When performing a protocol as in the study of Pilz et al. "...immunoglobulin therapy in sepsis and septic shock..." it is necessary to differentiate between those patients with generalized inflammation and those with bacterial sepsis. The Sepsis Severity Score and the Apache II score are mentioned as being insufficient to identify patients with bacterial sepsis. A proposal is formulated to use clinical data to collect patients with bacterial sepsis, to use the Apache II score for severity of disease, and to use a multiple organ failure score for follow-up.
Previous research on patient preferences in surgical decision making has suggested that most patients are willing to exchange a probability of immediate mortality of 10% for a 15% better 5-year survival rate. To study whether patients base their choices on extrapolations about future trends beyond year 5, we studied 101 consecutive patients seen in a university-based Department of Veterans Affairs Medical Center. Mean age was 66.7 years (SD = 8.87, range = 40-84); mean length of education was 12.8 years (SD = 11.40, range = 4-22 years). All patients were provided with a graph comparing two 5-year survival curves: one curve (worse shortterm, better long-term survival) had a 10% immediate risk of death and 37% 5-year survival; the other (better short-term, worse long-term survival) had 0% chance of immediate death and a 22% 5-year survival. Patients were then presented with two additional comparisons (a 6-year and a 10-year survival comparison); each included the same baseline 5-year survival data. In the 6-year comparison, both treatment curves had a O% chance of survival beyond year 6. In the 10-year comparison, the first curve had a 10% 10-year survival, and the second curve had a 5% 10-year survival. Patients were asked to give their treatment preference on each comparison and to report any assumptions they made when interpreting the original 5-year survival curve. Fewer than 15% of patients showed preference patterns consistent with a significant influence of data beyond 5 years. For most patients, 5-year results appear to be sufficient for choosing among alternative treatments. For a minority of patients, explicit information about data extrapolation leads to preference change. Ignoring this aspect of data interpretation could lead to miscommunication about patient preferences.
Although empiric antibiotic treatment may prevent the development of empyema following tube thoracostomy for isolated chest trauma, such treatment has been questioned because empyema is an uncommon occurrence. Therefore, a threshold analysis was performed to determine the values of empyema risk and antibiotic efficacy above which empiric antibiotic therapy is warranted in tube thoracostomy for trauma. These thresholds and the 95% confidence bands above and below the threshold curve were estimated by Monte Carlo simulation. Comparison of published estimates of empyema risk and drug efficacy with the estimated threshold shows that they lie well within the region favoring empiric antibiotic treatment. For example, if antibiotics decrease the risk of empyema by a factor of four or greater, then any risk of empyema greater than 1-2% is great enough to justify treatment.
The objective of this study was to provide the experimental basis for the use of partially demineralised bone matrix (PDBM) in a hospital bone bank as an alternative to allogeneic bone. Thirty cortical defects 0.6 cm in diameter in the tibia of 18 merino sheep were filled with allogeneic and autogenic cancellous bone, PDBM, and the hydroxyapatite ceramics Pyrost and Bio-Oss. The extent of new bone formation was ascertained by way of fluorescent-optical, microradiographical and histological examination. While, after a period of 6 weeks, implantation of autogenic cancellous bone and PDBM resulted in the virtually complete bridging of the defect, the new bone formation following implantation of hydroxyapatite ceramics showed no significant difference from the controls. The effect of different sterilisation techniques on the osteoinductive properties of PDBM was examined in a similar way. The evaluation of 44 cortical defects showed excellent new bone formation for PDBM sterilised with ethylene oxide, gamma irradiation and ethyl alcohol. In a third series, 5-cm-long diaphyseal defects in the left tibia of 25 merino sheep were stabilised by medullary nailing and filled with PDBM, varying in form and size. It was shown that transplantation of PDBM with a particle size of 750 mu m resulted in the bridging of the defect within 20 weeks, while larger transplants were predominantly resorbed. The addition of small amounts of bone marrow enhanced new bone formation significantly. We conclude that sterilised PDBM, which can easily be provided by hospital bone banks, represents an alternative to untreated allogeneic bone.
The randomized clinical trial is the preferred standard for assessing treatment effects. In the field of surgical infections a striking difference is observed between recommended methodological approaches and actually performed clinical trials. Major problems are inhomogeneous patient groups, nonstandardized or unfulfilled criteria for study entry, for severity of disease or for response to therapy, or analysis of the results in subgroups made a posteriori. Several approaches have been undertaken to improve clinical trials in this field; e.g. scores have been developed for defining seventy of disease, and standardised definitions have been agreed on with respect to diagnostic and outcome criteria. Unfortunately, information about definitions, classifications and scores is voluminous, and it is nearly impossible for a researcher to keep abreast of the state of the art. Today, several types of computer systems exist which can be used to support planning, performance and analysis of studies, such as literature retrieval systems, registries of clinical trials and expert systems. Still lacking are computer programs giving specific support for the planning of clinical trials in surgical infections. In cooperation with the Surgical Infection Society Europe, a computerized information system is under development at the University of Dusseldorf, Germany. The program will consist of three parts: (a) information about published studies on surgical infections, (b) information about ongoing studies in surgical infection, and (c) general study information. The first part of the program will contain basic data on performed randomized trials and specific information about definitions, classifications and scores. The second part provides information about ongoing trials and will contain study protocols. The third part covers general instructions for developing study protocols and addresses of the members of the Surgical Infection Society Europe and of other research teams working in the field of surgical infections. A demonstration version has already been developed and is available.
This paper comments on the proposed Pilz clinical trial to evaluate the efficacy of polyvalent immunoglobulin in severely ill patients with sepsis. It discusses methodological difficulties with this trial and with surgical trials in general, and proposes strategies which may be employed to overcome them. Some of the insights presented originate from the methods used to study the effects of anticancer therapy or computerised medical decision aids.
On the basis of a published study protocol about i.v. gammaglobulin treatment for septic patients some immunological aspects with regard to the patients and the treatment are discussed. One main point is the comparability of septic patients, which remains difficult despite scoring systems. From the immunological point of view, the substitution of IgG seems to be insufficient, because many other humoral and cellular systems are impaired in septic patients which are not improved by the IgG administration. Since IgG preparations also have an antiendotoxic effect, septic patients can profit decisively from i.v. gammaglobulin which neutralizes the bacterial toxins that induce multiple organ failure. The study should be completed with the determination of IgG subclasses, to get more information about subclass deficiencies in septic patients. The last point is the effective dosage of i.v. immunoglobulin therapy in septic patients. Is a fixed dosage the optimum, or should the dosage be correlated to the gammaglobulin or endotoxin concentration? As especially this question must remain open, the discussion will continue regardless to the outcome of the trial.
A mail survey of 283 members of the Isreali Association of Surgeons was conducted to document their current attitudes concerning the duration of antibiotic therapy following emergency operations for abdominal contamination and infection. The response rate to the questionnaire was 26.5%. Evaluation of responses demonstrated that about half of the answers supported an excessive use of postoperative antibiotics. It appears that failure to distinguish between contamination - requiring no or minimal postoperative administration - and infection - requiring a proper postoperative course - is currently the main reason for the unnecessarily prolonged use of antibiotics.
The trial of supplemental immunoglobulin therapy in sepsis and septic shock by Pilz et al. has several design flaws. These include: the questionable use of APACHE II scores to define responders; inadequate standardization of customary therapeutic maneuvers in septic patients; potentially inadequate sample size because of failure to account for protocol deviants and nonresponders to intravenous immunoglobulin (IVIG) therapy; lack of a formal sequential monitoring procedure for interim data analysis; lack of an independent data monitoring board to review the progress of the study and make decisions about its continuation or termination; and a primary analysis that excludes protocol deviants and is not according to intent to treat. These problems will impact upon the validity of the trial and may well prevent resolution of the controversy surrounding the use of IVIG therapy in septic patients.
Secondary deterioration after intracranial operation, spontaneous bleeding, or craniocerebral trauma is difficult to detect from clinical signs and symptoms in patients who are already in coma or under high-dose sedative/analgesic drugs. Pupillary changes are relevant in this situation, but they are late indicators of deterioration. In order to find out whether or not evoked potential (EP) monitoring can improve early detection of secondary deteriorations, we performed a prospective observational study on comatose patients in a neurosurgical intensive care unit. Somatosensory EPs were recorded bilaterally at predefined intervals (initially, every 4 h) and examined with regard to their power to predict secondary deterioration in 59 brain-injured patients. Pupillary pathology served as a gold standard of symptomatic deterioration. Receiver operating characteristics were used to identify the most powerful predictive EP parameter. The amplitude of the first cortical wave (after logarithmic transformation) proved to be the most effective predictive parameter, slightly superior to central conduction time. The cutoff point segregating safe from alarming values should be placed three standard deviations below the arithmetic mean of an appropriate reference population, when sensitivity and specificity are of equal importance. The warning time was between 4 and 68 h.
The argument is brought forth that double-blinding in the strict sense, i.e. the elimination of differential expectations concerning treatment effectiveness, can hardly be achieved in sepsis trials because of the complexity of the clinical problem and of available treatment regimens. Recommendations for an improved study design include assessments of doctors' expectancies concerning treatment outcome, or the experimental induction of optimistic expectations vs. neutral expectations. However, in planning and conducting such an experimental expectancy-control design, a number of ethical requirements have to be considered and met.
Fractal analysis is a method of quantifying complex shapes. Although initially described in purely mathematical terms, fractals and the fractal dimension have proved promising in characterization of the complex shapes of interest to the biomedical sciences. In surgery they have been applied to wound healing. There are many ways of calculating the fractal dimension, most of which require complex, tedious computations making them unpractical for clinical or research use. However, the box-counting method of fractal analysis is relatively easy to perform. This technique will be described in this article. Its advantages and limitations will also be addressed.
Algorithms have frequently been mistaken for the graphic format in which they are presented. However, an algorithm is neither a flow chart nor a list of instructions; it is a step-by-step approach to solving a problem. Likewise, a clinical algorithm (CA) is a step-by-step approach to solving a clinical problem. CAs are deterministic, which does not mean that they are rigid. They are practical rather than mathematical algorithms, that can be used only with clinical judgement, and must be tailored to each patient. There are a number of types of, or uses for, CAs that can improve sepsis management, including: diagnostic or severity score CAs; a management CA for managing sepsis, constructed according to recently published standards for use in teaching; research protocol algorithms that must be used to collect data or guide implementation of a clinical trial aimed at validating one or more decisions in the management CA; and finally, protocol-style CAs drawn from the management CA that should be validated using matching outcome studies.
Research into the cellular and biochemical mechanisms of wound healing has progressed rapidly in recent years, but assessment of wound healing has not kept pace with the basic sciences. As new and modem techniques for wound analysis, stereophotogrammetry, ultrasound and fractal analysis have been developed and applied. The latter implies specific conditions: self-similarity on several levels of structural organization and maintenance of complexity. However, fractal analysis of open wounds is still in its infancy and needs further development in demonstrating the fractal nature of wounds, methods of measuring the fractal dimensions of wounds and considering the changes in dimensions as a wound heals.
The goals of the project TELEGASTRO (telematics technology for harmonising and promoting quality in gastroenterology) are to develop via wide consultation a consensus view through which health care in specific areas of gastroenterology may be measured in a widely agreed, standardised and reproducible fashion, to develop using appropriate technology a multi-media package by which this information can be disseminated, and to distribute the multi-media package and measure the reaction to it. Within the project three computer disks are created: disc 1, providing decision support; disc 2, allowing data collection in the clinics, and disc 3, containing teaching programs. A major aspect of the project is the evaluation procedure. An independent international evaluation panel, consisting of members from gastroenterology, health care assessment and technology, has developed a protocol to guide the evaluation procedure in the TELEGASTRO project. The protocol covers all phases of evaluation, including (a) validation of the knowledge base piece by piece and as a whole, (b) evaluation of the functionality and usability of the program by laboratory and field testing, and (c) evaluation of the clinical impact in a field trial. The TELEGASTRO project has run for 2 of its allotted 3 years, and progress to date has been encouraging. Validation of the knowlege base and evaluation of the functionality and usability of the system have been completed. The results achieved so far indicate that the TELEGASTRO program could be a useful tool in supporting good clinical care.
A multicentre trial on the effect of IgG therapy on survival of patients in sepsis and septic shock is used as an example to discuss the limitations and short-comings of multicentre trials as they are currently performed in the field of sepsis and septic shock. This comment focuses mainly on the "case-mix" and "treatment-mix" problem. It is hypothesized that further methodological standards are needed to demonstrate potential benefits of novel therapeutic drugs in multicentre trials.
Reductionism is the process by which scientific theories are encompassed by more "inclusive" or "basic" theories. The thesis of this essay is that reductionism in the biological and medical sciences may be practically unattainable. This thesis is based on the relatively new theories of fractals and chaos. I hope to show that the concepts of self-similarity and sensitive dependence on initial conditions constitute huge theoretical obstacles to the reduction of biomedical theories to molecular biology.
