Blockchain Papers

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.

on behalf of the Neonatal Transport Study Group of the Italian Society of Neonatology (SIN), Maurizio Gente, Roberto Aufieri, Massimo Agosti · 8 authors

BACKGROUND: Despite regionalization of perinatal care provides for the "in utero" transfer of high-risk pregnancies, there will always be a number of neonates who undergo acute inter-facility transport. The presence of a well-organized Neonatal Emergency Transport Service (NETS) can prevent and reduce risks of transportation, especially for very preterm infants, and is therefore mandatory for any program of regionalization of perinatal care. Italian National Health System is highly decentralized and Regions are autonomous to structure, plan and delivery their regional health services. Consequently, organization models and resources available vary widely and significant regional differences in access and quality of health services have been reported in the past years. A national survey was conducted in 2015 by the neonatal transport study group of the Italian Society of Neonatology with the aim to describe neonatal transfer practices and to assess the Neonatal Emergency Transport Services (NETS) status in the 20 Italian regions. METHODS: A questionnaire regarding neonatal transfer practices and NETS activity for the previous year (2014) was sent to the 44 NETS operating in the 20 Italian regions. Demographic data were obtained from the Italian National Statistical Institute (ISTAT). RESULTS: The overall survey response rate was 100%. In 2014, only 12 (60%) of the 20 Italian regions were fully covered by NETS, 3 (15%) regions were partially covered, while neonatal transport was not available in 5 (25%) regions. Overall, in 2014, the 44 NETS operating in Italy transported a total of 6387 infants, including 522 (8.17%) having a gestational age < 28 weeks. CONCLUSIONS: The organization of NETS in Italy is devolved on a regional basis, resulting in a large heterogeneity of access and quality to services across the country. Where available, NETS are generally well-equipped and organized but limited volume of activities often cannot guarantee adequate levels of skills of personnel or an appropriate cost-efficiency ratio. The regions reported with lack of NETS have managed, or are trying, to fill the gap, but continuing efforts to reduce regional differences in the availability and quality of services are still needed.

Frank Shann

(See the article by Aaby et al, on pages 245–52.) There is now clear evidence that the simplistic conventional model of immunization is invalid [1]. We can no longer assume that a vaccine acts independently of other vaccines, or that it influences only infections caused by the target disease. Strong evidence from randomized trials suggests that bacillus Calmette-Guérin vaccine (BCG) reduces mortality from infections other than tuberculosis and that measles vaccine reduces mortality from infections other than measles [1–4]. However, there is worrying evidence that whole-cell diphtheria-tetanus-pertussis vaccine (DTP) may increase mortality from infections other than diphtheria, tetanus, or pertussis in high-mortality areas [1, 3–8]. These nonspecific effects of BCG, measles vaccine, and DTP are generally stronger in girls, appear to be maximal in the first 6 months after immunization, and are largely determined by the most recent vaccine administered [1]. Randomized trials show that measles vaccine has strong nonspecific effects. Providing it is not given after vitamin A or followed by DTP, measles vaccine reduces mortality from diseases other than measles by 45% (95% confidence interval [CI], 14%–65%) when given at 4.5 months of age [9], and by 47% (95% CI, 23%–63%) when given to girls at 9 to 10 months of age [1]. In this issue of the Journal, Aaby et al present further evidence, from Guinea-Bissau, that BCG has potent nonspecific effects on mortality [4]. Low-birth-weight neonates were randomized to receive BCG at birth or via the routine immunization program at an older age (median, 7.7 weeks). The biological effects of BCG are shown by the outcome during the first 4 weeks after randomization, before children in either group had been given DTP and when few children in the control group had received BCG. In this period, BCG reduced mortality by 45% (95% CI, 11%–66%); there were fewer deaths from sepsis and acute respiratory infection, and no deaths from tuberculosis (which is a rare cause of death at this age). This spectacular reduction in mortality is consistent with the results of 6 controlled trials performed in 45,662 children in the United States and the United Kingdom in the 1940s and 1950s, in which BCG reduced mortality from causes other than tuberculosis by 25% (95% CI, 6%–41%) [1, 2]. Although BCG reduced mortality in the first 4 weeks of life in the trial in Guinea-Bissau, investigators observed no difference in mortality after that age [4]. This is not surprising, because by 2 months of age 58% of the controls had received BCG and over 60% of children in both groups had received DTP. Consequently, BCG did not significantly reduce mortality in the first 12 months of life, the observed reduction being 17% (95% CI, −8% to 37%). This was the primary endpoint of the trial, which was underpowered because infant mortality was 101 deaths per 1000 live births, rather than 250 deaths per 1000 live births as predicted when the trial was designed. A lower-than-expected mortality often occurs when trial participants in a high-mortality area are offered free treatment, as in this study. This illustrates how difficult it is to do randomized trials in high-mortality areas, where we most need to obtain information about how to lower mortality. A worrying finding in this trial was that children who had received DTP by 2 months of age had an increased mortality between 2 and 6 months of age: Mortality was increased 4.3-fold (95% CI, 1.5–12.2-fold) in the BCG-at-birth group and 1.7-fold (95% CI, .7–4.0-fold) in the control group [4]. DTP was observed to have similar effects in a randomized trial of revaccination with BCG at 19 months of age in Guinea-Bissau [3]. In that trial, 60% of the participants had not received their last dose of DTP (DTP4) at the time of enrollment, and many of these children were given DTP4 after entering the study. Children who received BCG had a lower mortality than controls if they had received DTP4 before enrollment (hazard ratio, .36; 95% CI, .13–.99) but a higher mortality if they had not received DTP4 before enrollment (hazard ratio, 1.78; 95% CI, 1.04–3.04); the difference was highly significant (P = .006). Mortality was 0.36 deaths per 100 person-years if DTP4 had been given before BCG revaccination, 1.02 deaths per 100 person-years in controls who were not revaccinated with BCG (mortality was not affected by DTP4 status at enrollment), and 1.83 deaths per 100 person-years if DTP4 had not been given before BCG revaccination [3, 10]. These 2 studies suggest that BCG lowers mortality if it is given alone or after DTP, but that mortality may be increased if DTP is given after BCG as recommended in the schedule for the Expanded Program on Immunization (EPI) [3, 4]. The administration of DTP after BCG was not randomized in these studies, so the observed increase in mortality with DTP may have been caused by bias. However, this seems unlikely. In the trial of BCG in low-birth-weight babies [4], the infants who had received DTP by 2 months of age (and had increased mortality) were larger babies who would be expected to have a lower mortality in the absence of a nonspecific effect of DTP. In the trial of BCG revaccination at 19 months of age [3], mortality in the control group (no additional BCG) was not influenced by DTP4 status at the time of randomization, suggesting that this was not an independent risk factor. Even in unimmunized communities, diphtheria, tetanus, and pertussis cause far fewer deaths than pneumonia, sepsis, and diarrhea [11]; despite reducing mortality from diphtheria, tetanus, and pertussis, DTP will, therefore, increase total mortality if it causes even a small increase in mortality from pneumonia, sepsis, and diarrhea in high-mortality areas [12]. When DTP was first introduced into Guinea-Bissau, despite the absence of herd immunity, mortality was 5.1 deaths per 100 person-years among children who did not receive DTP but 11.3 deaths per 100 person-years among children who did receive DTP (risk ratio, 2.03; 95% CI, 1.17–3.52) [7]. I know of no other study of the introduction of DTP in a high-mortality area with sufficient power to test the effect on total mortality. No randomized trial has demonstrated that it is safe to give DTP to young infants in high-mortality areas, and there is now worrying evidence that DTP may increase mortality under these circumstances—especially when it is given after BCG as recommended in the EPI schedule [1, 3–8]. In 2002, 2003, and 2004, the WHO Global Advisory Committee on Vaccine Safety (GACVS) concluded that the evidence did not support an increased risk of mortality after DTP immunization [13]. However, the onus of proof is surely the reverse of this—we need clear evidence that a vaccine is safe when it is given routinely to all infants in high-mortality areas. In addition, the Committee based its conclusion on observational studies, all of which had one or more serious methodological problems [1, 5, 14–16]. First, any observational study (with nonrandom allocation of vaccines) may induce a spurious association between vaccination and survival [16]. Second, vaccination was often withheld in sick children, which causes selection bias in favor of DTP [5]. Third, many of the studies classified dead children as unvaccinated if there was no evidence they had been immunized; as some of these children will have been vaccinated, this causes survival bias in favor of DTP [1, 5, 14–16]. Fourth, most of the studies did not test the effect of the most recent vaccine received by each child over time: the first dose of DTP has different effects when given before, with, or after BCG [4, 5]; the last dose of DTP has different effects given before, with, or after measles vaccine [5, 6]; and the effects differ by sex [1]. Fifth, many children were given BCG at the same time as DTP, rather than at birth (6 weeks before DTP) as specified in the EPI schedule [5]. In 2008, GACVS finally endorsed the view that evidence for the safety of DTP is “unlikely to be obtained from observational studies” [17]. Given the very large number of lives at stake, it is disappointing that it took the Committee so long to decide that observational studies are unlikely to provide adequate evidence that it is safe to give DTP to infants who have been vaccinated with BCG at birth, and even more disappointing that international agencies have not funded randomized trials to test the effect of DTP on all-cause mortality in children in high-mortality areas [5, 18]. We could obtain this information while still immunizing against diphtheria, tetanus, and pertussis if we randomized children to receive the primary series of DTP at different ages, or to receive a booster dose of DTP at different ages [18, 19]. The current EPI schedule is BCG-polio at birth; DTP-polio at 6, 10, and 14 weeks; and measles vaccine at 9 months–but tuberculosis, polio, diphtheria, tetanus, pertussis, and measles are not the main causes of death in children, even in unimmunized communities [11]. The main reason that the EPI program has been beneficial may not be because it protects against these infections, but because the nonspecific effects of BCG and measles vaccines reduce the very large number of deaths from pneumonia, sepsis, and diarrhea. It is exciting that we may be able to save several million more lives each year just by making better use of the current EPI vaccines in an improved schedule—we urgently need randomized trials of the effects of the EPI vaccines on total mortality to help us design the optimal schedule [5, 18].