 cells modulate the systemic inflammatory response in sepsis. In this study, we conducted in vitro and in vivo experiments in order to investigate a putative role of B-1 cells in a murine model of LPS-induced sepsis. Macrophages and B-1 cells were studied in monocultures and in co-cultures. The B-1 cells produced the anti-inflammatory cytokine IL-10 in response to LPS. In the B-1 cell-macrophage co-cultures, production of proinflammatory mediators (TNF-α, IL-6 and nitrite) was lower than in the macrophage monocultures, whereas that of IL-10 was higher in the co-cultures. Co-culture of B-1 IL-10(-/-) cells and macrophages did not reduce the production of the proinflammatory mediators (TNF-α, IL-6 and nitrite). After LPS injection, the mortality rate was higher among Balb/Xid mice, which are B-1 cell deficient, than among wild-type mice (65.0% vs. 0.0%). The Balb/Xid mice also presented a proinflammatory profile of TNF-α, IL-6 and nitrite, as well as lower levels of IL-10. In the early phase of LPS stimulation, B-1 cells modulate the macrophage inflammatory response, and the main molecular pathway of that modulation is based on IL-10-mediated intracellular signaling.