Our Journey Toward Elimination of Necrotizing Enterocolitis RAY SATO, M.D. TACOMA GENERAL HOSPITAL NICU APRIL 2018 Disclosure Ray Sato, MD has no financial relationship to disclose or conflicts of interest to resolve. This presentation will not include discussion of unapproved or off-label use of drugs. Presentation Outline Necrotizing Enterocolitis Review of Necrotizing Enterocolitis (NEC) Pathogenesis of NEC Strategies to Prevent NEC NEC reduction at Tacoma General An acquired inflammatory disorder of the intestinal tract characterized by variable damage ranging from mucosal injury to full-thickness necrosis and perforation. Premature infants are at highest risk for NEC although term infants are also at risk (especially ones with birth depression, cyanotic heart disease, or gastroschisis.) Clinical Presentation of NEC Abdominal Findings in NEC Feeding Intolerance - emesis Abdominal Distention Respiratory Distress Abdominal Discoloration Blood in the Stool Signs of Sepsis including Apnea, Lethargy, Tachycardia and Temperature Instability 1
Common Laboratory Abormalities Associated with Necrotizing Enterocolitis Radiographic Findings in NEC Metabolic Acidosis Thrombocytopenia Hyperglycemia Leukocytosis Hyponatremia Pneumatosis Intestinalis Portal Venous Air Images of Perforated NEC Bell Staging Criteria (Modified) Football Sign Lateral X-ray Vermont Oxford Definitions for NEC To meet definition of NEC Surgical Exploration Postmortem Examination Clinical Criteria Must have at least ONE clinical sign AND at least ONE radiographic finding Clinical Signs Bilious gastric aspirate or emesis Abdominal Distention Occult or Gross Blood in stool without identified rectal fissure Necrotizing Enterocolitis Incidence Vermont Oxford Infants <=1500 grams at birth 2016: 5% 2015: 5.1% 2014: 5.4% 2013: 5.1% 2012: 5.4% Radiographic Findings Pneumatosis Intestinalis Hepato-biliary gas Pneumoperitoneum 2
Necrotizing Enterocolitis and Gestational Age Incidence decreases with increasing gestational age (Pediatrix data) Timing of NEC Onset Preterm infants with a birthweight >=1000 grams presented with NEC at a mean of 7 days Preterm infants with a birthweight <1000 grams had a delayed onset of NEC until a mean of 32 days. Guthrie et al, J of Perinatology 2003. Yee et al, Pediatrics 2012. Pathogenesis of Necrotizing Enterocolitis The etiology of NEC has not been definitively identified Compromised epithelial barrier leads to invasion by luminal microbiota leading to inflammation and intestinal injury. Immature epithelium with poor barrier function promoting bacterial translocation Underdeveloped immune system Pathogenic luminal microbiota Vascular compromise Pathogenesis of NEC Neu and Walker, NEJM 2011 NEC and Toll Like Receptor Proteins NEC Model TLRs are innate proteins which recognize specific markers on bacteria. Once bacteria breech physical barriers such as intestinal mucosa, the TLRs activate immune cell responses. TLR4 recognizes gram negative lipopolysaccharide and is found on premature ileum. Activation results in cell death in immature but not adult colon. TLR9 also recognizes gram negative lipopolysaccharide but acts as a brake to TLR4 activation Infants with NEC have been found to have more TLR4 and less TLR9. 6 substances have been found to inhibit TLR4, 5 of 6 are found in breast milk. Knockout mice without TLR4 do not get NEC when condition is induced. TLR9 is induced by probiotics. TLR9 Hackam, 2012 3
Result of NEC Short Term Complications of NEC Ileus Bowel Perforation Sepsis Shock Hyperkalemia Thrombocytopenia Hemorrhage Hyponatremia Acidosis Long Term Complications of NEC Best Practices for NEC Reduction Malabsorption Cholestatic Liver Disease Short Gut Syndrome Stricture Formation/Bowel Obstruction?CNS Injury from Inflammation Patel et al, Clinics in Perinatology 2017 Standardized Feeding Guidelines Feeding protocols generally incorporating early minimal enteral nutrition and defined advancement have shown reduction of NEC by many investigators. Optimal advancement rate not defined, 30 ml/kg-d vs 20 ml/kg-d found no adverse effect on NEC rate Early fortification at 20 ml/kg-d vs 100 ml/kg-d found no increase in NEC Exclusive Feedings of Maternal Breast Milk Own Mother s Milk has been associated with reduction in NEC Reduced intestinal permeability and antiinflammatory/anti-infective components can also modulate NEC risk 4
Donor Milk Instead of Formula Human Milk Based Fortifiers Donor milk undergoes pasteurization and processing which reduces natural anti-inflammatory and anti-infective activity Formula feeding has been associated with increased NEC rates. It is unclear if formula is harmful or donor breast milk is protective. The American Academy of Pediatrics recommends human milk (mother s if possible, donor if not) for premature infants. With the shift to exclusive human milk feeding, attention has been placed on fortification agents especially with the availability of human milk based products. Human milk based fortifiers have shown advantageous in limited studies. Methodologies have raised questions about the studies including use of controls either fed formula or utilizing historical controls. Prolacta Biosciences estimates a human milk based fortifier costs $5,600 to $10,000 per patient hospital stay. Depending on the relative rates of NEC, a cost advantage has been reported by some investigators. Prolacta Randomized Trial Prolacta vs Bovine Fortifier 53 infants with mean birth weight of just under 1000 grams and gestation just under 28 weeks were randomized between cow based formula vs exclusive human milk. In the exclusive human milk infants, statistically significant advantages included days on parental nutrition (27 vs 36), necrotizing enterocolitis (1 vs 5), and surgical NEC (0 vs 4). The overall NEC rate was 3% in the human milk group and 21% in the formula group. This small study showed the advantages of an exclusive human milk diet but the contribution of Prolacta was not demonstrated (which would require a MBM/DBM/HMF vs MBM/DBM/Prolacta trial) RETROSPECTIVE trial of 361 infants note the significantly smaller infants in the later exclusive human milk epoch. Group Formula Bovine Fortifier Gestation 29.1 28.1 26.7 Birth Wt 1177 1104 919 Exclusive Human NEC 8.6% 4.9% 2.3% Advanced NEC 4.3% 2.7% 2.3% (Cristafalo, et al, J Peds 2013) Huston et al, 2014 Prolacta A true multicenter prospective randomized trial data comparing human milk / bovine fortifier and human milk / Prolacta fortifier particularly controlled for donor breast milk use would be the gold standard to make decisions about Prolacta. Donor Breast Milk as standard of care for premature infant feeding make historical NEC rates less useful for comparison Decreased NEC rates from donor breast milk usage requires large number of infants to be enrolled to show statistical advantage in NEC rates which would make this a very challenging trial to complete. It would be hard to argue Prolacta wouldn t offer some advantage over bovine fortifier for NEC rates. Cost effectiveness is a different question. Antibiotic Stewardship Antibiotics alter gut flora preventing normal colonization and encourage growth of potentially pathogenic bacteria NICHD network data suggests that >5 days of empiric antibiotic treatment with sterile culture results was associated with increased NEC and death as well as NEC alone. A 7% increase in odds of NEC was noted for each additional day of empiric antibiotic treatment. 5
Avoiding Acid Suppression Medications Use of Probiotics The use of medications to reduce gastric acidity have been associated with increased risk of NEC, presumably by altering the intestinal flora Multiple trials have found an association with acid blockers and NEC. Numerous trials have investigated the use of probiotics in preterm infants to help establish a more normal intestinal flora Different probiotic formulas were used in different formulas and no FDA approved product is available. Meta-analysis by Cochrane Neonatal failed to find a benefit for probiotic use. Delayed Cord Clamping A delay of cord clamping after birth for 30-60 seconds is now the recommendation of both NRP as well as ACOG. In a Cochrane neonatal review of 15 studies, 5 showed a significant decrease in NEC with delayed cord clamping. The improvement may be related to improved hemodynamics, higher hemoglobin concentration, reduction in need for blood transfusions and/or transfusion of pluripotent stem cells. Anemia, Blood Transfusions and NEC NEC occurring within 48 hours after a blood transfusion has been reported although meta-analysis shows only a relationship given a low quality rating Gut injury from transfusion is postulated although pathogenesis is controversial Intestinal mucosal injury from less deformable transfused adult red cells Change in viscosity leading to decreased oxygen delivery Critical anemia leading to decreased oxygen delivery and increased susceptibility to mucosal injury and necrosis Feeding Tube Management NEC Reduction at Tacoma General Size, dwell time and aspiration all impact bacterial contamination of feeding tubes. 6
NEC Incidence by Birthweight at TG 2011-2013 1001-1500 gram birthweight 2011-2013: n= 259 <=1000 gram birthweight 2011-2013: n=166 Pre 2014 NEC Reduction Incorporation of Best Demonstrated Practices Percutaneous Centrally Placed Catheters Total Parental Nutrition on Admission Early Trophic Feeds Standardized Feeding Protocol Donor Breast Milk Avoidance of Acid Blockers Avoidance of Broad Spectrum Antibiotics especially Cefotaxime and Impenenem/Meropenem Quality Improvement Cycles 2014 Tacoma General NEC Reduction Task Force Formation of a multidisciplinary committee to look at every aspect of premature infant care which could influence necrotizing enterocolitis Review of literature and survey of national practices Solicit support from administration for funding Production of care plan Education of staff Followup meetings to check and adjust plans 2014 NEC Reduction Bundle Emphasis on feeding Own Mother s Milk Encouragement starting before birth from all caregivers including emphasizing benefits to infant, Instruction on pumping equipment use, lactation support Education and provision of supplies for collection of maternal milk including cleaning of equipment Change to Exclusive Human Milk Diets by substituting Prolacta Human Milk Fortifier for infants with birthweight <=1500 grams until reaching 34 weeks corrected age. Careful review of feeding tube management including specifications on size, dwell time, and an end to residual checks which could promote contamination without providing meaningful clinical information. Open venting of feeding tube if clinically needed. Continued avoidance of acid blockers and broad spectrum antibiotic use 2014 NEC Reduction Bundle (continued) Probiotics Although supporting data in the literature was mixed, on balance we decided to implement use in VLBW infants using the FloraBaby product which contains a combination of 4 strains bifidobacterial and1 strain of lactobacillus. We use doses of 500 mg daily with the start of trophic feeds and conclude at 2 weeks or 34 weeks corrected age, whichever is later. Transfusion Protocol Nationally, increasing attention over the issue resulted in many peer institutions holding feeds during the transfusion and for a period of time afterwards. We adopted a policy holding feeds commencing with the start of transfusion and ending 6 hours afterwards. 7
2014 NEC Reduction Bundle (continued) GUTCHECK To improve communication and focus attention on infants potentially manifesting early signs of NEC, we implemented GUTCHECK scoring the scoring system created by Gephart et al from the University of Arizona. The score incorporates risk including fixed historical factors (gestational age, race, transport status, NICU NEC rate), current care (human milk use, probiotics, transfusions, inotropes), and laboratory data (cultures and metabolic acidosis). Gutcheck scores and relevant data about feeding tolerance, abdominal exam/girth, and stooling was passed along to providers. 2014 NEC Reduction Bundle Feeding Protocol Standardized Feeding Protocols were modified and Human Milk based Fortifier (Prolacta) was incorporated. Preterm Infants <1500 grams at Birth 1. For first 72 hours of life give trophic feeds *10 ml/kg-d* ml every 6 hours using available maternal breast milk (use colostrum preferentially). Begin supplementation with donor breast milk if maternal supply is insufficient starting at 24 hours of age. 2. At 72 hours of age, change to nutritive feeds * 30 ml/kg-d * ml every 3 hours and infused over 30 minutes using maternal breast milk supplemented by donor breast milk if needed. Advance feeding volume by *20 ml/kg-d* ml daily to maximum feeding volume *140-165 ml/kg-d* ml. Check with LIP prior to advancing feeds in infants with umbilical artery catheters in place or who are receiving dopamine. 3. Prolacta fortifier was added originally at 90 ml/kg-d without interrupting feeding advancement schedule Check and Adjustment Tacoma General NICU Ongoing monitoring of NEC cases and review of protocols in bundle have continued Changes included earlier and more aggressive Prolacta fortification to improve nutritional status. Currently Prolacta +6 is added at 50 ml/kg-d and +8 (for infants <=1000 grams at birth) at 90 ml/kg-d. Feeding tubes are changed less frequently (weekly) for the most immature infants. 70 Bed Level IV NICU Year <=1500 grams infants <=1000 gram infants 2014 135 70 2015 163 77 2016 126 56 2017 135 68 NEC Reduction Bundle Data Infants <=1500 grams Necrotizing Enterocolitis Cases 2016 Gestation BW Type Onset Age Comment 23 650 Surgical 20 24 752 Surgical 15 29 1539 Surgical 21 Transfer from referring hospital 21 days old 32 1745 Surgical 7 Transfer from referring hospital 7 days old 8
Necrotizing Enterocolitis Cases 2017 Conclusions Gestation Birth Wt Type 23 714 Surgical 8 23 580 Surgical 31 23 620 Surgical 53 Onset Age Notes 29 900 Surgical 2 Transfer from referring hospital for 2 nd NEC surgery DOL 8 37 3110 Surgical 9 Complex vascular anomalies and hydrops Tacoma General has been able to achieve a low incidence of necrotizing enterocolitis despite our population with an atypical number of extremely low birthweight infants Despite concentration of remaining cases in the highest risk tiny infants, occasional infants who are considered at low risk do develop NEC and vigilance is needed for all patients PSDA Quality Improvement Projects offer an excellent framework to approach difficult to solve problems 9