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.

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.

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.

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.

Lupus anticoagulant is significantly associated with inflammatory reactions in patients with suspected deep vein thrombosis.

OBJECTIVE: Lupus anticoagulant (LA) and antiphospholipid antibodies (aPL) are suggested as risk factors for development of deep vein thrombosis (DVT) among patients without systemic lupus erythematosus (SLE). Other conditions, e.g. inflammation, are reported to induce LA and it is uncertain whether the association between LA and DVT is causal. In this study the associations between aPL, LA and inflammation were investigated in 170 consecutive patients without SLE, but with a tentative diagnosis of DVT. MATERIAL AND METHODS: DVT was diagnosed in 64 patients. LA was determined according to the criteria of the International Society of Thrombosis and Haemostasis. The concentration of anticardiolipin (aCL) and beta(2)-glycoprotein I (anti-beta(2)-GPI) antibodies as well as C-reactive protein (CRP) was determined with sensitive and precise methods. RESULTS: LA was demonstrated in 8 patients with DVT and in 10 patients without DVT, relative risk 1.33 (CI: 0.55-3.18). No significant association was observed between aCL or anti-beta(2)-GPI and DVT. Patients suffering from DVT had significantly higher concentrations of CRP than patients without DVT. However, CRP was also significantly higher in patients positive for LA than in patients without LA irrespective of the presence of DVT (p<0.001). CONCLUSIONS: The present study supports a strong association between inflammatory reactions and development of LA in patients with suspected DVT, whereas no significant association was demonstrated between LA or aPL and DVT.

Effects of inhaled plasminogen activator on the balance between coagulation and fibrinolysis in traumatized pigs.

A profibrinolytic state is normal in the alveoli, but this may change as a result of trauma, possibly leading to fibrin deposition, a characteristic of acute lung injury/acute respiratory distress syndrome. Therefore, the present study investigated in a double-blind, placebo-controlled manner the effect of severe trauma on the alveolar fibrinolytic/coagulation balance, and the effect here-upon of inhalation of single-chain urokinase plasminogen activator (scu-PA) in pigs. The study shows an increased concentration of scu-PA in the bronchoalveolar lavage fluid of the treated animals in association with an increased plasmin-dependent fibrinolytic activity without increased systemic fibrinolytic activity, the transient increase in the concentration of scu-PA in the plasma being minimal. In conclusion, the study shows that activatable scu-PA can be nebulized to the lower respiratory tract and can increase the alveolar fibrinolysis without any significant systemic effects.

The long-term consequences of lightning injuries.

The risk of being struck by lightning is extremely low. Although dying instantly through lightning-induced cardiac arrest is a well-documented cause of death, the majority of cases reported in the literature describe infrequently occurring and enormously disparate sequelae of this injury. A total number of 12 patients were treated in our burn intensive care unit following a lightning accident within a period of 12 years. We have analysed the incidence of cardiac, muscular and sensory disturbances, keraunographic skin markings and significant laboratory results, as well as episodes of audiovisual dysfunction and amnesia at the time of the initial admission. In order to determine possible long-term complications, ten of these 12 patients were evaluated at an average time of 6.7 years following the injury (range, 1 month-12.3 years). Considering specific findings during their hospital stay (average length, 1.58+/-0.23 days), patients were assessed for residual neurologic, ocular, oto-vestibular or psychological deficits. The outcome showed that none of the patients suffered from any deficits or long-term problems that could be related to the original lightning injury. Based on these findings and a literature review, we believe that the overall outcome of lightning injuries is more favourable than generally reported.

Activation of blood coagulation in pigs following lower limb gunshot trauma.

A standardized, quantifiable gunshot trauma to one hind leg of fourteen anaesthetized and sedated pigs was used to investigate the extent to which an isolated gunshot trauma causes activation of blood coagulation. The traumatized pigs were mechanically ventilated in intensive care for 48 h before they were euthanized. Blood samples were drawn at baseline (t = 0), 24, 27 and 48 h after trauma to examine the late effects on haemostasis. The median energy absorption in the pigs was 27.57 (22.6-31.7) J/kg. This gunshot injury caused increased creatine kinase and body temperature and led to a combined metabolic and respiratory alkalosis; the pigs remained circulatory stable. Within the haemostatic system the trauma caused increased activated partial thromboplastin time at 48 h (P < 0.05), prothrombin time at 24 and 27 h (P < 0.05), fibrinogen and soluble fibrin concentration at 48 h (P < 0.05), and 24 h (P < 0.05), respectively. The platelet count, protein C activity, tissue factor concentration and trombin-antithrombin concentration decreased throughout the experiment (P < 0.05); the changes of antithrombin activity did not reach statistical significance. In conclusion, this study in pigs demonstrates that a standardized gunshot trauma to a hind leg activates blood coagulation without signs of organ failure or disseminated intravascular coagulation within 48 h.

Acellular allograft dermal matrix: immediate or delayed epidermal coverage?

In a prospective, randomized study seventeen patients received skin grafts to a freshly excised burn wound. One group was grafted with a deantigenized dermal matrix and immediately overgrafted with thin autograft. The second group was grafted with dermal matrix, which was then covered with bank allograft for protection, and autografted 1 week later. Each group also received a standard split thickness control graft. Assessment was carried out for up to 1 year. There were no statistically significant differences of graft take between any of the groups, or in the Vancouver scar score at follow-up. Thin donor sites used for dermal matrix coverage healed faster than standard control graft sites, P<0.001. Immediate grafting of acellular dermal matrix with thin autograft works well and leads to an acceptable late result, with faster donor site healing than standard split thickness grafts.

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.

Personality predictors of injury-related posttraumatic stress disorder.

This longitudinal, cohort study examined the effect of personality traits on the emergence of posttraumatic stress disorder (PTSD) in a recently traumatized, civilian, mixed-gender sample with significant injuries. Burn survivors (N = 70) were administered the NEO-Personality Inventory (NEO-PI) and the Structured Clinical Interview for DSM III-R (SCID) at hospital discharge and readministered the SCID 4 and 12 months later. Overall, the sample of burn survivors scored significantly higher on neuroticism and extraversion and lower on openness, agreeableness, and conscientiousness relative to a normative national sample. Furthermore, multivariate analysis of variance revealed that PTSD symptom severity groups (i.e., single symptom, multiple symptoms, subthreshold PTSD, PTSD) were differentially related to neuroticism and extraversion. Planned comparisons indicated that neuroticism was higher and extraversion was lower in those who developed PTSD compared with those who did not develop PTSD.

Effect of early body image dissatisfaction on subsequent psychological and physical adjustment after disfiguring injury.

OBJECTIVE: The impact of body image dissatisfaction on quality of life after severe burn injury was investigated after controlling for other determinants of outcome (i.e., injury, distress, and preburn quality of life). METHODS: The postburn quality of life (2-months postdischarge) of groups with and without body image dissatisfaction was studied after controlling for preburn quality of life (measured 2-3 days postadmission). The patient population (N = 86) was 77.9% men, had an average total body surface area burned of 17.02%, and average full-thickness burn of 6.09%. Forty percent had facial injuries, 68.6% required surgery, most were injured by flame (39.5%), and 76.8% were employed. RESULTS: Multivariate analysis of covariance (covarying preburn level of Mental quality of life, facial injury, and size of burn) contrasting body image dissatisfaction groups found significantly lower psychosocial adjustment at 2-month follow-up in those with greater body image dissatisfaction (multivariate F = 3.61; p<.01). A second MANCOVA (covarying the preburn level of Physical quality of life and both facial injury and size of burn) found significantly lower physical functioning at 2-month follow-up in those with greater body image dissatisfaction (multivariate F = 2.78; p < .03). Adding two more covariates (depression and posttrauma distress) eliminated the effect of body image dissatisfaction on postburn Physical but not Mental adjustment. CONCLUSIONS: Body image dissatisfaction affects quality of life after severe burn injury. Distress moderates this impact on aspects of physical but not psychosocial health.

Jet and ultrasonic nebulization of single chain urokinase plasminogen activator (scu-PA).

Recent studies have indicated that the deposition of intra-alveolar fibrin may play a central role in the pathogenesis of acute respiratory distress syndrome (ARDS). Our aim was to study whether the indigenous fibrinolytic agent (urokinase) normally present in the alveoli can be administered locally by nebulization in a recombinant zymogen form as single chain urokinase plasminogen activator (scu-PA). We aimed to characterize the particle size distribution, drug output, and enzymatic activity of scu-PA after nebulization with a Ventstream jet nebulizer (Medic-Aid, Bognor Regis, UK) and a Syst'AM DP-100 ultrasonic nebulizer (Pulmolink, Kent, UK). The particle size distribution was measured with a laser diffraction method and the drug output was determined by collection on filters. The amount of protein on the filters was determined with the Lowry method, and the enzymatic activity after nebulization was measured with a microtiter fibrin plate assay. The mass median diameter (MMD) of the scu-PA aerosol generated with the ultrasonic nebulizer was 3.69 (3.53-3.83) microm and with the jet nebulizer 2.96 (2.91-3.03) microm (p < 0.001). The drug output from the two nebulizers did not differ between nebulizers (p = 0.054). Fibrinolytically active scu-PA was generated with both nebulizers, but in contrast to jet nebulization, ultrasonic nebulization caused partial inactivation of scu-PA (p < 0.001). In conclusion, nebulization of scu-PA with the jet nebulizer is superior to ultrasonic nebulization in terms of particle size distribution and preservation of fibrinolytic activity.

Prolonged adjustment difficulties among those with acute posttrauma distress following burn injury.

This study examined the impact of mild to moderate symptoms of in-hospital posttrauma distress (PTD) following severe burn injury on quality of life (QOL) at 2-month follow-up after controlling for preburn QOL, injury severity, and state Negative Affectivity (depression, body image dissatisfaction) and dispositional optimism-pessimism. Participants' (n = 86) self-report established PTD and non-PTD groups (median split on Davidson Trauma Scale). After covarying preburn level of psychosocial QOL, PTD groups differed on psychosocial functioning at follow-up. This effect remained after covarying injury severity, state NA, dispositional optimism-pessimism, and preburn Mental domain QOL. PTD groups also differed significantly on physical functioning at follow-up after covarying preburn physical functional status. This effect was removed by controlling preburn Physical domain QOL and either injury severity or state NA and dispositional optimism-pessimism. Therefore, PTD is related to significant impairments in the physical and psychosocial adjustment of survivors of severe burns regardless of pretrauma level of adjustment. Injury severity and state NA and dispositional optimism-pessimism moderate the impact of PTD on physical but not psychosocial adjustment.

Multicentre randomised study of computerised anticoagulant dosage. European Concerted Action on Anticoagulation.

BACKGROUND: The demand for anticoagulant treatment is increasing. We compared the benefits of computer-generated anticoagulant dosing with traditional dosing decided by experienced medical staff in achieving target international normalised ratios (INRs). METHODS: In five European centres we randomly assigned 285 patients in the stabilisation period and stabilised patients to the computer-generated-dose group (n=137) or traditional-dose group (n=148). Centres had a specialist interest in oral anticoagulation but no previous experience with computer-generated dosing. The computer program calculated doses and times to next visit. Our main endpoint was time spent in target INR range (Rosendaal method). FINDINGS: For all patients combined, computer-generated dosing was significantly beneficial overall in achieving target INR (p=0.004). The mean time within target INR range for all patients and all ranges was 63.3% (SD 28.0) of days in the computer-generated-dose group compared with 53.2% (27.7) in the traditional-dose group. For the stabilisation patients alone, computer-generated doses led to a non-significant benefit in all INR ranges (p=0.06), whereas in the stable patients the benefit was significant (p=0.02). INTERPRETATION: The computer program gave better INR control than the experienced medical staff and at least similar standards to the specialised centres should be generally available. Clinical outcome and cost effectiveness remain to be assessed.

Burns of the hand and upper limb--a review.

This review article addresses the principles and controversies associated with thermal injury to the hand and upper limb. Accepted principles are outlined and areas of controversy are discussed in a balanced manner. The importance of hand burns is described functionally and epidemiologically. Burns appropriate to outpatient care are defined and treatment discussed, including debridement, topical therapy, rehabilitation and follow-up. The general principles of inpatient management are given, including the controversial issue to timing of surgery and treatment of the exposed tendon or joint. The extent of surgery, methods of wound closure and difficult problem of palm burns are also discussed. Reconstructive principles are outlined and a problem oriented approach to the most common reconstructive problems given.