Intensive Care Ethics in Evolution

The ethics of treating the seriously and critically ill have not been static throughout the ages. Twentieth century medicine has inherited from the nineteenth century a science which places an inappropriate weight on diagnosis over prognosis and management, combined with a seventeenth century duty to prolong life. However other earlier ethical traditions, both Hippocratic and Christian, respected both the limitations of medicine and emphasised the importance of prognosis. This paper outlines some of the historical precedents for the treatment of the critically ill, and also how the current paradigm limits clinical practice and causes ethical tensions. An understanding that other paradigms have been ethically acceptable in the past allows wider consideration and acceptance of alternatives for the future. However future alternatives will also have to address the role of technology, given its importance in this area of medicine.     

Catalytic hydrolysis of DNA by metal ions and complexes

Biomimetic hydrolysis of DNA or RNA is of increasing importance in biotechnology and medicine. Most natural nuclease enzymes that mediate such reactions utilize metal ion cofactors. Recent progress in the design of synthetic metallonucleases has included complexes of antibiotics, peptides, nucleic acids, and other organic ligands. In this article, we review a number of synthetic catalyst systems that have been developed to achieve efficient DNA hydrolysis. Methods to evaluate their catalytic efficiencies are critically discussed, and a prognosis for future work in this area is presented.     

Decision making in critically ill patients with hematologic malignancy.

Hematologic neoplasms that were previously considered fatal are now potentially curable with techniques such as bone marrow transplantation. Such therapies also carry significant morbidity and mortality. With the increasing application of these therapies, a growing number of physicians are using medical decision making regarding critical care for these patients. The process by which ethical decisions are reached for these critically ill patients may be baffling because of several factors: rapidly evolving treatments, uncertain probabilities of the cure of the malignant disorder, the relatively young age of many of these patients, and the poor prognosis with critical illness. I discuss a process to reach acceptable decisions, providing a case example of the application of the process. This process is derived from the ethical principles that drive decision making in general medicine and attempts to maximize patients'' autonomy. It involves a consideration of accurate information regarding the disease process and the prognosis, a clear delineation of the goals of the medical care, and communication with patients. Appropriate, ethical, and consistent decisions regarding the critical care of patients with hematologic malignancy can be reached when these considerations are addressed.     

Venous blood lactate evaluation in equine neonatal intensive care

The use of blood lactate concentration as an indicator of prognosis and disease severity has become a common practice in equine medicine, especially with the validation of handheld analyzers. However, few authors described lactate concentration in critically ill foals, and there are no published studies about the use of handheld analyzers in neonatal foals. In this study, for the first time in the equine neonate, we validated the Lactate Scout analyzer, both in healthy and in critically ill foals. The study also describes the normal range for blood lactate in 26 healthy neonatal foals during the first 72 h of life. Moreover, the utility of venous lactate measurement in 88 critically ill foals was determined, describing lactate values in the most common neonatal pathologies, evaluating serial blood lactate measurements, and investigating its prognostic value. The comparison with the enzymatic-colorimetric reference method showed that the Lactate Scout analyzer is reliable. The mean difference (bias ±2SD) between the two methods was close to zero for all comparisons, and the SD of difference was ±0.76 with a 95% confidence interval from −1.58 to 1.40 mmol/L. In healthy foals, blood lactate concentrations at birth and at 12 h of life were statistically higher (P < 0.01) than lactate concentrations measured at subsequent times. In critically ill foals, the highest lactate concentration at admission was found in hemorrhagic shock, septic shock, and complicated perinatal asphyxia syndrome (PAS). Our results showed that hyperlactatemia, although it does not provide diagnostic information, indicates the severity of illness and the need for an early and aggressive intervention. This could be very useful both during hospitalization and in the field to support veterinarians in making a decision about referral. Furthermore lactatemia proved to be a reliable prognostic parameter: In nonsurviving foals, hyperlactatemia persisted during the entire hospitalization, whereas in survivors there were no significant differences after 24 h from admission. Because prognostic parameters have certain limitations, hyperlactatemia should not be used alone to decide whether to discontinue treatments in critically ill foals. A careful and complete clinical examination is always essential.     

危重症患者预后的危险因素及相关指标的预后预测价值分析

目的:探讨危重症患者预后的危险因素,并分析相关指标对患者预后的预测价值。方法:对2016年4月至2018年4月上海交通大学附属第六人民医院救治的5585例ICU危重症患者病例进行回顾性分析,收集患者一般资料、初始乳酸水平、24 h乳酸水平、24 h乳酸清除率以及APACHEII评分等,采用多因素logistic回归分析危重症患者预后的影响因素,ROC曲线评估多项指标预测患者预后的价值。结果:共纳入1465例危重症患者,多因素logistic回归分析显示,住ICU平均时间长、APACHEII评分高、初始乳酸水平大于4 mmol/L、24 h乳酸清除率低、术后肾功能异常是危重症患者住院期间死亡的危险因素(P0.05),24 h乳酸清除率、APACHEII评分及初始乳酸水平三者联合评估预测患者住院死亡率的ROC曲线下面积(ROC-AUC)为0.900,高于单独检测。结论:住ICU时间、APACHEII评分、初始乳酸水平、24 h乳酸清除率、术后肾功能是危重症患者住院期间死亡的影响因素,初始乳酸水平、24 h乳酸清除率和APACHEII评分联合使用可以更好地预测危重症患者的短期预后。     

Advances in cell lineage reprogramming

As a milestone breakthrough of stem cell and regenerative medicine in recent years,somatic cell reprogramming has opened up new applications of regenerative medicine by breaking through the ethical shackles of embryonic stem cells.However,induced pluripotent stem(iPS) cells are prepared with a complicated protocol that results in a low reprogramming rate.To obtain differentiated target cells,iPS cells and embryonic stem cells still need to be induced using step-by-step procedures.The safety of induced target cells from iPS cells is currently a further concerning matter.More broadly conceived is lineage reprogramming that has been investigated since 1987.Adult stem cell plasticity,which triggered interest in stem cell research at the end of the last century,can also be included in the scope of lineage reprogramming.With the promotion of iPS cell research,lineage reprogramming is now considered as one of the most promising fields in regenerative medicine,will hopefully lead to customized,personalized therapeutic options for patients in the future.     

Prognostic scoring system for osteosarcoma using network-regularized high-dimensional Cox-regression analysis and potential therapeutic targets

With the recent emphasis on the importance of personalized genomic medicine, studies have performed prognostic stratification using gene signatures in cancers. However, these studies have not considered gene networks with clinical data. Therefore, this study aimed to develop a novel prognostic score using grouped variable selection for patients with osteosarcoma. We assessed messenger RNA (mRNA) expression and clinical data from Gene Expression Omnibus to develop a novel prognostic scoring system for patients with osteosarcoma. Variable selection using Network-Regularized high-dimensional Cox-regression analysis with information regarding gene networks obtained from six large pathway databases was performed. We determined the risk score on the linear combination of regression coefficients and mRNA expression values. Log-rank test, UNO's c-index, and area under the curve (AUC) values were determined to evaluate the discriminatory power between the low- and high-risk groups. A recently reported next-generation Connectivity Map was used to identify future therapeutic targets for osteosarcoma. Our novel model had significantly high discriminatory power in predicting overall survival. An optimal c-index of 0.967 was obtained and time-dependent receiver operating characteristic analysis revealed an acceptable predictive value of AUC between 0.953 and 1.000. Knockdown of BACE2 or ING2 and linifanib treatment may improve the prognosis of patients with osteosarcoma. Herein, this novel prognostic scoring system would not only facilitate a more accurate prediction of patient prognosis, but also contribute to the selection of suitable therapeutic alternatives for osteosarcoma patients.     

Hacia el diagnóstico temprano de la candidiasis invasora en el paciente crítico

The management of invasive fungal infections in critically ill patients, from diagnosis to selection of the ther- apeutic protocol, is often a challenge. Early diagnosis and treatment are associated with a better prognosis, but apart from cases with positive cultures from blood or fluid/tissue biopsy, diagnosis is neither sensitive nor specific, and there is a need for specific markers in these diseases. Serodiagnostic assays such as mannan an-tigen, mannan antibodies, Candida albicans germ-tube antibodies or (1→3)-β-D-glucan detection, and mo-lecular techniques for the detection of fungal-specific DNA have been developed with promising results in critical care settings. One of the main features in diagnosis is the evaluation of risk factors for infection, which will identify patients in need of preemptive or empirical treatment. Clinical scores were built from those risk factors. The combination of prediction rules and non-culture microbiological tools could be currently be the key to improving the diagnosis and prognosis of invasive fungal infections in critically ill patients.     

The experiments with laboratory animals from a bioethical point of view--history, modern time, perspectives

The origin of laboratory animal science was called forth by violent development of experimental biology and medicine in the XIX century on the one hand, and on the other hand by the necessity to have standard healthy animals for experiments with strictly definite biological characteristics. With this aim in view management technology and animal use in experiments have been constantly improved. "Laboratory animal" notion has been formed by the end of the XIX century. At the beginning of laboratory animal science development ethical problems were not as urgent as they are now. It is established that the three Rs bioethical conception of W.M.S. Russel and R.L. Burch (1959) has influence on modern state and perspectives of the development of animal experimental methods. It is shown that the existence of laboratory animal protection laws and the reflection in them of compulsory ethical review of scientific project and statistics of used laboratory animals is absolutely necessary.     

Increased heme catabolism in critically ill patients: correlation among exhaled carbon monoxide, arterial carboxyhemoglobin, and serum bilirubin IXalpha concentrations

It has been reported that exhaled carbon monoxide (CO) concentrations and arterial carboxyhemoglobin (CO-Hb) concentration in blood may be increased in critically ill patients. However, there was no study that examined correlation among amount of CO in exhaled air, CO-Hb concentrations in erythrocytes, and bilirubin IXalpha (BR) in serum, i.e., the three major indexes of heme catabolism, within the same subject. Here, we examined CO concentrations in exhaled air, CO-Hb concentrations in arterial blood, and BR levels in serum in 29 critically ill patients. Measurements of exhaled CO, arterial CO-Hb, and serum total BR have been done in the intensive care unit. As control, exhaled CO concentration was also measured in eight healthy volunteers. A median exhaled CO concentration was significantly higher in critically ill patients compared with control. There was significant correlation between CO and CO-Hb and CO and total BR level. We also found CO concentrations correlated with indirect BR but not direct BR. Multivariate linear regression analysis for amount of exhaled CO concentrations also showed significant correlation with CO-Hb and total BR, despite the fact that respiratory variables of study subjects were markedly heterogeneous. We found no correlation among exhaled CO, patients' severity, and degree of inflammation, but we found a strong trend of a higher exhaled CO concentration in survivors than in nonsurvivors. These findings suggest there is an increased heme breakdown in critically ill patients and that exhaled CO concentration, arterial CO-Hb, and serum total BR concentrations may be useful markers in critically ill conditions.     

Prognostic Value of Blood Zinc, Iron, and Copper Levels in Critically Ill Children with Pediatric Risk of Mortality Score III

We aimed to explore the association of blood Zn, Fe, and Cu concentrations and changes in the pediatric risk of mortality (PRISM) score in critically ill children, to predict prognosis. We included 31 children (22 boys and 9 girls, 1 month to 5 years old), who had been admitted to the intensive care unit of our hospital and who were critically ill according to PRISM score of III. Another 20 children (12 boys, 8 girls, 3 months to 5 years old) who were brought to the hospital for a health checkup were included as controls. We recorded clinical data, time in the intensive care unit, prognosis, and PRISM III score for critically ill children. Blood Cu, Zn, and Fe values were measured by inductively coupled plasma atomic emission spectrophotometry. Zn and Fe levels were significantly lower in patients than in controls (all p?<?0.05). Cu levels differed between patients and controls, but not significantly (p?>?0.05). In ill children, blood Zn and Fe concentrations were inversely correlated with PRISM III score (Zn: r?=??0.36; Fe: r?=??0.50, both p?<?0.05), with no significant correlation of blood Cu level and PRISM III score (r?=??0.13, p?>?0.05). Serious illness in children may lead to decreased Zn and Fe blood concentrations. Zn and Fe supplements may be beneficial for critically ill children.     

'Hitting you over the head': oncologists' disclosure of prognosis to advanced cancer patients

The disclosure of prognosis to terminally ill patients has emerged as a recent concern given greater demands for patient involvement in medical decision-making in the United States. As part of the informed consent process, American physicians are legally and ethically obligated to provide information to such patients about the risks, benefits, and alternatives of all available treatment options including the use of experimental therapies. Although not legally required, the disclosure of a terminal prognosis is ethically justified because it upholds the principle of self-determination and enables patients to make treatment decisions consistent with their life goals. To understand oncologists' attitudes about disclosing prognostic information to cancer patients with advanced disease, we interviewed fourteen oncologists and conducted one focus group of medical fellows. Although oncologists reported to disclose prognosis in terms of cancer not being curable, they tend to avoid using percentages to convey prognosis. Oncologists' reported reluctance to disclosing prognosis was conveyed through the use of metaphors depicting the perceived violent impact of such information on patients. Oncologists' reluctance to disclose prognosis and preserve patient hope are held in check by their need to ensure that patients have 'realistic expectations' about therapy. We discuss these data in light of the cultural, ethical, and legal dimensions of prognosis disclosure, patient hope and the doctor–patient relationship, and recommend ways to enhance the communication process.     

Invasive fungal infections in critically ill patients: different therapeutic options and a uniform strategy

The high morbidity, mortality, and healthcare costs associated with the invasive fungal infections, especially in the critical care setting, is of importance since the prophylactic, empiric, and pre-emptive therapy interventions, based on early identification of risk factors, is of common occurrence. In the last years alone there have been important developments in antifungal pharmacotherapy. Evidence-based studies using new antifungal agents are now emerging as important players in the pharmacotherapy of invasive fungal infections in seriously ill and difficult patients. However, data on critically ill patients are more limited and usually recovered from general studies. This study shows the benefits obtained by the new antifungal agents on different clinical situations in critical care units. The increasing number of non-C. albicans species and the high mortality rates in these settings suggest that the application of early de-escalation therapy in critically ill patients with fungal infection should be mandatory. The possibility of using antifungal combination therapy in these types of patients should be considered.     

Biological substitutes for pesticides

In the 20th century an increasing number of pesticides, based on biocidal molecules, were the means for a substantial increase in food and fibre production and quality. Because of health and environmental concerns continued extensive use of such molecules is intensively debated and substitutes are often urgently required. Beside crop plant resistance, various biological control methods based on natural pest suppressing organisms are regarded as main alternatives. Several approaches and concepts also have been tested and commercial organism-based preparations are steadily increasing. However, further biotechnological efforts are required to give them status of being practical substitutes to pesticides. At present they are not comparable to pesticides in meeting efficacy, market and other expectations, but they still have a promising future, especially where genetically modified organisms can be used.     

血乳酸水平动态监测在危重症患者的应用的临床价值分析

目的:探讨动态监测动脉乳酸水平对危重患者的应用的临床价值分析。方法:对2010年2月~2011年6月间收治的危重病患者的血乳酸水平进行动态监测,通过比较死亡组患者和存活组患者乳酸水平及其它临床指标,比较不同乳酸水平组患者的临床资料来分析乳酸在危重症患者的应用价值。结果:死亡组和存活组患者在性别、年龄差异无明显的统计学意义(P>0.05);病死组乳酸水平、APACHEⅡ评分、住ICU时间(天)、机械通气时间明显高于生存组,差异有显著的统计学意义(P<0.01);严重乳酸酸中毒组患者在APACHEⅡ评分、休克发生率、MODS发生率、死亡发生率均明显高于乳酸酸中毒组和高乳酸血症组,差异有明显的统计学意义(P<0.05),乳酸酸中毒组休克发生率、MODS发生率、死亡发生率均明显高于高乳酸血症组,差异有明显的统计学意义(P<0.05)。结论:动态监测动脉乳酸水平是判断危重患者预后的一个良好指标,动脉乳酸越高,预后差。     

Somatic cell reprogramming for regenerative medicine: SCNT vs. iPS cells

Reprogramming of somatic cells to a pluripotent state holds huge potentials for regenerative medicine. However, a debate over which method is better, somatic cell nuclear transfer (SCNT) or induced pluripotent stem (iPS) cells, still persists. Both approaches have the potential to generate patient-specific pluripotent stem cells for replacement therapy. Yet, although SCNT has been successfully applied in various vertebrates, no human pluripotent stem cells have been generated by SCNT due to technical, legal and ethical difficulties. On the other hand, human iPS cell lines have been reported from both healthy and diseased individuals. A recent study reported the generation of triploid human pluripotent stem cells by transferring somatic nuclei into oocytes, a variant form of SCNT. In this essay, we discuss this progress and the potentials of these two reprogramming approaches for regenerative medicine.     

Treatment limitation decisions under uncertainty: the value of subsequent euthanasia

This paper examines how decisions to limit treatment to critically ill patients under uncertainty can be made rationally. Expected utility theory offers one way of making rational decisions under uncertainty. One problem with using this approach is that we may not know the value of each option. One rational course open is to treat until further information becomes available. However, treatment can limit the range of options open. With treatment, a patient may recover such that he no longer requires life-supporting treatment. However, his life may be not worth living. If active euthanasia of %on-terminal'conditions is prohibited, the option of dying will no longer be available. Taking a rational'wait and see'course may result in being trapped within an unbearable life. On the other hand, sometimes present practice'lets nature takes its course'. Critically ill patients are allowed to die because it is believed that their lives will be not worth living. It is likely that some patients are allowed to die when there is some objective chance of worthwhile future life. This paper argues that a policy of treating critically ill patients until the nature of future options can be better evaluated, in company with an offer of subsequent euthanasia where appropriate, allows a more rational and humane approach to treatment limitation decisions under uncertainty.     

Failures of Imagination: Disability and the Ethics of Selective Reproduction

The article addresses the problem of disability in the context of reproductive decisions based on genetic information. It poses the question of whether selective procreation should be considered as a moral obligation of prospective parents. To answer this question, a number of different ethical approaches to the problem are presented and critically analysed: the utilitarian; Julian Savulescu's principle of procreative beneficence; the rights‐based. The main thesis of the article is that these approaches fail to provide any appealing principles on which reproductive decisions should be based. They constitute failures of imagination which may result in counter‐intuitive moral judgments about both life with disability and genetic selection. A full appreciation of the ethical significance of recognition in procreative decisions leads to a more nuanced and morally satisfying view than other leading alternatives presented in the article.     

综述: 诱导重编程过程中的表观遗传重塑

多能干细胞(pluripotent stem cell,PSC)是一类具有自我更新能力和多向分化潜能的细胞,具有广泛的临床应用前景．诱导性多功能干细胞(induced pluripotent stem cell,iPS cell)的获得,解决了传统方式中的细胞来源和伦理学等问题,从理论研究和应用上实现了体细胞重编程的重大突破,也为疾病发生机制研究、药物筛选、个性化药物选择、细胞治疗和再生医学等研究创造了难得的机会,从而开启了多能干细胞应用的新纪元．iPS过程中有很多问题尚未得到解决,尤其是诱导重编程的分子机制方面,这也是近年来干细胞领域研究的热点．其中如何实现表观遗传的重编程被认为是亟待解决的核心问题之一．本文结合我们的研究,主要介绍诱导重编程领域表观遗传修饰重塑机制的研究进展,并展望未来研究中大规模信息整合分析的重要性．     

Extravascular lung water measurements and hemodynamic monitoring in the critically ill: bedside alternatives to the pulmonary artery catheter

The recently completed Fluid and Catheter Treatment Trial conducted by the National Institutes of Health ARDSNetwork casts doubt on the value of routine pulmonary artery catheterization for hemodynamic management of the critically ill. Several alternatives are available, and, in this review, we evaluate the theoretical, validation, and empirical databases for two of these: transpulmonary thermodilution measurements (yielding estimates of cardiac output, intrathoracic blood volume, and extravascular lung water) that do not require a pulmonary artery catheter, and hemodynamic measurements (including estimates of cardiac output and ejection time, a variable sensitive to intravascular volume) obtained by esophageal Doppler analysis of blood flow through the descending aorta. We conclude that both deserve serious consideration as a means of acquiring useful hemodynamic data for managing shock and fluid resuscitation in the critically ill, especially in those with acute lung injury and pulmonary edema, but that additional study, including carefully performed, prospective clinical trials demonstrating outcome benefit, is needed.