AVAILABLE KNOWLEDGE
Necrotizing enterocolitis (NEC) is an inflammatory gastrointestinal (GI) disease that is associated with high morbidity and mortality and high medical costs throughout life. Despite recent advances in neonatal care, there has been slow progress in the reduction of NEC cases. Reported rates range from 3% to 12%1-3 for mortality and 15% to 42% for mortality.2 Infants born below 1000 g birth weight (BW) are at highest risk, although approximately 7% to 15% of NEC cases occur in term or late preterm infants.4-7 Variations in regional demographics, specific unit practices, and perhaps unique local microbiomes contribute to varying prevalence between NICUs.2,3,5
The pathophysiology of NEC is complex and not well understood. Triggers of this inflammatory response include local gut ischemia, immature intestinal barrier function, and abnormal gut colonization. Introduction of a feeding substrate, especially non-human milk (HM), into the injured GI tract can trigger the cascade of events that defines NEC.3,5 Over the years, there is an increasing understanding of factors that contribute to and protect against GI inflammatory responses. This knowledge has been critical in identifying potentially modifiable risk factors over time.2,5-7
Extrauterine growth restriction (EUGR), traditionally defined as weight and head growth below the 10th percentile for expected growth at 36 weeks or at discharge, continues to be a significant problem. EUGR is associated with long-term neurodevelopmental deficits and long-term metabolic sequelae. Extremely preterm infants are at risk due to impaired placental nutrient transfer, insufficient nutrient intake, and increased metabolic needs with associated common comorbidities of prematurity.8-13 The American Academy of Pediatrics (AAP) recommends that extrauterine growth follow intrauterine growth trajectories, but it is still unclear what the optimal rate of growth should be for the most premature infants.8,12,14 Significant lags in weight, length, and head growth are associated with long-term nutritional deficits, decreased developmental scores, and increased risk of cerebral palsy.8,9,11 Reported rates of EUGR in very low birth-weight (VLBW) infants range from 36% to 79%,8,10,15,16 and many of these infants remain growth restricted at 2 years of age.8 Early aggressive nutritional support improves growth and may contribute to improved neurodevelopmental outcomes.9,11,13-15,17 Enteral nutrition is critical to optimizing growth, yet the characteristics of feeding substrates may contribute to NEC. It is important to recognize that feeding-associated NEC is triggered when developing enteral nutrition practices.
PROBLEM DESCRIPTION
The Total Preemie Nutrition (TPN) interdisciplinary quality improvement (QI) work group was formed in 2000 in the only level III regional referral center in Alaska. Because of its relative geographic isolation, the NICU has a strong cultural commitment to QI. The TPN work group has collegial representation from NICU stakeholders including bedside and advanced practice nurses, nursing leadership, neonatology, registered dietitians, and International Board of Lactation Consultant Examiners (IBLCE) certified lactation consultants. Various other NICU staff members have participated in specific projects over the years. This has allowed for a comprehensive approach to improvement work by tapping in on the expertise of each of these specialties.
The initial work of the TPN work group focused on standardizing enteral feeding practices. Standardization of care practices itself can improve outcomes by decreasing variation. Standardized evidence-based feeding protocols have been shown to decrease time to reach full-volume feedings, improve growth, and contribute to decreased risk of NEC.17-19
After extensive review of literature regarding timing of feeding introduction, rate of advancement, method of delivery, and use of fortification, the initial gestational age (GA)-based protocols were introduced in 2002. A standardized tool to help evaluate and manage signs of feeding intolerance was also implemented. Infants received both human milk-based (HMB) and bovine-based formula and fortification. Shortly after implementation, there was an improvement in growth.
In 2007-2008, there was an alarming rise in cases of NEC, defined as Bell stage IIA and above. Rates increased from a baseline of approximately 5% to more than 16%. Concurrently, there was an increase in NEC cases in infants more than 34 weeks' GA who traditionally are not thought to be at risk. The TPN work group redirected its focus to include NEC reduction. The work group adopted the informal name "TPN/NECZero" to communicate its combined focus on growth and NEC reduction.
SPECIFIC AIMS
The improvement in growth seen after the initial work of the TPN work group was exciting, but the concurrent rise in NEC cases was concerning. Recognizing that improvement does not happen in silos, the TPN work group and unit leaders strove to identify and address potentially contributing factors. The group initially focused on feeding practices along with the physical space of the NICU. Over time, work has expanded to other potentially modifiable risks. The aim has been to minimize incidence of NEC while supporting postnatal growth in the NICU. The ultimate goal is to achieve and maintain NECZero while optimizing postnatal growth outcomes.
LOCAL CONTEXT
The TPN work group has relied on the available but expanding evidence to identify best practices to lay foundations for improvement work. During the early work on NEC reduction, clinical leaders hosted several "fireside chats" in the NICU to get a better understanding of practice concerns. Information and insights gleaned from these casual conversations helped guide improvement work. A standardized tool was developed to critically review each NEC case (see Supplemental Digital Content Figure 1, available at: http://links.lww.com/ANC/A109). Every case of NEC has a concurrent interdisciplinary review. The tool allows the reviewer to identify specific perinatal and postnatal events that may contribute to gut ischemia. It also documents any clinical insights from all NICU staff members. Case summaries are then reviewed at interdisciplinary practice meetings. This tool has allowed for a safe, concurrent, and sustainable process for critical case reviews as well as identification of potential improvement opportunities.
EVALUATION OF IMPROVEMENT OVER TIME
This review highlights the practice changes that have contributed to significant and sustained reduction in NEC cases in one NICU while maintaining focus on growth and (HM) feedings. In addition, it illustrates the impact that a collaborative interdisciplinary work group can have while working in a supportive climate of change. Outcomes include local rates of NEC, growth at discharge, and sustained human milk feedings. Growth at discharge is defined as the percentage of infants discharged at weight less than 10th and 3rd percentiles for corrected age. Although the use of Z-score declines is now felt to be a more sensitive tool to evaluate growth and identify neonatal malnutrition,12,14 weight at discharge is used for consistency over time. Sustained HM feedings are reported as the percentage of infants discharged on a diet including mother's own milk (MOM). This approach allows for self-comparison over several years. Practice changes have often been implemented in bundles; therefore, the intent is not to measure the impact of individual changes but to highlight improvement over time. Timelines are used to help illustrate the impact of ongoing improvement work. These have been effective tools to map progress and redirect foci as needed. This review utilizes SQUIRE guidelines to highlight improvement work. Because the work has been done over 2 decades, practice changes are presented by theme rather than chronologically.
INTERVENTIONS/PRACTICE CHANGES
Feeding Practices
In response to the rise in NEC rates, especially in older preterm infants, feeding protocols were reviewed, with specific focus placed on the rate of feeding advancement and the use of bovine-based formula and fortification. Although there does not appear to be a direct association between rate of feeding advancement and NEC,20 the rate of advancement in infants more than 34 weeks' GA was slowed from 30 to 20 mL/kg/d to match that of younger infants. This change thoughtfully addressed concerns while maintaining a consistent and safe approach to feeding advancement. Protocols that slowed early feeding advancement for infants exposed to perinatal risks of NEC were reinforced. These include concerns for hypoxia, hypoperfusion, placental insufficiency, and other conditions that caused alterations in GI perfusion. These were dubbed the "at-risk" protocols (see Supplemental Digital Content Figure 2, available at: http://links.lww.com/ANC/A110).
Exclusive Human Milk Feedings in the NICU
The benefits of exclusive (HM) feedings are widely documented and include improved feeding tolerance, shorter time to full feedings, enhanced immunity, decreased infection, decreased respiratory illness, and improved long-term neurodevelopmental outcomes.21-25 Lactoferrin, oligosaccharides, secretory IgA, and other anti-inflammatory mediators found in a diet of MOM provide protection from NEC by preventing, mediating, and repairing bowel inflammation. These mediators are highly concentrated in the milk of mothers who have delivered prematurely, especially during the first postnatal weeks and there appears to be a dose-related effect for infants receiving greater than 50% of feedings with MOM.22,24 The immunoglobulin composition of HM will adapt to maternal pathogen exposure, which enhances the immunoprotective effects of MOM.26
There are challenges in providing an exclusive MOM diet in the NICU. At varying times during hospitalization, it is common that mothers are unable to provide the volume of milk needed to meet their infant's daily needs. Approximately 25% of infants in this NICU are air transported from remote Alaskan communities. During an infant's NICU stay, mothers often return to their villages to attend to other family responsibilities. Travel is predominantly by small aircraft due to the limited road systems in Alaska. Providing HM is therefore uniquely challenged. Supplementation with pasteurized donor milk (DM) is a better alternative to formula.26,27 The process of Holder pasteurization destroys many nutritional and immunosuppressive properties of HM, especially freshly expressed MOM.26 DM should be considered a supplement to, not a substitute for MOM.
Meeting the nutritional needs of VLBW infants is challenging, both during the acute and convalescing phases of NICU stay. Caloric and nutrient needs are high in order to support growth. The nutritional composition of MOM expressed after the first few weeks of life changes and often lacks the nutrient composition needed to meet the needs of preterm infants, especially the most premature infants.21,27 Fortification of both MOM and DM provides necessary nutrients and energy to help bridge that gap. Bovine-based preterm formulas and human milk fortifiers have historically been used to meet these needs. With growing evidence supporting use of HM diet, HMB fortifiers are now available options for fortification.23,27
During the rise in NEC cases, it became clear that the TPN work group should direct its focus toward promoting HM feedings. Lactation support increased and is now a collaboration between the NICU and maternal and infant services. DM was introduced in 2009 as a supplement to MOM supply for all infants less than 35 weeks' GA. This practice has expanded to include all gestations in the NICU. HMB fortifiers were introduced in 2012 for infants less than 1500 g BW. After an infant with gastroschisis developed NEC, pediatric surgery implemented an exclusive HM feeding protocol with standardized volume advancement.
With the introduction of DM to supplement mother's milk supply, there was a negative impact on sustained lactation and availability of MOM. This highlighted the importance of lactation support in the NICU. The work group recognized the need for better messaging about the physiologic importance of MOM by providers and staff to NICU families. An initiative to improve lactation was launched and included all mother-infant services. Parent volunteers added perspective to improvement work and helped provide education and support to families. Staff worked on processes to improve early lactation, with nurse assisted hand expression or pumping in labor and delivery. Early and frequent skin-to-skin holding sessions were promoted and barriers were addressed. Bedside nurses and respiratory therapists received training to provide safe transfers of critically ill ventilated infants.
Oral Immune Therapy
Colostrum contains enhanced immune properties derived from mother's circulation and is stimulated by mother's exposure to antigens. Oral immune therapy (OIT), providing drops of freshly expressed colostrum to the oral mucosa, stimulates the oropharyngeal associated lymphoid tissue system.22 This important system is bypassed in gavage feed infants. Although evidence remains inconclusive, OIT may contribute to improved feeding tolerance and protection from NEC by introducing milk biofactors into the oral mucosa.28-30 At best, though, OIT is well tolerated and the process of administration supports early lactation and parental involvement. Many centers have expanded this practice to using freshly expressed MOM until oral feedings are established. OIT was implemented in 2016. A fun rap style music video was made to promote staff awareness of the importance of OIT and early lactation support. When possible, hospitalized antenatal patients receive education on the importance of MOM and early expression, either manually or with hospital-grade pumps. The importance of MOM is reinforced during consults with neonatology. Newly delivered mothers are provided with a bag of supplies to begin colostrum collection. Fathers are engaged to help mothers establish consistent lactation practices, including early expression and delivery of colostrum for OIT. Parents are taught how to prepare and administer OIT. Parental involvement in OIT has been a positive reinforcement of the importance of colostrum and MOM in the medical management of infants.
Safe Storage of Human Milk
Efforts to improve availability of MOM included focusing on 2 processes that created barriers. These included protocols for storage of MOM and the practice of freezing MOM to reduce risk of acquired cytomegalovirus (CMV) infections in preterm infants. In early 2000, the NICU adopted the practice of freezing MOM for 72 hours to decrease CMV viral load for infants born less than 32 weeks' GA. CMV viral loads increase during pregnancy and lactation; therefore, HM is a common route for viral transmission, especially for infants born before 32 weeks' GA.31-33 Historically, the concern for systemic CMV infection prompted many centers to evaluate the safety of using freshly expressed MOM in preterm infants.
The TPN work group reevaluated the practice of freezing MOM. Review of literature highlighted the differences between congenital CMV and HM-acquired CMV illnesses. HM-acquired illness is usually mild and does not appear to contribute to long-term end-organ injury and neurodevelopmental sequelae associated with congenital infection.31-33 General consensus, including direction from the AAP,32 reinforce that the benefits of fresh MOM outweigh risk of acquired CMV illness.
The TPN work group also reviewed guidelines for refrigerator storage of freshly expressed MOM. Evidence supported the extension of refrigeration time, as there are not significant changes in milk composition or bacterial colony counts at 96 hours.34,35 New milk storage guidelines, reflective of these reviews, were implemented in 2018. New guidelines included elimination of routine freezing for reduction of CMV viral load and increasing refrigerator storage time to 96 hours. These changes increased the availability of freshly pumped MOM.
NICU Physical Space
At the time of the rise in NEC cases, the NICU was a 2-room open bay unit. It was built using available knowledge and standards for NICU design. It included elements thought to be neuroprotective including carpeting to decrease environmental noise. Limited bedside counter space was often crowded with diaper scales and other caregiving equipment. Milk preparation was completed at the bedside. There were communal sinks for washing equipment. Mothers pumped behind screens at the bedside and electric pumps were shared.
Some of the NEC cases seen in 2007-2008 occurred in the older infants who were established on full-volume fortified feedings. These infants often presented with fulminant sepsis and gut necrosis. Term infants who develop NEC often present early and timing is often associated with hypoxic or hypotensive events.8 This pattern was different. Clostridium perfringens and rotavirus organisms were identified in the stool cultures of several of these older infants. C perfringens is a gram-positive, rod-shaped, gas-producing anaerobic organism that forms spores.36-38 Spores can lay dormant for periods of time and then reactivate and multiply rapidly.36 They produce alpha toxin A, an enterotoxin that can cause profound gas gangrene in the bowel and portal air.36,37C perfringens-associated NEC presents with acute onset of symptoms with rapid progression of extensive bowel necrosis, coagulopathies, and shock.36,38,39 Mortality rates are reported to be as high as 44% to 80%.37,38
Information gathered from bedside chats in 2008-2009 directed the TPN work group focus on decreasing bedside clutter and contamination. Because of the personal commitment of a very engaged housekeeper, cleaning routines were optimized to effectively sanitize bedspaces with focus on C perfringens spores. Routine diaper weights were eliminated and beside scales removed. Carpeting was removed. A designated milk preparation area was created and staffed with technicians trained in the standards of aseptic milk preparation.40 Nurses raised concerns about the ability to maintain bedside cleanliness and patient separation during family visits with young siblings. The NICU visitation policy was changed to limit visitation of young siblings younger than 3 years. A new family health screening questionnaire was implemented, and families received education on the importance of deferring visits if family members were ill.
In 2013, the remodeled NICU opened. Lessons learned from several QI projects help guide the final design. It is now a 66-bed, single patient room unit, with living space for parents in each room. During design planning, care was taken to provide space and processes to decrease clutter and contamination throughout the unit. A hospital-grade breast pump is in each patient room and there is a defined process for cleaning and sterilizing individual pump supplies. Each room has its own refrigerator for infant feedings with guidelines posted on each refrigerator (Figure 1). Freshly expressed milk is initially stored in each infant's room. MOM is then delivered to a large 2-room milk preparation area where it is aseptically fortified, transferred to syringes for gavage administration, and then returned to infant rooms each day. This process is done by trained milk preparation technicians using current milk handling guidelines.41 Shortly after moving into the new unit, a NEC case review raised concern for how milk was warmed at the bedside. In 2014, waterless milk warmers were added to ensure safe handling of milk syringes throughout the entire feeding preparation process.35
Addressing Other Modifiable Risks
As a result of individualized NEC case reviews over the years, potentially modifiable risks were identified and practices were changed to address these risks. Some practice changes were hunches, others had evolving supporting evidence suggesting benefit, and some remain controversial. The TPN work group felt it was necessary to critically consider reasonable changes based on unit experiences.
In 2012, there were 2 cases of NEC presenting after red blood cell transfusion. The pathophysiology of transfusion-associated necrotizing enterocolitis (TANEC) is uncertain, but there are reports of NEC onset within 24 to 48 hours after transfusion. Theories include alterations in mesenteric blood flow, regional hypoxia, and regional inflammation.42-44 Withholding feedings around transfusions may reduce the impact of postprandial alterations in blood flow, which could be protective. Although the available evidence remains inconclusive,45,46 in 2012, the NICU adopted a protocol of gut rest around red blood cell transfusions.
High osmolar feedings can decrease GI motility and may contribute to feeding intolerance and possible gut injury including NEC.47,48 Osmolality of fortified feedings, both HM and formula, ranges from approximately 300 to 360 mOsmol/kg. The AAP recommends feeding osmolality to be no greater than 400 mOsmol/kg49; therefore, the addition of medications and other nutrients must be done with thoughtful caution. The osmolality of common enteral medications including electrolyte supplements and vitamins range from 85 to 8512 mOsmol/kg48; therefore, addition of medications into feedings can increase the osmolality above AAP recommendations.47-49 The practice of spacing enteral medications was introduced in late 2012 after a NEC review noted onset of symptoms 24 hours after introducing multivitamins in an infant who was otherwise receiving exclusive HM feedings. Pharmacists and dietitians continue to look at osmolality when introducing new medications. If considered high, alternative therapies are considered.
Altered gut biome contributes to the pathogenesis of NEC. Probiotic administration has been associated with a decrease in NEC. Outcome data for use of probiotics remain inconclusive, mostly due to inconsistencies in dosing and preparations.50,51 The evidence suggests benefits to NEC reduction in preterm infants.52,53 Probiotics were introduced in unit practice in 2018. Practice guidelines to decrease antibiotic exposure were implemented in 2018. Use of H2-blockers alters the biome of the GI tract. Although use is low, there are specific "stop" dates added during the ordering process to proactively manage duration of therapy.
Balancing NEC Work With Growth Outcomes
After the initial feeding protocol changes were made in response to feeding-related triggers for NEC, there was a reduction in NEC cases. Concurrently, there was a negative impact on growth outcomes. After a 7-year period of improved growth, more infants were discharged with anthropometric measurements below the 10th and 3rd percentile. In 2012, 52.5% of VLBW infants were discharged at weights below 10th percentile for age compared with 28.7% in 2008. The TPN work group took this as an opportunity to evaluate feeding practices while concurrently addressing growth and NEC risks.
Early NEC work fostered a strong commitment to maintain HM diet until 34 weeks postmenstrual age (PMA). It was clear that delays in fortification of human milk contributed to the decline in growth outcomes. In 2012, NICU leaders obtained institutional support to introduce HMB fortifiers for infants less than 1500 g BW. This allowed for HM-fortified feedings until 34 weeks PMA while delaying introduction of bovine-based products until the GI tract was more mature. By reviewing outcomes annually, the protocols have been adapted and include earlier fortification with HMB fortifiers, and earlier transition to bovine-based products. These changes have allowed for improved growth while balancing NEC outcomes and maintaining institutional financial stewardship.
Other feeding practice changes were made in 2017. These include changing feeding administration from intermittent drip to bolus to minimize nutrient loss through feeding administration, implementation of updated protocols on feeding tube care,35 and routine sodium chloride supplementation to prevent late-onset hyponatremia. Renal sodium losses in preterm infants can contribute to hyponatremia and poor growth.54 In 2018, guaranteed 22 and 24 calorie per ounce DM became available for VLBW infants who require more than 50% supplementation of daily feedings with DM. The dietitian role has been formally expanded to include daily presence in bedside rounds. Dietitians provide ongoing growth and nutritional assessments and make recommendations for diet changes based on growth and tolerance.
LOCAL FINDINGS
Over the 20-year journey of the TPN QI work group, many practice changes have been made to decrease NEC while maintaining a focus on growth. Initial work on standardizing feeding protocols was initiated in 2001. Group focus expanded to NEC beginning 2007-2008 when rates increased to 16.2% in VLBW infants along with a concurrent rise in the number of older infants developing NEC. In the prior 5 years, the average rate was 5.1%, with annual incidence ranging from 3.9% to 7.8%. Initial work focusing on NEC reduction included increasing availability of HM feedings, improving feeding preparation processes, and decreasing contamination in our physical space. Initiatives were frequently introduced in bundles. NEC rates decreased over the next 2 years to 7.9% in 2009 and there continued to be a sustained decline over the next several years. In November 2018, NECZero was achieved in inborn infants. This success has continued into the second quarter of 2021.
In 2000, approximately 78% of VLBW infants had discharge weights that were below the 10th percentile for GA and approximately 50% of VLBW infants had discharge weights below the 3rd percentile. These remained relatively constant until 2004, 2 years after implementing the first feeding protocols. Growth outcomes then improved. In 2008, 28.7% and 14.9% of VLBW infants were discharged at weights below the 10th percentile and 3rd percentile, respectively. Trends for head growth at discharge (occipital frontal circumference) in VLBW infants showed similar trends. After introduction of feeding practices to address NEC, this trend reversed. More infants were discharged with anthropometric measurements consistent with growth restriction. In 2013, 54.2% and 26.5% of VLBW infants were discharged with weights below the 10th percentile and 3rd percentile, respectively. NEC rates continued to decline, but growth outcomes prompted cautious reevaluation of feeding practices that limited the availability and fortification of a HM diet. Expansion of the dietitian role provided consistent assessment of individual growth. Growth outcomes improved and are now consistent with other NICUs, but they have not returned to the patterns seen in 2008 (Figure 2). The use of HMB fortifiers has contributed to the improvement in growth and has allowed for delayed introduction of bovine based fortification. The TPN work group recognizes the cost associated with HMB fortifiers. Recent changes in protocols that support earlier transition to bovine products have decreased their financial impact by 25% without increasing the incidence of NEC.
It is difficult to accurately measure impact of lactation support in the NICU. HM feedings at discharge is a relatively indirect assessment that has been used over time. Most VLBW infants require fortification of MOM; therefore, it is uncommon that this group of infants is discharged on exclusive MOM feedings. Over the last 20 years, the percentage of infants discharged on any HM has remained relatively constant, with a median of 53.7%. Between years 2008 and 2014, there was a consistent decline, with a nadir of 38.9% in 2011. It was felt that the availability of DBM may have contributed to decreased lactation. After implementation of institutional practice changes to support lactation, rates have improved. In 2016, 67.8% of VLBW infants were discharged on a diet including HM and currently 71% of infants are being discharged on HMB feedings.
The focused work on early and sustained lactation has improved availability of fresh MOM feedings throughout hospitalization. One former member reminds us that recognition of MOM as the preferred milk in the NICU was the keystone intervention that drove our practice. Supporting mothers to provide milk at the bedside led to an array of practices that made the critical difference both in reducing gut infection and in improving the health and well-being of NICU infants overall.
DISCUSSION
NEC remains a devastating disease with high mortality and long-term morbidity. Using principles of QI, the TPN work group addressed these risks in the context of a single NICU setting. The team tapped into the uniquely creative thoughts and perspectives of each team member and worked to engage participation and buy-in of staff and families. Early work on improved HM feedings and environmental changes made a dramatic impact on NEC rates. Ongoing work, often identified after focused NEC reviews, contributed to the sustained reduction in NEC cases (Table 1). PDSA (Plan-Do-Study-Act) cycles of change and driver diagrams were used to guide work. Our experiences highlight the fact that QI does not happen in silos. Using the same principles of improvement, cautious changes in feeding practices were implemented to address growth while sustaining progress toward elimination of NEC (Figure 3).
There are many opportunities for ongoing outcome improvement. It is important to be aware of unintended consequences of specific practice changes and to remain focused on composite outcomes. We need to improve programs focused on sustained lactation in the NICU to ensure a diet of MOM through discharge. There are better ways to assess growth using neonatal malnutrition indicators. As care practices in the NICU evolve, it is important to recognize the impact of specific interventions on the infant overall. Recently noninvasive respiratory support has decreased ventilator days, but there is a growing concern about the effect of "CPAP belly" on the maturing GI tract. Does gaseous distension from swallowed air alter mesenteric blood flow or affect bowel absorption and motility? Knowledge grows from all caregivers asking critical questions and exploring solutions. Collegial participation from bedside stakeholders is critical. Finally, QI is a continuous journey. Use of a historical perspective and an evolving scientific understanding can guide ongoing improvement in local settings.
References