Cardiovascular events in patients undergoing hip fracture surgery treated with remote ischaemic preconditioning: 1-year follow-up of a randomised clinical trial.

Remote ischaemic preconditioning reduces the risk of myocardial injury within 4 days of hip fracture surgery. We aimed to investigate the effect of remote ischaemic preconditioning on the incidence of major adverse cardiovascular events 1 year after hip fracture surgery. We performed a phase-2, multicentre, randomised, observer-blinded, clinical trial between February 2015 and September 2017. We studied patients aged ≥ 45 years with a hip fracture and a minimum of one cardiovascular risk factor. Patients were allocated randomly to remote ischaemic preconditioning applied just before surgery or no treatment (control group). Remote ischaemic preconditioning was performed on the upper arm with a tourniquet in four cycles of 5 min ischaemia and 5 min reperfusion. Primary outcome was the occurrence of major adverse cardiovascular events within 1 year of surgery. A total of 316 patients were allocated randomly to the remote ischaemic preconditioning group and 309 patients to the control group. Major adverse cardiovascular events occurred in 43 patients (13.6%) in the remote ischaemic preconditioning group compared with 51 patients (16.5%) in the control group (adjusted hazard ratio (95%CI) 0.83 (0.55-1.25); p = 0.37). Fewer patients in the remote ischaemic preconditioning group had a myocardial infarction (11 (3.5%) vs. 22 (7.1%); hazard ratio (95%CI) 0.48 (CI 0.23-1.00); p = 0.04). Remote ischaemic preconditioning did not reduce the occurrence of major adverse cardiovascular events within 1 year of hip fracture surgery. The effect of remote ischaemic preconditioning on clinical cardiovascular outcomes in non-cardiac surgery needs confirmation in appropriately powered randomised clinical trials.

New oral anticoagulants: clinical indications, monitoring and treatment of acute bleeding complications.

New oral anticoagulants like the direct thrombin inhibitor, dabigatran (Pradaxa®), and factor Xa-inhibitors, rivaroxaban (Xarelto®) and apixaban (Eliquis®) are available for prophylaxis and treatment of thromboembolic disease. They are emerging alternatives to warfarin and provide equal or better clinical outcome together with reduced need for routine monitoring. Methods for measuring drug concentrations are available, although a correlation between plasma drug concentrations and the risk of bleeding has not been firmly established. Standard laboratory measures like prothrombin time and activated partial thromboplastin time are not sensitive enough to detect thrombin or factor Xa inhibition provided by new oral anticoagulants. Thus, these standard tests may only be used as a crude estimation of the actual anticoagulation status. Further challenges regarding patients receiving new oral anticoagulants who presents with major bleeding or need for emergency surgery pose a unique problem. No established agents are clinically available to reverse the anticoagulant effect, although preclinical data report prothrombin complex concentrate as more efficient than fresh frozen plasma or other prohaemostatic agents. This review summaries current knowledge on approved new oral anticoagulants and discusses clinical aspects of monitoring, with particular focus on the management of the bleeding patient.

Immunohistochemical demonstration of IgG in Reed-Sternberg and other cells in Hodgkin's disease.

Spleens and lymph nodes fixed lightly for optimal immunocytochemistry or processed routinely for surgical diagnosis disclosed strong selective immunostaining for IgG in numerous immunocytes in tumor-free areas. Areas involved by Hodgkin's disease revealed, in addition, strong immunostaining for IgG but not IgM in Reed-Sternberg cells and faint to strong staining in Hodgkin cells as well. Ultrastructurally the Reed-Sternberg and Hodgkin cells displayed abundant polyribosomes and sparse granular reticulum and appeared to form unexportable IgG on unbound ribosomes.

The impact of HIV-1 co-infection on long-term mortality in patients with hepatitis C: a population-based cohort study.

OBJECTIVE: To investigate the impact of HIV co-infection on mortality in patients infected with hepatitis C virus (HCV). METHODS: From a nationwide Danish database of HCV-infected patients, we identified individuals diagnosed with HCV subsequent to an HIV diagnosis. For each co-infected patient, four control HCV patients without HIV were matched on age, gender and year of HCV diagnosis. Data on comorbidity, drug abuse, alcoholism and date of death were extracted from two healthcare databases. We constructed Kaplan-Meier curves and used Cox regression analyses to estimate mortality rate ratios (MRRs), controlling for comorbidity. RESULTS: We identified 483 HCV-HIV co-infected and 1932 HCV mono-infected patients, yielding 2192 and 9894 person-years of observation with 129 and 271 deaths, respectively. The 5-year probability of survival was 0.74 [95% confidence interval (CI) 0.69-0.80] for HCV-HIV co-infected patients and 0.87 (95% CI 0.85-0.89) for HCV mono-infected patients. Co-infection was associated with substantially increased mortality (MRR 2.1, 95% CI 1.7-2.6). However, prior to the first observed decrease in CD4 counts to below 300 cells/muL, HIV infection did not increase mortality in HCV-infected patients (MRR 0.9, 95% CI 0.5-1.50). CONCLUSIONS: HIV infection has a substantial impact on mortality among HCV-infected individuals, mainly because of HIV-induced immunodeficiency.

A changing landscape: Temporal trends in incidence and characteristics of patients hospitalized with venous thromboembolism 2006-2015.

BACKGROUND: Venous thromboembolism (VTE) has major clinical and public health impact. However, only sparse data on calendar time trends in incidence from unselected populations reflecting current clinical practice are available. OBJECTIVES: To examine temporal trends in the incidence and characteristics of patients hospitalized with first-time VTE in Denmark between 2006 and 2015. PATIENTS/METHODS: Using nationwide health care registries, we calculated yearly hospitalization rates for first-time VTE from 2006 to 2015. The rates were standardized to the age and sex distribution in 2006. Based on the hospitalization and prescription history of each patient, we assessed the risk profile and evaluated changes over time. RESULTS: We identified 67,426 patients with a first-time VTE hospitalization. The age- and sex-standardized incidence rate increased from 12.6 (95% CI: 12.3-12.9) per 10,000 person years at risk in 2006 to 15.1 (95% CI: 14.7-15.4) in 2015, corresponding to an increase of 19.8%. The increase was due to a 73.9% increase in the standardized incidence rate of pulmonary embolism (PE), whereas no increase was observed for deep vein thrombosis. The risk profile changed with an increasing proportion of elderly patients and patients with comorbidity (proportion of patients with a Charlson's Comorbidity Index score of ≥1). CONCLUSIONS: The hospitalization rate of first-time VTE, and particularly PE, has increased substantially within the last decade in Denmark. In addition, the risk profile of the VTE population has changed with more elderly and more patients with comorbidity being diagnosed. Further efforts are warranted to explore the changes in VTE epidemiology and the clinical implications.

Dietary factor VII activation does not increase plasma concentrations of prothrombin fragment 1+2 in patients with stable angina pectoris and coronary atherosclerosis.

Studies in healthy subjects showed that blood coagulation factor VII (FVII) is activated postprandially after consumption of high-fat meals, but accompanying thrombin formation has not been demonstrated. In patients with coronary atherosclerosis, the arterial intima is supposed to present more tissue factor, the cofactor of FVII, to circulating blood; therefore, thrombin formation in response to FVII activation is more likely to occur in such patients. This hypothesis was tested in a randomized crossover study of 30 patients (aged 43 to 70 years) with stable angina pectoris and angiographically verified coronary atherosclerosis. They were served a low-fat (5% of energy from fat) breakfast and lunch and a high-fat (40% of energy from fat) breakfast and lunch on 2 different days. Venous blood samples were collected at 8:15 AM (fasting), 12:30 PM, 2:00 PM, 3:30 PM, and 4:45 PM and analyzed for triglycerides, activated FVII (FVIIa), FVII protein concentration (FVII:Ag), prothrombin fragment 1+2 (F1+2), and soluble fibrin. Triglyceride levels increased from fasting levels on both diets, but they increased most markedly on the high-fat diet. FVIIa and FVIIa/FVII:Ag increased with the high-fat diet and decreased with the low-fat diet. For both diets, FVII:Ag and F1+2 decreased slightly. No postprandial changes were observed for soluble fibrin. Postprandial mean values of triglycerides, FVIIa, FVII:Ag, and FVIIa/FVII:Ag were significantly higher for the high-fat diet than for the low-fat diet. Our findings confirm that high-fat meals cause immediate activation of FVII. The clinical implication is debatable because FVII activation was not accompanied by an increase in plasma F1+2 concentrations in patients with severe atherosclerosis. However, a local thrombin generation on the plaque surface cannot be excluded.

Inhibition of apoptosis in polymorphonuclear neutrophils from burn patients.

Normal human polymorphonuclear neutrophils (PMN) undergo rapid apoptosis during in vitro culture. In contrast, apoptosis is inhibited in PMN from patients with severe burns. This inhibition is not an inherent property of the cells but is caused by thermolabile factors present in the plasma. Endotoxin and the proinflammatory cytokines interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) do not appear to be directly responsible. The ability of burn plasma to inhibit apoptosis was reduced by neutralizing antibodies to human granulocyte macrophage colony-stimulating factor (GM-CSF). GM-CSF levels could not be detected in the burn plasma. However, the incubation of burn-derived or normal leukocyte populations consisting primarily of PMN in burn plasma induced the production of GM-CSF. The results suggest that activation of GM-CSF synthesis by factor(s) in burn plasma may play a role in regulating inflammation by the inhibition of apoptosis.

Posttraumatic adaptation and distress among adult burn survivors.

OBJECTIVE: The purpose of this study was to examine the prevalence, natural history, and psychosocial impact of posttraumatic symptoms in adult burn survivors. METHOD: Forty-three adult inpatients at a regional burn center were assessed at discharge with standardized instruments to determine the presence of psychiatric disorder, assess personality, and quantify depression. Thirty-one patients were evaluated 4 months after discharge. RESULTS: Posttraumatic stress disorder was diagnosed in 7% of patients at discharge and in over 22% of patients at follow-up. Symptoms of avoidance and emotional numbing (DSM-III-R criterion C symptoms) tended to emerge after discharge from the hospital. While posttraumatic symptoms were associated with symptoms of depression, they were not strongly associated with psychosocial adjustment to illness; psychosocial adjustment was more strongly related to aspects of personality, the injury itself, and its treatment. CONCLUSIONS: Since adult burn survivors often develop new symptoms of posttraumatic distress after leaving the hospital, longitudinal surveillance is required to detect new cases and provide appropriate treatment. Survivors at risk for poor psychosocial adjustment after discharge may be identifiable during hospitalization, and preventive treatment strategies should be developed and tested for this population.

The preparation of stable phosphorylcholine-erythrocyte conjugates for use in plaque assays.

A method for the preparation of stable phosphorylcholine-conjugated erythrocytes is described. This method employs the formation of active esters of phosphorylcholine hydroxyphenylacetic acid (PC-HPA) and results in coupled red cells which are completely stable for 2-3 weeks. Using this procedure up to 80% of the activity was demonstrable after 6 weeks. Cells coupled with PC-HPA are suitable for the demonstration of anti-idiotype effects in a plaquing assay.

Immunologic response of trauma and burns. An overview.

Immunologic alterations occur after elective surgery, accidental injuries, and burns. These alterations are dose-related, that is, minor insults bring about minor alterations that appear to be of no clinical relevance, but major accidents and extensive burns cause major alterations, which have been correlated with the incidence of life-threatening septic complications. Because many aspects of the immune system seem to be affected, a concerted move in the direction of immunologic manipulation of the surgically injured patient has been difficult. Nevertheless, several potentially promising avenues of immune modulation are currently undergoing clinical trials.

Increased vascular pedicle width preceding burn-related pulmonary edema.

Widening of the vascular pedicle on the chest roentgenogram is a recently identified sign of increased circulating blood volume. To determine whether vascular pedicle enlargement can be detected during the initial day of burn resuscitation and whether this change correlates with the early development of pulmonary edema, we reviewed the serial chest roentgenograms of 42 patients with cutaneous burns and risk factors for inhalation injury. Although no patient had pulmonary edema at the time of vascular pedicle measurements, 18 (42.9 percent) developed this complication during the 3.3 +/- 1.5 days after injury. These patients were significantly older (p less than 0.025) and had received more resuscitative fluid (P less than 0.005) than those without pulmonary edema. Initial vascular pedicle width was similar in both groups (5.9 +/- 0.9 vs 6.0 +/- 1.0 cm) and did not change in patients without pulmonary edema (5.8 +/- 0.7 cm). Vascular pedicle width increased (6.9 +/- 1.2 cm, p less than 0.01) in patients who subsequently developed pulmonary edema, and 12 of the 13 patients who had changes exceeding +1.0 cm had this problem. Enlargement of the vascular pedicle is associated with early burn-related pulmonary edema and might provide a clinically useful predictor of this cardiopulmonary complication.

Cerium nitrate-silver sulfadiazine cream in the treatment of burns: a prospective evaluation.

In a prospective, randomized study of patients with major burns, the efficacy of cerium nitrate-silver sulfadiazine cream was compared with that of silver sulfadiazine cream alone. Sixty patients were studied, in two groups, with matching mean ages and mean burns sizes. Patients with associated injuries, smoke inhalation, or major medical illnesses were excluded from the study. The total number of deaths and the total number of deaths from sepsis were equal in both groups. The total number of patients whose quantitative burns wound biopsies indicated light (10(2) to 10(5) organisms/gm) or heavy (over 10(5) organisms/gm) colonization by microorganisms was not statistically different between the two groups. The distribution of bacterial isolates by organism was similar in both groups. In vitro sensitivity determinations indicated a comparable efficacy between the two agents. In this study no clear-cut superiority of one topical agent over the other could be demonstrated.

Endotoxemia in burn patients: levels of circulating endotoxins are related to burn size.

With use of a quantitative limulus assay, the levels of circulating endotoxins were examined in a population of burn patients with injuries covering 1% to 88% of the total body surface area (TBSA). In cases in which the injury was less than 20% TBSA, the increases in endotoxins were only 35% as compared with those of normal controls. As the extent of injury increased, the levels of endotoxins also increased: burns between 21% and 40% TBSA showed average increases of over 350% and burns in excess of 40% showed increases of 500%. The relationship between burn size and total endotoxin burden was significant (p = less than 0.01). Time-course studies indicated that in most cases, peak endotoxin levels occurred 3 to 4 days after injury. The data also showed that there was no relationship between the age of the patient and the extent of the endotoxin increase.

Impairment of human lymphocyte function by bile salts.

Since there appears to be an association between depressed lymphocyte function and liver disease, the effect of bile salts on lymphocyte function was determined in vitro. Peripheral lymphocytes from normal volunteers were incubated with varying concentrations of three bile salts (chenodeoxycholate, deoxycholate, or ursodeoxycholate) and stimulated by the mitogens phytohemagglutinin or concanavalin. The three bile salt concentrations used in these experiments were 75, 100, and 250, mumol/L, which are similar to serum levels found in various types of liver disease. Blast transformation, as measured by tritiated thymidine incorporation, was significantly depressed by all three bile salts at all concentrations and with both mitogens. Suppression increased with the higher bile salt concentrations. However, ursodeoxycholate suppressed lymphocyte function significantly less than did either chenodeoxycholate or deoxycholate. These data suggest that elevated serum bile levels associated with liver disease may contribute to immunosuppression and that ursodeoxycholate, an epimer of chenodeoxycholate that is used for gallstone dissolution, depresses lymphocyte function significantly less than does chenodeoxycholate.

The effect of antibiotics on cell-mediated immunity.

Normal human lymphocytes in culture were stimulated by the addition of phytohemagglutinin, and deoxyribonucleic acid (DNA) synthesis was measured by the incorporation of tritiated thymidine. The effect of 11 commonly used antibiotics on DNA synthesis then was measured by adding each antibiotic to the culture in concentrations ranging from 2 to 64 microng/ml, a range which covers the plasma levels obtained during customary clinical therapy. Severe dose-dependent suppression of DNA synthesis was found in the presence of two preparations of minocycline, oxytetracycline, and the ascorbic acid salt of tetracycline. Less severe but stil significant suppression was found in the presence of chloramphenicol, clindamycin, tetracycline, and ascorbic acid alone. No effect was noted when penicillin, carbenicillin, or cephalothin was added, and slight stimulation was found in the presence of gentamicin. It is postulated that these findings may help to explain fungal and viral superinfection following antibiotic therapy and that they may play a role in the failure of antibiotic therapy to eliminate some infections.

Netilmicin. A new aminoglycoside in the treatment of septic burn patients.

Netilmicin sulfate, a new aminoglycoside antibiotic, was administered to ten patients with thermal burns who were suffering from septic complications, usually burn wound sepsis. There were seven survivors. Eighty-three percent of all clinical isolates recovered showed sensitivity to the drug. No renal or auditory side effects were noted in any of the patients.

Inhibitory effects of interleukin 6 on immunity. Possible implications in burn patients.

Certain disease states are associated with abnormal increases in the monokine interleukin 6. Increased levels of interleukin 6 have been demonstrated in serum from patients with burns and are associated with systemic increases in endotoxin levels. Using a murine in vitro experimental model, we have studied the effects of interleukin 6 on various measures of immunity. Our data indicate that levels equivalent to the concentrations found in serum of burn victims inhibit T-cell proliferation. The inhibitory effect is dose and time dependent, is specific for T cells, is not due to impairment of interleukin 2 production or of interleukin 2 receptor expression, and is dependent on macrophages. These data suggest that extraordinary increases in interleukin 6 levels may be related to impaired T-cell responses and to an increased susceptibility to infection in the patient with burns.

Neutrophil intracellular kill following thermal injury. Different bactericidal capability for patients' organisms and laboratory organisms.

Sixteen patients with septic complications of severe thermal injury were studied with respect to neutrophil intracellular-killing power against clinical isolates from the patients themselves and against other laboratory organisms. Simultaneous measurements of neutrophil chemotaxis, helper/suppressor lymphocyte ratios, and serum IgG concentrations were also carried out. Neutrophils from patients who survived had diminished intracellular-killing capacity for their own organisms, but normal capacity for killing laboratory organisms either matched or unmatched with the patients' own isolate's species. In these patients, the chemotactic index, the lymphocyte helper/suppressor ratio, and the serum IgG concentration remained within normal limits. Neutrophils from patients who died failed to kill their own, as well as laboratory, organisms. In these patients, the chemotactic index, lymphocyte helper/suppressor ratio, and IgG concentration were significantly diminished. The biological implications of these findings are noted.

Suppression of lymphocyte function after aortic reconstruction. Use of nonimmunosuppressive anesthesia.

Serial estimations of lymphocyte responses to antigens and mitogens and in mixed lymphocyte culture in 13 major vascular surgical patients were carried out before and after operation, which was performed using anesthetic agents that have been shown not to depress lymphocyte function. All responses were significantly depressed up to five to eight days, and some up to nine to 11 days. Such depression, attributable to surgical trauma, may underline the vulnerability to infection of these patients who are having prostheses inserted.

Cell-mediated immune responses to Pseudomonas aeruginosa.

Of six healthy laboratory workers with no history of illness caused by Pseudomonas aeruginosa, four exhibited positive skin responses at 24 hours, strong inhibition of leukocyte migration, and marked stimulation of blastogenesis of peripheral lymphocytes when exposed to a "cocktail" of three phenol-killed strains of P aeruginosa. There was no correlation between the extent of these responses with serum hemagglutinin titers. It is postulated that cell-mediated immunity against P aeruginosa may have a biologic role in host defense.