Anesthesia blunts carbon dioxide effects on glymphatic cerebrospinal fluid dynamics in mechanically ventilated rats.

BACKGROUND: Impaired glymphatic clearance of cerebral metabolic products and fluids contribute to traumatic and ischemic brain oedema and neurodegeneration in preclinical models. Glymphatic perivascular cerebrospinal fluid (CSF) flow varies between anesthetics possibly due to changes in vasomotor tone and thereby in the dynamics of the periarterial CSF-containing space. To better understand the influence of anesthetics and carbon dioxide levels on CSF dynamics, we studied the effect of periarterial size modulation on CSF distribution by changing blood carbon dioxide levels and anesthetic regimens with opposing vasomotor influences - vasoconstrictive ketamine-dexmedetomidine (K/DEX) and vasodilatory isoflurane (ISO). METHODS: End-tidal carbon dioxide (EtCO2) was modulated with either supplemental inhaled carbon dioxide to reach hypercapnia (EtCO2 80 mmHg) or hyperventilation (EtCO2 20 mmHg) in tracheostomized and anesthetized female rats. Distribution of intracisternally infused radiolabeled CSF tracer 111In-diethylamine pentaacetate was assessed for 86 minutes in 1) normoventilated (EtCO2 40 mmHg) K/DEX, 2) normoventilated ISO, 3) hypercapnic K/DEX, and 4) hyperventilated ISO groups using dynamic whole-body single-photon emission tomography. CSF volume changes were assessed with magnetic resonance imaging. RESULTS: Under normoventilation, cortical CSF tracer perfusion, perivascular space size around middle cerebral arteries (MCAs), and intracranial CSF volume were higher under K/DEX compared with ISO (cortical Cmax ratio 2.33 [95% CI 1.35 to 4.04], perivascular size ratio 2.20 [95% CI 1.09 to 4.45], and intracranial CSF volume ratio 1.90 [95% CI 1.33 to 2.71]). Under ISO, tracer was directed to systemic circulation. Under K/DEX, the intracranial tracer distribution and CSF volume were uninfluenced by hypercapnia compared with normoventilation. Intracranial CSF tracer distribution was unaffected by hyperventilation under ISO despite a 28% increase in CSF volume around MCAs. CONCLUSIONS: K/DEX and ISO overrode carbon dioxide as a regulator of CSF flow. K/DEX could be used to preserve CSF space and dynamics in hypercapnia whereas hyperventilation was insufficient to increase cerebral CSF perfusion under ISO.

Influence of Intravenous S-Ketamine on the Pharmacokinetics of Oral Morphine in Healthy Volunteers.

BACKGROUND: Subanesthetic ketamine may reduce perioperative consumption of opioids. We studied whether intravenous S-ketamine alters the pharmacokinetics of oral morphine in healthy volunteers. METHODS: In this paired, randomized, double-blind, crossover trial, 12 participants under a 2-hour intravenous S-ketamine (0.57 mg/kg/h) or placebo infusion received oral morphine (0.2 mg/kg) at 30 minutes. Plasma concentrations of ketamine, morphine, and their major metabolites were quantified for 24 hours. The primary end point was area under the curve (AUC) 0-24 of morphine. Other pharmacokinetic variables for morphine and its metabolites were studied as secondary end points. The data were analyzed as between-phase comparisons for each participant using Wilcoxon matched-pairs signed-rank tests ( tmax ) or paired t -tests on log-transformed variables (other variables). RESULTS: While the AUC 0-24 was similar between the 2 phases, S-ketamine reduced the AUC 0-1.5 of oral morphine by 69% (ratio to control, 0.31; 90% confidence interval [CI], 0.15-0.65; P = .0171) and increased its tmax from 0.5 (range, 0.50-1.5) to 1.0 hour (range, 0.50-4.0; P = .010). The AUC 0-1.5 of morphine-6-glucuronide (M6G) was reduced by 84% (0.16; 90% CI, 0.07-0.37; P = .0025) and maximum plasma concentration ( Cmax ) by 43% (0.57; 90% CI, 0.40-0.81; P = .0155), while its tmax was increased from 1.5 (range, 1.0-2.0) to 4.0 (range, 1.0-8.0; P = .0094) hours by S-ketamine. Similarly, the AUC 0-1.5 of morphine-3-glucuronide (M3G) was reduced by 85% (0.15; 90% CI, 0.05-0.43; P = .0083), and tmax increased from 1.0 (range, 0.5-1.5) to 4.0 hours (range, 1.0-8.0; P = .0063). In addition, the M6G-to-morphine and M3G-to-morphine metabolic AUC ratios were decreased by 47% (0.53; 90% CI, 0.39-0.71; P = .0033) and 52% (0.48; 90% CI, 0.27-0.85; P = .0043) during 0 to 1.5 hours and by 15% (0.85; 90% CI, 0.78-0.92; P = .0057) and 10% (0.90; 90% CI, 0.83-0.98; P = .0468) during 0 to 24 hours, respectively. One participant was excluded from the analyses due to vomiting in the S-ketamine phase. CONCLUSIONS: Intravenous S-ketamine inhibited the metabolism of oral morphine and delayed its absorption, resulting in a net reduction in the exposure to morphine during the first 1.5 hours. Intravenous S-ketamine may delay the absorption and impair the efficacy of orally administered analgesics and other drugs.

Introduction of an electrochemical point-of-care assay for quantitative determination of paracetamol in finger-prick capillary whole blood samples.

AIMS: Measuring venous plasma paracetamol concentrations is time- and resource-consuming. We aimed to validate a novel electrochemical point-of-care (POC) assay for rapid paracetamol concentration determinations. METHODS: Twelve healthy volunteers received 1 g oral paracetamol, and its concentrations were analysed 10 times over 12 h for capillary whole blood (POC), venous plasma (high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS)), and dried capillary blood (HPLC-MS/MS). RESULTS: At concentrations >30 µM, POC showed upward biases of 20% (95% limits of agreement [LOA] -22 to 62) and 7% (95% LOA -23 to 38) compared with venous plasma and capillary blood HPLC-MS/MS, respectively. There were no significant differences between mean concentrations for the paracetamol elimination phase. CONCLUSIONS: Upward biases in POC compared with venous plasma HPLC-MS/MS were likely due to higher paracetamol concentrations in capillary blood than in venous plasma and to faulty individual sensors. The novel POC method is a promising tool for paracetamol concentration analysis.

Glymphatic-assisted perivascular brain delivery of intrathecal small gold nanoparticles.

Nanoparticles are ultrafine particulate matter having considerable potential for treatment of central nervous system (CNS) disorders. Despite their tiny size, the blood-brain barrier (BBB) restricts their access to the CNS. Their direct cerebrospinal fluid (CSF) administration bypasses the BBB endothelium, but still fails to give adequate brain uptake. We present a novel approach for efficient CNS delivery of 111In-radiolabelled gold nanoparticles (AuNPs; 10-15 nm) via intra-cisterna magna administration, with tracking by SPECT imaging. To accelerate CSF brain influx, we administered AuNPs intracisternally in conjunction with systemic hypertonic saline, which dramatically increased the parenchymal AuNP uptake, especially in deep brain regions. AuNPs entered the CNS along periarterial spaces as visualized by MRI of gadolinium-labelled AuNPs and were cleared from brain within 24 h and excreted through the kidneys. Thus, the glymphatic-assisted perivascular network augment by systemic hypertonic saline is a pathway for highly efficient brain-wide distribution of small AuNPs.

Blood-brain barrier permeable ß-blockers linked to lower risk of Alzheimer's disease in hypertension.

Alzheimer's disease is a neurodegenerative disorder in which the pathological accumulation of amyloid-ß and tau begins years before symptom onset. Emerging evidence suggests that ß-blockers (ß-adrenergic antagonists) increase brain clearance of these metabolites by enhancing CSF flow. Our objective was to determine whether ß-blocker treatments that easily cross the blood-brain barrier reduce the risk of Alzheimer's disease compared to less permeable ß-blockers. Data from the Danish national registers were used to identify a retrospective cohort of individuals with hypertension, and those treated with ß-blockers were included in the analysis. People with indications for ß-blocker use other than hypertension (e.g. heart failure) were only retained in a sensitivity analysis. ß-blockers were divided into three permeability groups: low, moderate and high. We used multivariable cause-specific Cox regression to model the effect of ß-blocker blood-brain barrier permeability on time to dementia outcomes, adjusting for baseline comorbidities, demographics and socioeconomic variables. Death was modelled as a competing risk. The 10-year standardized absolute risk was estimated as the averaged person-specific risks per treatment. In a cohort of 69 081 (median age = 64.4 years, 64.8% female) people treated with ß-blockers for hypertension, highly blood-brain barrier-permeable ß-blockers were associated with reduced risk of Alzheimer's disease versus low permeability ß-blockers (-0.45%, P < 0.036). This effect was specific to Alzheimer's diagnoses and did not extend to dementia in general. Propensity score analysis matching high and low blood-brain barrier-permeable patients also detected a decreased Alzheimer's risk (-0.92%, P < 0.001) in the high permeability group compared to the low, as did a 1-year landmark analysis (-0.57%, P < 0.029) in which events within the first year of follow-up were ignored as likely unrelated to treatment. Our results suggest that amongst people taking ß-blockers for hypertension, treatment with highly blood-brain barrier permeable ß-blockers reduces the risk of Alzheimer's disease compared to low permeability drugs. Our findings support the hypothesis that highly permeable ß-blockers protect against Alzheimer's disease by promoting waste brain metabolite clearance.

Could dexmedetomidine be repurposed as a glymphatic enhancer?

Cerebrospinal fluid (CSF) flows through the central nervous system (CNS) via the glymphatic pathway to clear the interstitium of metabolic waste. In preclinical studies, glymphatic fluid flow rate increases with low central noradrenergic tone and slow-wave activity during natural sleep and general anesthesia. By contrast, sleep deprivation reduces glymphatic clearance and leads to intracerebral accumulation of metabolic waste, suggesting an underlying mechanism linking sleep disturbances with neurodegenerative diseases. The selective α2-adrenergic agonist dexmedetomidine is a sedative drug that induces slow waves in the electroencephalogram, suppresses central noradrenergic tone, and preserves glymphatic outflow. As recently developed dexmedetomidine formulations enable self-administration, we suggest that dexmedetomidine could serve as a sedative-hypnotic drug to enhance clearance of harmful waste from the brain of those vulnerable to neurodegeneration.

The glymphatic system: implications for drugs for central nervous system diseases.

In the past decade, evidence for a fluid clearance pathway in the central nervous system known as the glymphatic system has grown. According to the glymphatic system concept, cerebrospinal fluid flows directionally through the brain and non-selectively clears the interstitium of metabolic waste. Importantly, the glymphatic system may be modulated by particular drugs such as anaesthetics, as well as by non-pharmacological factors such as sleep, and its dysfunction has been implicated in central nervous system disorders such as Alzheimer disease. Although the glymphatic system is best described in rodents, reports using multiple neuroimaging modalities indicate that a similar transport system exists in the human brain. Here, we overview the evidence for the glymphatic system and its role in disease and discuss opportunities to harness the glymphatic system therapeutically; for example, by improving the effectiveness of intrathecally delivered drugs.

Rifampin Reduces the Plasma Concentrations of Oral and Intravenous Hydromorphone in Healthy Volunteers.

BACKGROUND: Several opioids are metabolized by the inducible cytochrome P450 (CYP) 3A isozymes. Coadministration with strong inducers of drug metabolism, such as rifampin, can dramatically reduce systemic exposure to these opioids. As the CYP metabolism of hydromorphone is of minor importance, we studied in healthy volunteers whether hydromorphone would be an effective analgesic for patients who concomitantly receive the prototypical enzyme inducer rifampin. METHODS: In this paired, randomized, crossover study, 12 participants received oral placebo or rifampin for 8 days. Oral hydromorphone (2.6 mg) was administered on day 6 followed by intravenous hydromorphone (0.02 mg/kg) on day 8. Hydromorphone and hydromorphone-3-glucuronide (HM3G) plasma concentrations were measured for 24 hours and psychomotor responses, including perceived drug effect, change in pupil diameter, and cold pressor threshold were evaluated for 6 hours. Our primary outcome was the change in the area under the concentration-time curve (AUC0-last) of oral and intravenous hydromorphone after pretreatment with rifampin or placebo. Pharmacodynamic parameters and other pharmacokinetic parameters were analyzed as secondary outcomes. RESULTS: Rifampin reduced the AUC0-last of oral and intravenous hydromorphone by 43% (ratio to control: 0.57, 90% confidence interval [CI], 0.50-0.65) and 26% (ratio to control: 0.74, 90% CI, 0.69-0.79), respectively. The maximum concentration of oral hydromorphone was reduced by 37% (ratio to control: 0.63, 90% CI, 0.55-0.72), and oral bioavailability decreased from 33% to 26% (ratio to control: 0.78, 90% CI, 0.67-0.91) in the rifampin phase compared with placebo. The HM3G-to-hydromorphone ratio increased by 50% (90% CI, 25-79) and 42% (90% CI, 29-55) after oral and intravenous hydromorphone, respectively. Rifampin did not significantly affect the pharmacodynamic parameters. CONCLUSIONS: Rifampin significantly reduces the concentrations of oral and intravenous hydromorphone. This interaction is due to an increase in the first-pass and systemic metabolism of hydromorphone, likely involving induction of uridine 5'-diphospho- glucuronosyltransferase enzymes by rifampin. The enhancement of hydromorphone elimination should be considered when managing pain of patients who are treated with strong enzyme inducers.

Comparing socioeconomic inequalities between early neonatal mortality and facility delivery: Cross-sectional data from 72 low- and middle-income countries.

Facility delivery should reduce early neonatal mortality. We used the Slope Index of Inequality and logistic regression to quantify absolute and relative socioeconomic inequalities in early neonatal mortality (0 to 6 days) and facility delivery among 679,818 live births from 72 countries with Demographic and Health Surveys. The inequalities in early neonatal mortality were compared with inequalities in postneonatal infant mortality (28 days to 1 year), which is not related to childbirth. Newborns of the richest mothers had a small survival advantage over the poorest in unadjusted analyses (-2.9 deaths/1,000; OR 0.86) and the most educated had a small survival advantage over the least educated (-3.9 deaths/1,000; OR 0.77), while inequalities in postneonatal infant mortality were more than double that in absolute terms. The proportion of births in health facilities was an absolute 43% higher among the richest and 37% higher among the most educated compared to the poorest and least educated mothers. A higher proportion of facility delivery in the sampling cluster (e.g. village) was only associated with a small  decrease in early neonatal mortality. In conclusion, while socioeconomically advantaged mothers had much higher use of a health facility at birth, this did not appear to convey a comparable survival advantage.

Does facility birth reduce maternal and perinatal mortality in Brong Ahafo, Ghana? A secondary analysis using data on 119 244 pregnancies from two cluster-randomised controlled trials.

BACKGROUND: Maternal and perinatal mortality are still unacceptably high in many countries despite steep increases in facility birth. The evidence that childbirth in facilities reduces mortality is weak, mainly because of the scarcity of robust study designs and data. We aimed to assess this link by quantifying the influence of major determinants of facility birth (cluster-level facility birth, wealth, education, and distance to childbirth care) on several mortality outcomes, while also considering quality of care. METHODS: Our study is a secondary analysis of surveillance data on 119 244 pregnancies from two large population-based cluster-randomised controlled trials in Brong Ahafo, Ghana. In addition, we specifically collected data to assess quality of care at all 64 childbirth facilities in the study area. Outcomes were direct maternal mortality, perinatal mortality, first-day and early neonatal mortality, and antepartum and intrapartum stillbirth. We calculated cluster-level facility birth as the percentage of facility births in a woman's village over the preceding 2 years, and we computed distances from women's regular residence to health facilities in a geospatial database. Associations between determinants of facility birth and mortality outcomes were assessed in crude and multivariable multilevel logistic regression models. We stratified perinatal mortality effects by three policy periods, using April 1, 2005, and July 1, 2008, as cutoff points, when delivery-fee exemption and free health insurance were introduced in Ghana. These policies increased facility birth and potentially reduced quality of care. FINDINGS: Higher proportions of facility births in a cluster were not linked to reductions in any of the mortality outcomes. In women who were wealthier, facility births were much more common than in those who were poorer, but mortality was not lower among them or their babies. Women with higher education had lower mortality risks than less-educated women, except first-day and early neonatal mortality. A substantially higher proportion of women living in areas closer to childbirth facilities had facility births and caesarean sections than women living further from childbirth facilities, but mortality risks were not lower despite this increased service use. Among women who lived in areas closer to facilities offering comprehensive emergency obstetric care (CEmOC), emergency newborn care, or high-quality routine care, or to facilities that had providers with satisfactory competence, we found a lower risk of intrapartum stillbirth (14·2 per 1000 deliveries at >20 km from a CEmOC facility vs 10·4 per 1000 deliveries at ≤1 km; odds ratio [OR] 1·13, 95% CI 1·06-1·21) and of composite mortality outcomes than among women living in areas where these services were further away. Protective effects of facility birth were restricted to the two earlier policy periods (from June 1, 2003, to June 30, 2008), whereas there was evidence for higher perinatal mortality with increasing wealth (OR 1·09, 1·03-1·14) and lower perinatal mortality with increasing distance from childbirth facilities (OR 0·93, 0·89-0·98) after free health insurance was introduced in July 1, 2008. INTERPRETATION: Facility birth does not necessarily convey a survival benefit for women or babies and should only be recommended in facilities capable of providing emergency obstetric and newborn care and capable of safe-guarding uncomplicated births. FUNDING: The Baden-Württemberg Foundation, the Daimler and Benz Foundation, the European Social Fund and Ministry of Science, Research, and the Arts Baden-Württemberg, WHO, US Agency for International Development, Save the Children, the Bill & Melinda Gates Foundation, and the UK Department for International Development.

Impact of results-based financing on effective obstetric care coverage: evidence from a quasi-experimental study in Malawi.

BACKGROUND: Results-based financing (RBF) describes health system approaches addressing both service quality and use. Effective coverage is a metric measuring progress towards universal health coverage (UHC). Although considered a means towards achieving UHC in settings with weak health financing modalities, the impact of RBF on effective coverage has not been explicitly studied. METHODS: Malawi introduced the Results-Based Financing For Maternal and Neonatal Health (RBF4MNH) Initiative in 2013 to improve quality of maternal and newborn health services at emergency obstetric care facilities. Using a quasi-experimental design, we examined the impact of the RBF4MNH on both crude and effective coverage of pregnant women across four districts during the two years following implementation. RESULTS: There was no effect on crude coverage. With a larger proportion of women in intervention areas receiving more effective care over time, the overall net increase in effective coverage was 7.1%-points (p = 0.07). The strongest impact on effective coverage (31.0%-point increase, p = 0.02) occurred only at lower cut-off level (60% of maximum score) of obstetric care effectiveness. Design-specific and wider health system factors likely limited the program's potential to produce stronger effects. CONCLUSION: The RBF4MNH improved effective coverage of pregnant women and seems to be a promising reform approach towards reaching UHC. Given the short study period, the full potential of the current RBF scheme has likely not yet been reached.

The influence of distance and quality of care on place of delivery in rural Ghana.

Facility delivery is an important aspect of the strategy to reduce maternal and newborn mortality. Geographic access to care is a strong determinant of facility delivery, but few studies have simultaneously considered the influence of facility quality, with inconsistent findings. In rural Brong Ahafo region in Ghana, we combined surveillance data on 11,274 deliveries with quality of care data from all 64 delivery facilities in the study area. We used multivariable multilevel logistic regression to assess the influence of distance and several quality dimensions on place of delivery. Women lived a median of 3.3 km from the closest delivery facility, and 58% delivered in a facility. The probability of facility delivery ranged from 68% among women living 1 km from their closest facility to 22% among those living 25 km away, adjusted for confounders. Measured quality of care at the closest facility was not associated with use, except that facility delivery was lower when the closest facility provided substandard care on the EmOC dimension. These results do not imply, however, that we should increase geographic accessibility of care without improving facility quality. While this may be successful in increasing facility deliveries, such care cannot be expected to reduce maternal and neonatal mortality.

Competence of health workers in emergency obstetric care: an assessment using clinical vignettes in Brong Ahafo region, Ghana.

OBJECTIVES: To assess health worker competence in emergency obstetric care using clinical vignettes, to link competence to availability of infrastructure in facilities, and to average annual delivery workload in facilities. DESIGN: Cross-sectional Health Facility Assessment linked to population-based surveillance data. SETTING: 7 districts in Brong Ahafo region, Ghana. PARTICIPANTS: Most experienced delivery care providers in all 64 delivery facilities in the 7 districts. PRIMARY OUTCOME MEASURES: Health worker competence in clinical vignette actions by cadre of delivery care provider and by type of facility. Competence was also compared with availability of relevant drugs and equipment, and to average annual workload per skilled birth attendant. RESULTS: Vignette scores were moderate overall, and differed significantly by respondent cadre ranging from a median of 70% correct among doctors, via 55% among midwives, to 25% among other cadres such as health assistants and health extension workers (p<0.001). Competence varied significantly by facility type: hospital respondents, who were mainly doctors and midwives, achieved highest scores (70% correct) and clinic respondents scored lowest (45% correct). There was a lack of inexpensive key drugs and equipment to carry out vignette actions, and more often, lack of competence to use available items in clinical situations. The average annual workload was very unevenly distributed among facilities, ranging from 0 to 184 deliveries per skilled birth attendant, with higher workload associated with higher vignette scores. CONCLUSIONS: Lack of competence might limit clinical practice even more than lack of relevant drugs and equipment. Cadres other than midwives and doctors might not be able to diagnose and manage delivery complications. Checking clinical competence through vignettes in addition to checklist items could contribute to a more comprehensive approach to evaluate quality of care. TRIAL REGISTRATION NUMBER: NCT00623337.

Quality along the continuum: a health facility assessment of intrapartum and postnatal care in Ghana.

OBJECTIVE: To evaluate quality of routine and emergency intrapartum and postnatal care using a health facility assessment, and to estimate "effective coverage" of skilled attendance in Brong Ahafo, Ghana. METHODS: We conducted an assessment of all 86 health facilities in seven districts in Brong Ahafo. Using performance of key signal functions and the availability of relevant drugs, equipment and trained health professionals, we created composite quality categories in four dimensions: routine delivery care, emergency obstetric care (EmOC), emergency newborn care (EmNC) and non-medical quality. Linking the health facility assessment to surveillance data we estimated "effective coverage" of skilled attendance as the proportion of births in facilities of high quality. FINDINGS: Delivery care was offered in 64/86 facilities; only 3-13% fulfilled our requirements for the highest quality category in any dimension. Quality was lowest in the emergency care dimensions, with 63% and 58% of facilities categorized as "low" or "substandard" for EmOC and EmNC, respectively. This implies performing less than four EmOC or three EmNC signal functions, and/or employing less than two skilled health professionals, and/or that no health professionals were present during our visit. Routine delivery care was "low" or "substandard" in 39% of facilities, meaning 25/64 facilities performed less than six routine signal functions and/or had less than two skilled health professionals and/or less than one midwife. While 68% of births were in health facilities, only 18% were in facilities with "high" or "highest" quality in all dimensions. CONCLUSION: Our comprehensive facility assessment showed that quality of routine and emergency intrapartum and postnatal care was generally low in the study region. While coverage with facility delivery was 68%, we estimated "effective coverage" of skilled attendance at 18%, thus revealing a large "quality gap." Effective coverage could be a meaningful indicator of progress towards reducing maternal and newborn mortality.

Quality of newborn care: a health facility assessment in rural Ghana using survey, vignette and surveillance data.

OBJECTIVE: To assess the structural capacity for, and quality of, immediate and essential newborn care (ENC) in health facilities in rural Ghana, and to link this with demand for facility deliveries and admissions. DESIGN: Health facility assessment survey and population-based surveillance data. SETTING: Seven districts in Brong Ahafo Region, Ghana. PARTICIPANTS: Heads of maternal/neonatal wards in all 64 facilities performing deliveries. MAIN OUTCOME MEASURES: Indicators include: the availability of essential infrastructure, newborn equipment and drugs, and personnel; vignette scores and adequacy of reasons given for delayed discharge of newborn babies; and prevalence of key immediate ENC practices that facilities should promote. These are matched to the percentage of babies delivered in and admitted to each type of facility. RESULTS: 70% of babies were delivered in health facilities; 56% of these and 87% of neonatal admissions were in four referral level hospitals. These had adequate infrastructure, but all lacked staff trained in ENC and some essential equipment (including incubators and bag and masks) and/or drugs. Vignette scores for care of very low-birth-weight babies were generally moderate-to-high, but only three hospitals achieved high overall scores for quality of ENC. We estimate that only 33% of babies were born in facilities capable of providing high quality, basic resuscitation as assessed by a vignette plus the presence of a bag and mask. Promotion of immediate ENC practices in facilities was also inadequate, with coverage of early initiation of breastfeeding and delayed bathing both below 50% for babies born in facilities; this represents a lost opportunity. CONCLUSIONS: Unless major gaps in ENC equipment, drugs, staff, practices and skills are addressed, strategies to increase facility utilisation will not achieve their potential to save newborn lives. TRIAL REGISTRATION: http://clinicaltrials.gov NCT00623337.

Distance to care, facility delivery and early neonatal mortality in Malawi and Zambia.

BACKGROUND: Globally, approximately 3 million babies die annually within their first month. Access to adequate care at birth is needed to reduce newborn as well as maternal deaths. We explore the influence of distance to delivery care and of level of care on early neonatal mortality in rural Zambia and Malawi, the influence of distance (and level of care) on facility delivery, and the influence of facility delivery on early neonatal mortality. METHODS AND FINDINGS: National Health Facility Censuses were used to classify the level of obstetric care for 1131 Zambian and 446 Malawian delivery facilities. Straight-line distances to facilities were calculated for 3771 newborns in the 2007 Zambia DHS and 8842 newborns in the 2004 Malawi DHS. There was no association between distance to care and early neonatal mortality in Malawi (OR 0.97, 95%CI 0.58-1.60), while in Zambia, further distance (per 10 km) was associated with lower mortality (OR 0.55, 95%CI 0.35-0.87). The level of care provided in the closest facility showed no association with early neonatal mortality in either Malawi (OR 1.02, 95%CI 0.90-1.16) or Zambia (OR 1.02, 95%CI 0.82-1.26). In both countries, distance to care was strongly associated with facility use for delivery (Malawi: OR 0.35 per 10km, 95%CI 0.26-0.46). All results are adjusted for available confounders. Early neonatal mortality did not differ by frequency of facility delivery in the community. CONCLUSIONS: While better geographic access and higher level of care were associated with more frequent facility delivery, there was no association with lower early neonatal mortality. This could be due to low quality of care for newborns at health facilities, but differential underreporting of early neonatal deaths in the DHS is an alternative explanation. Improved data sources are needed to monitor progress in the provision of obstetric and newborn care and its impact on mortality.