An ethical analysis of proxy and waiver of consent in critical care research.

It is a central principle in medical ethics that vulnerable patients are entitled to a degree of protection that reflects their vulnerability. In critical care research, this protection is often established by means of so-called proxy consent. Proxy consent for research participation constitutes a substituted judgement by a close relative or friend, based on knowledge of patient's values, preferences, and view of life. For the consent to be genuine, the proxy must be informed of and understand three fundamental aspects of research practice: (1) that participation is voluntary and the consent can be withdrawn at any time; (2) that the research is designed to benefit future patients and society as a whole, and not the individual study participant; and (3) that participation involves an incremental non-therapeutic risk. If this is not fulfilled because the research is to be conducted under circumstances where the proxy is unavailable, adequate protection of the patient must be ensured by other means. Thus, the research must be designed specifically to benefit critically ill patients, and the incremental non-therapeutic risk must only comprise a minimal risk.

The secret art of managing healthcare expenses: investigating implicit rationing and autonomy in public healthcare systems.

Rationing healthcare is a difficult task, which includes preventing patients from accessing potentially beneficial treatments. Proponents of implicit rationing argue that politicians cannot resist pressure from strong patient groups for treatments and conclude that physicians should ration without informing patients or the public. The authors subdivide this specific programme of implicit rationing, or "hidden rationing", into local hidden rationing, unsophisticated global hidden rationing and sophisticated global hidden rationing. They evaluate the appropriateness of these methods of rationing from the perspectives of individual and political autonomy and conclude that local hidden rationing and unsophisticated global hidden rationing clearly violate patients' individual autonomy, that is, their right to participate in medical decision-making. While sophisticated global hidden rationing avoids this charge, the authors point out that it nonetheless violates the political autonomy of patients, that is, their right to engage in public affairs as citizens. A defence of any of the forms of hidden rationing is therefore considered to be incompatible with a defence of autonomy.

Cortical changes to experimental sensitization of the human esophagus.

Topographical organization in the neocortex shows experience-dependent plasticity. We hypothesized that experimental sensitization of the esophagus results in changes of the topographical distribution of the evoked potentials and the corresponding dipole source activities to painful stimulation. An endoscopic method was used to deliver 35 electrical stimuli at the pain threshold to a fixed area of the mucosa in 10 healthy volunteer men and women. The stimulations were repeated after 30 min (reproducibility experiment), and after 60 min following perfusion of 200 ml 0.1 N hydrochloric acid (sensitization experiment). During stimulation the electroencephalogram was recorded from 64 surface electrodes. The sensitization resulted in a decrease in the pain threshold (F=6.2; P=0.004). The topographic distribution of the evoked potentials showed reproducible negative (N1, N2) and positive (P1, P2) components. After acid perfusion a reduced latency and a change in localization was seen for the P1 subdivided into frontal and occipital components (F=29.5, P<0.001; F=53.7, P<0.001). Furthermore the sensitization resulted in a reduction of the latency for P2 (F=6.2, P=0.009). The source analysis showed consistent dipolar activity in the bilateral opercular-insular cortex before and after acid perfusion. For the anterior cingulate dipole there was a reduction in latency (P=0.03) and a posterior shift (P=0.0002) following acid perfusion. The findings indicate that short-term sensitization of the esophagus results in central neuroplastic changes involving the cingulate gyrus, which also showed pathological activation in functional diseases of the gut, thus reflecting the importance of this region in visceral pain and hyperalgesia.

Patients' perceptions of informed consent in acute myocardial infarction research: a questionnaire based survey of the consent process in the DANAMI-2 trial.

OBJECTIVE: To analyse how patients in the acute phase of a myocardial infarct experience the informed consent procedure of a clinical trial. DESIGN: A questionnaire based follow up survey including patients who gave informed consent as well as patients who did not consent to the trial. PATIENTS: 103 patients who gave informed consent and 78 who did not consent to the second Danish acute myocardial infarction trial (DANAMI-2). RESULTS: 76% of the trial participants and 63% of the non-participants agreed or mostly agreed that they felt able to make a decision about whether or not to participate in the trial; 50% of the trial participants and 34% of the non-participants found it acceptable that patients in their situation have to make such a decision. Only 28% of the trial participants and 7% of the non-participants read the information sheet before they made the decision. CONCLUSIONS: Informed consent should be sought in acute myocardial infarction trials despite the emergency situation and the medical condition of the patients. Patients' self assessed ability to make a decision should be explicitly addressed during the informed consent process and patients should not be pressurised into decision making. Physicians and research ethics committees should focus specifically on improving the oral information.

Patient-physician communication concerning participation in cancer chemotherapy trials.

Cancer patients demand a high level of involvement in decisions concerning treatment. Many patients are informed about experimental trials, and especially the first consultation may be crucial for the future communication and treatment process. Patients with nonresectable non-small-cell lung cancer or colorectal cancer informed about experimental chemotherapy completed a questionnaire on satisfaction with the communication process, general attitude towards experimental treatments, the substance of information, and personal contact with the physician following their first consultation in a medical oncology unit. Physicians completed a questionnaire on their perception of the patients' satisfaction. Among 68 physician-cancer patient pairs, 29 patients were informed on chemotherapy in randomised trials and 39 in nonrandomised studies. The general attitude towards experimental treatment was positive or very positive in 71% of patients. Information on the treatment was perceived as completely adequate in 93% of patients informed on randomised and in 67% informed on nonrandomised trials. Physicians underestimated the patients' satisfaction with the overall communication process, the personal contact, the patients' perceived sufficiency of the specific treatment information and their ability to decide on study entry. In conclusion, considerable differences were observed between patients informed about experimental chemotherapy in randomised and nonrandomised trials, both with respect to their perception of how adequate the information on the specific treatments were, and whether it was sufficient for decisions on study entry. This study type effect should be accounted for in future evaluations of communication and patient satisfaction. The data also support the fact that cancer patients have a desire for and ability to understand rather detailed and comprehensive treatment information.

Absence of dysfunctional ileal sodium-bile acid cotransporter gene mutations in patients with adult-onset idiopathic bile acid malabsorption.

BACKGROUND: A congenital form of idiopathic intestinal bile acid malabsorption (IBAM) has been associated with dysfunctional mutations in the ileal apical sodium-dependent bile acid transporter (ASBT). The aim of this study was to determine whether mutations in the ASBT gene (SLC10A2) predispose to the development of adult-onset idiopathic bile acid malabsorption and chronic watery diarrhea. METHODS: Genomic DNA was obtained from 13 adult IBAM patients previously diagnosed on the basis of clinical data, response to cholestyramine, and abnormal 75Se-homocholic acid taurine (SeHCAT) test values. The ASBT gene was screened for the presence of mutations or polymorphisms by single-stranded conformation polymorphism analysis (SSCP) and DNA sequencing. RESULTS: ASBT gene polymorphisms were detected in 5 of the 13 adult IBAM patients. Four patients were heterozygous for a common polymorphism in exon 3, leading to an alanine to serine substitution at codon 171 (A171S). An additional subject was heterozygous for a polymorphism in exon 1 that causes a valine to isoleucine substitution at codon 98 (V981). These functional polymorphisms were also found in unaffected subjects and do not appear to affect ASBT function. CONCLUSIONS: Adult-onset IBAM is not directly related to dysfunctional mutations in the coding region or intron/exon junctions of the SLC10A2 gene. In the absence of apparent ileal disease or intestinal motility defects, inappropriate down-regulation of the ileal bile acid transporter or defects in ileocyte transfer of bile acids into the portal circulation could explain this form of adult IBAM.

Sensitivity and distensibility of the rectum and sigmoid colon in patients with irritable bowel syndrome.

BACKGROUND: Hyperalgesia to visceral stimuli is a biological marker of the irritable bowel syndrome (IBS). Abnormal pain processing is probably of most importance, but biomechanical abnormalities of the gut wall may also contribute to the findings. In the current study, we investigated the sensation of the gut to electrical stimuli as well as the distensibility of the rectum and sigmoid colon in IBS patients and a control group. METHODS: Nine patients with IBS and 11 controls entered the study. The pain threshold to electrical stimuli at the rectosigmoid junction was determined with bipolar electrodes integrated on the biopsy forceps for the endoscope. Subsequently, controlled distensions of the sigmoid colon and rectum were performed with a balloon integrated on a probe for impedance planimetry, providing the possibility to measure the cross-sectional area (CSA), wall tension and strain to different pressures together with the sensation ratings. RESULTS: The pain detection thresholds to electrical stimuli at the rectosigmoid junction were 12.5 (range 7-39) mA in controls and 7.5 (range 0.75-12) mA in IBS patients (P = 0.03). The calculated pressures at the pain detection threshold in the sigmoid colon were lower in the IBS patients (31.5 (range 5-58) versus 5 cm (range 5-25) water; P = 0.03), otherwise no differences were seen in sensation rating to the different distension pressures. The CSA was slightly higher in controls to the different pressures, whereas no differences between the groups were seen in strain and tension of the rectum and sigmoid colon. CONCLUSION: The visceral hypersensitivity in IBS seems to be related to alterations in the nervous system rather than biomechanical parameters such as the tension and strain of the gut wall. Treatment of pain in IBS should therefore be based on drugs with documented action on the nociceptive pathways in the central nervous system.

Cerebral response to electric stimulation of the colon and abdominal skin in healthy subjects and patients with irritable bowel syndrome.

BACKGROUND: Visceral hyperalgesia may play an important part in the pathophysiology of the irritable bowel syndrome (IBS). We investigated the neuronal afferent pathways in healthy volunteers and IBS patients by recording evoked potentials (EPs) elicited by electrical stimulation of the colon and abdominal skin inside and outside the referred pain area. METHODS: Six healthy subjects and nine IBS patients met the inclusion criteria. Morphology and topography of EPs to painful electrical stimuli were estimated in the rectosigmoid junction and on the skin inside/outside the referred pain areas. RESULTS: The EPs to painful stimuli of the gut showed a shorter latency and a smaller amplitude of the first positive peak (P1) in the IBS group. The controls had a mid-latency frontal positive component after 100 ms, whereas no reliable early activation was seen in the IBS patients. In controls, a single late (>150 ms) positive component was seen, whereas the late component was biphasic in the IBS group. The EPs to painful stimuli of the two skin areas differed in IBS patients, but not in controls. CONCLUSION: Differences in the EPs to electrical painful stimulation of the sigmoid colon and skin inside/outside the experimentally evoked referred pain area were seen comparing healthy subjects and IBS patients. The results indicate altered central nervous system responses.

Sensory and biomechanical responses to distension of the normal human rectum and sigmoid colon.

BACKGROUND: Visceral pain is a major clinical problem. The aim of the present study was to compare the pain and biomechanical responses to standardized distension of the human colon. METHODS: The relation between pain intensity and pressure, cross-sectional area (CSA) and tension-strain relations of the rectum and sigmoid colon were studied in 11 normal subjects following standardized distension using impedance planimetry. The bag was inflated stepwise with pressures up to 6 kPa. The subjects, who were blinded for the distension procedure, rated their pain intensity using an aggregate visual analogue score (VAS) combining the intensity of the feeling of air, urge to defecate and pain. RESULTS: The distensions produced an initial rapid increase in CSA followed by a phase of slow increase until a steady state CSA was reached after 0.5-1 min. Several phasic contractions (observed as short-term decreases in the CSA) were recorded in the rectum from the end of the rapid phase to the end of distension at pressures from 1 to 5 kPa. The CSA in the rectum and sigmoid colon was 3,706 +/- 426 mm(2) and 2,305 +/- 426 mm(2) at the maximum bag pressure of 6 kPa (F = 52.4, p < 0.001). The tension-strain relation did not differ between the normal rectum and sigmoid colon. The VAS score for every modality (air, defecation and pain) revealed an increase in intensity as a function of pressure. The VAS score in the rectum and the sigmoid colon as a function of tension and strain did not show any differences. CONCLUSIONS: The biomechanical properties in the sigmoid colon and rectum were alike. For a given wall tension and circumferential strain the sensibility seems equal in the rectum and the sigmoid colon. The observed difference in perception between the two segments was related to the greater CSA in the rectum.

Cognitive studies of ethical reasoning based on the KARDIO-simulator.

Empirical investigations in medical ethics are often questionnaire studies relying on the respondents' written responses about their attitudes and actions. This approach is valuable, but there may be quite large discrepancies between responses and actual behaviour. Unfortunately actual behaviour is often difficult to observe, especially where sensitive or very time dependent clinical decisions are concerned. We have tried to circumvent this problem by using a micro-world computer simulation of a cardiac care unit to study treatment decisions in "life or death" situations. The task facing the physician in this simulation is to be in charge of a 6-bed cardiac care unit for a period of 14 "days" controlling admissions, discharges, and treatment of all patients. The simulation dynamically generates the disease states of the patients in the unit including physical findings, laboratory findings, ECG, X-ray descriptions etc., as well as the patients responses to treatment. The simulation also presents new patients from the emergency room, thereby forcing the physician to decide whether the new patient should be admitted, and whether one of the present patients should be discharged or moved to another ward if no bed is free. The paper describes this simulator, the mathematical model underlying the simulation of patients with acute myocardial infarction, and the results of the initial studies using the simulator.

Pain produced by electric stimulation of the rectum in patients with irritable bowel syndrome: further evidence of visceral hyperalgesia.

BACKGROUND: Visceral hyperalgesia is most likely a phenomenon of substantial clinical importance and may also play a role in the pathophysiology of the irritable bowel syndrome (IBS). We investigated the manifestation of visceral hyperalgesia in IBS patients by nociceptive electric stimulation of the rectosigmoid junction and rectum. METHODS: Twelve IBS patients fulfilling the Rome criteria and 9 healthy controls were studied. Visceral single and repeated electric burst stimuli were applied with a bipolar electric stimulator inserted through the sigmoidoscope. The sensation (ST) and pain detection (PDT) thresholds were determined in response to single and repeated stimuli at the rectosigmoid junction, and PDT to repeated stimuli at four different positions in the rectum. Cutaneous single and repeated electric stimuli were applied to the lateral aspect of the foot, determining ST and PDT. RESULTS: Cutaneous stimulation showed no significant differences for ST and PDT between patients and controls. The rectosigmoid junction showed significantly lower ST for single stimuli (P<0.01) and a significantly lower PDT for single and for repeated stimuli (P<0.05 and P<0.02) in IBS patients. In the rectum the IBS patients had a significantly lower PDT than controls (P<0.001). CONCLUSIONS: For cutaneous electric stimulation no differences in the pain thresholds between the two groups were found, showing that there is no generalized hyperalgesia in IBS patients. The IBS patients had a specific decrease of the pain thresholds in the rectum and rectosigmoid junction, indicating visceral hyperalgesia. These results point to central visceral hyperexcitability as an important factor in the pathophysiology of IBS.

A computer-based information system for epilepsy and electroencephalography.

This paper describes a standardised computer-based information system for electroencephalography (EEG) focusing on epilepsy. The system was developed using a prototyping approach. It is based on international recommendations for EEG examination, interpretation and terminology, international guidelines for epidemiological studies on epilepsy and classification of epileptic seizures and syndromes and international classification of diseases. It is divided into: (1) clinical information and epilepsy relevant data; and (2) EEG data, which is hierarchically structured including description and interpretation of EEG. Data is coded but is supplemented with unrestricted text. The resulting patient database can be integrated with other clinical databases and with the patient record system and may facilitate clinical and epidemiological research and development of standards and guidelines for EEG description and interpretation. The system is currently used for teleconsultation between Gentofte and Lisbon.

Prognosis of adult-onset idiopathic bile acid malabsorption.

BACKGROUND: From 1986 to 1993, 150 patients were investigated with the 75Se-homocholic acid taurine (SeHCAT) test as a late step in the investigation of chronic diarrhoea. On basis of low SeHCAT values and response to cholestyramine treatment, 33 patients were initially classified as having idiopathic bile acid malabsorption (IBAM). The aim was to describe the long-term clinical course of the disease and to assess the reliability of the SeHCAT test in diagnosing IBAM. METHODS: The methods included 1) clinical follow-up with patient interview combined with information from medical records and 2) repeated SeHCAT test. RESULTS: The diagnosis of IBAM had to be revised in three cases (inflammatory bowel disease in two patients, Clostridium difficile infection in one). Six patients were lost to follow-up and a further four patients were excluded from re-examination either because of old age (>80 years) or bowel resection, leaving 20 patients for re-examination, of which 16 completed both clinical follow-up and a new SeHCAT test. The median duration of symptoms before initial SeHCAT test was 2.5 (1-30) years. In 13 of 16 patients symptoms persisted, and SeHCAT values remained low and almost identical to the initial value after a median observation time of 88 (51-113) months. Despite initial response to treatment with cholestyramine, six patients had to discontinue treatment because of adverse effects or other compliance problems. In three patients the SeHCAT value showed a considerable increase, and bowel function had correspondingly normalized in these cases. CONCLUSION: The study confirms the reliability of the SeHCAT test in diagnosing IBAM. Despite adult onset of symptoms, only a few patients improve after several years' observation. Treatment with cholestyramine is generally effective but not always tolerated.

Can the written information to research subjects be improved?--an empirical study.

OBJECTIVES: To study whether linguistic analysis and changes in information leaflets can improve readability and understanding. DESIGN: Randomised, controlled study. Two information leaflets concerned with trials of drugs for conditions/diseases which are commonly known were modified, and the original was tested against the revised version. SETTING: Denmark. PARTICIPANTS: 235 persons in the relevant age groups. MAIN MEASURES: Readability and understanding of contents. RESULTS: Both readability and understanding of contents was improved: readability with regard to both information leaflets and understanding with regard to one of the leaflets. CONCLUSION: The results show that both readability and understanding can be improved by increased attention to the linguistic features of the information.

Fluconazole therapy in Candida albicans spondylodiscitis.

A case of Candida albicans spondylodiscitis in a 20-year-old female liver transplant recipient is reported. The patient was successfully treated with sequential therapy with liposomal amphotericin B and fluconazole. A review of the literature showed 10 cases of Candida albicans spondylodiscitis successfully treated either with fluconazole alone or a sequential therapy with amphotericin B and fluconazole. If long-term amphotericin B therapy is not feasible, a prolonged course of fluconazole in a daily dose of 200-400 mg may be considered as an alternative.

[What does the Danish population know about the scientific ethics committees?]. / Hvad ved den danske befolkning om det videnskabsetiske komitésystem?

The Danish system of research ethical committees (RECs) was established in 1978 and formal legislation on RECs was passed in 1992. We have investigated the general knowledge about the RECs through a telephone survey of a random sample of the adult Danish population. Among the 1137 respondents only 342 (30%) were aware of the existence of an official body which controls medical research, and only a small minority was aware of the composition of the RECs and that the laymembers outnumber the professional members. Knowledge about RECs was positively correlated to higher education, young age, and being male. It is argued that there is a need for increased public information about the existence and composition of the Danish RECs.