Impact of immunosuppressive therapy on therapy-neutralizing antibodies in transplanted patients with Fabry disease.

BACKGROUND: Inhibitory antibodies towards enzyme replacement therapy (ERT) are associated with disease progression and poor outcome in affected male patients with lysosomal disorders such as Fabry disease (FD). However, little is known about the impact of immunosuppressive therapy on ERT inhibition in these patients with FD. METHODS: In this retrospective study, we investigated the effect of long-term immunosuppression on ERT inhibition in male patients with FD (n = 26) receiving immunosuppressive therapy due to kidney (n = 24) or heart (n = 2) transplantation. RESULTS: No ERT-naïve transplanted patient (n = 8) developed antibodies within follow-up (80 ±72 months) after ERT initiation. Seven (26.9%) patients were tested ERT inhibition positive prior to transplantation. No de novo ERT inhibition was observed after transplantation (n = 18). In patients treated with high dosages of immunosuppressive medication such as prednisolone, tacrolimus and mycophenolate-mofetil/mycophenolate acid, ERT inhibition decreased after transplantation (n = 12; P = 0.0160). Tapering of immunosuppression (especially prednisolone) seemed to re-increase ERT inhibition (n = 4, median [range]: 16.6 [6.9; 36.9] %; P = 0.0972) over time. One ERT inhibition-positive patient required interventions with steroid therapy and increased doses of tacrolimus, which also lowered ERT inhibition. CONCLUSION: We conclude that the immunosuppressive maintenance therapy after transplantations seems to be sufficient to prevent de novo ERT inhibition in ERT-naïve patients. Intensified high dosages of immunosuppressive drugs are associated with decreased antibody titres and decreased ERT inhibition in affected patients, but did not result in long-term protection. Future studies are needed to establish ERT inhibition-specific immunosuppressive protocols with long-term modulating properties to warrant an improved disease course in ERT inhibition-positive males.

Penetrating trauma in patients older than 55 years: a case-control study.

BACKGROUND: Multiple studies have compared young and elderly blunt trauma patients, and concluded that, because elderly patients have outcomes similar to young patients, aggressive resuscitation should be offered regardless of age. Similar data on penetrating trauma patients are limited. STUDY DESIGN: In a retrospective review, 79 patients with penetrating injuries and age > or =55 were blindly matched for Injury Severity Score (ISS) and Abbreviated Injury Scores (AIS) with 79 penetrating trauma patients aged 15-35 years, who were admitted to the hospital over the same 4 year period (June 1994-June 1998). Mortality rates and length of stay in the intensive care unit (ICU) and the hospital were compared between the two groups. RESULTS: The average ISS for all patients was 12 (range 1-75) and identical for both groups. Both groups had similar injuries and were evaluated by an equal number and type of diagnostic studies. The mean ISS was not different between severely injured older and younger patients who required ICU admission or died. Among 32 nonsurvivors (18 older and 14 younger), older patients were more likely than younger patients to present with normal vital signs, although the comparison did not reach statistical significance (50% vs. 13%, P=0.25). There was a clinically significant trend for longer ICU (15+/-30 vs. 3+/-2 days, P=0.096) and hospital stay (10+/-18 vs. 6+/-8 days, P=0.08) among older patients, but mortality rates were similar (23% in older vs. 18% in younger, P=NS). Furthermore, these outcome parameters showed no difference when both groups were classified according to severity of injury or physiologic response. CONCLUSIONS: Following penetrating trauma, older patients arriving alive and admitted to the hospital are as likely to survive as younger patients who have injuries of similar severity, but at the expense of longer ICU and hospital stays.

An evidence-based cost-effectiveness model on methods of prevention of posttraumatic venous thromboembolism.

BACKGROUND: Venous thromboembolism (VT) after injury is a major health problem. Literature data on methods of VT prophylaxis are not consistent with regard to safety and efficacy, and a recent evidence-based report could not conclude that any method was superior to any other or to no prophylaxis. Because no study exists on the cost-effectiveness (C-E) of the different methods of prophylaxis, data from the evidence-based report were used to design a C-E analysis. This analysis will assist in the design of future randomized trials with adequate power to show significant outcome differences. METHODS: A decision-tree model was designed on the basis of outcomes from the evidence-based report or relevant literature. We then calculated the cost of prevention of VT by one of the most commonly used methods-low-dose heparin (LDH), low-molecular-weight heparin (LMWH), or sequential compression devices (SCDs)-using different probabilities of incidence of VT. Finally, we adjusted the cost for expected years of life after the episode of VT to calculate the cost per life-year saved by preventing VT. RESULTS: We produced two tables that can be used to calculate the cost per life-year saved for any patient according to his or her age and the method of prophylaxis used. VT prophylaxis becomes less cost-effective as age progresses, because of decreased life-expectancy. With a widely accepted cost limit of $50,000 per life-year saved to indicate cost-effective treatment, LDH is more cost-effective than LMWH or SCDs. CONCLUSION: Our C-E model can help future investigators plan VT-related research with appropriate sample sizes to evaluate cost-effective methods of prophylaxis. LMWH and SCDs must demonstrate substantial improvements in measured outcomes to be more cost-effective than LDH. C-E must be incorporated as a primary outcome in future studies comparing different methods of VT prophylaxis.

Prevention of venous thromboembolism after injury: an evidence-based report--part II: analysis of risk factors and evaluation of the role of vena caval filters.

OBJECTIVE: In part II, we describe the results of the literature search and data analysis concerning risk factors for venous thromboembolism and the role of vena caval filters (VCF) in preventing pulmonary embolism. METHODS: The methodology used in part I was used in part II. RESULTS: Spinal fractures and spinal-cord injuries increase the risk for development of deep venous thrombosis (DVT) by twofold and threefold, respectively. Patients with DVT were an average of 9 years older than patients without DVT. No specific age cut-off point for increased risk could be established because data could not be combined across studies. Patients with prophylactically inserted VCF had a lower incidence of pulmonary embolism (0.2%) compared with concurrently managed patients without VCF (1.5%) or historical controls without VCF (5.8%). These results are reported on uncontrolled studies with observational design. CONCLUSION: Spinal injuries, spinal cord injuries, and age are risk factors for development of DVT. Prophylactic placement of VCF in selected trauma patients may decrease the incidence of pulmonary embolism. Future research with well-designed studies is required to provide definitive answers.

Prevention of venous thromboembolism after injury: an evidence-based report--part I: analysis of risk factors and evaluation of the role of vena caval filters.

BACKGROUND: Trauma surgeons use a variety of methods to prevent venous thromboembolism (VT). The rationale for their use frequently is based on conclusions from research on nontrauma populations. Existing recommendations are based on expert opinion and consensus statements rather than systematic analysis of the existing literature and synthesis of available data. The objective is to produce an evidence-based report on the methods of prevention of VT after injury. METHODS: A panel of 17 national authorities from the academic, private, and managed care sectors helped design and review the project. We searched three electronic databases (MEDLINE, EM-BASE, and Cochrane Controlled Trial Register) to identify articles relevant to four key questions: methods of prophylaxis, methods of screening, risk factors for VT, and the role of vena caval filters. The initial 4,093 titles yielded 73 articles for meta-analysis. A random-effects model was used for all pooled results. Study quality was evaluated by previously published quality scores. In this article (part I), we report on the question ranked by the experts as the most important, i.e., Which is the best method to prevent VT?, and also on the incidence of deep venous thrombosis and pulmonary embolism in trauma patients. RESULTS: The incidence of deep venous thrombosis and pulmonary embolism reported in different studies varies widely. The pooled rates are 11.8% for deep venous thrombosis and 1.5% for pulmonary embolism. Only a few randomized controlled trials have evaluated the methods of VT prophylaxis among trauma patients, and combining their data is difficult because of different designs and preventive methods used. The quality of most studies is low. Meta-analysis shows no evidence that low-dose heparin, mechanical prophylaxis, or low-molecular-weight heparin are more effective than no prophylaxis or each other. However, the 95% confidence intervals of many of the comparisons are wide; therefore, a clinically important difference may exist. CONCLUSION: The trauma literature on VT prophylaxis provides inconsistent data. There is no evidence that any existing method of VT prophylaxis is clearly superior to the other methods or even to no prophylaxis. Our results cast serious doubt on the existing policies on VT prophylaxis, and we call for a large, high-quality, multicenter trial that can provide definitive answers.

The prevalence and effect of alcohol and drug abuse on cohort-matched critically injured patients.

A prospective study was undertaken at a Level I trauma center to evaluate the prevalence of substance use among victims of major trauma, along with the impact on clinical outcome. Five hundred sixteen patients had urine toxicology and blood alcohol screens performed and correlated with pattern and severity of injury, hospital course, and outcome. Three hundred seventy-one patients (71%) screened positive for alcohol or drugs, or both. Fifty-two per cent had positive alcohol screens, and 42 per cent had positive drug screens (cocaine and opiates represented 91% of positive drug screens). Univariate analysis revealed patterns of alcohol/drug use varied among subgroups according to demographics (less use among patients older than 55 years, females and Asians; more drug use in blacks; more alcohol use in Hispanics), mechanism of injury (non-use in blunt trauma patients and use of both in penetrating trauma patients) and body region injured (non-use in head-injured patients). Septic complications and mortality were more correlative with severity of injury, but not with use or non-use of alcohol or drugs. We conclude that alcohol and drug use remains a major comorbid factor in major trauma, and that injury prevention efforts should include a strong focus on counseling regarding these lifestyle choices.

Use of large databases for resolving critical care problems.

Large databases allow for rapid access to large volumes of data. To convert raw data to information, large numbers of data points must be correlated into a descriptive pattern that can be interpreted by the user. Databases must be constructed so as to allow reliable extraction of the raw data into a format that supports analysis of events in a meaningful, objective, and reproducible manner. Databases must be responsive to a variety of users. They must not demand unrealistic amounts of effort on those responsible for data entry. Standard protocols in various stages of development will make databases easier to use and more reliable. Database management tools such as the Internet and the National Library of Medicine will become more integrated into the practice of critical care medicine at all levels, including administration, clinical care, and research. This article provides an overview of the capabilities and difficulties associated with large databases. The major areas of use of large databases in the hospital setting are administration, bibliographic, patient care, research, and education. Each of these areas has different requirements and is supported by different types of databases. The advantages and disadvantages of linear, relational, and object-oriented databases are discussed. Issues relating to methods of data entry and the accuracy and reliability of data are discussed. The challenges involving integration of various sources of data and the interfacing of devices are reviewed.