Predicting time to asystole following withdrawal of life-sustaining treatment: a systematic review.

The planned withdrawal of life-sustaining treatment is a common practice in the intensive care unit for patients where ongoing organ support is recognised to be futile. Predicting the time to asystole following withdrawal of life-sustaining treatment is crucial for setting expectations, resource utilisation and identifying patients suitable for organ donation after circulatory death. This systematic review evaluates the literature for variables associated with, and predictive models for, time to asystole in patients managed on intensive care units. We conducted a comprehensive structured search of the MEDLINE and Embase databases. Studies evaluating patients managed on adult intensive care units undergoing withdrawal of life-sustaining treatment with recorded time to asystole were included. Data extraction and PROBAST quality assessment were performed and a narrative summary of the literature was provided. Twenty-three studies (7387 patients) met the inclusion criteria. Variables associated with imminent asystole (<60 min) included: deteriorating oxygenation; absence of corneal reflexes; absence of a cough reflex; blood pressure; use of vasopressors; and use of comfort medications. We identified a total of 20 unique predictive models using a wide range of variables and techniques. Many of these models also underwent secondary validation in further studies or were adapted to develop new models. This review identifies variables associated with time to asystole following withdrawal of life-sustaining treatment and summarises existing predictive models. Although several predictive models have been developed, their generalisability and performance varied. Further research and validation are needed to improve the accuracy and widespread adoption of predictive models for patients managed in intensive care units who may be eligible to donate organs following their diagnosis of death by circulatory criteria.

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.

Changing to an Opt Out System for Organ Donation-Reflections From England and Netherlands.

Recently England and Netherlands have changed their consent system from Opt In to Opt Out. The reflections shared in this paper give insight and may be helpful for other nation considering likewise. Strong support in England for the change in legislation led to Opt Out being introduced without requiring a vote in parliament in 2019. In Netherlands the bill passed by the smallest possible majority in 2018. Both countries implemented a public campaign to raise awareness. In England registration on the Donor Register is voluntary. Registration was required in Netherlands for all residents 18 years and older. For those not already on the register, letters were sent by the Dutch Government to ask individuals to register. If people did not respond they would be legally registered as having "no objection." After implementation of Opt Out in England 42.3% is registered Opt In, 3.6% Opt Out, and 54.1% has no registration. In contrast in Netherlands the whole population is registered with 45% Opt In, 31% Opt Out and 24% "No Objection." It is too soon to draw conclusions about the impact on the consent rate and number of resulting organ donors. However, the first signs are positive.

Assessing whether COVID-19 patients will benefit from critical care, and an objective approach to capacity challenges during a pandemic: An Intensive Care Society clinical guideline.

This national professional society guidance lays out operational and ethical principles for decision-making during a pandemic, in the immediate context of COVID-19 in the early 2020 surge iteration but with potential ongoing relevance. It identifies the different phases of a pandemic and the implications for capacity and mutual aid within a national healthcare system, and introduces a revised CRITCON-PANDEMIC framework for shared operational responsibilities and clinical decision-making. Usual legal and ethical frameworks should continue to apply while capacity and mutual aid are available (CRITCON-PANDEMIC levels 0-3); clinicians should focus on current clinical needs and should not treat patients differently because of anticipated future pressures. In conditions of resource limitation (CRITCON-PANDEMIC 4), a structured and equitable approach is necessary and an objective Decision Support Aid is proposed. In producing this guidance, we emphasise that all patients must be treated with respect and without discrimination, because everyone is of equal value. The guidance has been put together with input from patient and public groups and aims to provide standards that are fair to everyone. We acknowledge that COVID-19 is a new disease with a partial and evolving knowledge base, and aim to provide an objective clinical decision-making framework based on the best available information. It is recognised that a factual assessment of likely benefit may take into account age, frailty and comorbidities, but the guidance emphasises that every assessment must be individualised on a balanced, case by case, basis and may inform clinical judgement but not replace it. The effects of a comorbidity on someone's ability to benefit from critical care should be individually assessed. Measures of frailty should be used with care, and should not disadvantage those with stable disability.

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.

The rise of organ donation after circulatory death: a narrative review.

Solid organ transplantation saves and transforms lives. The original type of organ donation from deceased patients was controlled donation after circulatory death, previously referred to as non-heart beating organ donation. The rise of donation after circulatory death in the UK came about through advances in critical care and transplant medicine and support from several key organisations in developing a robust ethical, legal and professional framework. The transplant waiting list reached a historic peak in 2009-2010 of 8000 patients, but fell by 25% to 6000 in 2017-2018. There has also been a steady rise in the number of deceased donors and the number of donations after circulatory death. The contribution of donation after circulatory death to the total number of donations rose steadily between 2000 and 2012 and has remained about 40% since. Although the situation has improved for patients waiting for a transplant, deaths and long waits remain common. Changes to legislative, technical and peri-mortem procedures may greatly change future practices in donation after circulatory death in the UK.

Permanent brain arrest as the sole criterion of death in systemic circulatory arrest.

Historically, there has been a tendency to think that there are two types of death: circulatory and neurological. Holding onto this tendency is making it harder to navigate emerging resuscitative technologies, such as extracorporeal membrane oxygenation and the recent well-publicised experiment that demonstrated the possibility of restoring cellular function to some brain neurons 4 h after normothermic circulatory arrest (decapitation) in pigs. Attempts have been made to respond to these difficulties by proposing a unified brain-based criterion for human death, which we call 'permanent brain arrest'. The clinical characteristics of permanent brain arrest are the permanent loss of capacity for consciousness and permanent loss of all brainstem functions, including the capacity to breathe. These losses could arise from a primary brain injury or as a result of systemic circulatory arrest. We argue that permanent brain arrest is the true and sole criterion for the death of human beings and show that this is already implicit in the circulatory-respiratory criterion itself. We argue that accepting the concept of permanent cessation of brain function in patients with systemic permanent circulatory arrest will help us better navigate the medical advances and new technologies of the future whilst continuing to provide sound medical criteria for the determination of death.

The effect on consent rates for deceased organ donation in Wales after the introduction of an opt-out system.

Organ transplantation saves and transforms lives. Failure to secure consent for organ retrieval is widely regarded as the single most important obstacle to transplantation. A soft opt-out system of consent for deceased organ donation was introduced into Wales in December 2015, whilst England maintained the existing opt-in system. Cumulative data on consent rates in Wales were compared with those in England, using a two-sided sequential procedure that was powered to detect an absolute difference in consent rates between England and Wales of 10%. Supplementary risk-adjusted logistic regression analysis examined whether any difference in consent rates between the two nations could be attributed to variations in factors known to influence UK consent rates. Between 1 January 2016 and 31 December 2018, 8192 families of eligible donors in England and 474 in Wales were approached regarding organ donation, with overall consent rates of 65% and 68%, respectively. There was a steady upward trend in the proportion of families consenting to donation after brain death in Wales as compared with England and after 33 months, this reached statistical significance. No evidence of any change in the donation after circulatory death consent rate was observed. Risk-adjusted logistic regression analysis revealed that by the end of the study period the probability of consent to organ donation in Wales was higher than in England (OR [95%CI] 2.1 [1.26-3.41]). The introduction of a soft opt-out system of consent in Wales significantly increased organ donation consent though the impact was not immediate.

Examining consent for interventional research in potential deceased organ donors: a narrative review.

In the last decade, research in transplant medicine has focused on developing interventions in the management of the deceased organ donor to improve the quality and quantity of transplantable organs. Despite the promise of interventional donor research, there remain debates about the ethics of this research, specifically regarding gaining research consent. Here, we examine the concerns and ambiguities around consent for interventional donor research, which incorporate questions about who should consent for interventional donor research and what people are being asked to consent for. We highlight the US and UK policy responses to these concerns and argue that, whereas guidance in this area has done much to clarify these ambiguities, there is little consideration of the nature, practicalities and context around consent in this area, particularly regarding organ donors and their families. We review wider studies of consent in critical care research and social science studies of consent in medical research, to gain a broader view of consent in this area as a relational and contextual process. We contend a lack of consideration has been given to: what it might mean to consent to interventional donor research; how families, patients and health professionals might experience providing and seeking this consent; who is best placed to have these discussions; and the socio-institutional contexts affecting these processes. Further, empirical research is required to establish an ethical and sensitive model for consent in interventional donor research, ensuring the principles enshrined in research ethics are met and public trust in organ donation is maintained.

Diagnosis of death using neurological criteria in adult patients on extracorporeal membrane oxygenation: Development of UK guidance.

The diagnosis of death using neurological criteria is an important legal method of establishing death in the UK. The safety of the diagnosis lies in the exclusion of conditions which may mask the diagnosis and the testing of the fundamental reflexes of the brainstem including the apnoea reflex. Extracorporeal membrane oxygenation for cardiac or respiratory support can impact upon these tests, both through drug sequestration in the circuit and also through the ability to undertake the apnoea test. Until recently, there has been no nationally accepted guidance regarding the conduct of the tests to undertake the diagnosis of death using neurological criteria for a patient on extracorporeal membrane oxygenation. This article considers both the background to and the process of guideline development.

Identification of Heparan-Sulfate Rich Cells in the Loose Connective Tissues of the Axolotl (Ambystoma mexicanum) with the Potential to Mediate Growth Factor Signaling during Regeneration.

Limb regeneration is the outcome of a complex sequence of events that are mediated by interactions between cells derived from the tissues of the amputated stump. Early in regeneration, these interactions are mediated by growth factor/morphogen signaling associated with nerves and the wound epithelium. One shared property of these proregenerative signaling molecules is that their activity is dependent on interactions with sulfated glycosaminoglycans (GAGs), heparan sulfate proteoglycan (HSPG) in particular, in the extracellular matrix (ECM). We hypothesized that there are cells in the axolotl that synthesize specific HSPGs that control growth factor signaling in time and space. In this study we have identified a subpopulation of cells within the ECM of axolotl skin that express high levels of sulfated GAGs on their cell surface. These cells are dispersed in a grid-like pattern throughout the dermis as well as the loose connective tissues that surround the tissues of the limb. These cells alter their morphology during regeneration, and are candidates for being a subpopulation of connective tissue cells that function as the cells required for pattern-formation during regeneration. Given their high level of HSPG expression, their stellate morphology, and their distribution throughout the loose connective tissues, we refer to these as the positional information GRID (Groups that are Regenerative, Interspersed and Dendritic) cells. In addition, we have identified cells that stain for high levels of expression of sulfated GAGs in mouse limb connective tissue that could have an equivalent function to GRID cells in the axolotl. The identification of GRID cells may have important implications for work in the area of Regenerative Engineering.

Role of the XylA gene, encoding a cell wall degrading enzyme, during common wheat, durum wheat and barley colonization by Fusarium graminearum.

Fusarium graminearum is the main causal agent of fusarium head blight (FHB) of wheat and barley. This filamentous fungus is able to produce hydrolytic enzymes, such as xylanases, that cause cell wall degradation, permitting host colonization. This study investigated the role of the F. graminearum XylA (FGSG_10999) gene during infection, using a knockout mutant in strain CS3005. Assays were carried out on common wheat, durum wheat and barley to compare virulence of a XylA knockout to that of wild type strain. These assays were conducted on wheat and barley seedling roots, seedling stem bases and heads. Furthermore, additional in vitro experiments were conducted to investigate the role of XylA gene in the utilisation of D-xylose, the main component of cereals cell wall. In planta assays showed the importance of XylA gene for F. graminearum virulence towards its main hosts. A positive correlation between symptom incidence and fungal biomass development was also observed for both the wild type and the knockout strains. Finally, gene expression studies performed in a liquid medium enriched with D-xylose, a known xylanase inducer in other fungi, showed that the absence of the gene in the FGSG_10999 locus was not compensated by two other F. graminearum xylanase encoding genes analysed (loci FGSG_06445 and FGSG_11478).

Are food exposures obtained through commercial market panels representative of the general population? Implications for outbreak investigations.

Current methods of control recruitment for case-control studies can be slow (a particular issue for outbreak investigations), resource-intensive and subject to a range of biases. Commercial market panels are a potential source of rapidly recruited controls. Our study evaluated food exposure data from these panel controls, compared with an established reference dataset. Market panel data were collected from two companies using retrospective internet-based surveys; these were compared with reference data from the National Diet and Nutrition Survey (NDNS). We used logistic regression to calculate adjusted odds ratios to compare exposure to each of the 71 food items between the market panel and NDNS participants. We compared 2103 panel controls with 2696 reference participants. Adjusted for socio-demographic factors, exposure to 90% of foods was statistically different between both panels and the reference data. However, these differences were likely to be of limited practical importance for 89% of Panel A foods and 79% of Panel B foods. Market panel food exposures were comparable with reference data for common food exposures but more likely to be different for uncommon exposures. This approach should be considered for outbreak investigation, in conjunction with other considerations such as population at risk, timeliness of response and study resources.