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Extracorporeal Circulation in Neonatal Respiratory Failure: A Prospective Randomized Study
Abstract
A prospective controlled randomized study of the use of extracorporeal membrane oxygenation to treat newborns with respiratory failure was carried out using the "randomized play-the-winner" statistical method. In this method the chance of randomly assigning an infant to one treatment or the other is influenced by the outcome of treatment of each patient in the study. If one treatment is more successful, more patients are randomly assigned to that treatment. A group of 12 infants with birth weight greater than 2 kg met objective criteria for high mortality risk. One patient was randomly assigned to conventional treatment (that patient died); 11 patients were randomly chosen for extracorporeal membrane oxygenation (all survived). Intracerebral hemorrhage occurred in one of 11 surviving children. Extracorporeal membrane oxygenation allows lung rest and improves survival compared to conventional ventilator therapy in newborn infants with severe respiratory failure.
... Since its first use in the 1970s there have been more than 170,000 ECLS runs in adults and children (ELSO 2022). Studies in neonates (Bartlett et al. 1985;Mugford et al. 2008;O'Rourke et al. 1989) and adults (Noah et al. 2011;Peek et al. 2009) have demonstrated favorable outcomes in patients treated with ECLS. However, ECLS is a high-risk therapy that can result in severe bleeding and clotting complications due to hemocompatibility limitations of the oxygenator (Dalton et al. 2015;Mazzeffi et al. 2016). ...
Extracorporeal life support is an advanced therapy that circulates blood through an extracorporeal oxygenator, performing gas exchange outside the body. However, its use is limited by severe complications, including bleeding, clotting, and hemolysis. Semiconductor silicon-based membranes have emerged as an alternative to traditional hollow-fiber semipermeable membranes. These membranes offer excellent gas exchange efficiency and the potential to increase hemocompatibility by improving flow dynamics. In this work, we evaluate two next-generation silicon membrane designs, which are intended to be mechanically robust and efficient in gas exchange, while simultaneously reducing fabrication complexity. The “window” design features 10 µm pores on one side and large windows on the back side. The “cavern” design also uses 10 µm pores but contains a network of interconnected buried caverns to distribute the sweep gas from smaller inlet holes. Both designs were shown to be technically viable and able to be reproducibly fabricated. In addition, they both were mechanically robust and withstood 30 psi of transmembrane pressure without breakage or bubbling. At low sweep gas pressures, gas transfer efficiency was similar, with the partial pressure of oxygen in water increasing by 10.7 ± 2.3 mmHg (mean ± standard deviation) and 13.6 ± 1.9 mmHg for the window and cavern membranes, respectively. Gas transfer efficiency was also similar at higher pressures. At 10 psi, oxygen tension increased by 16.8 ± 5.7 mmHg (window) and 18.9 ± 1.3 mmHg (cavern). We conclude that silicon membranes featuring a 10 µm pore size can simplify the fabrication process and improve mechanical robustness while maintaining excellent efficiency.
Graphical Abstract
... We include it since RPW has a long history in clinical trials methodology, and because its use helps explain why few response-adaptive clinical trials have occurred in practice. Indeed, the infamous Extracorporeal Circulation in Neonatal Respiratory Failure (ECMO) trial [42] used RPW to allocate patients. Due to the extreme treatment imbalance and highly controversial interpretation, the ECMO trial is regarded as a key example against the use of response-adaptive designs in clinical trials [43,44]. ...
When comparing the performance of multi-armed bandit algorithms, the potential impact of missing data is often overlooked. In practice, it also affects their implementation where the simplest approach to overcome this is to continue to sample according to the original bandit algorithm, ignoring missing outcomes. We investigate the impact on performance of this approach to deal with missing data for several bandit algorithms through an extensive simulation study assuming the rewards are missing at random. We focus on two-armed bandit algorithms with binary outcomes in the context of patient allocation for clinical trials with relatively small sample sizes. However, our results apply to other applications of bandit algorithms where missing data is expected to occur. We assess the resulting operating characteristics, including the expected reward. Different probabilities of missingness in both arms are considered. The key finding of our work is that when using the simplest strategy of ignoring missing data, the impact on the expected performance of multi-armed bandit strategies varies according to the way these strategies balance the exploration-exploitation trade-off. Algorithms that are geared towards exploration continue to assign samples to the arm with more missing responses (which being perceived as the arm with less observed information is deemed more appealing by the algorithm than it would otherwise be). In contrast, algorithms that are geared towards exploitation would rapidly assign a high value to samples from the arms with a current high mean irrespective of the level observations per arm. Furthermore, for algorithms focusing more on exploration, we illustrate that the problem of missing responses can be alleviated using a simple mean imputation approach.
... Extracorporeal membrane oxygenation (ECMO) can reduce the mortality of neonates with reversible cardiopulmonary failure, which is difficult to treat with conventional mechanical ventilation (1,2), approximately from 80 to 20%. The outcomes of neonates with critical illnesses such as congenital diaphragmatic hernia, persistent . ...
Extracorporeal membrane oxygenation (ECMO) is a superior life support technology, commonly employed in critical patients with severe respiratory or hemodynamic failure to provide effective respiratory and circulatory support, which is especially recommended for the treatment of critical neonates. However, the vascular management of neonates with veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is still under controversy. Reconstruction or ligation for the right common carotid artery (RCCA) after ECMO is inconclusive. This review summarized the existed studies on hemodynamics and neurological function after vascular ligation or reconstruction hoping to provide better strategies for vessel management in newborns after ECMO. After reconstruction, the right cerebral blood flow can increase immediately, and the normal blood supply can be restored rapidly. But the reconstructed vessel may be occluded and stenotic in long-term follow-ups. Ligation may cause lateralization damage, but there could be no significant effect owing to the establishment of collateral circulation. The completion of the circle of Willis, the congenital anomalies of cerebral or cervical vasculature, the duration of ECMO, and the vascular condition at the site of arterial catheterization should be assessed carefully before making the decision. It is also necessary to follow up on the reconstructed vessel sustainability, and the association between cerebral hemodynamics and neurological function requires further large-scale multi-center studies.
The study of rare diseases has long been an area of challenge for medical researchers, with agonizingly slow movement towards improved understanding of pathophysiology and treatments compared with more common illnesses. The push towards evidence-based medicine (EBM), which prioritizes certain types of evidence over others, poses a particular issue when mapped onto rare diseases, which may not be feasibly investigated using the methodologies endorsed by EBM, due to a number of constraints. While other trial designs have been suggested to overcome these limitations (with varying success), perhaps the most recent and enthusiastically adopted is the application of artificial intelligence to rare disease data. This paper critically examines the pitfalls of EBM (and its trial design offshoots) as it pertains to rare diseases, exploring the current landscape of AI as a potential solution to these challenges. This discussion is also taken a step further, providing philosophical commentary on the weaknesses and dangers of AI algorithms applied to rare disease research. While not proposing a singular solution, this article does provide a thoughtful reminder that no ‘one-size-fits-all’ approach exists in the complex world of rare diseases. We must balance cautious optimism with critical evaluation of new research paradigms and technology, while at the same time not neglecting the ever-important aspect of patient values and preferences, which may be challenging to incorporate into computer-driven models.
Objective
This scoping review sought to map the breadth of literature on the use of adaptive design trials in eating disorder research.
Method
A systematic literature search was conducted in Medline, Scopus, PsycInfo, Emcare, Econlit, CINAHL and ProQuest Dissertations and Theses. Articles were included if they reported on an intervention targeting any type of eating disorder (including anorexia nervosa, bulimia nervosa, binge‐eating disorder, and other specified feeding or eating disorders), and employed the use of an adaptive design trial to evaluate the intervention. Two independent reviewers screened citations for inclusion, and data abstraction was performed by one reviewer and verified by a second.
Results
We identified five adaptive design trials targeting anorexia nervosa, bulimia nervosa and binge‐eating disorder conducted in the USA and Australia. All employed adaptive treatment arm switching based on early response to treatment and identified a priori stopping rules. None of the studies included value of information analysis to guide adaptive design decisions and none included lived experience perspectives.
Discussion
The limited use of adaptive designs in eating disorder trials represents a missed opportunity to improve enrolment targets, attrition rates, treatment outcomes and trial efficiency. We outline the range of adaptive methodologies, how they could be applied to eating disorder research, and the specific operational and statistical considerations relevant to adaptive design trials.
Public significance
Adaptive design trials are increasingly employed as flexible, efficient alternatives to fixed trial designs, but they are not often used in eating disorder research. This first scoping review identified five adaptive design trials targeting anorexia nervosa, bulimia nervosa and binge‐eating disorder that employed treatment arm switching adaptive methodology. We make recommendations on the use of adaptive design trials for future eating disorder trials.
Extracorporeal Circulation in Neonatal Respiratory Failure: A Prospective Randomized Study. By RH Bartlett, DW Roloff, RG Cornell, AF Andrews, PW Dillon, JB Zwischenberger. Pediatrics 1985; 76:479–87.
Extracorporeal membrane oxygenation (ECMO) is the use of mechanical devices to replace cardiac and pulmonary function in critical care. In the 1960s, laboratory research showed that extracorporeal circulation could be maintained for days using a membrane oxygenator. In the 1970s, the first clinical trials showed that ECMO could sustain life in severe cardiac and pulmonary failure for days or weeks, leading to organ recovery. From 1980 to 2000, ECMO became standard practice for neonatal and pediatric respiratory and cardiac failure. The critical clinical trial was a prospective randomized trial of ECMO in newborn respiratory failure, published in 1985. This is the classic article reviewed in this publication. This was the first use of a randomized, adaptive design trial to minimize the potential ethical dilemma inherent to clinical trials in which the endpoint is death. Other randomized trials followed, and ECMO is now standard practice for severe respiratory and cardiac failure in all age groups.
Augmentation of out-of-hospital cardiac arrest (OHCA) survival by deploying extracorporeal life support (ECLS) continues to perplex clinicians. The post hoc Bayesian re-analysis of the INCEPTION trial by Heuts et al. in this issue of the European Heart Journal: Acute Cardiovascular Care attempts to frame favourable neurologic outcomes with a probabilistic interpretation. Extracorporeal life support after cardiac arrest is challenging to study, however. Designing and conducting trials under very acute scenarios with narrow inclusion windows pose several challenges for trialists and clinicians alike. These include defining the appropriate question, defining inclusion and exclusion criteria that capture the population of interest, training, and intervention deployment. Unsurprisingly, randomized clinical trials (RCTs) under this scenario tend to be small due to a combination of costs, number of eligible patients, and recruitability.1,2
Randomized clinical trials are generally designed under a specific frequentist framework.² Defining trial sample size is a key aspect, usually designed with the specific capacity to detect a given effect size of interest (‘power’) while controlling for false-positive results (Type 1 events). The estimated sample size is a consequence of the effect size of interest and the desired power and Type 1 event control. The lower the effect size of interest, the higher the power, and the lower the tolerance for type 1 events, the higher the required sample size. In addition, the less granular the primary endpoint, the higher the required sample size. For example, trials targeting mortality, a binary endpoint, will require sample sizes orders of magnitude higher than trials aimed at detecting changes in continuous endpoints. This explains why many trials in critical care medicine moved from traditional binary endpoints to more granular outcomes, such as ordinal scales (which were common during COVID-19 pandemic) and continuous scales that penalize death, such as days alive and free of a given condition.³ It is common that trials on acute respiratory distress syndrome use days alive and free of the ventilator as endpoint of choice and penalize death by attributing zero or minus one to patients that die. While this strategy greatly increases statistical power, it does hamper interpretability of the results.
Procedure-related registries in general surgical practice offer a platform for prospective trials, the pooling of data, and detailed outcome analysis. Recommendations by the Idea, Development, Exploration, Assessment, and Long-term follow-up (IDEAL) collaboration and Outcome4Medicine have further improved the uniform reporting of complications and adverse events.
In the pediatric surgical network, disease-specific registries for rare and inherited congenital anomalies are gaining importance, fostering international collaborations on studies of low-incidence diseases. However, to date, reporting of complications in the pediatric surgical registries has been inconsistent. Therefore, the European Reference Network for Rare Inherited and Congenital Anomalies (ERNICA) recently endorsed the validation of the first severity grading system for children. The planned reform of the European Paediatric Surgical Audit (EPSA) registry, which includes the implementation of the Clavien–Madadi classification, represents a further effort to establish uniform outcome reporting.
This article provides an overview of experiences with surgical registries and complication reporting, along with the potential application of this knowledge to future pediatric surgical practice.
Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is used to support patients with reversible cardiopulmonary insufficiency. Although it is a lifesaving technology, bleeding, inflammation, and thrombosis are well-described complications of ECMO. Adult porcine models of ECMO have been used to recapitulate the physiology and hemostatic consequences of ECMO cannulation in adults. However, these models lack the unique physiology and persistence of fetal forms of coagulation factors and fibrinogen as in human infants. We aimed to describe physiologic and coagulation parameters of piglets cannulated and supported with VA-ECMO. Four healthy piglets (5.7–6.4 kg) were cannulated via jugular vein and carotid artery by cutdown and supported for a maximum of 20 hours. Heparin was used with a goal activated clotting time of 180–220 seconds. Arterial blood gas (ABG) was performed hourly, and blood was transfused from an adult donor to maintain hematocrit (Hct) > 24%. Rotational thromboelastometry (ROTEM) was performed at seven time points. All animals achieved adequate flow with a patent circuit throughout the run (pre- and post-oxygenator pressure gradient <10 mmHg). There was slow but significant hemorrhage at cannulation, arterial line, and bladder catheter sites. All animals required the maximum blood transfusion volume available. All animals became anemic after exhaustion of blood for transfusion. ABG showed progressively declining Hct and adequate oxygenation. ROTEM demonstrated decreasing fibrin-only ROTEM (FIBTEM) clot firmness. Histology was overall unremarkable. Pediatric swine are an important model for the study of pediatric ECMO. We have demonstrated the feasibility of such a model while providing descriptions of physiologic, hematologic, and coagulation parameters throughout. Weak whole-blood clot firmness by ROTEM suggested defects in fibrinogen, and there was a clinical bleeding tendency in all animals studied. This model serves as an important means to study the complex derangements in hemostasis during ECMO.
Response-Adaptive Randomization (RAR) is part of a wider class of data-dependent sampling algorithms, for which clinical trials are typically used as a motivating application. In that context, patient allocation to treatments is determined by randomization probabilities that change based on the accrued response data in order to achieve experimental goals. RAR has received abundant theoretical attention from the biostatistical literature since the 1930's and has been the subject of numerous debates. In the last decade, it has received renewed consideration from the applied and methodological communities, driven by well-known practical examples and its widespread use in machine learning. Papers on the subject present different views on its usefulness, and these are not easy to reconcile. This work aims to address this gap by providing a unified, broad and fresh review of methodological and practical issues to consider when debating the use of RAR in clinical trials.
Extracorporeal membrane oxygenation (ECMO) or extracorporeal life support (ECLS) is a form of heart lung bypass that is used to support neonates with cardiorespiratory failure for days or weeks until organ recovery or transplantation. Primary pulmonary hypertension, meconium aspiration syndrome (MAS), and congenital diaphragmatic hernia (CDH) are common indications for ECMO. Venoarterial (VA) and venovenous (VV) ECMO are the most common modes of support. The use of neonatal respiratory ECMO has been declining over the last two decades, while adult respiratory ECMO has been growing especially since the H1N1 influenza pandemic in 2009. This review provides an overview of ECMO use in neonates and a description of basic principles, circuit components, complications, outcomes, intraoperative conduct of anesthesia, and monitoring during surgical procedures, as well as a look into the future.KeywordsCongenital diaphragmatic herniaDouble-lumen cannulaECMOExtracorporeal life supportExtracorporeal membrane oxygenationInternal jugular veinRespiratory failureVenoarterialVenovenous
This chapter discusses some principal ethical issues regarding the conduct of clinical research. It will shed light on the main grounding theories behind the conduct of research and how it differs from bedside patient care. This chapter also examines the ethical dimension of three main topics in clinical research: RCT and the problem of prescribing a placebo, Informed Consent, its main elements and philosophical bases, and lastly, Conflict of Interest, including the moral psychology behind this issue.
The field of pediatric heart failure is evolving, and the patient population is growing as survival after complex congenital heart surgeries is improving. Mechanical circulatory support and extracorporeal respiratory support in critically ill children has progressed to a mainstay rescue modality in pediatric intensive care medicine. The need for mechanical circulatory support is growing, since the number of organ donors does not meet the necessity. This article aims to review the current state of available mechanical circulatory and respiratory support systems in acute care pediatrics, with an emphasis on the literature discussing the challenges associated with these complex support modalities.
This practical high-level guidebook offers an in-depth understanding of the newly emerging clinical trial designs in adaptive trial designs and master protocols. Both concise and readable without shying away from technical discussion, the book introduces the most innovative approaches in clinical trial research such as adaptive trial designs, master protocols, platform trial, basket trial, and umbrella trial designs. Featuring a revisionist history of clinical research before moving on to case-study based discussion and practical considerations from collective experience. The book enables readers to understand the strengths and limitations of these novel designs as well as their application to individual areas of research and clinical practice. Supplemented by real-world examples from the recent developments in medical research efficiency instigated by both personalized medicine and high-profile diseases like COVID-19 and cancer. The first book of its kind, it is the go-to resource for medical students and researchers working in clinical trial research.
Extracorporeal membrane oxygenation (ECMO) was first started for humans in early 1970s by Robert Bartlett. Since its inception, there have been numerous challenges with extracorporeal circulation, such as coagulation and platelet activation, followed by consumption of coagulation factors and platelets, and biocompatibility of tubing, pump, and oxygenator. Unfractionated heparin (heparin hereafter) has historically been the defacto anticoagulant until recently. Also, coagulation monitoring was mainly based on bedside activated clotting time and activated partial thromboplastin time. In the past 50 years, the technology of ECMO has advanced tremendously, and thus, the survival rate has improved significantly. The indication for ECMO has also expanded. Among these are clinical conditions such as postcardiopulmonary bypass, sepsis, ECMO cardiopulmonary resuscitation, and even severe coronavirus disease 2019 (COVID-19). Not surprisingly, the number of ECMO cases has increased according to the Extracorporeal Life Support Organization Registry and prolonged ECMO support has become more prevalent. It is not uncommon for patients with COVID-19 to be on ECMO support for more than 1 year until recovery or lung transplant. With that being said, complications of bleeding, thrombosis, clot formation in the circuit, and intravascular hemolysis still remain and continue to be major challenges. Here, several clinical ECMO experts, including the “Father of ECMO”—Dr. Robert Bartlett, describe the history and advances of ECMO.
The history of extracorporeal membrane oxygenation or briefly ECMO is tight to the history of cardiac surgery. Among the many individuals who have shaped the history of ECMO, two in particular deserve to be singled out by name. The first person is the surgeon John Gibbon, who spent 20 years of his life researching the possibility of an extracorporeal lung and circulatory support with his wife. He lived in the first half of the last century and he is credited with the first open heart surgery using a heart–lung machine. The second late half of the last century was marked by Robert Bartlett, who still lives in Michigan, USA and is still actively involved in several research projects at the University of Michigan at the Extracorporeal Life Support Laboratory. In this chapter all other important points of the history of ECMO are presented including the most important randomized trials.
Extracorporeal life support via extracorporeal membrane oxygenation (ECMO) has served the sickest of neonates for almost 50 years. Naturally, the characteristics of neonates receiving ECMO have changed. Advances in care have averted the need for ECMO for some, while complex cases with uncertain outcomes, previously not eligible for ECMO, are now considered. Characterizing the disease states and outcomes for neonates on ECMO is challenging as many infants do not fall into classic categories, i.e. meconium aspiration syndrome (MAS), respiratory distress syndrome (RDS), or congenital diaphragmatic hernia (CDH). Since 2017, over one third of neonatal respiratory ECMO runs reported to the Extracorporeal Life Support Organization Registry are grouped as Other, a catch-all that encompasses those with a diagnosis not included in the classic categories. This review summarizes the historical neonatal ECMO population, reviews advances in therapy and technology impacting neonatal care, and addresses the unknowns in the ever-growing category of Other.
The epidemiology, diagnostic and management approach to severe hypoxemic respiratory failure in the term and near-term neonate has evolved over time, as has the need for extracorporeal membrane oxygenation (ECMO) support in this patient population. Many patients who historically would have required ECMO support now respond to less invasive therapies, with patients requiring ECMO generally representing a higher risk and more heterogenous group of underlying diagnoses. This review will highlight these changes over time and the current available evidence for the diagnosis and management of these infants, as well as the current indications and relative contraindications to ECMO support when oxygen delivery cannot meet demand with less invasive management.
Neonates with progressive respiratory failure should be referred early for subspecialty evaluation and lung transplantation consideration. ECMO should be considered for patients with severe cardiopulmonary dysfunction and a high likelihood of death while on maximal medical therapy, either in the setting of reversible medical conditions or while awaiting lung transplantation. While ECMO offers hope to neonates that experience clinical deterioration while awaiting transplant, the risks and benefits of this intervention should be considered on an individual basis. Owing to the small number of infant lung transplants performed yearly, large studies examining the outcomes of various bridging techniques in this age group do not exist. Multiple single-centre experiences of transplanted neonates have been described and currently serve as guidance for transplant teams. Future investigation of outcomes specific to neonatal transplant recipients bridged with advanced devices is needed.
Venovenous extracorporeal membrane oxygenation (ECMO) is recommended in adult patients with refractory acute respiratory failure (ARF), but there is limited evidence for its use in patients with less severe hypoxemia. Prior research has suggested a lower PaO2/FiO2 at cannulation is associated with higher short-term mortality, but it is unclear whether this is due to less severe illness or a potential benefit of earlier ECMO support. In this exploratory cardinality-matched observational cohort study, we matched 668 patients who received venovenous ECMO as part of a national severe respiratory failure service into cohorts of "less severe" and "very severe" hypoxemia based on the median PaO2/FiO2 at ECMO institution of 68 mmHg. Before matching, ICU mortality was 19% in the 'less severe' hypoxemia group and 28% in the "very severe" hypoxemia group (RR for mortality = 0.69, 95% CI 0.54-0.88). After matching on key prognostic variables including underlying diagnosis, this difference remained statistically present but smaller: (23% vs. 30%, RR = 0.76, 95% CI 0.59-0.99). This may suggest the observed survival benefit of venovenous ECMO is not solely due to reduced disease severity. Further research is warranted to examine the potential role of ECMO in ARF patients with less severe hypoxemia.
This comprehensive textbook, now fully revised, rewritten and updated in its fourth edition, provides an authoritative account of all aspects of perioperative care for surgical patients. All areas of medical disease are discussed with clear recommendations for work up and management in the perioperative period. Basic discussions of surgical procedures are included to help non-surgeons understand the procedures and their implications for patient care. This definitive account includes numerous contributions from leading experts at national centers of medical excellence. It will serve as a significant work of reference for internists, anesthesiologists and surgeons.
Résumé
L’assistance respiratoire et circulatoire extracorporelle (ECMO), hors situation postopératoire d’une cardiotomie, correspond à l’ensemble des techniques de réanimation utilisées chez le nouveau-né comme chez l’enfant, ayant pour objectif la suppléance cardiaque et pulmonaire. L’ECMO comprend différentes modalités techniques selon le type de défaillance d’organe pris en charge. Les principales indications des ECMO sont à la fois respiratoires (syndrome de détresse respiratoire aigu, asthme aigu grave, pleuropneumopathie hypoxémiante, inhalation méconiale et hypertension artérielle pulmonaire) et hémodynamiques (choc cardiogénique, choc septique réfractaire, arrêt cardiorespiratoire réfractaire). Les principales contre-indications sont la prématurité < 34 semaines d’aménorrhée et un poids de naissance < 2 kg, l’existence d’une pathologie pulmonaire sévère irréversible, d’un déficit immunitaire sévère, d’une pathologie neurodégénérative ou d’une anomalie congénitale de l’hémostase ne permettant pas une anticoagulation efficace. Les principales complications sont d’ordre hémorragique (saignement intracrânien), infectieux (infections secondaires), neurologique (convulsions et accidents vasculaires cérébraux) et néphrologique (nécrose tubulaire aiguë). Le taux de survie global est de 60 % mais il varie de 80 % pour les inhalations de liquide méconial à moins de 10 % pour les arrêts cardiaques réfractaires extra-hospitaliers. Depuis plus récemment, les patients atteints d’une défaillance vitale circulatoire ou respiratoire trop instable pour être transportés peuvent bénéficier de l’implantation d’une ECMO sur leur lieu d’hospitalisation par une unité mobile d’assistance circulatoire (UMAC).
Introduction:
Pregnant women are routinely excluded from clinical trials, leading to the absence or delay in even the most basic pharmacokinetic (PK) information needed for dosing in pregnancy. When available, pregnancy PK studies use a small sample size, resulting in limited safety information. We discuss key study design elements that may enhance the timely availability of pregnancy data, including the role and timing of randomized controlled trials (RCTs) to evaluate pregnancy safety; efficacy and safety outcome measures; stand-alone protocols, platform trials, single arm studies, sample size and the effect that follow-up time during gestation has on analysis interpretations; and observational studies.
Discussion:
Pregnancy PK should be studied during drug development, after dosing in non-pregnant persons is established (unless non-clinical or other data raise pregnancy concerns). RCTs should evaluate the safety during pregnancy of priority new HIV agents that are likely to be used by large numbers of females of childbearing age. Key endpoints for pregnancy safety studies include birth outcomes (prematurity, small for gestational age and stillbirth) and neonatal death, with traditional adverse events and infant growth also measured (congenital anomalies are best studied through surveillance). We recommend that viral efficacy be studied as a secondary endpoint of pregnancy RCTs, once PK studies confirm adequate drug exposure in pregnancy. RCTs typically use a stand-alone protocol for new agents. In contrast, master protocols using a platform design can add agents over time, possibly speeding safety data ascertainment. To speed accrual, stand-alone pregnancy trial protocols can include pre-specified starting rules based upon adequate PK levels in pregnancy; and seamless master protocols or platform trials can include a pregnancy PK and safety component. When RCTs are unethical or cost-prohibitive, observational studies should be conducted, preferably using target trial emulation to avoid bias.
Conclusions:
Pregnancy PK needs to be obtained earlier in drug evaluation. Timely RCTs are needed to understand safety in pregnancy for high-priority new HIV agents. RCTs that enrol pregnant women should focus on outcomes unique to pregnancy, and observational studies should focus on questions that RCTs are not equipped to answer.
The Acute Stroke Therapy by Inhibition of Neutrophils (ASTIN) study, initiated in November of the year 2000, is now widely recognized as having been a landmark study in the history of clinical trials. We look at why this is the case by considering its key features and impact. These key features are: the use of Bayesian design and analysis; the use of the normal dynamic linear model; the response adaptive nature of the study; the use of real‐time dosing decisions; and the use of an integrated model to predict 90‐day response on the Scandinavian Stroke Scale. Our overall conclusion is that the ASTIN study's main impact came from showing the clinical trial community the feasibility of the novel design and analysis used when most of these key features were rarely used in industry trials, let alone used together in one trial in a disease area with a tremendous unmet medical need.
Acute Respiratory Distress Syndrome (ARDS) accounts for 10% of ICU admissions and affects 3 million patients each year. Despite decades of research, it is still associated with one of the highest mortality rates in the critically ill. Advances in supportive care, innovations in technologies and insights from recent clinical trials have contributed to improved outcomes and a renewed interest in the scope and use of Extracorporeal life support (ECLS) as a treatment for severe ARDS, including high flow veno-venous Extracorporeal Membrane Oxygenation (VV-ECMO) and low flow Extracorporeal Carbon Dioxide Removal (ECCO2R). The rationale being that extracorporeal gas exchange allows the use of lung protective ventilator settings, thereby minimizing ventilator-induced lung injury (VILI). Ventilation strategies are adapted to the patient's condition during the different stages of ECMO support. Several areas in the management of mechanical ventilation in patients on ECMO, such as the best ventilator mode, extubation-decannulation sequence and tracheostomy timing, are tailored to the patients' recovery. Reduction in sedation allowing mobilization, nutrition and early rehabilitation are subsequent therapeutic goals after lung rest has been achieved.
Extracorporeal life support (ECLS) is a treatment for acute respiratory failure that can provide extracorporeal gas exchange, allowing lung rest. However, while most patients remain mechanically ventilated during ECLS, there is a paucity of evidence to guide the choice of ventilator settings. We studied the associations between ventilator settings 24 hours after ECLS initiation and mortality in pediatric patients using a retrospective analysis of data from the Extracorporeal Life Support Organization Registry. 3497 patients, 29 days to 18 years of age, treated with ECLS for respiratory failure between 2015 and 2021, were included for analysis. 93.3% of patients on ECLS were ventilated with conventional mechanical ventilation. Common settings included positive end-expiratory pressure (PEEP) of 10 cm H2O (45.7%), delta pressure ([DELTA]P) of 10 cm H2O (28.3%), rate of 10-14 breaths per minute (55.9%), and fraction of inspired oxygen (FiO2) of 0.31-0.4 (30.3%). In a multivariate model, PEEP >10 cm H2O (versus PEEP < 8 cm H2O, odds ratio [OR]: 1.53, 95% CI: 1.20-1.96) and FiO2 >=0.45 (versus FiO2 < 0.4; 0.45 <= FiO2 < 0.6, OR: 1.31, 95% CI: 1.03-1.67 and FiO2 >= 0.6, OR: 2.30; 95% CI: 1.81-2.93) were associated with higher odds of mortality. In a secondary analysis of survivors, PEEP 8-10 cm H2O was associated with shorter ECLS run times (versus PEEP < 8 cm H2O, coefficient: -1.64, 95% CI: -3.17 to -0.11), as was [DELTA]P >16 cm H2O (versus [DELTA]P < 10 cm H2O, coefficient: -2.72, 95% CI: -4.30 to -1.15). Our results identified several categories of ventilator settings as associated with mortality or ECLS run-time. Further studies are necessary to understand whether these results represent a causal relationship.
Breast cancer (BC) is well-known for its diversified clinical behaviors despite the similar histopathological characteristics at diagnosis. Research studies on molecular pathogenesis of BC reveal that it is a multitude of various diseases having variable molecular basis that regulate therapeutic responses, long-term survival, and disease-free intervals. Remarkable similarities between the molecular progression of BC and normal development suggest that BC might be caused by mammary cancer stem cells. Various signaling pathways such as the HER2, ER, and PR regulate mammary stem cells and normal breast development by controlling stem cell motility, differentiation, proliferation, and cell death. Recent studies suggest that non-coding RNAs and epigenetic regulations might play an important part in the metastasis and heterogeneity of BC specifically for triple-negative BC (TNBC). Traditionally used therapeutic strategies depend upon the expression levels of PR, ER, and HER2. Even though the methods used for clinical classification help choose targeted therapies, the prediction of patient responses and their long-term survival remains difficult. Recent advances in the field of molecular biology (multigene assays, next-generation sequencing) have led to innovations in BC diagnostics and therapeutics. Numerous multigene assays like Oncotype DX, MammaPrint, etc. have been developed for better prediction and prognosis at the early stages of BC. The concept of personalized medicine is gaining attention due to its potential role in developing effective BC treatment regimens. The recent identification of various molecular biomarkers via gene expression profiling might help in the prediction of drug response and intensity of cancer-related symptoms. The molecular biomarkers can also help in determining optimal drug choice/drug dosage and to identify more molecular targets leading towards the development of more personalized treatment strategies. For the practical implementation of personalized BC therapies, proper evaluation and analysis of molecular specifications of BC in each patient is needed. Moreover, the epigenetic and genetic changes should also be considered in management of BC patients. Finally, clinical trials are the link between chains of knowledge and determine the role of therapeutic advances. Out of the various clinical trial designs being used, adaptive clinical trials are most frequently used as they aim at reducing the resources, lessen the completion time, and improve the possibility of detecting the effects of treatments.KeywordsGene sequencingImmunotherapyLymphangiogenesisPrognosisTumor markers
We propose the use of Bayesian estimation of risk preferences of individuals for applications of behavioral welfare economics to evaluate observed choices that involve risk. Bayesian estimation provides more systematic control of the use of informative priors over inferences about risk preferences for each individual in a sample. We demonstrate that these methods make a difference to the rigorous normative evaluation of decisions in a case study of insurance purchases. We also show that hierarchical Bayesian methods can be used to infer welfare reliably and efficiently even with significantly reduced demands on the number of choices that each subject has to make. Finally, we illustrate the natural use of Bayesian methods in the adaptive evaluation of welfare.
Chest CT in pediatric patients on extracorporeal membrane oxygenation (ECMO) can be done safely and provide valuable high-quality diagnostic images to help guide patient management. An understanding of the basics of the ECMO circuit, cannula locations, where and how to inject contrast media, and how to time image acquisition is vital for the radiologist. Additionally, understanding the precautions associated with performing these exams is essential to ensure the safety of the child. This article provides a brief review of pediatric ECMO and its challenges and considerations, as well as a stepwise approach to perform and optimize these exams safely.
DSMB Monitoring of Clinical Trials for Early EfficacyIn this article in the NEJM Evidence DSMB mini-series, Dodd and Proschan review the clinical, ethical, and statistical issues that confront a DSMB when trial data suggest that the treatment under test is highly efficacious. Examples of such trials are reviewed.
Background
Adaptive designs offer added flexibility in the execution of clinical trials, including the possibilities of allocating more patients to the treatments that turned out more successful, and early stopping due to either declared success or futility. Commonly applied adaptive designs, such as group sequential methods, are based on the frequentist paradigm and on ideas from statistical significance testing. Interim checks during the trial will have the effect of inflating the Type 1 error rate, or, if this rate is controlled and kept fixed, lowering the power.
Results
The purpose of the paper is to demonstrate the usefulness of the Bayesian approach in the design and in the actual running of randomized clinical trials during phase II and III. This approach is based on comparing the performance of the different treatment arms in terms of the respective joint posterior probabilities evaluated sequentially from the accruing outcome data, and then taking a control action if such posterior probabilities fall below a pre-specified critical threshold value. Two types of actions are considered: treatment allocation, putting on hold at least temporarily further accrual of patients to a treatment arm, and treatment selection, removing an arm from the trial permanently. The main development in the paper is in terms of binary outcomes, but extensions for handling time-to-event data, including data from vaccine trials, are also discussed. The performance of the proposed methodology is tested in extensive simulation experiments, with numerical results and graphical illustrations documented in a Supplement to the main text. As a companion to this paper, an implementation of the methods is provided in the form of a freely available R package ’barts’ .
Conclusion
The proposed methods for trial design provide an attractive alternative to their frequentist counterparts.
For many decades, persistent pulmonary hypertension of the newborn (PPHN) remained a baffling disorder, often confused with cyanotic congenital heart disease, with a very high mortality. Originally described as a condition characterized by clear lung fields and profound hypoxemia, modern diagnostic techniques and novel therapeutics have improved the outcomes of affected newborns. This paper will review the historical aspects of PPHN and enable the reader to see how far we have come but also how far we have to go in conquering this unique disorder.
Résumé
Les assistances extracorporelles respiratoires et circulatoires sont des techniques de sauvetage permettant de suppléer transitoirement la fonction circulatoire ou la fonction respiratoire en cas de défaillance réfractaire aux traitements dits conventionnels. De par leur haute technicité, les patients ayant bénéficié de ces thérapeutiques de sauvetage sont à risque de multiples complications parmi lesquelles les hémorragies ou ischémies cérébrales, les insuffisances rénales et les infections secondaires. La grande variabilité de gabarit inhérente à la population pédiatrique et néonatale complexifie la procédure avec de multiples possibilités d’abord vasculaire en fonction des poids et âges des patients. Le pronostic des assistances extracorporelles reste étroitement lié à la défaillance initialement prise en charge ainsi qu’à la technique d’assistance utilisée. Les patients ayant bénéficié d’une assistance respiratoire ont un meilleur pronostic que ceux ayant bénéficié d’une assistance circulatoire. Cependant, la situation clinique avant la pose d’une assistance extracorporelle est aussi étroitement liée à la survie. Certaines populations spécifiques comme les patients immunodéprimés ou les nouveau-nés prématurés ont un pronostic plus sombre que les autres patients. Les assistances respiratoires et circulatoires extracorporelles sont des traitements de pointe disponibles uniquement dans quelques hôpitaux. Afin de permettre la mise à disposition de ces techniques à tous les patients de métropole, des unités mobiles d’assistance extracorporelle sont disponibles et couvrent l’ensemble du territoire français.
To identify predictors of neonatal ECMO circuit health, a retrospective analysis of circuit functional pressure and flow parameters as well as infant clotting values were collected 48 h prior to and 24 h post circuit change. Circuit impairment was defined as need for partial or total circuit change. Statistical analysis used multivariate statistics and non-parametric Mann–Whitney U-test with possible non-normality of measurements. A total of 9764 ECMO circuit and clotting values in 21 circuits were analyzed. Circuit delta-P mean, and maximum values increased from 8.62 to 48.59 mmHg (p < 0.011) and 16.00 to 53.00 mmHg (p < 0.0128) respectively prior to need for circuit change. Maximum and mean Pump Flow Revolutions per minute (RPM) increased by 75% (p < 0.0043) and 81% (p < 0.0057), respectively. Mean plasma free hemoglobin (pfHb) increased from 26.45 to 76.00 mg/dl, (p < 0.0209). Sweep, venous pressure, and clotting parameters were unaffected. ECMO circuit delta-P, RPM, and pfHb were early predictors of circuit impairment.
Les unités mobiles d’assistance circulatoire et respiratoire de l’enfant et du nouveau-né se sont développées au cours des dix dernières années. En effet, la mise en place d’une suppléance extracorporelle respiratoire ou circulatoire nécessite une équipe expérimentée et n’est pas disponible dans tous les centres hospitaliers pédiatriques. Or, les enfants atteints d’une défaillance circulatoire ou respiratoire réfractaire ne sont, pour la plupart, pas déplaçables vers une unité délivrant ce type de traitement de sauvetage. Les unités mobiles ont donc pour objectif de mettre à disposition ces technologies d’exception sur l’ensemble du territoire afin de garantir une égalité d’accès aux soins. Cependant, la haute technicité de ces thérapeutiques nécessite une équipe entraînée sachant poser et régler une assistance extracorporelle, prendre en charge un patient en défaillance respiratoire et/ou hémodynamique réfractaire et aguerrie à ces transports à haut risque. Le territoire français était jusqu’en 2014 très mal couvert par les unités mobiles pédiatriques et néonatales. Depuis, la création de plusieurs unités a permis une couverture totale du territoire. L’objectif de cette revue narrative sur les unités mobiles pédiatriques et néonatales est de résumer les différentes modalités de suppléance respiratoire et hémodynamique extracorporelle, d’en illustrer leurs différentes missions et leurs modalités de fonctionnement. Nous finirons par une description de leur efficacité en termes de survie et de survenue d’incidents en cours de transport.
This review addresses the challenges of neuroanesthesiologic research: the population, the methodology and the outcomes. In addition we discuss the opportunities of adaptive trial designing neuroanesthesiologic research
Introduction: Goodpasture's syndrome is a life-threatening autoimmune type IV collagen disease characterized by the presence anti–glomerular basement membrane antibodies, rapid progressive glomerulonephritis and/or pulmonary hemorrhage.
Methods: Here, we describe new therapeutic options, which take recent advances in unraveling Goodpasture's pathogenesis into account.
Results: In a 17-year old male, severe Goodpasture's syndrome resulted in acute respiratory distress syndrome (ARDS). Within 1 day after hospital admission, the patient required extracorporeal membrane oxygenation (ECMO). Despite steroid-pulse and plasmapheresis, ARDS further deteriorated. Eleven days after admission, the patient was in a pre-final stage. At last, we decided to block the complement-driven lung damage by Eculizumab. Three days after, lung-failure has stabilized in a way allowing us to initiate Cyclophosphamide-therapy. As mechanical ventilation further triggers Goodpasture-epitope exposure, the patient was taken from pressure support - breathing spontaneously by the help of maintaining ECMO therapy. After a total of 24 days, ECMO could be stopped and pulmonary function further recovered.
Conclusions: In conclusion, our findings suggest that life-threatening organ-damage in Goodpasture's syndrome can be halted by Eculizumab as well as by lung-protective early withdrawal from pressure support by the help of ECMO. Both therapeutic options serve as new tools in otherwise hopeless situations to prevent further organ-damage and to gain time until the established immunosuppressive therapy works in otherwise lethal autoimmune-diseases.
Two major barriers to conducting user studies are the costs involved in recruiting participants and researcher time in performing studies. Typical solutions are to study convenience samples or design studies that can be deployed on crowdsourcing platforms. Both solutions have benefits but also drawbacks. Even in cases where these approaches make sense, it is still reasonable to ask whether we are using our resources – participants’ and our time – efficiently and whether we can do better. Typically user studies compare randomly-assigned experimental conditions, such that a uniform number of opportunities are assigned to each condition. This sampling approach, as has been demonstrated in clinical trials, is sub-optimal. The goal of many Information Retrieval (IR) user studies is to determine which strategy (e.g., behaviour or system) performs the best. In such a setup, it is not wise to waste participant and researcher time and money on conditions that are obviously inferior. In this work we explore whether Best Arm Identification (BAI) algorithms provide a natural solution to this problem. BAI methods are a class of Multi-armed Bandits (MABs) where the only goal is to output a recommended arm and the algorithms are evaluated by the average payoff of the recommended arm. Using three datasets associated with previously published IR-related user studies and a series of simulations, we test the extent to which the cost required to run user studies can be reduced by employing BAI methods. Our results suggest that some BAI instances (racing algorithms) are promising devices to reduce the cost of user studies. One of the racing algorithms studied, Hoeffding, holds particular promise. This algorithm offered consistent savings across both the real and simulated data sets and only extremely rarely returned a result inconsistent with the result of the full trial. We believe the results can have an important impact on the way research is performed in this field. The results show that the conditions assigned to participants could be dynamically changed, automatically, to make efficient use of participant and experimenter time.
This paper shows the scale of global health research and the context in which we frame the subsequent papers in the Series. In this Series paper, we provide a historical perspective on clinical trial research by revisiting the 1948 streptomycin trial for pulmonary tuberculosis, which was the first documented randomised clinical trial in the English language, and we discuss its close connection with global health. We describe the current state of clinical trial research globally by providing an overview of clinical trials that have been registered in the WHO International Clinical Trial Registry since 2010. We discuss challenges with current trial planning and designs that are often used in clinical trial research undertaken in low-income and middle-income countries, as an overview of the global health trials landscape. Finally, we discuss the importance of collaborative work in global health research towards generating sustainable and culturally appropriate research environments.
Clinical trials usually involve efficient and ethical objectives. Different adaptive designs have been proposed to satisfy these needs. We combine interim analysis, the sequential estimation‐adjusted urn model (SEU), and sample size re‐estimation (SSR) in one clinical trial. We show that the asymptotic distribution, under the null hypothesis, of the proposed sequential statistic follows Brownian motion by simultaneously addressing the three sequential procedures (allocation of patients, urn composition, and sequential parameter estimators) and the sequential statistics with revised information time due to SSR. Therefore, to control the type I error rate, traditional critical values for sequential monitoring based on Brownian motion can be used for the proposed procedure. Numerical studies with three types of urn models demonstrate that our proposed approach can control the type I error rate well and also achieve efficient and ethical objectives.
Objective
The COVID-19 pandemic requires thinking about alternatives to establish ECMO when often-limited hardware resources are exhausted. Heart-lung-machines may potentially be used for ECMO but contain roller pumps as compared to centrifugal pumps in ECMO-circuits. We here tested roller pumps as rescue pump for ECMO-establishment.
Methods
We set up in vitro circuits on roller pumps from C5 heart-lung-machine with 5 l/minutes flow. In two series, we placed either PVC or silicon tubing for an ECMO circuit into the roller pump. We assessed the mechanical stress on the tubing (aiming to run the pump for at least 1 week), measured the temperature increase generated by the friction and assessed flow characteristics and its measurement in simulated situations resembling tube kinking and suction.
Results
The roller pumps led to expected and unexpected adverse events. PVC tubing burst between 36 and 78 hours, while silicon tubing lasted for at least 7 days. At 7 days, the silicone tubing showed significant signs of roller pump wear visible on the outside. The inside, however, was free of surface irregularities. Using these tubings in a roller pump led to a remarkable increase in circuit temperature (PVC: +12.0°C, silicone +2.9°C). Kinking or suction on the device caused the expected dramatic flow reduction (as assessed by direct measurement) while the roller pump display continued to show the preset flow. The roller pump is therefore not able to reliably determine the true flow rate.
Conclusion
Roller pumps with silicone tubing but not PVC tubing may be used for running ECMO circuits. Silicone tubing may endure the roller pump shear forces for up to 1 week. Thus, repeated tubing repositioning may be a solution. Circuit heating and substantial limitations in flow detection should increase attention if clinical use in situations of crisis is considered.
Extracorporeal life support (ECLS) has grown in its application since its first clinical description in the 1970s. The technology has been used to support a wide variety of mechanical support modalities and diseases, including respiratory failure, cardiorespiratory failure, and cardiac failure. Over many decades and safety and efficacy studies, followed by randomized clinical trials and thousands of clinical uses, ECLS is considered as an accepted treatment option for severe pulmonary and selected cardiovascular failure. Extracorporeal life support involves the use of support artificial organs, including a membrane lung and blood pump. Over time, changes in the technology and the management of ECLS support devices have evolved. This manuscript describes the use of membrane lungs and blood pumps used during ECLS support from 2002 to 2017 in over 65,000 patients reported to the Extracorporeal Life Support Organization Registry. Device longevity and complications associated with membrane lungs and blood pump are described and stratified by age group: neonates, pediatrics, and adults.
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