Blockchain Papers

Sara C. Auld, Mark Caridi-Scheible

On March 6, 2020, the first patient diagnosed with coronavirus disease 2019 (COVID-19) at our institution was admitted to the Emory Serious Communicable Disease Unit (SCDU), which was initially established for the care of patients with Ebola and other special pathogens. The demand for ICU beds quickly outstripped the SCDU capacity: within days, we converted ordinary ICUs to receive the influx of COVID patients. Our teams struggled with fear, anxiety, and uncertainty about our safety and that of our families. We struggled much more wondering about the best care for our patients. Our institutional guidelines initially recommended against the use of both noninvasive positive pressure ventilation (NIPPV) and high-flow nasal oxygen, also referred to as heated high-flow nasal cannula and high-flow nasal cannula. This recommendation emerged from a desire to avoid unnecessary staff exposure to aerosolized viral particles. Global guidance in March 2020 similarly cautioned against high-flow nasal oxygen, out of concern for limited efficacy and high failure rates (1). During those early weeks, patients under our care who remained hypoxemic or tachypneic despite a 100% nonrebreather mask were promptly intubated. As believers in the robust data supporting the use of high-flow nasal oxygen who have been using it as part of our armamentarium to care for patients in the last several years (2,3), we could not dismiss our nagging doubt that we may have been doing a disservice to our patients by withholding this modality. Upon further review of evidence demonstrating minimal additional air dispersion as compared with traditional face masks (4), our institutional guidelines were relaxed on March 25, 2020, to allow for the use of high-flow nasal oxygen. It was at this time that we initially were assigned to review the article by Xia et al (5), published in this issue of Critical Care Medicine. They reported their experience caring for 43 patients with COVID-19 who were treated with high-flow nasal oxygen at three tertiary-care hospitals in Wuhan, China, in the earliest days of the outbreak. Just under half of the patients in their cohort failed high-flow nasal oxygen, requiring escalation to either noninvasive or invasive mechanical ventilation. Patients who failed were older, more commonly male, and had a lower oxygen saturation (Spo2) at admission. They were also more likely to have an increase in their respiratory rate (RR) and a decrease in their ratio of Spo2/Fio2 to RR (ROX) index after initiation of high-flow nasal oxygen. As has been reported in other settings (6), patients with failure of high-flow nasal oxygen had a high mortality rate (65%), whereas no patients died among those who did not require escalation of their respiratory support. Although this was not a randomized trial of high-flow nasal oxygen use, it offers some reassurance to providers that there is a role for this modality in the treatment of COVID-19 and identifies clinical risk factors for treatment failure. The early experience of Xia et al (5) from Wuhan felt like a lifeline in March when the manuscript first reached our hands. Several months later, many of us have cared for our own patients with COVID-19 and these early data no longer feel novel. Yet, it is important that they are published and read. In reviewing and publishing this report, the editors have faced the “challenge of discerning signal amidst noise,” steadily walking the fine line between expediting critical reporting and ensuring a thorough and comprehensive review process (7). Surprisingly, there are few data to guide our use of high-flow nasal oxygen in COVID-19. As of July 9, 2020, a search of the terms “high-flow nasal oxygen” and “high-flow nasal cannula” on LitCovid, a curated hub of articles related to COVID-19 in PubMed, revealed 37 articles written in English, out of more than 30,603 total articles. Thirteen of those articles were reviews or guidelines, three reported on the use of high-flow nasal oxygen in periprocedural settings, 10 were observational studies that reported the use of high-flow nasal oxygen in their cohorts but did not explicitly focus on the modality, eight were small case series of fewer than 10 patients—leaving just three articles reporting on patient outcomes in the context of high-flow nasal oxygen use, two of which examined the use of high-flow nasal oxygen in conjunction with awake prone positioning (8–10). We found an additional preprint manuscript reporting, similar to Xia et al (5), that the ROX index was predictive of failure of high-flow nasal oxygen and the need for invasive mechanical ventilation, with greater mortality in the group that progressed to invasive mechanical ventilation (11). The role for high-flow nasal oxygen in critically ill patients with COVID-19 remains unclear. Although several reports have found that patients who received high-flow nasal oxygen had higher mortality than those who did not, these observational studies cannot account for confounding by indication, whereby the sickest patients would have been those most likely to receive high-flow nasal oxygen in the first place (9,12). The same uncertainty holds for NIPPV. Although there are hospitals that have used NIPPV in the care of patients with COVID-19 (13,14) (including a hospital in Singapore where 20 healthcare workers wore a simple surgical mask while caring for an NIPPV patient who was later found to have COVID-19—and none became ill [15]), our institutional guidelines still recommend against noninvasive ventilation because of concern for aerosol generation with leakage around the face mask. Anecdote is not evidence. Observations are not proof. The patient phenotypes and clinical trajectories are changing. Yet the continuing flow of COVID-19 patients demands that we choose treatment in the face of distressing uncertainty. So what can we do? We start with what we know—or at least what we think we know—about best practices for viral pneumonia, acute respiratory distress syndrome, and general critical care. Inevitably, some of our choices will eventually be proven “wrong.” It is for precisely this reason that reports such as that of Xia et al (5)—and of our own (16)—must be written, reviewed, and published. We started our COVID-19 response by consolidating current best practices in non-COVID critical care and management of respiratory failure into pragmatic guidelines. In ordinary circumstances, we would wait for evidence to accumulate and then modify our practice. History tells us that circumspection is ordinarily best: the history of critical care is littered with good intentions that were ineffective or frankly harmful (17). Prudence asserts equipoise, awaiting evidence that is large-scale, rigorous, and undeniable. The onward global march of COVID-19 denies us this equipoise. The number of infected patients’ lives at stake grows ominously with every passing day. This is not business as usual. We cannot wait. They cannot wait. How has our healthcare system moved forward? We have paid close attention to every patient’s evolution, assembled subject matter experts, formed working groups, shared and analyzed internal data, reviewed the emerging (albeit limited and imperfect) literature, and week by week (sometimes day by day) integrated that new knowledge into our institutional guidelines. When new avenues of uncertainty arose, from how to handle higher than normal rates of ventilator dyssynchronies to unprecedented rates of filter clotting for patients on continuous renal replacement therapy, we pivoted our efforts to assess, evaluate, and respond. We formed a microcosm, sharing observations, reviewing experience, and challenging our own logic and outcomes. We collated ideas and data, digested them, put them up for debate, and attempted to place them in perspective as we made changes in practice. Absent the sort of evidence that comes from randomized, controlled trials, we did the best we could with what we had. Observational comparative studies like the one of high-flow nasal oxygen by Xia et al (5) are reassuring. Each provides additional data in what remains a largely data-free zone, supporting cautious, ongoing changes in our practice. These small adjustments are slow moves toward perfect care. Increments are preferred to big changes in these parlous times. We understood that the report by Xia et al (5) was not a perfect study, that there was selection bias for administration of high-flow nasal oxygen, that the sample size was somewhat limited, among other potential critiques. Yet the study by Xia et al (5) informed our own decision to incorporate high-flow nasal oxygen into our care. Although the study by Xia et al (5) did not provide a definitive answer to high-flow nasal oxygen use, it allowed us to take one more step toward rigorous practice. With publication of their peer-reviewed revised report, Xia et al (5) now create more confidence for readers that high-flow nasal oxygen is an appropriate choice for some patients with COVID-19. Only 19 weeks ago, we admitted our first COVID-19 patient. We have just admitted our 580th. She will receive more informed care that is shaped by local and global experience. Like Xia et al (5), we have written, submitted, revised, and ultimately published in Critical Care Medicine. By continuing to submit our reports of experiences to peer-review, we—and the authors of the other 30,602 papers—join an invisible college. We do so in the hope of informing the best care today and of delivering even better care tomorrow.

Hamish Graham, Ayobami A. Bakare, Chizoba Fashanu, Owens Wiwa · 6 authors

Oxygen is one of the most basic medical therapies we have for acute respiratory illnesses and it has been an established part of medical practice for over 100 years. However, most patients who may benefit from oxygen in low- and middle-income countries will not receive it—either because oxygen is not available or because their need for oxygen is unrecognized. This gap takes an enormous toll, with modeling estimates suggesting that improved pulse oximetry and oxygen access could avert 148 000 under-five child pneumonia deaths annually in the 15 countries with the highest pneumonia burden1. This commentary explores the reasons for this gap, using Nigeria as an illustrative case study in how oxygen access can be improved globally, and concluding with key actions for policy and practice. Nigeria is a large lower middle-income country that ranks second in the number of child pneumonia deaths globally, contributing one-sixth of under-five pneumonia deaths globally.1, 2 Pneumonia causes 18% of under-five deaths in Nigeria, followed by malaria (14%), complications of prematurity (12%), neonatal encephalopathy and trauma (11%), and diarrheal diseases (10%).2 Nigerian studies suggest that hypoxemia affects approximately 14% of children admitted to hospital, including 28% to 49% of children with pneumonia and 22% to 41% of neonates.3-6 Hypoxemia ranks alongside severe acute malnutrition as a major predictor of mortality, with recent data from 12 Nigerian hospitals showing that children with hypoxemia had seven-fold higher risk of death than those who did not.3 Despite the high burden of hypoxemia and increasing recognition of its position as a key sign of illness severity, pulse oximetry, and oxygen therapy have been inadequately used in most Nigerian hospitals. Facility evaluations of Nigerian hospitals have shown that oxygen supply is often not available on pediatric wards, pulse oximeters are uncommonly used outside operating theaters, and healthcare workers lack training on how to use oxygen and pulse oximeters.7, 8 These findings in Nigeria are echoed globally. Hypoxemia is common and deadly,9, 10 yet access to oxygen and pulse oximeters remains limited and healthcare worker skills and confidence using oxygen is low11-14—especially in health centers and smaller hospitals where most sick children first present. At the hospital level, there are three key barriers to improving oxygen access and use. A recent study in 12 south-west Nigerian hospitals found that 92% (11/12) of hospitals had some access to oxygen supplies, 42% (5/12) had oxygen available on pediatric wards at the time of evaluation, and 8% (1/12) used pulse oximetry for pediatric care.7 Testing of 57 oxygen concentrators revealed that 5% (3/57) were producing medical-grade oxygen (defined as >85% purity), and 48% (24/50) of those that turned on and blew gas were simply blowing out air.7 Data from hospitals in northern Nigeria showed that the situation was even worse in these poorer, more rural, locations—11% of hospital pediatric wards had functional oxygen, 2% had pulse oximeters.8 In both regions, procurement of oxygen equipment was haphazard, motivated by price and availability of donated items, with little regard to quality or appropriateness. Hospitals lacked preventive maintenance programs and many technicians reported that they were not aware of the procurement of oxygen equipment until it was brought to them broken for repair.7 Oxygen therapy is unlike most other medications, being administered using equipment and titrated by nurses based on serial clinical assessments (including pulse oximetry). Clinical use of oxygen is not complicated, but healthcare workers do require some basic knowledge and skills. In Nigeria, most nurses receive little training on oxygen, and no training on pulse oximetry, either in nursing school or in-service training—unless they work in anesthetics/theater.7 As such, pulse oximetry is rarely used on pediatric wards, and oxygen (when it is available) is used at excessive flow rates and primarily for those with very obvious respiratory distress; many hypoxemic patients will not receive oxygen.7, 8 Maintaining supply of medical oxygen is expensive, and is made costlier by faulty equipment (eg, leaky cylinders and piping), and poor clinical practices (eg, without pulse oximetry to guide therapy). In Nigeria, oxygen-related patient fees are substantial, typically around ₦3,900 per day7 (USD$21, 2015). These costs fall most heavily on those who are sickest and require longer hospitalization and may result in treatment refusal or discharge against medical advice. In Nigeria (and many other countries), health financing deficiencies result in patients facing substantial out-of-pocket costs in accessing hospital care. The decentralized hospital system in Nigeria gives individual hospitals more autonomy and responsibility for procuring and maintaining medical equipment. However, without technical support or a strong regulatory framework, hospitals often end up with a haphazard array of cheap equipment that they are unable to maintain or repair—exacerbated further by poorly considered equipment donation programs. Nigerian clinicians, hospital administrators, and policymakers have made substantial progress towards improving oxygen access and use. At the national policy level, the Federal Ministry of Health has revised the essential medicines and equipment lists to include oxygen and oxygen-related products, updated the pneumonia clinical guidelines, created a new clinical guideline and hospital policy on oxygen,15 and developed a national strategy for scaling up oxygen nationally.16 This strategy includes the nomination of personnel in the Federal and State Ministries of Health who will be responsible for addressing oxygen access issues in their jurisdiction. Demonstration projects in Nigeria, have shown that the barriers to improving oxygen services can be overcome using existing commercially available equipment, local maintenance teams, and team-based approaches to learning and quality improvement. Results from these projects have demonstrated improved pulse oximetry use on pediatric wards (from <20% to >75%), improved oxygen provision to hypoxaemic children (from <20% to >85%), and reduced mortality from child pneumonia.17, 18 Global policies have also shifted to better support oxygen systems strengthening. In 2013, WHO/UNICEF added oxygen to the Global Action Plan for Pneumonia and Diarrhea, correcting an omission from the first edition.19, 20 This establishes oxygen therapy as a core treatment in the Protect, Prevent, Treat framework (Figure 1). In the past 4 years, the WHO has revised the Model List of Essential Medicines for Children to include oxygen for the treatment of hypoxemia in children,21 published technical specifications for concentrators22 and other oxygen therapy devices,23 and released a new oxygen clinical guidelines for children24—all of which have been used and adapted by Nigeria and other countries. Oxygen therapy is an essential medical therapy for hospital care and should be recognized as a cost-effective investment for improving health care quality and health outcomes. We identify the following key opportunities for improving oxygen therapy for children globally. First, existing evidence shows that improving oxygen systems is a cost-effective intervention that improves the quality of health services and health outcomes. Just as healthcare workers understand the value of oxygen as a basic medical therapy, policy-makers should now be able to recognize that oxygen is a sound financial investment that will make health services better overall. Better oxygen systems should not only improve access to oxygen therapy but also strengthen broader hospital quality of care systems and stimulate the adoption of other essential health technologies as well. Second, we know enough to enact national-scale implementation of improved oxygen systems. Experiences from Nigeria, Ethiopia, Papua New Guinea, and elsewhere, have identified contextual challenges and solutions to improving oxygen systems. These solutions will not be situated within vertically structured programming, but by accepting oxygen therapy as a basic hospital service within a universal health coverage agenda. Policymakers and program managers can be guided by policy documents and technical specifications from WHO and UNICEF22-24 and Every Breath Counts and United for Oxygen consortiums. However, national oxygen strategies must adopt this guidance to local contexts, defining specific responsibilities for those involved in pharmaceutical, medical device, and financing services. Third, pulse oximetry is a low-cost, relatively easily implemented, component of oxygen systems. Essential to the identification of hypoxemia, pulse oximetry is also embraced by healthcare workers as a valuable tool in assessing and monitoring sick patients that improves the quality of care more generally. As such, pulse oximetry scale-up represents “low-hanging fruit” for improving hospital care, and may also play an important role in facilitating referral from primary care.14, 25 Fourth, existing oxygen technologies are suboptimal in hot, humid, dusty conditions, or environments that lack strong maintenance structures. We need better technology to provide reliable oxygen in places where power failures are common, produce and store oxygen locally, and efficiently deliver oxygen from the oxygen source to patients. Fifth, previous studies have demonstrated the mortality impact of pulse oximetry and improved oxygen systems for young children with pneumonia, but little data exist for other children or neonates (in whom oxygen is also used commonly). The neonatal cohort represents a particular group of interest, as they can suffer adverse effects from administration of excessive oxygen (eg, retinopathy of prematurity, bronchopulmonary dysplasia).26, 27 Oxygen therapy is an essential medical therapy that is poorly available and suboptimally used in many low- and middle-income countries. Recent policy and programmatic experience in Nigeria has shown how oxygen services can be improved for the benefit of children and health services. Hamish Graham, Ayobami A. Bakare, Chizoba Fashanu, Owens Wiwa, Trevor Duke, and Adegoke G. Falade received payment for services related to this paper from the Bill and Melinda Gates Foundation (OPP1123577 and OPP1133417). HG drafted the manuscript. AAB, CF, OQ, TD, and AGF provided substantial comments to the writing of the manuscript. All authors read and approved the final manuscript.