Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial

Background Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein processed from cow's milk, prevents infections and associated complications. The aim of this large randomised controlled trial was to collect data to enhance the validity and applicability of the evidence from previous trials to inform practice. Methods In this randomised placebo-controlled trial, we recruited very preterm infants born before 32 weeks' gestation in 37 UK hospitals and younger than 72 h at randomisation. Exclusion criteria were presence of a severe congenital anomaly, anticipated enteral fasting for longer than 14 days, or no realistic prospect of survival. Eligible infants were randomly assigned (1:1) to receive either enteral bovine lactoferrin (150 mg/kg per day; maximum 300 mg/day; lactoferrin group) or sucrose (same dose; control group) once daily until 34 weeks' postmenstrual age. Web-based randomisation minimised for recruitment site, gestation (completed weeks), sex, and single versus multifetal pregnancy. Parents, caregivers, and outcome assessors were unaware of group assignment. The primary outcome was microbiologically confirmed or clinically suspected late-onset infection (occurring >72 h after birth), which was assessed in all participants for whom primary outcome data was available by calculating the relative risk ratio with 95% CI between the two groups. The trial is registered with the International Standard Randomised Controlled Trial Number 88261002. Findings We recruited 2203 participants between May 7, 2014, and Sept 28, 2017, of whom 1099 were assigned to the lactoferrin group and 1104 to the control group. Four infants had consent withdrawn or unconfirmed, leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group. Primary outcome data for 2182 infants (1093 [99·5%] of 1098 in the lactoferrin group and 1089 [99·0] of 1101 in the control group) were available for inclusion in the modified intention-to-treat analyses. 316 (29%) of 1093 infants in the intervention group acquired a late-onset infection versus 334 (31%) of 1089 in the control group. The risk ratio adjusted for minimisation factors was 0·95 (95% CI 0·86–1·04; p=0·233). During the trial there were 16 serious adverse events for infants in the lactoferrin group and 10 for infants in the control group. Two events in the lactoferrin group (one case of blood in stool and one death after intestinal perforation) were assessed as being possibly related to the trial intervention. Interpretation Enteral supplementation with bovine lactoferrin does not reduce the risk of late-onset infection in very preterm infants. These data do not support its routine use to prevent late-onset infection and associated morbidity or mortality in very preterm infants. Funding UK National Institute for Health Research Health Technology Assessment programme (10/57/49)

Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial

Background Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein processed from cow's milk, prevents infections and associated complications. The aim of this large randomised controlled trial was to collect data to enhance the validity and applicability of the evidence from previous trials to inform practice. Methods In this randomised placebo-controlled trial, we recruited very preterm infants born before 32 weeks' gestation in 37 UK hospitals and younger than 72 h at randomisation. Exclusion criteria were presence of a severe congenital anomaly, anticipated enteral fasting for longer than 14 days, or no realistic prospect of survival. Eligible infants were randomly assigned (1:1) to receive either enteral bovine lactoferrin (150 mg/kg per day; maximum 300 mg/day; lactoferrin group) or sucrose (same dose; control group) once daily until 34 weeks' postmenstrual age. Web-based randomisation minimised for recruitment site, gestation (completed weeks), sex, and single versus multifetal pregnancy. Parents, caregivers, and outcome assessors were unaware of group assignment. The primary outcome was microbiologically confirmed or clinically suspected late-onset infection (occurring >72 h after birth), which was assessed in all participants for whom primary outcome data was available by calculating the relative risk ratio with 95% CI between the two groups. The trial is registered with the International Standard Randomised Controlled Trial Number 88261002. Findings We recruited 2203 participants between May 7, 2014, and Sept 28, 2017, of whom 1099 were assigned to the lactoferrin group and 1104 to the control group. Four infants had consent withdrawn or unconfirmed, leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group. Primary outcome data for 2182 infants (1093 [99·5%] of 1098 in the lactoferrin group and 1089 [99·0] of 1101 in the control group) were available for inclusion in the modified intention-to-treat analyses. 316 (29%) of 1093 infants in the intervention group acquired a late-onset infection versus 334 (31%) of 1089 in the control group. The risk ratio adjusted for minimisation factors was 0·95 (95% CI 0·86–1·04; p=0·233). During the trial there were 16 serious adverse events for infants in the lactoferrin group and 10 for infants in the control group. Two events in the lactoferrin group (one case of blood in stool and one death after intestinal perforation) were assessed as being possibly related to the trial intervention. Interpretation Enteral supplementation with bovine lactoferrin does not reduce the risk of late-onset infection in very preterm infants. These data do not support its routine use to prevent late-onset infection and associated morbidity or mortality in very preterm infants. Funding UK National Institute for Health Research Health Technology Assessment programme (10/57/49)

Impaired vision in children prenatally exposed to methadone: an observational cohort study

Background/objectives: To examine prevalence of failed visual assessment at 8–10 years in children born to methadone-maintained opioid dependent (MMOD) mothers and relate this to known in utero substance exposure. Subjects/methods: Follow up of observational cohort study of methadone-exposed and comparison children matched for birthweight, gestation and postcode of residence at birth. Participants were 144 children (98 exposed, 46 comparison). Prenatal drug exposure was previously established via comprehensive maternal and neonatal toxicology. Children were invited to attend for visual assessment and casenotes were reviewed. Presence of acuity poorer than 0.2 logMAR, strabismus, nystagmus and/or impaired stereovision constituted a ‘fail’. Fail rates were compared between methadone-exposed and comparison children after adjusting for known confounding variables. Results: 33 children attended in person: data were also derived from casenote review for all children. After controlling for maternal reported tobacco use, methadone-exposed children were more likely to have a visual ‘fail’ outcome, adjusted odds ratio 2.6, 95% CI 1.1–6.2; adjusted relative risk 1.8 (95% CI 1.1–3.4). Visual ‘fail’ outcome rates did not differ between methadone-exposed children who had (n = 47) or had not (n = 51) received pharmacological treatment for neonatal abstinence/opioid withdrawal syndrome (NAS/NOWS); fail rate 62% vs 53% (95% CI of difference—11–27%). Conclusions: Children born to MMOD mothers are almost twice as likely as unexposed peers to have significant visual abnormalities at primary school age. Prenatal methadone exposure should be considered in the differential diagnosis of nystagmus. Findings support visual assessment prior to school entry for children with any history of prenatal opioid exposure. Trial registration: The study was prospectively registered on ClinicalTrials.gov (NCT03603301), https://clinicaltrials.gov/ct2/show/NCT03603301

Estimating risk of encapsulating peritoneal sclerosis accounting for the competing risk of death

Background: Risk of Encapsulating Peritoneal Sclerosis (EPS) is strongly associated with the duration of peritoneal dialysis (PD), such that patients who have been on PD for some time may consider elective transfer to haemodialysis to mitigate risk of EPS. There is a need to determine this risk to better inform clinical decision-making, but previous studies have not allowed for the competing risk of death. Methods: This study included new adult PD patients in either Australia and New Zealand (ANZ 1990-2010) or Scotland (2000-2008) followed until 2012. Age, time on PD, primary renal disease, gender, dataset and diabetic status were evaluated as predictors at start of PD, then at three and five years after starting PD using flexible parametric competing risks models. Results: In 17,396 patients (16,162 ANZ, 1,234 Scotland), EPS was observed in 99 (0.57%) patients less frequently in ANZ patients (n=65, 0.4%) than in Scottish patients (n=34, 2.8%). The estimated risk of EPS was much lower when the competing risk of death was taken into account (1-KM=0.0126, CIF=0.0054). Strong predictors of EPS included age, primary renal disease and time on PD. The risk of EPS was reasonably discriminated at the start of PD (C-statistic = 0.74 to 0.79) and this improved at 3 and 5 years after starting PD (C-statistic = 0.81 to 0.92). Conclusions: EPS risk estimates are lower when calculated using competing risk of death analyses. A patient’s estimated risk of EPS is country-specific, and can be predicted using age, primary renal disease and duration of PD

Impact of Nutrition on Non-Relapse Mortality and Acute Graft Versus Host Disease during Allogeneic Hematopoietic Cell Transplantation for Hematologic Malignancies

Abstract The process of allogeneic hematopoietic cell transplantation (HCT) is often associated with poor oral intake and as a result, nutritional status declines. Although it might seem obvious that optimal nutrition is likely to improve outcomes of transplantation, there are no clinical data that directly support this assumption. It is also unclear whether artificial nutrition support (ANS) should be provided as enteral tube feeding (ETF) or parenteral nutrition (PN). In this study we analysed day 100 non-relapse mortality (NRM) and incidence and severity of acute graft versus host disease (GvHD) according to both the route and adequacy of nutritional intake together with other known prognostic factors. A total of 484 patients who underwent HCT for hematological malignancy at a single institution between 2000 and 2014 were included. Myeloablative conditioning was used in 285 (59%) patients, 272 of whom received a TBI based regimen. Reduced intensity conditioning was given to 199 (41%) patients. For the 236 (49%) unrelated donor cell recipients in vivo T-cell depletion with alemtuzumab was used. Myeloablative HCT recipients were advised to have an enteral feeding tube inserted prophylactically at day 1 post HCT. ANS was initiated in 228 (47%) patients who met pre-defined feeding criteria that include actual or anticipated oral intake below 1/3 of estimated requirement for 5 or more days or significant weight loss or low body mass index. Total of 245 (51%) patients had adequate enteral nutrition (EN) either orally (N=198) or with use of ETF (N=47). Patients in whom ETF could not be established received PN (N=148, 31%) in order to provide adequate nutrition. The remaining 91 (19%) patients had inadequate nutrition due to either curtailed ANS (N=33) or a failure to start ANS because of a lack of feeding access via any route (N=58). The effects of patient, disease and transplant factors were studied in univariate analyses on NRM, acute GvHD and engraftment, following which multivariate analyses showed significant associations of NRM with age \u3e 50 years (hazard ratio (HR) 2.3; 95% confidence interval (CI) 1.4 - 3.7; P=0.001); previous autograft (HR 2.4; 95% CI 1.3 - 4.5; P=0.007) and positive recipient CMV serology (HR 1.9; 95% CI 1.1 - 3.2; P=0.019). In addition, HRs were significantly increased in the PN and inadequate nutrition groups compared to those with adequate enteral intake: adequate PN: HR 3.2; 95% CI 1.7 - 6.0, inadequate nutrition: HR 4.4; 95% CI 2.4 - 8.0; all P\u3c0.001 (Figure). There were increased incidences of gastrointestinal GvHD of any stage and acute GvHD \u3e grade 1 in patients who received PN (HR 2.0; 95% CI 1.2 - 3.3; P=0.006, and HR 1.8; 95% CI 1.1 - 3.0; P=0.018, respectively), but not in those with inadequate nutrition compared to adequate EN. Other significant covariates in the model for both increased overall and gut GvHD were the use of myeloablative versus reduced intensity conditioning P=0.001 and P\u3c0.001 and female donor to male recipient versus other combinations P=0.047 and P=0.025 respectively. In conclusion the data show that adequate nutrition during allogeneic HCT is associated with improved non-relapsed mortality at 100 days. Adequate EN is associated with significantly better results for this outcome than adequate PN. Furthermore adequate EN, predominantly via oral intake may be associated with lower incidence of overall and gut GvHD when compared to PN, perhaps because of its ability to maintain gut mucosal integrity and for support of the gastrointestinal tract environment, including gut microflora. Although the retrospective nature of this study can only indicate association, the significant hazard ratios reported warrant further research into optimising enteral nutrition in recipients of HCT. Figure Figure. Disclosures Milojkovic: Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria; Ariad: Honoraria. Apperley:Incyte: Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Ariad: Honoraria, Speakers Bureau

Using behavioural theories to optimise shared haemodialysis care: a qualitative intervention development study of patient and professional experience

Background Patients in control of their own haemodialysis report better outcomes than those receiving professional controlled care in a hospital setting, even though home and hospital haemodialysis are largely equivalent from mechanical and physiological perspectives. Shared Haemodialysis Care (SHC) describes an initiative in which hospital haemodialysis patients are supported by dialysis staff to become as involved as they wish in their own care; and can improve patient safety, satisfaction and may reduce costs. We do not understand why interventions to support self-management in other conditions have variable effects or how to optimise the delivery of SHC. The purpose of this study was to identify perceived patient and professional (nurses and healthcare assistants) barriers to the uptake of SHC, and to use these data to identify intervention components to optimise care. Methods Individual semi-structured interviews with patients and professionals were conducted to identify barriers and facilitators. Data were coded to behavioural theory to identify solutions. A national UK learning event with multiple stakeholders (patients, carers, commissioners and professionals) explored the salience of these barriers and the acceptability of solutions. Results A complex intervention strategy was designed to optimise SHC for patients and professionals. Interviews were conducted with patients (n = 15) and professionals (n = 7) in two hospitals and three satellite units piloting SHC. Data from patient and professional interviews could be coded to behavioural theory. Analyses identified key barriers (knowledge, beliefs about capabilities, skills and environmental context and resources). An intervention strategy that focuses on providing, first, patients with information about the shared nature of care, how to read prescriptions and use machines, and second, providing professionals with skills and protected time to teach both professionals/patients, as well as providing continual review, may improve the implementation of SHC and be acceptable to stakeholders. Conclusions We have developed an intervention strategy to improve the implementation of SHC for patients and professionals. While this intervention strategy has been systematically developed using behavioural theory, it should be rigorously tested in a subsequent effectiveness evaluation study prior to implementation to ensure that shared haemodialysis care can be delivered equitably, efficiently and safely for all patients

Quantitative modeling of the physiology of ascites in portal hypertension

Although the factors involved in cirrhotic ascites have been studied for a century, a number of observations are not understood, including the action of diuretics in the treatment of ascites and the ability of the plasma-ascitic albumin gradient to diagnose portal hypertension. This communication presents an explanation of ascites based solely on pathophysiological alterations within the peritoneal cavity. A quantitative model is described based on experimental vascular and intraperitoneal pressures, lymph flow, and peritoneal space compliance. The model's predictions accurately mimic clinical observations in ascites, including the magnitude and time course of changes observed following paracentesis or diuretic therapy

Global overview of the management of acute cholecystitis during the COVID-19 pandemic (CHOLECOVID study)

Background: This study provides a global overview of the management of patients with acute cholecystitis during the initial phase of the COVID-19 pandemic. Methods: CHOLECOVID is an international, multicentre, observational comparative study of patients admitted to hospital with acute cholecystitis during the COVID-19 pandemic. Data on management were collected for a 2-month study interval coincident with the WHO declaration of the SARS-CoV-2 pandemic and compared with an equivalent pre-pandemic time interval. Mediation analysis examined the influence of SARS-COV-2 infection on 30-day mortality. Results: This study collected data on 9783 patients with acute cholecystitis admitted to 247 hospitals across the world. The pandemic was associated with reduced availability of surgical workforce and operating facilities globally, a significant shift to worse severity of disease, and increased use of conservative management. There was a reduction (both absolute and proportionate) in the number of patients undergoing cholecystectomy from 3095 patients (56.2 per cent) pre-pandemic to 1998 patients (46.2 per cent) during the pandemic but there was no difference in 30-day all-cause mortality after cholecystectomy comparing the pre-pandemic interval with the pandemic (13 patients (0.4 per cent) pre-pandemic to 13 patients (0.6 per cent) pandemic; P = 0.355). In mediation analysis, an admission with acute cholecystitis during the pandemic was associated with a non-significant increased risk of death (OR 1.29, 95 per cent c.i. 0.93 to 1.79, P = 0.121). Conclusion: CHOLECOVID provides a unique overview of the treatment of patients with cholecystitis across the globe during the first months of the SARS-CoV-2 pandemic. The study highlights the need for system resilience in retention of elective surgical activity. Cholecystectomy was associated with a low risk of mortality and deferral of treatment results in an increase in avoidable morbidity that represents the non-COVID cost of this pandemic