Biological (microfloral) factors of influence on cytogenetic stability during chemical mutagenesis.

The article presents the results of a study of chromosomal mutations in residents living in the Aral Sea disaster zone. The present study was designed to evaluate the impact of the combined effect of a chemical mutagen (nickel) and bacterial microflora on the level of chromosomal aberrations (CA) in peripheral blood lymphocytes. This study used classical methods of cell cultivation, methods for determining chromosomal aberrations, a cytomorphological method for assessing epithelial cells, and an atomic absorption method for determining trace elements in the blood. The article shows that with an increase of chemical agent in the blood, the number of cells with features of damage and cells with contamination by microflora increases. Both of these factors cause an increase in the frequency of chromosomal aberrations. The article demonstrates how being exposed to a chemical factor increases chromosomal mutations, and also damages membrane components, which leads to a decrease in the barrier and protective function of the cell, and as a result also affects the level of chromosomal aberrations.

The use of cerebral computed tomographic angiography as an ancillary investigation to support a clinical diagnosis of death using neurological criteria: a consensus guideline.

This multidisciplinary consensus statement was produced following a recommendation by the Faculty of Intensive Care Medicine to develop a UK guideline for ancillary investigation, when one is required, to support the diagnosis of death using neurological criteria. A multidisciplinary panel reviewed the literature and UK practice in the diagnosis of death using neurological criteria and recommended cerebral CT angiography as the ancillary investigation of choice when death cannot be confirmed by clinical criteria alone. Cerebral CT angiography has been shown to have 100% specificity in supporting a diagnosis of death using neurological criteria and is an investigation available in all acute hospitals in the UK. A standardised technique for performing the investigation is described alongside a reporting template. The panel were unable to make recommendations for ancillary testing in children or patients receiving extracorporeal membrane oxygenation.

The impact of COVID-19 on organ donation and transplantation in the UK: lessons learned from the first year of the pandemic.

The COVID-19 pandemic had a major impact on UK deceased organ donation and transplantation activity. We used national audit data from NHS Blood and Transplant to explore in detail the effects of the pandemic in comparison with 12 months pre-pandemic, and to consider the impact of the mitigating strategies and challenges placed on ICU by 'waves' of patients with COVID-19. Between 11 March 2020 and 10 March 2021, referrals to NHS Blood and Transplant of potential organ donors were initially inversely related to the number of people with COVID-19 undergoing mechanical ventilation in intensive care (incident rate ratio (95%CI) per 1000 patients 0.93 (0.88-0.99), p = 0.018), although this pattern reversed during the second wave (additional incident rate ratio (95%CI) 1.12 (1.05-1.19), p < 0.001). Adjusted numbers of donors (incident rate ratio (95%CI) 0.71 (0.61-0.81), p < 0.001) and organs retrieved (incident rate ratio (95%CI) 0.89 (0.82-0.97), p = 0.007) were inversely dependent on COVID-19 workload, though weekly numbers of transplants were unrelated (incident rate ratio (95%CI) 0.95 (0.86-1.04), p = 0.235). Non-COVID-19 mortality fell from 15,007 to 14,087 during the first wave (rate ratio (95%CI) 0.94 (0.92-0.96), p < 0.001) but climbed from 18,907 to 19,372 during the second wave (rate ratio (95%CI) 1.02 (1.00-1.05), p = 0.018). There were fewer in-hospital deaths from cardiac arrest and intracranial catastrophes throughout (rate ratio (95%CI) 0.83 (0.81-0.86), p < 0.001 and rate ratio (95%CI) 0.88 (0.85-0.91), p < 0.001, respectively). There were overall fewer eligible donors (n = 4282) when compared with pre-pandemic levels (n = 6038); OR (95%CI) 0.58 (0.51-0.66), p < 0.001. The total number of donations during the year fell from 1620 to 1140 (rate ratio (95%CI) 0.70 (0.65-0.76), p < 0.001), but the proportion of eligible donors who proceeded to donation (27%) was unchanged (OR (95%CI) 0.99 (0.91-1.08), p = 0.821). The reduction in donations and transplantation during the pandemic was multifactorial, but these data highlight the impact in the UK of a fall in eligible donors and an inverse relationship of referrals to COVID-19 workload. Despite the challenges faced, the foundations underpinning the UK deceased organ donation programme remained strong.

Validation of the factors influencing family consent for organ donation in the UK.

Between 2013 and 2019, there was an increase in the consent rate for organ donation in the UK from 61% to 67%, but this remains lower than many European countries. Data on all family approaches (16,896) for donation in UK intensive care units or emergency departments between April 2014 and March 2019 were extracted from the referral records and the national potential donor audit held by NHS Blood and Transplant. Complete data were available for 15,465 approaches. Consent for donation after brain death was significantly higher than for donation after circulatory death, 70% (4260/6060) vs. 60% (5645/9405), (OR 1.58, 95%CI 1.47-1.69). Patient ethnicity, religious beliefs, sex and socio-economic status, and knowledge of a patient's donation decision were strongly associated with consent (p < 0.001). These factors should be addressed by medium- to long-term strategies to increase community interventions, encouraging family discussions regarding donation decisions and increasing registration on the organ donor register. The most readily modifiable factor was the involvement of an organ donation specialist nurse at all stages leading up to the approach and the approach itself. If no organ donation specialist nurse was present, the consent rates were significantly lower for donation after brain death (OR 0.31, 95%CI 0.23-0.42) and donation after cardiac death (OR 0.26, 95%CI 0.22-0.31) compared with if a collaborative approach was employed. Other modifiable factors that significantly improved consent rates included less than six relatives present during the formal approach; the time from intensive care unit admission to the approach (less for donation after brain death, more for donation after cardiac death); family not witnessing neurological death tests; and the relationship of the primary consenter to the patient. These modifiable factors should be taken into consideration when planning the best bespoke approach to an individual family to discuss the option of organ donation as an end-of-life care choice for the patient.

Current status of organ donation after brain death in the UK.

Organ donation after brain death remains the deceased organ donation pathway of choice. In the UK, the current identification and referral rate for potential donation after brain death donors is 99%, the testing rate for determining death using neurological criteria is 86% and the approach to families for donation is 91%. Increasing donation after brain death donation will primarily require a large increase in the current consent rate of 72% to one matching the consent rate of 80-90% achieved in other European countries. Implementing the use of evidence-based donor optimisation bundles may increase the number of organs available for transplantation. Alternatively, the UK will need to look at more challenging ways of increasing the pool of potential donors after brain death. The first would be to delay the withdrawal of life-sustaining treatment in patients with devastating brain injury to allow progression to brain death after the family have given consent to organ donation and with their consent to this delay. Even more challenging would be the consideration of re-introducing intensive care to facilitate organ donation programmes that have been so successful at increasing the number of organ donors elsewhere.

Organ donation after circulatory death: current status and future potential.

The continuing shortage of deceased donor organs for transplantation, and the limited number of potential donors after brain death, has led to a resurgence of interest in donation after circulatory death (DCD). The processes of warm and cold ischemia threaten the viability of DCD organs, but these can be minimized by well-organized DCD pathways and new techniques of in situ organ preservation and ex situ resuscitation and repair post-explantation. Transplantation survival after DCD is comparable to donation after brain death despite higher rates of primary non-function and delayed graft function. Countries with successfully implemented DCD programs have achieved this primarily through the establishment of national ethical, professional and legal frameworks to address both public and professional concerns with all aspects of the DCD pathway. It is unlikely that expanding standard DCD programs will, in isolation, be sufficient to address the worldwide shortage of donor organs for transplantation. It is therefore likely that reliance on extended criteria donors will increase, with the attendant imperative to minimize ischemic injury to candidate organs. Normothermic regional perfusion and ex situ perfusion techniques allow enhanced preservation, assessment, resuscitation and/or repair of damaged organs as a way of improving overall organ quality and preventing the unnecessary discarding of DCD organs. This review will outline exemplar controlled and uncontrolled DCD pathways, highlighting practical and logistical considerations that minimize warm and cold ischemia times while addressing potential ethical concerns. Future perspectives will also be discussed.

Mortality from Listeria monocytogenes meningoencephalitis following escalation to alemtuzumab therapy for relapsing-remitting Multiple Sclerosis.

We report the case of a patient who died from the rare complication of Listeriosis in the immediate phase following alemtuzumab administration one month after discontinuing dimethyl fumarate (DMF). There is considerable overlap with typical post-infusion symptoms therefore high surveillance and low threshold for empirical or possible prophylactic antibiotic therapy is advocated.

Management of perceived devastating brain injury after hospital admission: a consensus statement from stakeholder professional organizations.

Patients with severe grades of life-threatening brain injury are commonly characterized as having devastating brain injury (DBI), which we have defined as: 'any neurological condition that is assessed at the time of hospital admission as an immediate threat to life or incompatible with good functional recovery AND where early limitation or withdrawal of therapy is being considered'. The outcome in patients with DBI is often death or severe disability, and as a consequence rapid withdrawal of life sustaining therapies is commonly contemplated or undertaken. However, accurate prognostication in life-threatening brain injury is difficult, particularly at an early stage. Evidence from controlled studies to guide decision-making is limited, and there is a risk of a 'self-fulfilling prophecy', with early prognostication leading to early withdrawal of life sustaining therapies and death. The Joint Professional Standards committee of the Faculty of Intensive Care Medicine and the Intensive Care Society convened a consensus group with representation from stakeholder professional organizations to develop clear professional guidance in this area. It recognized that the weak evidence base makes GRADE guidelines difficult to justify. We have made 12 practical, pragmatic recommendations to help clinicians deliver safe, effective, equitable, and justifiable care within resource constrained healthcare systems. In the situation where patient-centred outcomes are recognized to be unacceptable, regardless of the extent of neurological improvement, then early transition to palliative care is appropriate. These recommendations are intended to apply where the primary pathology is DBI, rather than where DBI has compounded a progressive and irreversible deterioration in other life-threatening comorbidities.

Factors influencing the family consent rate for organ donation in the UK.

The refusal rate for organ donation in the UK is 42%, among the highest in Europe. We extracted data on every family approach for donation in UK ICUs or Emergency Departments between 1st April 2012 and 30th September 2013, and performed multiple logistic regression to identify modifiable factors associated with consent. Complete data were available for 4703 of 4899 approaches during the study period. Consent for donation after brain death was 68.9%, and for donation after circulatory death 56.5% (p < 0.0001). Patient ethnicity, knowledge of a patient's wishes and involvement of a specialist nurse in organ donation in the approach were strongly associated with consent (p < 0.0001). The impact of the specialist nurse was stronger for donation after circulatory death than for donation after brain death, even after accounting for the impact of prior knowledge of patients' wishes. Involvement of the specialist nurse in the approach, encouraging family discussions about donation wishes and promotion of the organ donor register are key strategies to increase UK consent rates, and are supported by this study.

Role of therapeutic hypothermia in improving outcome after traumatic brain injury: a systematic review.

This systematic review delineates the effect of primary therapeutic hypothermia (PTH) (initiated on presentation of the patient) on both mortality and neurological outcome in patients with traumatic brain injury. The safety profile of the therapy is also assessed. A systematic search of the following databases was performed: MEDLINE, EMBASE, Zetoc database of conference proceedings, the Cochrane Database of Systematic Reviews, and the clinicaltrials.gov website, up to July 28, 2011. Relevant journals were hand-searched for further articles and reference lists were checked against the retrieved results for additional resources. The retrieved results were filtered for randomized controlled trials in English where systemic hypothermia was applied for ≥ 12 h in the treatment arm and outcome was assessed at a minimum of 3 months. Randomized controlled trials were assessed for quality of evidence using the GRADE system. Eighteen randomized controlled trials (1851 patients) were identified. The overall relative risk of mortality with PTH when compared with controls was 0.84 [95% confidence interval (CI)=0.72-0.98] and of poor neurological outcome was 0.81 (95% CI=0.73-0.89). However, when only high-quality trials were analysed, the relative risks were 1.28 (95% CI=0.89-1.83) and 1.07 (95% CI=0.92-1.24), respectively. Hypothermia was associated with cerebrovascular disturbances on rewarming and possibly with pneumonia in adult patients. Given the quality of the data currently available, no benefit of PTH on mortality or neurological morbidity could be identified. The therapy should therefore only be used within the confines of well-designed clinical trials.

Donation after circulatory death.

Donation after circulatory death (DCD) describes the retrieval of organs for the purposes of transplantation that follows death confirmed using circulatory criteria. The persisting shortfall in the availability of organs for transplantation has prompted many countries to re-introduce DCD schemes not only for kidney retrieval but increasingly for other organs with a lower tolerance for warm ischaemia such as the liver, pancreas, and lungs. DCD contrasts in many important respects to the current standard model for deceased donation, namely donation after brain death. The challenge in the practice of DCD includes how to identify patients as suitable potential DCD donors, how to support and maintain the trust of bereaved families, and how to manage the consequences of warm ischaemia in a fashion that is professionally, ethically, and legally acceptable. Many of the concerns about the practice of both controlled and uncontrolled DCD are being addressed by increasing professional consensus on the ethical and legal justification for many of the interventions necessary to facilitate DCD. In some countries, DCD after the withdrawal of active treatment accounts for a substantial proportion of deceased organ donors overall. Where this occurs, there is an increased acceptance that organ and tissue donation should be considered a routine part of end-of-life care in both intensive care unit and emergency department.

International perspective on the diagnosis of death.

There is growing medical consensus in a unifying concept of human death. All human death involves the irreversible loss of the capacity for consciousness, combined with the irreversible loss of the capacity to breathe. Death then is a result of the irreversible loss of these functions in the brain. This paper outlines three sets of criteria to diagnose human death. Each set of criteria clearly establishes the irreversible loss of the capacity for consciousness, combined with the irreversible loss of the capacity to breathe. The most appropriate set of criteria to use is determined by the circumstances in which the medical practitioner is called upon to diagnose death. The three criteria sets are somatic (features visible on external inspection of the corpse), circulatory (after cardiorespiratory arrest), and neurological (in patients in coma on mechanical ventilation); and represent a diagnostic standard in which the medical profession and the public can have complete confidence. This review unites authors from Australia, Canada, and the UK and examines the medical criteria that we should use in 2012 to diagnose human death.

Experiences in the development of non-heart beating organ donation scheme in a regional neurosciences intensive care unit.

BACKGROUND: In the UK demand for organ transplantation continues to outstrip supply and one strategy aimed at reversing this trend is the introduction of non-heart beating donor (NHBD) schemes. In this paper we describe our experience after the introduction of the NHBD scheme at a regional neuroscience intensive care unit (ICU) that also provides general intensive care. METHODS: We describe the steps taken to establish the scheme and present our results from the time of its implementation in July 2002 until March 2007. RESULTS: Of the 100 patients whom we referred to the transplant co-ordinators, 71 were identified as potential NHBDs and of these 29 went on to become actual donors (conversion rate of 40.8%). Fifty-six kidneys were retrieved and 53 successfully transplanted. In addition, two livers were retrieved but subsequently found to be unsuitable for transplantation, while eight pancreas were retrieved and used for islet cell research. The serum creatinine at 1 yr demonstrates that there is no significant difference between transplanted kidney function from NHBDs and heart-beating donors (HBDs). CONCLUSIONS: We believe that by establishing the NHBD organ donation scheme we are able to fulfil the wishes of more patients who have indicated that they would like to donate their organs while increasing the availability of solid organs for transplantation. With careful preparation, audit, and communication our experience demonstrates that the NHBD scheme can be successfully introduced in an ICU and expanded to other ICUs in a region.

Controlled non-heart beating organ donation: neither the whole solution nor a step too far.

While many intensive care clinicians in the UK continue to express significant concerns regarding controlled non-heart beating organ donation, others are involved in established programmes that make an increasingly significant contribution to the total number of cadaveric donations each year. The successful introduction of a controlled non-heart beating organ donation programme requires local resolution of any apparent ethicolegal obstacles to the process, with specific attention needing to be given to three areas: the potential conflict of interest between decision making over futility and any subsequent approach regarding organ donation; a belief that it may be unlawful to adjust in any way an end of life care pathway in order to allow donation to take place, and, finally, an uncertainty over how soon after cardiac death organ retrieval can begin. It is proposed that recent changes in legislation provide, through an emphasis on patient autonomy and best interests, a solid ethicolegal foundation for donation after cardiac death.