Human milk (HM) is usually fortified using standard fortification (STD) to improve nutrition of preterm infants. However, the protein component may still be insufficient. HM could be further ...fortified with additional protein to improve STD.
The primary objective was to compare changes in body weight (g/day, g/kg/day), length, and head circumference (mm/day) between preterm neonates fed HM with STD and those fed HM with adjustable fortification (ADJ).
This study was a prospective, single-blinded, randomized controlled study in preterm infants of gestational age <32 weeks and weighing ≤1,800 g, admitted to the neonatal unit of the Queen Sirikit National Institute of Child Health. Once the infants received full HM feed with STD at 24 kcal/oz, they were randomized to either continue with STD or with ADJ group by adding additional protein to the STD and making further protein adjustments based on the blood urea nitrogen levels.
Thirty preterm infants completed the study and were randomized into two groups of 15 each. The baseline characteristics, total fluid, and energy intake were similar. Compared with the STD group, infants in the ADJ group exhibited significantly greater weight gain (36.46 ± 6.09 vs. 25.78 ± 8.81 g/day;
= 0.001) and greater length gain (1.93 ± 0.57 vs. 1.12 ± 0.64 mm/day;
= 0.001). Protein intake significantly correlated with both weight (
= 0.632,
< 0.001) and length gain (
= 0.577,
= 0.001); however, no correlation was found between energy intake, volume intake, and growth outcomes.
Preterm infants fed with ADJ had significantly higher weight and length gains than those fed with STD, suggesting that additional protein intake may play an important role in growth.
Antimicrobial resistance (AMR) poses a major threat to human health around the world. Previous publications have estimated the effect of AMR on incidence, deaths, hospital length of stay, and ...health-care costs for specific pathogen–drug combinations in select locations. To our knowledge, this study presents the most comprehensive estimates of AMR burden to date.
We estimated deaths and disability-adjusted life-years (DALYs) attributable to and associated with bacterial AMR for 23 pathogens and 88 pathogen–drug combinations in 204 countries and territories in 2019. We obtained data from systematic literature reviews, hospital systems, surveillance systems, and other sources, covering 471 million individual records or isolates and 7585 study-location-years. We used predictive statistical modelling to produce estimates of AMR burden for all locations, including for locations with no data. Our approach can be divided into five broad components: number of deaths where infection played a role, proportion of infectious deaths attributable to a given infectious syndrome, proportion of infectious syndrome deaths attributable to a given pathogen, the percentage of a given pathogen resistant to an antibiotic of interest, and the excess risk of death or duration of an infection associated with this resistance. Using these components, we estimated disease burden based on two counterfactuals: deaths attributable to AMR (based on an alternative scenario in which all drug-resistant infections were replaced by drug-susceptible infections), and deaths associated with AMR (based on an alternative scenario in which all drug-resistant infections were replaced by no infection). We generated 95% uncertainty intervals (UIs) for final estimates as the 25th and 975th ordered values across 1000 posterior draws, and models were cross-validated for out-of-sample predictive validity. We present final estimates aggregated to the global and regional level.
On the basis of our predictive statistical models, there were an estimated 4·95 million (3·62–6·57) deaths associated with bacterial AMR in 2019, including 1·27 million (95% UI 0·911–1·71) deaths attributable to bacterial AMR. At the regional level, we estimated the all-age death rate attributable to resistance to be highest in western sub-Saharan Africa, at 27·3 deaths per 100 000 (20·9–35·3), and lowest in Australasia, at 6·5 deaths (4·3–9·4) per 100 000. Lower respiratory infections accounted for more than 1·5 million deaths associated with resistance in 2019, making it the most burdensome infectious syndrome. The six leading pathogens for deaths associated with resistance (Escherichia coli, followed by Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa) were responsible for 929 000 (660 000–1 270 000) deaths attributable to AMR and 3·57 million (2·62–4·78) deaths associated with AMR in 2019. One pathogen–drug combination, meticillin-resistant S aureus, caused more than 100 000 deaths attributable to AMR in 2019, while six more each caused 50 000–100 000 deaths: multidrug-resistant excluding extensively drug-resistant tuberculosis, third-generation cephalosporin-resistant E coli, carbapenem-resistant A baumannii, fluoroquinolone-resistant E coli, carbapenem-resistant K pneumoniae, and third-generation cephalosporin-resistant K pneumoniae.
To our knowledge, this study provides the first comprehensive assessment of the global burden of AMR, as well as an evaluation of the availability of data. AMR is a leading cause of death around the world, with the highest burdens in low-resource settings. Understanding the burden of AMR and the leading pathogen–drug combinations contributing to it is crucial to making informed and location-specific policy decisions, particularly about infection prevention and control programmes, access to essential antibiotics, and research and development of new vaccines and antibiotics. There are serious data gaps in many low-income settings, emphasising the need to expand microbiology laboratory capacity and data collection systems to improve our understanding of this important human health threat.
Bill & Melinda Gates Foundation, Wellcome Trust, and Department of Health and Social Care using UK aid funding managed by the Fleming Fund.
Nutrition is an important aspect in the care of very low birth weight (VLBW) preterm infants. Human milk fortified with human milk fortifiers (HMF) is best for enteral feeding of premature infants. ...HMF is expensive and not easily available in Thailand. Post discharge formula (PDF) has been routinely used to fortify human milk at Queen Sirikit National Institute of Child Health (QSNICH) but there is lack of supportive data regarding efficacy and safety.
To study and compare anthropometrics, biochemical markers and complications in VLBW infants fed human milk fortified with either HMF or PDF.
This was a prospective, randomized pilot study conducted in the neonatal unit of QSNICH from 1 March 2010 to 28 February 2011. Very low birth weight neonates, whose mothers had adequate breast milk within 96 hours of birth, were enrolled in the study and received parenteral nutrition and enteral feeding as per protocol. Once the babies were feeding 100 cc/kg/day of human milk, they were randomly divided into two groups: the human milk fortified group (HMF group) and the post discharge formula fortified group (PDF group). Body weight was recorded daily while head circumference and length were recorded weekly. Hematocrit, Blood Urea Nitrogen (BUN), creatinine, electrolytes (including phosphorus and calcium), alkaline phosphatase and albumin were checked at the beginning of the study (feeding 100 cc/kg/day), 3 weeks later and when on full oral breast feeding or reached a weight of 2,000 grams, which ever came first.
Thirty-eight infants were enrolled in the study but eventually only 33 remained (18 in HMF group, 15 in PDF group). Both groups had similar baseline demographic data, nutritional management, postnatal morbidities and length of stay. There were no statistically significant differences in growth parameters and serum biochemical markers between the groups. Definite NEC was not different between the groups. Other complications of prematurity including osteopenia of prematurity were similar in both the groups. The cost of breast milk fortification per person in the PDF and HMF group was 605 and 11,655 baht, respectively.
Human milk fortifiers are best for fortification of human milk in VLBW babies but using PDF as a fortifier may be considered as an alternative for VLBW infant in resource limited, developing countries. However, it should always be additionally supplemented with multivitamins especially vitamin D, iron, calcium and phosphorus. Complications like feeding intolerances and suspected NEC should be monitored closely. Larger studies focusing on short and long-term outcomes are needed in the future.
There is limited data on antibiotic treatment in hospitalized neonates in low- and middle-income countries (LMICs). We aimed to describe patterns of antibiotic use, pathogens, and clinical outcomes, ...and to develop a severity score predicting mortality in neonatal sepsis to inform future clinical trial design.
Hospitalized infants <60 days with clinical sepsis were enrolled during 2018 to 2020 by 19 sites in 11 countries (mainly Asia and Africa). Prospective daily observational data was collected on clinical signs, supportive care, antibiotic treatment, microbiology, and 28-day mortality. Two prediction models were developed for (1) 28-day mortality from baseline variables (baseline NeoSep Severity Score); and (2) daily risk of death on IV antibiotics from daily updated assessments (NeoSep Recovery Score). Multivariable Cox regression models included a randomly selected 85% of infants, with 15% for validation. A total of 3,204 infants were enrolled, with median birth weight of 2,500 g (IQR 1,400 to 3,000) and postnatal age of 5 days (IQR 1 to 15). 206 different empiric antibiotic combinations were started in 3,141 infants, which were structured into 5 groups based on the World Health Organization (WHO) AWaRe classification. Approximately 25.9% (n = 814) of infants started WHO first line regimens (Group 1-Access) and 13.8% (n = 432) started WHO second-line cephalosporins (cefotaxime/ceftriaxone) (Group 2-"Low" Watch). The largest group (34.0%, n = 1,068) started a regimen providing partial extended-spectrum beta-lactamase (ESBL)/pseudomonal coverage (piperacillin-tazobactam, ceftazidime, or fluoroquinolone-based) (Group 3-"Medium" Watch), 18.0% (n = 566) started a carbapenem (Group 4-"High" Watch), and 1.8% (n = 57) a Reserve antibiotic (Group 5, largely colistin-based), and 728/2,880 (25.3%) of initial regimens in Groups 1 to 4 were escalated, mainly to carbapenems, usually for clinical deterioration (n = 480; 65.9%). A total of 564/3,195 infants (17.7%) were blood culture pathogen positive, of whom 62.9% (n = 355) had a gram-negative organism, predominantly Klebsiella pneumoniae (n = 132) or Acinetobacter spp. (n = 72). Both were commonly resistant to WHO-recommended regimens and to carbapenems in 43 (32.6%) and 50 (71.4%) of cases, respectively. MRSA accounted for 33 (61.1%) of 54 Staphylococcus aureus isolates. Overall, 350/3,204 infants died (11.3%; 95% CI 10.2% to 12.5%), 17.7% if blood cultures were positive for pathogens (95% CI 14.7% to 21.1%, n = 99/564). A baseline NeoSep Severity Score had a C-index of 0.76 (0.69 to 0.82) in the validation sample, with mortality of 1.6% (3/189; 95% CI: 0.5% to 4.6%), 11.0% (27/245; 7.7% to 15.6%), and 27.3% (12/44; 16.3% to 41.8%) in low (score 0 to 4), medium (5 to 8), and high (9 to 16) risk groups, respectively, with similar performance across subgroups. A related NeoSep Recovery Score had an area under the receiver operating curve for predicting death the next day between 0.8 and 0.9 over the first week. There was significant variation in outcomes between sites and external validation would strengthen score applicability.
Antibiotic regimens used in neonatal sepsis commonly diverge from WHO guidelines, and trials of novel empiric regimens are urgently needed in the context of increasing antimicrobial resistance (AMR). The baseline NeoSep Severity Score identifies high mortality risk criteria for trial entry, while the NeoSep Recovery Score can help guide decisions on regimen change. NeoOBS data informed the NeoSep1 antibiotic trial (ISRCTN48721236), which aims to identify novel first- and second-line empiric antibiotic regimens for neonatal sepsis.
ClinicalTrials.gov, (NCT03721302).
The clinical guidance for human milk (HM) feeding for sick and premature babies in Thailand was developed in 2013 to help improve their breastfeeding rates.
Objective
To expand breastfeeding (BF) for ...sick and premature babies using the clinical guidance, develop a monitoring system, and to integrate the practice into the national routine newborn care for sick babies.
Method
Volunteer tertiary care hospitals were recruited to implement the clinical guidance. The development of a monitoring and evaluation system was done by the multidisciplinary team and volunteer hospitals. The integration into routine national care practice was done by including it in the national neonatal service plan of Thailand.
Results
Thirty-eight pilot tertiary care hospitals volunteered for implementing the program. The proposed outcome indicators of rate of exclusive BF sick babies at hospital discharge and at 6 months of life for the volunteer hospitals were 62.97% and 41.76%, respectively. Since its integration into the national service plan in 2019, a total of 98 hospitals have been included in the program.
Conclusion
The integration of the clinical guidance into the national service plan is essential for sustaining BF of sick, premature babies in the country.
Background There is limited data on antibiotic treatment in hospitalized neonates in low- and middle-income countries (LMICs). We aimed to describe patterns of antibiotic use, pathogens, and clinical ...outcomes, and to develop a severity score predicting mortality in neonatal sepsis to inform future clinical trial design. Methods and findings Hospitalized infants <60 days with clinical sepsis were enrolled during 2018 to 2020 by 19 sites in 11 countries (mainly Asia and Africa). Prospective daily observational data was collected on clinical signs, supportive care, antibiotic treatment, microbiology, and 28-day mortality. Two prediction models were developed for (1) 28-day mortality from baseline variables (baseline NeoSep Severity Score); and (2) daily risk of death on IV antibiotics from daily updated assessments (NeoSep Recovery Score). Multivariable Cox regression models included a randomly selected 85% of infants, with 15% for validation. A total of 3,204 infants were enrolled, with median birth weight of 2,500 g (IQR 1,400 to 3,000) and postnatal age of 5 days (IQR 1 to 15). 206 different empiric antibiotic combinations were started in 3,141 infants, which were structured into 5 groups based on the World Health Organization (WHO) AWaRe classification. Approximately 25.9% (n = 814) of infants started WHO first line regimens (Group 1—Access) and 13.8% (n = 432) started WHO second-line cephalosporins (cefotaxime/ceftriaxone) (Group 2—“Low” Watch). The largest group (34.0%, n = 1,068) started a regimen providing partial extended-spectrum beta-lactamase (ESBL)/pseudomonal coverage (piperacillin-tazobactam, ceftazidime, or fluoroquinolone-based) (Group 3—“Medium” Watch), 18.0% (n = 566) started a carbapenem (Group 4—“High” Watch), and 1.8% (n = 57) a Reserve antibiotic (Group 5, largely colistin-based), and 728/2,880 (25.3%) of initial regimens in Groups 1 to 4 were escalated, mainly to carbapenems, usually for clinical deterioration (n = 480; 65.9%). A total of 564/3,195 infants (17.7%) were blood culture pathogen positive, of whom 62.9% (n = 355) had a gram-negative organism, predominantly Klebsiella pneumoniae (n = 132) or Acinetobacter spp. (n = 72). Both were commonly resistant to WHO-recommended regimens and to carbapenems in 43 (32.6%) and 50 (71.4%) of cases, respectively. MRSA accounted for 33 (61.1%) of 54 Staphylococcus aureus isolates. Overall, 350/3,204 infants died (11.3%; 95% CI 10.2% to 12.5%), 17.7% if blood cultures were positive for pathogens (95% CI 14.7% to 21.1%, n = 99/564). A baseline NeoSep Severity Score had a C-index of 0.76 (0.69 to 0.82) in the validation sample, with mortality of 1.6% (3/189; 95% CI: 0.5% to 4.6%), 11.0% (27/245; 7.7% to 15.6%), and 27.3% (12/44; 16.3% to 41.8%) in low (score 0 to 4), medium (5 to 8), and high (9 to 16) risk groups, respectively, with similar performance across subgroups. A related NeoSep Recovery Score had an area under the receiver operating curve for predicting death the next day between 0.8 and 0.9 over the first week. There was significant variation in outcomes between sites and external validation would strengthen score applicability. Conclusion Antibiotic regimens used in neonatal sepsis commonly diverge from WHO guidelines, and trials of novel empiric regimens are urgently needed in the context of increasing antimicrobial resistance (AMR). The baseline NeoSep Severity Score identifies high mortality risk criteria for trial entry, while the NeoSep Recovery Score can help guide decisions on regimen change. NeoOBS data informed the NeoSep1 antibiotic trial (ISRCTN48721236), which aims to identify novel first- and second-line empiric antibiotic regimens for neonatal sepsis. Trial registration ClinicalTrials.gov, (NCT03721302). James Neal Russell and colleagues report a global neonatal sepsis observational cohort study (NeoOBS) exploring patterns of antibiotic use, pathogens and prediction of mortality in hospitalised neonates and young infants with sepsis. Author summary Why was this study done? Increasing trends in antimicrobial resistance (AMR) disproportionately affect neonates and young infants with sepsis in LMIC settings and undermine the effectiveness of WHO-recommended antibiotics. Despite this, longitudinal data on antibiotic management strategies and outcomes of hospitalized neonates and young infants with sepsis in low- and middle-income country (LMIC) settings are extremely limited, impeding the design of robust antibiotic trials. There is limited data to define risk stratification, inclusion, and escalation criteria in trials of sepsis in hospitalized neonates and young infants. What did the researchers do and find? In this large global, prospective, hospital-based observational study across 4 continents, including LMIC settings, there was a high mortality among infants with culture positive sepsis (almost 1 in 5), and a significant burden of antibiotic resistance. This study highlights wide variations in standard of care (SOC) for sepsis in neonates and young infants, with more than 200 different antibiotic combinations, significant divergence from WHO-recommended regimens, and frequent switching of antibiotics. A NeoSep Severity Score that defined patterns of mortality risk at baseline was developed from 4 non-modifiable and 6 modifiable factors that are feasible to measure across a range of LMIC hospital contexts. A NeoSep Recovery Score including the same modifiable factors (with the addition of cyanosis) predicted mortality on the following day during treatment. What do these findings mean? These data demonstrate that patterns of routine antibiotic use are now markedly divergent from global guidance. There is an urgent need for large pragmatic randomized controlled trials to address optimal empiric first- and second-line antibiotic treatment strategies in LMIC hospital settings with a significant AMR burden. The wide range of multiple antibiotic regimens routinely used as SOC suggests the need for novel trial designs. The NeoSep Severity Score and NeoSep Recovery Score informed inclusion and escalation criteria in the NeoSep1 antibiotic trial (ISRCTN48721236) that aims to identify novel first- and second-line empiric antibiotic regimens for neonatal sepsis.
Patent ductus arteriosus (PDA) is a frequently encountered defect in infants born extremely premature (≤26 weeks’ gestation). Historically, closure of the PDA was performed using cyclooxygenase ...inhibitor medications or by surgical ligations. However, the benefits of PDA closure using these therapies have never been demonstrated, albeit studies have previously not focused on the extremely premature infants. Therefore, there was a worldwide trend toward conservative management of the PDA. With improved survival of extremely premature infants, comorbidities associated with the PDA has increased, resulting in finding alternate treatments such as transcatheter patent ductus arteriosus closure (TCPC) for this population. Currently, there is a renewed interest toward selective treatment of the PDA in this high-risk cohort of small infants. This Comprehensive Review article inspects the globally changing trends in the management of the PDA in premature infants, with a special focus on the rising adoption of TCPC. Moreover, this article compiles data from several neonatal networks worldwide to help understand the problem at hand. Understanding the current management of premature infants and their outcomes is fundamentally essential if pediatric cardiologists are to offer TCPC as a viable therapeutic option for this population. This article aims to serve as a guide for pediatric cardiologists on this topic by compiling the results on landmark clinical trials on PDA management and the controversies that arise from these trials. Comparative outcomes from several countries are presented, including interpretations and opinions of the data from experts globally. This is a step toward coming to a global consensus in PDA management in premature infants.
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•Improved survival of ELBWI has led to rise in comorbidities associated with PDA•There is a worldwide rising adoption of TCPC for PDA closure in premature infants•This manuscript compiles data from several neonatal networks from around the world•Comparative outcomes from several countries are presented•This is a step toward a global consensus in PDA management in premature infants
Persistent pulmonary hypertension of the newborn (PPHN) is the most serious condition that causes high mortality in term and post term infants. The authors have an experience of using high frequency ...oscillatory ventilation (HFOV) and inhaled nitric oxide (iNO) for treatment of this condition with a good result. However, due to high cost of iNo, other pulmonary vasodilators have been use. Sildenafil had some side effects of systemic hypotension. Thus, inhaled iloprost was introduced for treatment of PPHN at our institute.
To evaluate the outcome of inhaled iloprost for the treatment of PPHN.
This was a retrospective study. The data from medical records of newborns, diagnosed as persistent pulmonary hypertension of the newborn and had received inhaled iloprost from October 1st, 2008-October 31st, 2012, were reviewed.
Nineteen cases of PPHN treated with inhaled iloprost were reviewed. Male to female ratio was 1.3 7:1 (11:8). Mean birth weight and gestational age of these patients were 2,997 ± 531.63 grams and 37.9 ± 2.51 weeks, respectively. Meconium aspiration syndrome was the leading underlying cause of this condition. The mortality rate in this study was 21% (4 from 19 cases). After the addition of inhaled iloprost, the oxygen index (OI) in the survivor group decreased significantly at one hour after treatment (from 32.89 to 22.06, 18.76, 13. 76 at 1, 6, 12 hours, respectively). Oxygen saturation (SpO2) continued increasing after treatment in the survivor group (from 82.40% to 92.20%, 95.00%, 95.80% at 1, 6, 12 hours, respectively) with significant difference at one hour. There was a significant difference of OI and SpO2 between the survivor and non-survivor groups after treatment. Low Apgar score at 5 minutes and early diagnosis of PPHN were found statistically significant different in the non-survivor compared to the survivor groups.
Inhaled iloprost could be used as an alternative treatment of PPHN without side effects of systemic hypotension.
Persistent pulmonary hypertension of the newborn (PPHN) is a common problem in the neonates with a high mortality rate. The prevalence ranges from 0.38-0.99 per 1,000 live births at Queen Sirikit ...National Institute of Child Health. The survival rate has improved after the advent of high-frequency ventilation and inhaled nitric oxide. However, inhaled nitric oxide is expensive and unavailable in most neonatal centers in Thailand. Sildenafil is a phosphodiesterase inhibitor type 5 that selectively reduces pulmonary vascular resistance and hence may play a role in the treatment of PPHN.
To evaluate effectiveness and short-term side effects of oral sildenafil for infants > 36 weeks gestational age who have PPHN.
The present study was conducted between January 2006 and December 2008 in the neonatal intensive care unit (NICU) at Queen Sirikit National Institute of Child Health. All infants > or = 36 weeks gestational age who were diagnosed as PPHN by echocardiogram and had an oxygenation index > or = 20 were included in the study. Oral sildenafil was given as per study protocol with a starting dose of 0.25-0.5 mg/kg/dose. Oxygenation index (OI), oxygen saturations (SpO2), alveolar arterial oxygen gradient (A-aDO2) and mean arterial blood pressure (MAP) were monitored serially.
A total of 40 infants were diagnosed with PPHN during this period. Eleven infants were included in the present study. The initial median OI was 31.95 (24.25-48.25). All infants received standard therapy with mechanical ventilation, sedation and inotropic drugs. OI decreased 4.6% from base line after the first hour of starting oral sildenafil and progressively decreased by 13%, 27%, 37%, 41% and 90% at 2, 4, 6, 12 and 24 hours respectively. Oral sildenafil was discontinued in one infant. It was combined with inhaled iloprost in 2 infants due to systemic hypotension and with inhaled nitric oxide in one infant due to deterioration. One infant died during the present study.
Oral sildenafil may be effective in improving oxygenation in some infants with persistent pulmonary hypertension of the newborn. Systemic hypotension was a cause for concern in the present study. Further studies are needed to assess the pharmacokinetics, efficacy and long-term side effects of this drug.
Respiratory failure in term and near term infants is often associated with persistent pulmonary hypertension of the newborn and contributes to hypoxemia in these infants. Inhaled nitric oxide (iNO) ...is currently used as a pulmonary vasodilator to improve oxygenation in neonates with severe respiratory failure.
To determine outcome of administration of iNO in severe hypoxic respiratory failure.
The present study was conducted from 1999 to 2004 in the neonatal intensive care unit (NICU) at Queen Sirikit National Institute of Child Health. Patients were selected from all infants > or = 34 weeks gestational age who required high frequency oscillatory ventilation (SLE 2000 HFO, SLE, UK) or conventional mechanical ventilation for hypoxemic respiratory failure caused by PPHN. Diagnosis was confirmed by 2-D echocardiogram visualization with right to left shunt through the foramen ovale or patent ductus arteriosus. Inhaled nitric oxide was given as standard therapy in patients who had two oxygenation indices > or = 20 at least 30 minutes apart after being on a mechanical ventilator.
Fifty-five cases were enrolled and male to female ratio was 22.2 tol. The survival rate was 76.4 percent. Inhaled nitric oxide significantly improved oxygenation index, arterial alveolar oxygen tension ratio (a/A O2), and alveolar arterial oxygen gradient in survivors at one hour after treatment. The earliest improvement in oxygen saturation was within ten minutes. Meconium aspiration syndrome was the most common underlying cause of PPHN. No acute complication was found during nitric oxide administration. Chronic lung diseases, delayed development and severe hearing loss in long-term follow up were found in 10, 5, and 2 cases, respectively.
Inhaled nitric oxide should be used early in severe hypoxic respiratory failure with persistent pulmonary hypertension of newborn and can improve survival rates without any major immediate side effects.
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