Elevated fecal calprotectin levels during necrotizing enterocolitis are associated with activated neutrophils extruding neutrophil extracellular traps.

OBJECTIVE: Neonates with necrotizing enterocolitis (NEC) have higher calprotectin levels in stool than do healthy neonates. However, it is not known whether high stool calprotectin at the onset of bowel symptoms identifies neonates who truly have NEC vs other bowel disorders. STUDY DESIGN: Neonates were eligible for this study when an x-ray was ordered to 'rule-out NEC'. Stool calprotectin was quantified at that time and in a follow-up stool. Each episode was later categorized as NEC or not NEC. The location of calprotectin in the bowel was determined by immunohistochemistry. RESULTS: Neonates with NEC had higher initial and follow-up stool calprotectin levels than did neonates without NEC. Calprotectin in bowel from neonates with NEC was within neutrophil extracellular traps (NETs). CONCLUSION: At the onset of signs concerning for NEC, fecal calprotectin is likely to be higher in neonates with NEC. Calprotectin in their stools is exported from neutrophils via NETs.

End-tidal carbon monoxide as an indicator of the hemolytic rate.

In the first days of life, low grade jaundice is essentially universal. The source of the elevated bilirubin level giving rise to "physiological jaundice of the newborn" is only partly known. We hypothesized that it is, at least in part, the result of active and specific hemolysis involving a physiological mechanism to lower the high fetal hematocrit, appropriate for the relatively low oxygen environment in utero, to a lower level appropriate for the state of oxygen abundance after birth. We tested this by quantifying end tidal carbon monoxide (ETCO) as a marker of the rate of heme metabolism to bilirubin. We found that ETCO values of 20 neonates and children with known hemolytic disorders were higher than 20 age-matched healthy controls (p<0.0001), indicating that this instrumentation recognizes hemolysis in neonates and children. We also found that ETCO reference intervals were indeed higher in healthy neonates during the first three days after birth (5th to 95th percentile reference range, 1.4 to 1.7ppm) than after 1month of age (all ≤1.0ppm, p<0.0001). These results suggest to us that hemolysis is physiological during the first days after birth. The cellular and molecular mechanisms responsible for transient hemolysis after birth are topics of current investigation.

Why do four NICUs using identical RBC transfusion guidelines have different gestational age-adjusted RBC transfusion rates?

OBJECTIVE: To compare neonatal red blood cell (RBC) transfusion rates in four large Intermountain Healthcare NICUs, all of which adhere to the same RBC transfusion guidelines. STUDY DESIGN: This retrospective analysis was part of a transfusion-management quality-improvement project. De-identified data included RBC transfusions, clinical and laboratory findings, the anemia-prevention strategies in place in each NICU, and specific costs and outcomes. RESULT: Of 2389 NICU RBC transfusions given during the 4-year period studied, 98.9 ± 2.1% (mean ± S.D.) were compliant with our transfusion guidelines, with no difference in compliance between any of the four NICUs. However, RBC transfusion rates varied widely between the four, with averages ranging from 4.6 transfusions/1000 NICU days to 21.7/1000 NICU days (P < 0.00001). Gestational age-adjusted transfusion rates were correspondingly discordant (P < 0.00001). The lower-transfusing NICUs had written anemia-preventing guidelines, such as umbilical cord milking at very low birth weight delivery, use of cord blood for admission laboratory studies, and darbepoetin dosing for selected neonates. Rates of Bell stage ⩾ 2 necrotizing enterocolitis and grade ⩾ 3 intraventricular hemorrhage were lowest in the two lower-transfusing NICUs (P < 0.0002 and P < 0.0016). Average pharmacy costs for darbepoetin were $84/dose, with an average pharmacy cost of $269 per transfusion averted. With a cost of $900/RBC transfusion, the anemia-preventing strategies resulted in an estimated cost savings to Intermountain Healthcare of about $6970 per 1000 NICU days, or about $282,300 annually. CONCLUSION: Using transfusion guidelines has been shown previously to reduce practice variability, lower transfusion rates and diminish transfusion costs. Based on our present findings, we maintain that even when transfusion guidelines are in place and adhered to rigorously, RBC transfusion rates are reduced further if anemia-preventing strategies are also in place.

Estimating the nucleated red blood cell 'emergence time' in neonates.

OBJECTIVE: The time between onset of fetal hypoxia and first appearance of nucleated red blood cells (NRBCs) in the blood can conceptually be divided into two periods; (1) the 'erythropoietin (EPO) generation time', which previous fetal studies suggest is 4 to 5 h, and (2) the 'NRBC emergence time'. In this study, we estimated the latter as the time required for NRBC to appear in the blood after administering a dose of recombinant EPO. STUDY DESIGN: This was a retrospective analysis of data from a multihospital healthcare system (Intermountain Healthcare). Data were included only for neonates born ≥34 weeks gestation between the dates 1 January 2005 and 31 October 2012 and only if they received a dose of darbepoetin during their neonatal intensive care unit stay and had one or more complete blood cell counts (CBCs) obtained during the 3-day period before the dose was given and one or more CBCs in the 7-day period after the dose. RESULT: The study involved 31 neonates who received 34 doses of darbepoetin. Seven doses were 4 µg kg(-1) and twenty-seven doses were 10 µg kg(-1). Twenty-six CBCs were obtained during the 24-h period following the darbepoetin dose and none had NRBC identified. NRBC first appeared in the blood between 24 and 36 h after the dose. Recipients of the higher dose generally had a higher peak NRBC count but the NRBC 'emergence time' did not appear to depend on dose. CONCLUSION: Following fetal hypoxia, transcription and translation of the EPO gene result in an elevation in plasma EPO concentration. Previous fetal studies suggest this process requires 4 to 5 h. The present studies suggest that, following the increase in plasma EPO, NRBC emerge into the circulation in ≥24 h. If this model serves as a reasonable estimate, it suggests that neonates with an elevated NRBC count at birth had the onset of hypoxia at least 28 to 29 h before birth.

Using umbilical cord blood for the initial blood tests of VLBW neonates results in higher hemoglobin and fewer RBC transfusions.

OBJECTIVE: We previously described a method for reducing early phlebotomy losses from very low birth weight (VLBW) neonates by obtaining the initial blood tests from otherwise discarded fetal blood from the placenta. In the present study we sought to; (1) measure the feasibility of performing this method in actual practice, (2) test the hypothesis that this method would result in higher hemoglobin concentrations and lower erythrocyte transfusion rates in the first week after birth. METHODS: We conducted two studies in three Intermountain Healthcare NICUs. The first was a feasibility analysis involving 96 VLBW neonates, measuring the success of obtaining the NICU admission laboratory blood tests this way. The second study used case-control methodology to test the hypothesis that this method would result in a higher blood hemoglobin 12 to 24 h after birth, and a lower proportion receiving an erythrocyte transfusion in the first week. RESULT: In 91 of 96 VLBW neonates (95%) the initial blood tests were successfully obtained with this method. The success rate was not diminished by delayed cord clamping or cord milking, as it was successful in 35 of 36 (97%) such instances. Cases and controls were well matched on demographic and level of illness comparisons. Among cases the hemoglobin generally increased between birth and 12 to 24 h later, but among controls the hemoglobin generally decreased (P<0.05). In the week following birth fewer cases received vasopressors (P<0.01) and erythrocyte transfusions (P<0.001). CONCLUSION: We judge that it is feasible to collect the initial blood tests of VLBW neonates using otherwise discarded umbilical cord/placental blood, in that this can be accomplished in about 95% of VLBW deliveries. This method, which can be used in addition to either delayed clamping of the umbilical cord or cord milking, results in higher hemoglobin concentrations, less vasopressor use and fewer transfusions in the first week.

Severe neonatal anemia from fetomaternal hemorrhage: report from a multihospital health-care system.

OBJECTIVE: The incidence of fetomaternal hemorrhage that is severe enough to cause neonatal anemia is not known. Owing to its relative rarity, much of the literature describing this condition is in the form of case reports and small case series. We performed a large, muiticentered, sequential, case series to determine the incidence, antecedents and outcomes. STUDY DESIGN: From the multicentered databases of Intermountain Healthcare, we obtained records of all neonates with hematocrit (Hct) <30% or hemoglobin (Hgb) <10 g dl(-1) on the day of birth, who had Kleihauer-Betke staining or flow cytometric evidence of fetomaternal hemorrhage. RESULT: Among 219,853 live births, 24 had anemia with evidence of fetomaternal hemorrhage (incidence estimate, 1 per 9160 live births). The initial Hgb ranged from 1.4 to 10.2 g dl(-1) (Hct 29.8%). The initial Hgb was <7 g dl(-1) in 18 (67%), <5 g dl(-1) in 12 (50%) and was <3 g dl(-1) in 7 (29%). All 7 mothers in whom neonatal Hgb was <3 g dl(-1) had reported absent fetal movement, as did 13 of 18 mothers when the initial Hgb was <7 g dl(-1). Outcomes were poorer in those with the lowest initial Hgb; in the two lowest, one died on day 1, and the other developed a grade 4 intraventricular hemorrhage (IVH). The adverse outcomes of death, IVH, periventricular leukomalacia, bronchopulmonary dysplasia or hypoxic-ischemic encephalopathy were common; occurring in 71% (17 of the 24), including all with an initial Hgb <5 g dl(-1) and all born at ≤35 weeks of gestation. CONCLUSION: Fetomaternal hemorrhage is a rare but sometimes devastating condition. Those with fetomaternal hemorrhage and an initial Hgb of <5 g dl(-1) are expected to need resuscitation at birth, to receive emergent transfusion support and to be at risk for death and major morbidities. Antenatal suspicion of this diagnosis should occur when absent fetal movement is reported. Improvements in rapid diagnosis are needed to prepare first responders and transfusion services.

Neonates presenting with bloody stools and eosinophilia can progress to two different types of necrotizing enterocolitis.

OBJECTIVE: We hypothesized that neonates with bloody stools and concomitant eosinophilia are likely to have atopic enteropathy rather than necrotizing enterocolitis (NEC). STUDY DESIGN: This was a retrospective cross-sectional study using electronic medical records and paper charts. Records of neonates admitted to any Intermountain Healthcare NICU between 1 January 2005 and 30 June 2010 were eligible if 'bloody stools' were listed in any archive. Qualifying records were divided into two groups depending on whether or not within 72 h of passing bloody stool eosinophil counts were above the 95th percentile reference range limit for age. RESULT: Bloody stools were identified in 275 predominantly Caucasian neonates. Fifty-four of these had eosinophilia and 221 had normal eosinophil counts. Those with eosinophilia were born at a slightly younger gestational age (31.3 ± 4.6 vs 32.6 ± 4.0 weeks, mean ± s.d., P=0.032). Contrary to our hypothesis, those with eosinophilia did not have a lower rate of pneumatosis or bowel resection, or death ascribed to NEC. Eosinophilia was more common among those who had a red blood cell (RBC) transfusion within 48 h before passing bloody stools (P<0.001). Those with a recent RBC transfusion were the only neonates to have NEC surgery or to die from NEC. Preceding the bloody stools, those with no antecedent transfusion had been fed a larger volume (P=0.014), and had trends toward receiving calorically enriched feedings (P=0.055) and recent addition of human milk fortifier (P=0.060). Eosinophil counts following RBC transfusion tended to increase for 3-6 days, but when bloody stools were not preceded by transfusion the eosinophil counts were more static over that period. CONCLUSION: In this predominantly Caucasian group of neonates with bloody stools, the presence of eosinophilia did not identify a benign condition distinct from NEC. A total of 44% of these neonates had transfusion-associated NEC. Eosinophils could have a previously unrecognized role in the pathogenesis of this NEC subtype.

Fulminant necrotizing enterocolitis in a multihospital healthcare system.

OBJECTIVE: A subset of necrotizing enterocolitis (NEC) cases is fulminant, characterized by rapid progression to death with massive bowel necrosis found at laparotomy or autopsy. We sought to identify and report all such cases in a multihospital healthcare system during the past 9 years and to characterize this entity using case-control methodologies. STUDY DESIGN: This was a multicentered, cross-sectional, historic cohort study conducted using Intermountain Healthcare hospital patient data. All neonates who died of NEC within 48 h of onset, during 2001 to 2009, were compared with two matched control groups: (1) demographically matched controls who developed non-fulminant NEC, (2) demographically matched controls that did not develop NEC. RESULT: During this period, 2 71 327 live births occurred in the Intermountain Healthcare hospitals. Of these, 318 had a diagnosis of NEC (Bell stage ≥II). Also during this period, 205 other neonates were transferred into an Intermountain hospital for treatment of NEC. Of these 523 NEC cases, 35 (6.7%) had a fulminant course. Compared with the non-fulminant cases, the fulminant group were born at lower weight (1088±545 vs 1652±817 g, P=0.000) and earlier gestational age (27.5±3.3 vs 31.1±4.4 weeks, P=0.000), and were more likely to have: (1) radiographic evidence of portal venous air (P=0.000), (2) hematocrit <22% (P=0.000), (3) increase in feeding volume >20 ml/kg/day (P=0.003), (4) immature to total (I/T) neutrophil ratio >0.5 (P=0.005), (5) blood lymphocyte count <4000/µl (P=0.018), (6) an increase in concentration of human milk fortifier within 48 h before developing NEC (P=0.020). CONCLUSION: Portal venous air, anemia, rapid feeding escalation, a high I/T neutrophil ratio, a low lymphocyte count and recent increases in fortifier may all be associated with fulminant NEC.

Effect of ampicillin on bleeding time in very low birth-weight neonates during the first week after birth.

OBJECTIVE: On the day of birth, the bleeding time of very low birth-weight (VLBW, <1500 g) neonates is generally prolonged, compared with term neonates. However, their bleeding time generally improves (shortens) over the next 7 to 10 days. Ampicillin can prolong the bleeding times of term and late preterm neonates, but its effect on VLBW neonates, who already have a somewhat prolonged bleeding time initially, is not known. STUDY DESIGN: This was a prospective, single-centered, paired, before vs after test of the effect of ampicillin on template bleeding time and PFA-100 time (platelet function analyzer). Ampicillin was dosed at every 12 h intravenously, but decisions about discontinuation were made by the responsible clinician, independent of this study. RESULT: A total of 20 VLBW neonates were studied. They ranged from 23- to 30-weeks gestation at birth and weighed 500 t 1410 g. Initial bleeding times averaged 166 s (95% CI, 138 to 194) and initial PFA-100 times averaged 119 s (95% CI, 90 to 148). In all, 10 had ampicillin dosing stopped after a shorter course (4 to 7 doses) and 10 had it continued for a longer course (10 to 15 doses). Blood cultures were sterile in all 20, and no differences in laboratory or clinical features were found between those treated with a shorter vs longer course. After stopping the ampicillin following a short course the bleeding times and PFA-100 times were similar to the initial values. However, after a longer course the bleeding times were prolonged by an average of 2 min, to 284 s (95% CI, 242 to 326; P=0.001 vs initial). The PFA-100 times also trended longer by an average of 44 s (P=0.07). The number of doses of ampicillin received in the first week correlated with the degree of prolongation in bleeding time (r=0.68). CONCLUSION: Over the first week of life, a period when the bleeding time of VLBW neonates normally shortens, the opposite occurred (the bleeding time lengthened) if ≥ 10 doses of ampicillin were administered.

Very low birth weight infants qualifying for a 'late' erythrocyte transfusion: does giving darbepoetin along with the transfusion counteract the transfusion's erythropoietic suppression?

OBJECTIVE: Red blood cell (RBC) transfusions can suppress erythropoiesis. On this basis, RBC transfusions administered to very low birth weight (VLBW) neonates potentially render them more likely to qualify for a subsequent transfusion. STUDY DESIGN: We hypothesized that 'late' (>14 days after birth) RBC transfusions given to VLBW neonates result in a decrease in reticulocyte count persisting for at least 7 to 10 days. We also hypothesized that a single dose of darbepoetin given along with the transfusion would have the opposite effect, increasing the reticulocyte count for at least 7 to 10 days. To test this, we conducted a single-centered randomized trial with 20 VLBW neonates who, according to our transfusion guidelines, qualified for a late transfusion. RESULT: VLBW infants about to receive a late RBC transfusion were randomized (1:1) to also receive vs not receive (controls) a single subcutaneous dose of darbepoetin (10 µg kg(-1)). Reticulocyte counts diminished significantly in the controls (a drop of 85±62 × 10(3) µl(-1) (mean±s.d.) at 7 to 10 days), but increased significantly in the darbepoetin recipients (an increase of 177±120 × 10(3) µl(-1) at 7 to 10 days, P<0.0001). At 7 to 10 days after the transfusion, hematocrits of the controls were 8.1±4.9 points above their pre-transfusion values and of the darbepoetin group were 12.4±2.7 points above their pre-transfusion values (P=0.033). CONCLUSION: This was a limited-scope, single-centered, randomized trial intended to pilot-test a new concept in neonatal transfusion practice. Namely, we tested whether a late RBC transfusion suppressed reticulocytosis and whether a concomitant single dose of darbepoetin counteracted that suppression. Using the pilot data presented in this study, larger trials can now be designed to address meaningful clinical outcomes such as transfusion avoidance using this approach.

Effect of ampicillin on the bleeding time of neonatal intensive care unit patients.

OBJECTIVE: Studies in adults indicate that ampicillin, in a dose-dependent manner, impairs platelet function and moderately prolongs the bleeding time (generally by 60 to 90 s). Unlike aspirin, the inhibition induced by ampicillin involves both reversible and irreversible mechanisms and is not observed immediately after initial dosing (generally requiring approximately 24 h). Ampicillin is administered commonly to neonatal intensive care unit (NICU) patients, but its effect on bleeding time in this population has not been reported earlier. STUDY DESIGN: We performed neonatal template bleeding times and platelet function analyzer (PFA)-100 tests on 15 NICU patients before and at various intervals after intravenous ampicillin dosing. RESULT: Neonates were only studied if no beta-lactam antibiotics were administered to their mother during labor, and if they had ampicillin ordered by the clinician at a dose of 50 to 100 mg kg(-1) every 12 h. Subjects ranged from 33 to 41 weeks gestation and weighed 1760 to 3835 g. Bleeding times before the first ampicillin dose (n=15) averaged 134 s (95% confidence interval (CI), 120 to 148 s) and PFA-100 times averaged 123 s (95% CI, 96 to 149 s). After the first dose of ampicillin (n=5), bleeding times and PFA-100 times did not increase, but after the third (n=5) and fourth doses (n=4) bleeding times lengthened by an average of 60 s (95% CI, 37 to 83 s, P<0.001) and PFA-100 times lengthened by an average of 20 s (95% CI, -20 to 60 s, P=0.15). CONCLUSION: Ampicillin administered intravenously to NICU patients prolongs the bleeding time, with a magnitude-of-effect and time-to-effect similar to that shown earlier in adults.

Antecedents of Bell stage III necrotizing enterocolitis.

OBJECTIVE: New biopharmaceuticals hold promise for preventing or treating necrotizing enterocolitis. However, it is unclear whether any such biopharmaceutical that requires enteral administration could be administered using an 'early-treatment' paradigm. This study was undertaken to assess this issue based on data from every case of Bell stage III NEC cared for during the past 7 years at Intermountain Healthcare. STUDY DESIGN: Patients with Bell stage III NEC were identified from electronic medical record repositories and the diagnosis was validated using operative reports. Electronic and paper records of each patient were then used to identify potential clinical and laboratory antecedents occurring within the 48 h period preceding the diagnosis of NEC. RESULT: One hundred eighteen patients had Stage III NEC. The earliest recognized antecedents were nonspecific for NEC (apnea/bradycardia, skin mottling and irritability). These were recorded at 2.8+/-2.1, 4.5+/-3.1 and 5.4+/-3.7 (mean+/-s.d.) hours, respectively, before NEC was diagnosed. The most commonly identified gastrointestinal antecedents were blood in the stools, increased abdominal girth and elevated pre-feeding gastric residuals or emesis. These were identified 2.0+/-1.9, 2.8+/-3.1 and 4.9+/-4.0 h before NEC was recognized. Thirty-eight percent had a blood transfusion (18+/-12 h) preceding the NEC. Tachycardia, tachypnea, hypotension and diarrhea were rarely identified as antecedents and no consistent laboratory antecedents were discovered. CONCLUSION: We judge that an 'early treatment of NEC' paradigm testing any pharmacological agent that must be administered enterally is not feasible. The first recognized antecedents of Bell stage III NEC are nonspecific for gastrointestinal pathology and insufficient time exists for dosing between the first gastrointestinal signs and placement of the gastric decompression tube.

Ibuprofen lysine administration to neonates with a patent ductus arteriosus: effect on platelet plug formation assessed by in vivo and in vitro measurements.

OBJECTIVE: Ibuprofen might have advantages over indomethacin, when used to effectuate closure of a neonate's patent ductus arteriosus (PDA). Several previous studies indicate that platelet plug formation is impaired after administration of indomethacin, but it is not clear whether a similar impairment occurs following ibuprofen dosing. STUDY DESIGN: We performed template bleeding times and PFA-100 tests (platelet function analyzer) on 20 neonates who had a PDA, before and again at various preset intervals following ibuprofen dosing. RESULT: Patients ranged from 23 to 40 weeks gestation and weighed 511 to 2566 g. Their first dose of ibuprofen was administered at 72 h (18 to 363 h) after birth (median, range). None of the subjects had clinical bleeding problems noted during the days they received ibuprofen dosing. The template bleeding times before dosing ranged from 135 to 450 s. Repeat tests were performed in groups of four, at 2 h, 4 to 6 h, 12 to 18 h, 24 h after the first dose, and at 2 h after the third dose of ibuprofen. No changes in bleeding times were detected. (P=0.299) A PFA-100 time was performed on all 20 patients before and again after the ibuprofen administration. However, 3 of the 40 tests were unsuccessful, because of microclots in the blood sample (n=1) or failure of the analyzer for an unspecified reason (n=2). Before the dosing the PFA-100 time ranged from 52 to 300 s. A paired t-test showed a slight but statistically significant lengthening in PFA-100 time after the ibuprofen administration (P=0.019). The correlation between the bleeding time and the PFA-100 was poor (R(2)=0.212, P=0.576). CONCLUSION: On the basis of our present studies, we speculate that ibuprofen lysine administration to neonates with a PDA, when used according to the manufacturer's recommendations, has little adverse effect on platelet plug formation. This information might be a factor to consider when deciding whether to select indomethacin or ibuprofen for PDA closure.

Using umbilical cord tissue to detect fetal exposure to illicit drugs: a multicentered study in Utah and New Jersey.

OBJECTIVE: We assessed umbilical cord tissue as a means of detecting fetal exposure to five classes of drugs of abuse. STUDY DESIGN: In a multicentered study in Utah and New Jersey, we collected umbilical cord tissue when high-risk criteria were met for maternal illicit drug use. The deidentified umbilical cord specimens were analyzed for five drug classes: methamphetamine, opiates, cocaine, cannabinoids and phencyclidine. For each umbilical cord specimen, an enzyme-linked immunosorbent assay (ELISA)-based screening test was compared with a 'gold standard' test, consisting of gas or liquid chromatography tandem mass spectrometry. RESULT: A total of 498 umbilical cord samples were analyzed of which 157 (32%) were positive using mass spectrometric detection. The sensitivity and specificity of the ELISA-based test for each class of drugs tested were as follows: methamphetamine 97 and 97%, opiates 90 and 98%, cocaine 90 and 100%, cannabinoids 96 and 98% and phencyclidine (only 1 of the 498 umbilical cord sample was positive for phencyclidine) 100 and 100%. CONCLUSION: We judge that the performances of the ELISA-based tests are sufficient for clinical testing of fetal exposure to methamphetamine, opiates, cocaine and cannabinoids. Studies obtained on umbilical cord tissue can result in a more rapid return to the clinician than meconium testing, because waiting for meconium to be passed sometimes requires many days. Moreover, in some cases the meconium is passed in utero making collection impossible, whereas umbilical cord tissue should always be available for drug testing.

Necrotizing enterocolitis during the first week of life: a multicentered case-control and cohort comparison study.

OBJECTIVE: Necrotizing enterocolitis (NEC) is rare during the first week of life; most cases occur after 2 to 4 weeks. We hypothesized that when NEC develops in the first week, certain predisposing factors and feeding practices are identifiable. To test this, we sought to identify every case of NEC diagnosed during the first week within the Intermountain Healthcare system during the most recent 6-year period. STUDY DESIGN: Data were collected from neonates admitted to any Intermountain Healthcare neonatal intensive care unit (NICU) with a date of birth from 1 January 2001 through 31 December 2006. Electronic and paper records were obtained for all with a diagnosis of NEC (Bell stage >or=II) within the first 168 h. X-rays, physician notes, nursing records, laboratory reports and operative reports were subjected to critical review to reexamine the diagnosis of NEC. Among those with confirmed NEC, we recorded underlying conditions and every feeding given prior to the diagnosis of NEC. Comparisons were made with patients that did not develop NEC, yet were cared for in the same NICUs, during the same period of time, and of the same gestational ages. RESULT: A total of 28 neonates were identified electronically as having NEC during the first week. Critical review confirmed this in 21, but 5 were determined at laparotomy to have had spontaneous intestinal perforation, and 2 others were found on surgical reports to have had a congenital infarction of the colon. Total 20 of the 21 confirmed cases developed NEC while in a NICU being treated for another condition. The exception was a small-for-gestational-age neonate in a well baby nursery. Compared to 6100 controls, the 21 with early NEC were more likely to have had a meconium-positive test for illicit drug exposure (P<0.005), early onset sepsis (P<0.034) and respiratory distress (P<0.039). They were less likely than case-controls to have been fed human milk (P=0.003) and were more likely to have been fed formula exclusively (P=0.019). None who were fed human milk exclusively developed early NEC. Twelve of the twenty-one were fed (by gavage or bottle) amounts exceeding the upper limit of volumes taken by breastfed neonates. CONCLUSION: We speculate that the prevalence of NEC during the first week could be reduced by identifying at-risk patients, feeding them human milk exclusively for the first week and using feeding volumes that do not exceed that taken by healthy breastfed neonates.

Adherence to NICU transfusion guidelines: data from a multihospital healthcare system.

OBJECTIVE: We critically reviewed every NICU blood component transfusion (packed erythrocytes, platelets, frozen plasma (FP) and cryoprecipitate) administered during a one-year period. This was done to determine the proportion of transfusions given out of compliance with the Intermountain Healthcare transfusion guidelines, and to look for patterns of non-compliance that could be addressed by quality improvement measures. STUDY DESIGN: A detailed review was made of every transfusion administered to patients with a date of birth of 1 January 2006 through 31 December 2006, in any of three level III, perinatal-center-associated NICUs within Intermountain Healthcare. RESULT: During 2006 the three NICUs cared for 1759 neonates. Seventeen percent of these received one or more (median 3) erythrocyte transfusions, 4% received one or more (median 3) platelet transfusions, 6% received one or more (median 1) FP infusions and 2% received cryoprecipitate (median 1 dose). Seventy percent of the erythrocyte transfusions were given in compliance with the guidelines, as were 69% of the platelet transfusions, 65% of the FP transfusions and 94% of the cryoprecipitate administrations. Patients who received large numbers of transfusions were more likely to receive transfusion that violated the guidelines. Forty-five percent of patients who received 1 to 3 transfusions received all transfusions within guidelines. However, only 18% of patients who received 4 to 10 transfusions received all within guidelines. No patient who received >10 transfusions received all within the guidelines. Erythrocyte transfusions given early in the hospital course were likely to be within guidelines; 72% (588/818) in the first 29 days were compliant with guidelines, but compliance fell to 61% (144/237) for transfusions administered after 29 days (P=0.002). About half of the platelet transfusions given early in the hospital course were in violation of guidelines, but after day 9, 83% of platelet transfusions were compliant with guidelines (P=0.000). CONCLUSION: Opportunities exist in our healthcare system to improve compliance with our transfusion guidelines. Such opportunities are greatest among neonates receiving multiple transfusions, among those receiving erythrocyte transfusions late in their NICU course and among those receiving platelet transfusions early in their NICU course.

Do platelet transfusions in the NICU adversely affect survival? Analysis of 1600 thrombocytopenic neonates in a multihospital healthcare system.

OBJECTIVE: Several studies have indicated a correlation between the number of platelet transfusions received by newborn intensive care unit (NICU) patients and the mortality rate. The number of platelet transfusions might be a marker for level of illness, and thus predictive of mortality. However, an alternative hypothesis is that multiple platelet transfusions themselves are harmful in this population. STUDY DESIGN: We evaluated data from all thrombocytopenic neonates cared for in the Intermountain Healthcare NICUs in the past 4 years, seeking associations between the lowest platelet count recorded, number of platelet transfusions received and mortality rate. We also conducted a sensitivity analysis to examine the hypothesis that platelet transfusions were responsible for some fraction of the mortality rate. RESULT: Transfusion and outcome data were examined from 1600 thrombocytopenic NICU patients. At any level of platelet count, some patients received platelet transfusions but others did not. However, at all levels of platelet count, those that received platelet transfusions had a higher mortality rate. Neonates not given any platelet transfusions had a mortality rate of 2%, those with 1 or 2 transfusions had a mortality rate of 11% (P<0.001); those with >10 had a mortality rate of 35% (P<0.001); and those with > or = 20 had a mortality rate of 50% (P<0.001). A sensitivity analysis suggested that the platelet transfusions themselves were very likely responsible for some fraction of the increasing mortality rate. CONCLUSION: The number of platelet transfusions administered in the NICU predicts the mortality rate. Some of this correlation is ascribable to unknown and unmeasured factors such as level of illness. However, the present data and the sensitivity analysis both suggest that some of this correlation is due to harmful effects of multiple platelet transfusions in this group of patients.

ETCare: a randomized, controlled, masked trial comparing two solutions for upper airway care in the NICU.

BACKGROUND: Small quantities of normal saline are sometimes instilled into the endotracheal tube of intubated neonates, to assist with the removal of thick secretions and maintain patency of the endotracheal tube. However, saline is detrimental to the innate immune system of the upper airway mucosa, rapidly unfolding and inactivating antimicrobial peptides such as LL-37. We previously reported the preparation and feasibility testing of 'ETCare', a low-sodium, physiologically based solution for airway care, and we now report results of a randomized, masked, controlled, two-centered study testing ETCare vs sterile saline among 60 intubated NICU patients. STUDY DESIGN: Sixty intubated NICU patients were randomized to having their airway care with ETCare vs saline. Three hypotheses were tested: (1) tolerance - patients will tolerate ETCare for airway care as well as they tolerate saline, (2) nosocomial infections - ETCare will result in fewer tracheal aspirates where organisms grow and fewer cases of nosocomial sepsis, and (3) chronic lung disuse - ETCare will result in fewer patients discharged home on supplemental O2. RESULTS: Thirty NICU patients with an endotracheal tube in place were randomized to receive their airway care with ETCare, and 30 to receive their care with saline. Only the pharmacist was aware of the randomization; the two solutions were visually indistinguishable and were dispensed in identical syringes. Tolerance of the solutions was similar. The ETCare recipients had trends toward fewer positive blood cultures (odds ratios (OR), 0.48; 95% confidence interval (CI), 0.13 to 1.68), and fewer discharges home on supplemental O2 (OR, 0.43; 95% CI, 0.14 to 1.32; P=0.075). CONCLUSIONS: On the basis of this study and our previous 10-patient feasibility trial, we maintain that, for airway care, intubated NICU patients tolerate ETCare as well as saline. Data from this study can be used in estimating the sample sizes needed for a phase III trial. We speculate that such a trial will demonstrate that, compared with saline, ETCare will result in fewer nosocomial infections and less chronic lung disease.

Identifying patients, on the first day of life, at high-risk of developing parenteral nutrition-associated liver disease.

BACKGROUND: Prolonged use of parenteral nutrition (PN) in neonates can lead to parenteral nutrition-associated liver disease (PNALD), manifested by elevated direct bilirubin concentrations, and in some cases progressing to hepatic failure. When new potential means of preventing PNALD in the neonatal intensive care unit (NICU), such as Omegaven usage, are tested in clinical trials, the studies should enroll neonates at a very high risk of developing PNALD. However, it is not always clear, in the first days of life, which neonates are most likely to develop PNALD. Therefore, preparatory to devising studies of prophylaxis against PNALD, we conducted an evaluation of all NICU patients who received PN for >or=14 day, assessing their likelihood of developing PNALD. METHODS: We performed an historic cohort analysis of all neonates in the Intermountain Healthcare system, receiving PN for 14 days or more during their stay, with dates of birth between 1 January, 2002 and 30 June, 2006. RESULTS: During the 4(1/2)-year period, 9861 neonates were cared for in the Intermountain Healthcare NICUs. Of these, 9547 (96.8%) survived for at least 28 days, and of these 6543 (68.5%) received PN. Twenty-one percent (1366 patients) of those receiving PN, received it for >or=14 days. PNALD was ascertained in this group by a direct bilirubin >or=2.0 mg/dl. Neonates receiving PN for 14-28 days had a 14% incidence of PNALD, those receiving PN for 29-56 days had a 43% incidence, those receiving PN for 57-100 days had a 72% incidence and those receiving PN for >100 days had a 85% incidence. Groups of patients identifiable on the first day of life as having the highest risk of developing PNALD were birth weight <500 g (odds ratio (OR), 30.7), birth weight 500-749 g (OR, 13.1), gastrochisis (OR, 20.3) and jejunal atresia (OR, 24.0). Among 357 patients who developed PNALD, the highest direct bilirubin concentrations correlated with the highest serum alkaline phosphatase and transaminase concentrations. Deaths after 28 days were much more common in those with the highest direct bilirubin and transaminase concentrations (P<0.0001). CONCLUSIONS: In the first days of life, certain NICU patients can be identified as being at very high risk for developing PNALD. These are patients <750 g birth weight, those with gastrochisis and those with jejunal atresia. We speculate that these groups would be reasonable subjects for including in a PNALD prophylaxis trial, testing new preventative strategies such as Omegaven usage.

Necrotizing enterocolitis in term neonates: data from a multihospital health-care system.

OBJECTIVE: In the past 5(1/2) years, 30 term or near-term neonates in the Intermountain Healthcare system developed necrotizing enterocolitis (NEC) Bell's stage > or =II. We sought to identify possible explanations for why these patients developed NEC, by comparing them with 5847 others that did not develop NEC, from the same hospitals and of the same gestational ages, cared for during the same 5 1/2-year period. STUDY DESIGN: Data were collected from neonates admitted to any of the Intermountain Healthcare NICUs with a birth date from 1 January 2001 to 30 June 2006, and a gestational age >36 weeks. A variety of patient features and feeding practices were compared between those that did vs did not develop NEC. RESULT: Forty-one neonates >36 weeks gestation were listed in the discharge records as having NEC of Bell's stage II or higher. However, on review of these 41 medical records, 11 were seen to have had NEC of Bell's stage I, whereas the remaining 30 had radiographs and clinical courses indicative of Bell's stage > or =II. Those 30 formed the basis of this study. Twenty-eight of the 30 developed NEC after having been admitted to an NICU for some other reason; the other two developed NEC at home, within 2 days of being discharged from an NICU. The 30 that developed NEC were more likely than the 5847 that did not develop NEC, to have congenital heart disease (P=0.000), polycythemia (P=0.002), early-onset bacterial sepsis (P=0.004) or hypotension (P=0.017). All 30 received enteral feedings before NEC developed; 29 were fed either artificial formula or a mixture of formula and breast milk. The one that was exclusively fed human milk was fed human milk with added fortifier (24 cal/oz). The 30 that developed NEC were more likely to be fed formula exclusively (P=0.000). Seven of the 30 had a laparotomy for NEC; two of the seven had total bowel necrosis and support was withdrawn. The other five had perforations and bowel resections. The mortality rate was 13% (4/30). CONCLUSION: In our series, NEC among term or near-term neonates was exclusively a complication developing among patients already admitted to a NICU for some other reason. We speculate that the combination of reduced mesenteric perfusion and feeding with artificial formula were factors predisposing them to develop NEC.