Photoacoustic imaging for non-invasive assessment of biomarkers of intestinal injury in experimental necrotizing enterocolitis.

BACKGROUND: Necrotizing enterocolitis (NEC) is an often-lethal disease of the premature infant intestinal tract, exacerbated by significant diagnostic difficulties. In NEC, the intestine exhibits hypoperfusion and dysmotility, contributing to disease pathogenesis. However, these features cannot be accurately and quantitively assessed with current imaging modalities. We have previously demonstrated the ability of photoacoustic imaging (PAI) to non-invasively assess intestinal tissue oxygenation and motility in a healthy neonatal rat model. METHODS: In this first-in-disease application, we evaluated NEC using PAI to assess intestinal health biomarkers in an experimental model of NEC. NEC was induced in neonatal rats from birth to 4-days. Healthy breastfed (BF) and NEC rat pups were imaged at 2- and 4-days. RESULTS: Intestinal tissue oxygen saturation was measured with PAI, and NEC pups showed significant decreases at 2- and 4-days. Ultrasound and PAI cine recordings were used to capture intestinal peristalsis and contrast agent transit within the intestine. Intestinal motility, assessed using computational intestinal deformation analysis, demonstrated significant reductions in both early and established NEC. NEC damage was confirmed with histology and dysmotility was confirmed by small intestinal transit assay. CONCLUSION: This preclinical study presents PAI as an emerging diagnostic imaging modality for intestinal disease assessment in premature infants. IMPACT: Necrotizing enterocolitis (NEC) is a devastating intestinal disease affecting premature infants with significant mortality. NEC presents significant clinical diagnostic difficulties, with limited diagnostic confidence complicating timely and effective interventional efforts. This study is an important foundational first-in-disease preclinical study that establishes the utility for PAI to detect changes in intestinal tissue oxygenation and intestinal motility with NEC disease induction and progression. This study demonstrates the feasibility and exceptional promise for the use of PAI to non-invasively assess oxygenation and motility in the healthy and diseased infant intestine.

Surgical interventions and short-term outcomes for preterm infants with post-haemorrhagic hydrocephalus: a multicentre cohort study.

OBJECTIVE: To (1) describe differences in types and timing of interventions, (2) report short-term outcomes and (3) describe differences among centres from a large national cohort of preterm infants with post-haemorrhagic hydrocephalus (PHH). DESIGN: Cohort study of the Children's Hospitals Neonatal Database from 2010 to 2022. SETTING: 41 referral neonatal intensive care units (NICUs) in North America. PATIENTS: Infants born before 32 weeks' gestation with PHH defined as acquired hydrocephalus with intraventricular haemorrhage. INTERVENTIONS: (1) No intervention, (2) temporising device (TD) only, (3) initial permanent shunt (PS) and (4) TD followed by PS (TD-PS). MAIN OUTCOME MEASURES: Mortality and meningitis. RESULTS: Of 3883 infants with PHH from 41 centres, 36% had no surgical intervention, 16% had a TD only, 19% had a PS only and 30% had a TD-PS. Of the 46% of infants with TDs, 76% were reservoirs; 66% of infants with TDs required PS placement. The percent of infants with PHH receiving ventricular access device placement differed by centre, ranging from 4% to 79% (p<0.001). Median chronological and postmenstrual age at time of TD placement were similar between infants with only TD and those with TD-PS. Infants with TD-PS were older and larger than those with only PS at time of PS placement. Death before NICU discharge occurred in 12% of infants, usually due to redirection of care. Meningitis occurred in 11% of the cohort. CONCLUSIONS: There was significant intercentre variation in rate of intervention, which may reflect variability in care or referral patterns. Rate of PS placement in infants with TDs was 66%.

Photoacoustic Imaging as a Novel Non-invasive Biomarker to Assess Intestinal Tissue Oxygenation and Motility in Neonatal Rats.

BACKGROUND: Within the premature infant intestine, oxygenation and motility play key physiological roles in healthy development and disease such as necrotizing enterocolitis. To date, there are limited techniques to reliably assess these physiological functions that are also clinically feasible for critically ill infants. To address this clinical need, we hypothesized that photoacoustic imaging (PAI) can provide non-invasive assessment of intestinal tissue oxygenation and motility to characterize intestinal physiology and health. METHODS: Ultrasound and photoacoustic images were acquired in 2-day and 4-day old neonatal rats. For PAI assessment of intestinal tissue oxygenation, an inspired gas challenge was performed using hypoxic, normoxic, and hyperoxic inspired oxygen (FiO2). For intestinal motility, oral administration of ICG contrast agent was used to compare control animals to an experimental model of loperamide-induced intestinal motility inhibition. RESULTS: PAI demonstrated progressive increases in oxygen saturation (sO2) as FiO2 increased, while the pattern of oxygen localization remained relatively consistent in both 2-day and 4-day old neonatal rats. Analysis of intraluminal ICG contrast enhanced PAI images yielded a map of the motility index in control and loperamide treated rats. From PAI analysis, loperamide significantly inhibited intestinal motility, with a 32.6% decrease in intestinal motility index scores in 4-day old rats. CONCLUSION: These data establish the feasibility and application of PAI to non-invasively and quantitatively measure intestinal tissue oxygenation and motility. This proof-of-concept study is an important first step in developing and optimizing photoacoustic imaging to provide valuable insight into intestinal health and disease to improve the care of premature infants.

Photoacoustic Imaging for Non-Invasive Assessment of Physiological Biomarkers of Intestinal Injury in Experimental Necrotizing Enterocolitis.

Background: Necrotizing enterocolitis (NEC) is an often-lethal disease of the premature infants' intestinal tract that is exacerbated by significant difficulties in early and accurate diagnosis. In NEC disease, the intestine often exhibits hypoperfusion and dysmotility, which contributes to advanced disease pathogenesis. However, these physiological features cannot be accurately and quantitively assessed within the current constraints of imaging modalities frequently used in the clinic (plain film X-ray and ultrasound). We have previously demonstrated the ability of photoacoustic imaging (PAI) to non-invasively and quantitively assess intestinal tissue oxygenation and motility in a healthy neonatal rat model. As a first-in-disease application, we evaluated NEC pathogenesis using PAI to assess intestinal health biomarkers in a preclinical neonatal rat experimental model of NEC. Methods: NEC was induced in neonatal rat pups from birth to 4 days old via hypertonic formula feeding, full-body hypoxic stress, and lipopolysaccharide administration to mimic bacterial colonization. Healthy breastfed (BF) controls and NEC rat pups were imaged at 2- and 4-days old. Intestinal tissue oxygen saturation was measured with PAI imaging for oxy- and deoxyhemoglobin levels. To measure intestinal motility, ultrasound and co-registered PAI cine recordings were used to capture intestinal peristalsis motion and contrast agent (indocyanine green) transit within the intestinal lumen. Additionally, both midplane two-dimensional and volumetric three-dimensional imaging acquisitions were assessed for oxygenation and motility. Results: NEC pups showed a significant decrease of intestinal tissue oxygenation as compared to healthy BF controls at both ages (2-days old: 55.90% +/- 3.77% vs 44.12% +/- 7.18%; 4-days old: 56.13% +/- 3.52% vs 38.86% +/- 8.33%). Intestinal motility, assessed using a computational intestinal deformation analysis, demonstrated a significant reduction in the intestinal motility index in both early (2-day) and established (4-day) NEC. Extensive NEC damage was confirmed with histology and dysmotility was confirmed by small intestinal transit assay. Conclusions: This study presents PAI as a successful emerging diagnostic imaging modality for both intestinal tissue oxygenation and intestinal motility disease hallmarks in a rat NEC model. PAI presents enormous significance and potential for fundamentally changing current clinical paradigms for detecting and monitoring intestinal pathologies in the premature infant.

Clinical Correlates of Cholestasis in Preterm Infants with Surgical Necrotizing Enterocolitis.

Background: We sought to investigate the clinical determinants and outcomes of cholestasis in preterm infants with surgical necrotizing enterocolitis (sNEC). Methods: Retrospective comparison of clinical information in preterm infants who developed cholestasis vs those who did not. Results: Sixty-two (62/91, 68.1%) infants with NEC developed cholestasis at any time following the onset of illness. Cholestasis was seen more frequently in those who had received ionotropic support at 24 hours following sNEC diagnosis (87.1% vs 58.6%; p = 0.002), had higher mean C-reactive protein levels 2 weeks after NEC diagnosis (p = 0.009), had blood culture-positive sepsis [25 (40.3%) vs 4 (13.8%); p = 0.011], received parenteral nutrition (PN) for longer durations (108.4 ± 56.63 days vs 97.56 ± 56.05 days; p = 0.007), had higher weight-for-length z scores at 36 weeks' postmenstrual age [-1.0 (-1.73, -0.12) vs -1.32 (-1.76, -0.76); p = 0.025], had a longer length of hospital stay (153.7 ± 77.57 days vs 112.51 ± 85.22 days; p = 0.024), had intestinal failure more often (61% vs 25.0%, p = 0.003), had more surgical complications (50% vs 27.6%; p = 0.044), and had >1 complication (21% vs 3.4%; p = 0.031). Using linear regression, the number of days after surgery when feeds could be started [OR 15.4; confidence interval (CI) 3.71, 27.13; p = 0.009] and the postoperative ileus duration (OR 11.9, CI 1.1, 22.8; p = 0.03) were independently associated with direct bilirubin between 2 and 5 mg/dL (mild-moderate cholestasis) at 2 months of age. The duration of PN was independently associated with direct bilirubin >5 mg/dL (severe cholestasis) at 2 months of age in these patients. Conclusion: Cholestasis was seen in 68% of infants following surgical NEC. The most likely contributive factors are intestinal failure and subsequent PN dependence for longer periods. Our data suggest that identification and prevention of risk factors such as sepsis and surgical complications and early feeds following NEC surgery may improve outcomes.

Photoacoustic Imaging as a Novel Non-Invasive Biomarker to Assess Intestinal Tissue Oxygenation and Motility in Neonatal Rats.

Background: Within the premature infant intestine, oxygenation and motility play key physiological roles in healthy development and disease such as necrotizing enterocolitis. To date, there are limited techniques to reliably assess these physiological functions that are also clinically feasible for critically ill infants. To address this clinical need, we hypothesized that photoacoustic imaging (PAI) can provide non-invasive assessment of intestinal tissue oxygenation and motility to characterize intestinal physiology and health. Methods: Ultrasound and photoacoustic images were acquired in 2-day and 4-day old neonatal rats. For PAI assessment of intestinal tissue oxygenation, an inspired gas challenge was performed using hypoxic, normoxic, and hyperoxic inspired oxygen (FiO2). For intestinal motility, oral administration of ICG contrast agent was used to compare control animals to an experimental model of loperamide-induced intestinal motility inhibition. Results: PAI demonstrated progressive increases in oxygen saturation (sO2) as FiO2 increased, while the pattern of oxygen localization remained relatively consistent in both 2-day and 4-day old neonatal rats. Analysis of intraluminal ICG contrast enhanced PAI images yielded a map of the motility index in control and loperamide treated rats. From PAI analysis, loperamide significantly inhibited intestinal motility, with a 32.6% decrease in intestinal motility index scores in 4-day old rats. Conclusion: These data establish the feasibility and application of PAI to non-invasively and quantitatively measure intestinal tissue oxygenation and motility. This proof-of-concept study is an important first step in developing and optimizing photoacoustic imaging to provide valuable insight into intestinal health and disease to improve the care of premature infants. Highlights: Intestinal tissue oxygenation and intestinal motility are important biomarkers of intestinal physiology in health and disease of premature infants.This proof-of-concept preclinical rat study is the first to report application of photoacoustic imaging for the neonatal intestine.Photoacoustic imaging is demonstrated as a promising non-invasive diagnostic imaging method for quantifying intestinal tissue oxygenation and intestinal motility in premature infants.

Mixed Oil-Based Lipid Emulsions vs Soybean Oil-Based Lipid Emulsions on Incidence and Severity of Intestinal Failure-Associated Liver Disease in a Neonatal Intensive Care Unit.

BACKGROUND: Neonates requiring long-term parenteral nutrition (PN) are at risk for developing intestinal failure-associated liver disease (IFALD). The purpose of this study was to compare the incidence and severity of IFALD in a highly surgical neonatal population receiving mixed oil-based lipid emulsions (MOLEs) vs soybean oil-based lipid emulsions (SOLEs) for long-term PN. METHODS: This retrospective cohort study evaluated patients admitted to a neonatal intensive care nursery that received PN for ≥14 days. Patients were separated into 2 cohorts; those who received SOLE and those who received MOLE. The primary outcome of this study was the occurrence of IFALD. Secondary outcomes included time to IFALD, peak bilirubin level during therapy, incidence of hypertriglyceridemia, bronchopulmonary dysplasia, and retinopathy of prematurity. RESULTS: A total of 107 patients were included in the study, IFALD occurred in 44.8% of patients receiving SOLE compared with 30% of patients receiving MOLE (relative risk, 0.67; 95% CI, 0.39-1.15). In the multivariable analysis, adjusting for the known confounders (prematurity, necrotizing enterocolitis, presence of ostomy, and duration of PN and lipids), the type of lipids was not a significant predictor for development of IFALD. Duration of PN and duration of lipids were determined to be significant risk factors for IFALD, regardless of type of lipid emulsion (odds ratio, 1.03; 95% CI, 1.01-1.05). CONCLUSIONS: Use of MOLE resulted in no significant difference in the outcomes studied when compared with SOLE. Duration of PN and duration of lipids were significant risk factors for development of IFALD.

Improving care collaboration for NICU patients to decrease length of stay and readmission rate.

BACKGROUND: Medically complex patients in neonatal intensive care units (NICUs) typically require long hospitalisations and care from multiple subspecialists. Scheduled multidisciplinary discussions could improve collaboration and continuity of care and thereby improve patient outcomes. The specific aims of the project were to decrease the average length of hospitalisation by at least 1 day and improve parent satisfaction ratings on a standard questionnaire by the end of our project's first year, and to maintain a stable (or decreased) cause-related (30-day) readmission rate. METHODS: We designed a quality improvement project to enhance collaboration and continuity of care for medically complex infants cared for in the NICU of Brenner Children's Hospital. Weekly multidisciplinary team meetings were held to discuss the long-term plan for patients who met specific criteria. Attendees included attending neonatologists, paediatric surgeons, a physical therapist, an occupational therapist, a speech therapist, a social worker, a nurse coordinator for palliative care, a family support coordinator, the NICU Nurse Manager, a hospital chaplain, mid-level providers, bedside nurses, a nurse quality improvement leader and the leaders and database manager for the quality improvement project. When needed for specific patients, a bioethicist was included. RESULTS: One year after implementing the project, the average duration of hospitalisation had decreased by 6.5 days. Cause-related readmission rates decreased from 3.33% to 0.95%. Parent satisfaction scores did not change significantly. CONCLUSIONS: Weekly multidisciplinary meetings to coordinate and provide continuity of care for medically complex neonates in our NICU was associated with improved patient outcomes.

Randomized controlled trial of early enteral fat supplement and fish oil to promote intestinal adaptation in premature infants with an enterostomy.

OBJECTIVE: To test the hypothesis that early enteral supplementing fat and fish oil decreases the duration of parenteral nutrition (PN) and increases enteral nutrition (EN) before bowel reanastomosis in premature infants with an enterostomy. STUDY DESIGN: Premature infants (<2 months old) who had an enterostomy and tolerated enteral feeding at 20 mL/kg/day were randomized to usual care (control=18) or early supplementing enteral fat supplement and fish oil (treatment=18). Intravenous lipid was decreased as enteral fat intake was increased. Daily weight, clinical and nutrition data, and weekly length and head circumference were recorded. The primary outcomes were the duration of PN and volume of EN intake, and the secondary outcomes were weight gain (g/day), ostomy output (mL/kg/d), and serum conjugated bilirubin level (mg/dL) from initiating feeding to reanastomosis. Data were analyzed by Student t test or Wilcoxon rank sum test. RESULTS: There were no differences in the duration of PN, ostomy output, and weight gain between the 2 groups before reanastomosis. However, supplemented infants received less intravenous lipid, had greater EN intake, and lower conjugated bilirubin before reanastomosis, and they also received greater total calorie, had fewer sepsis evaluations and less exposure to antibiotics and central venous catheters before reanastomosis, and had greater weight and length gain after reanastomosis (all P<.05). CONCLUSION: Early enteral feeding of a fat supplement and fish oil was associated with decreased exposure to intravenous lipid, increased EN intake, and reduced conjugated bilirubin before reanastomosis and improved weight and length gain after reanastomosis in premature infants with an enterostomy.

Early enteral fat supplement and fish oil increases fat absorption in the premature infant with an enterostomy.

OBJECTIVE: To test the hypothesis that in the premature infant with an enterostomy, early enteral supplementation with Microlipid (fat supplement) and fish oil increases enteral fat absorption and decreases the requirement for Intralipid (intravenous fat emulsion). STUDY DESIGN: Premature infants (<2 months old) with an enterostomy after surgical treatment for necrotizing enterocolitis or spontaneous intestinal perforation and tolerating enteral feeding at 20 mL/kg/day were randomized to usual care (control 18 infants) or early supplementing enteral fat and fish oil (treatment 18 infants). Intravenous fat emulsion was decreased as enteral fat intake was increased. Daily weight, ostomy output, and nutrition data were recorded. Weekly 24-hour ostomy effluent was collected until bowel reanastomosis, and fecal fat, fecal liquid, and dry feces were measured. Fat absorption (g/kg/d) was calculated by subtracting fecal fat from dietary fat. The fecal liquid and dry feces were reported as mg/g wet stool. Date were analyzed by using ANOVA and mixed-effects model. RESULTS: The interval from initial postoperative feeding to bowel reanastomosis varied from 2 to 10 weeks. The treatment group received more dietary fat and less intravenous fat emulsion and had higher enteral fat absorption, less fecal liquid, and drier feces than the control group. These effects were greater among infants with a high ostomy compared with those with a low ostomy. Enteral fat intake was significantly correlated with fat absorption. CONCLUSION: Early enteral fat supplement and fish oil increases fat absorption and decreases the requirement for intravenous fat emulsion. This approach could be used to promote bowel adaptation and reduce the use of intravenous fat emulsion in the premature infant with an enterostomy.

Early enteral fat supplementation with microlipid® and fish oil in the treatment of two premature infants with short bowel.

The infusion of Intralipid® is a main risk factor for parenteral nutrition-associated cholestasis in infants with short bowel syndrome. Early provision of enteral fat to reduce the use of Intralipid while providing adequate fat for the growth of infants with short bowel has not been reported. We present 2 cases of premature infants with short bowel who received early supplementation of enteral Microlipid® and fish oil. This approach allowed us to discontinue Intralipid shortly after initiating feedings. The infants tolerated Microlipid/fish oil well without adverse reactions, had appropriate weight gain and ostomy output. They underwent bowel reanastomosis 3 weeks after enteral feeding began, and were discharged on full oral feedings. In case 1, the infant did not develop parenteral nutrition-associated cholestasis; in case 2, cholestasis had developed before initiating feeds, but was not aggravated by enteral fat and was improving prior to discharge.

Sepsis-associated electroencephalographic changes in extremely low gestational age neonates.

BACKGROUND: Sepsis in premature infants is associated with adverse neurodevelopmental outcomes. No previous studies have assessed acute changes in brain function during sepsis that might precede these adverse outcomes. METHODS: We performed amplitude-integrated electroencephalography (aEEG) monthly, from 28 weeks until 36 weeks of postmenstrual age, on 108 premature infants born before 28 weeks of gestation. Additional aEEG recordings were performed during infants' first episode of sepsis. Two independent readers who were blinded to the infant's gestational age at birth and chronologic age, as well as to whether the infant had sepsis, evaluated aEEG recordings for the presence of burst suppression and assigned a maturation score. RESULTS: Burst supression was found in 22% of aEEG recordings from infants without sepsis and 57% of recordings from infants with sepsis at the time of the recording (odds ratio=4.2; 95% confidence limits=2.4, 7.2; p<0.001). After adjustment for postmenstrual age at the time of the recording, the association between sepsis and burst suppression persisted (odds ratio=2.4; 95% confidence limits=1.2, 4.8; p=0.01). No statistically significant difference was found in the rate of increase in aEEG maturation score between infants with sepsis and those without. CONCLUSION: Sepsis is associated with acute electroencephalographic changes, as indicated by burst supression, but not with a decreased rate of brain wave maturation.