Actual and Potential Impact of a Home Nasogastric Tube Feeding Program for Infants Whose Neonatal Intensive Care Unit Discharge Is Affected by Delayed Oral Feedings.

OBJECTIVE: To compare healthcare use and parent health-related quality of life (HRQL) in 3 groups of infants whose neonatal intensive care unit (NICU) discharge was delayed by oral feedings. STUDY DESIGN: This was a prospective, single-center cohort of infants in the NICU from September 2018 to March 2020. After enrollment, weekly chart review determined eligibility for home nasogastric (NG) feeds based on predetermined criteria. Actual discharge feeding decisions were at clinical discretion. At 3 months' postdischarge, we compared acute healthcare use and parental HRQL, measured by the PedsQL Family Impact Module, among infants who were NG eligible but discharged with all oral feeds, discharged with NG feeds, and discharged with gastrostomy (G) tubes. We calculated NICU days saved by home NG discharges. RESULTS: Among 180 infants, 80 were orally fed, 35 used NG, and 65 used G tubes. Compared with infants who had NG-tube feedings, infants who had G-tube feedings had more gastrointestinal or tube-related readmissions and emergency encounters (unadjusted OR 3.97, 95% CI 1.3-12.7, P = .02), and orally-fed infants showed no difference in use (unadjusted OR 0.41, 95% CI 0.1-1.7, P = .225). Multivariable adjustment did not change these comparisons. Parent HRQL at 3 months did not differ between groups. Infants discharged home with NG tubes saved 1574 NICU days. CONCLUSIONS: NICU discharge with NG feeds is associated with reduced NICU stay without increased postdischarge healthcare use or decreased parent HRQL, whereas G-tube feeding was associated with increased postdischarge healthcare use.

Reining in Nasogastric Tubes: Implementation of a Pediatric Bridle Program.

Nasogastric tubes (NG) used for enteral nutrition support of medically complex children (MCC) are often inadvertently removed, risking frequent replacements. Bridles have been shown to provide a safe securement method for NGs in adult patients, but are not widely used in pediatrics. Furthermore, nutritional management of MCC is often fragmented. We established a pediatric NG bridle program to bridge the gap amongst disciplines and improve patient outcomes. In January 2018, a multidisciplinary work group involving nurses, physicians, clinical dietitians, advanced practice providers, and speech-language pathologists was established to develop criteria for patient referral and policies, procedures, and order sets for nutritional management of MCC children with bridled NG tubes. Formal teaching sessions engaged clinicians and administrators to participate in building a successful program. Relevant outcomes of interest are tracked continuously for process performance improvement measures and are reviewed quarterly by the core work group. Patient enrollment began in May 2018 and to date, 244 patients have been enrolled. Adhering to strict enrollment criteria, competency modules and review of patient status provided a solid core for the program and process review. Successful implementation of an NG Bridle program was achieved. Outcomes of interest continue to be monitored for process improvement. Balancing measures are also being tracked for potential downstream effects.

A Pilot Randomized Controlled Trial of Outcomes Associated with Parent-Nurse Controlled Analgesia vs. Continuous Opioid Infusion in the Neonatal Intensive Care Unit.

PURPOSE: Prospectively compare parent/nurse controlled analgesia (PNCA) to continuous opioid infusion (COI) in the post-operative neonatal intensive care unit (NICU) population. DESIGN/METHODS: A randomized controlled trial compared neonates treated with morphine PNCA to those treated with morphine COI. The primary outcome was average opioid consumption up to 3 post-operative days. Secondary outcomes included 1) pain intensity, 2) adverse events that may be directly related to opioid consumption, and 3) parent and nurse satisfaction. RESULTS: The sample consisted of 25 post-operative neonates and young infants randomized to either morphine PNCA (n = 16) or COI (n = 9). Groups differed significantly on daily opioid consumption, with the PNCA group receiving significantly less opioid (P = .02). Groups did not differ on average pain score or frequency of adverse events (P values > .05). Parents in both groups were satisfied with their infant's pain management and parents in the PNCA group were slightly more satisfied with their level of involvement (P = .03). Groups did not differ in nursing satisfaction. CONCLUSIONS: PNCA may be an effective alternative to COI for pain management in the NICU population. This method may also substantially reduce opioid consumption, provide more individualized care, and improve parent satisfaction with their level of participation. CLINICAL IMPLICATIONS: Patients in the NICU represent one of our most vulnerable patient populations. As nurses strive to provide safe and effective pain management, results of this study suggest PNCA may allow nurses to maintain their patients' comfort while providing less opioid and potentially improving parental perception of involvement. STUDY TYPE: Treatment study. LEVEL OF EVIDENCE: I.

Risk Factors Linked to Central Catheter-Associated Thrombosis in Critically Ill Infants in the Neonatal Intensive Care Unit.

OBJECTIVE: Our study identified risk factors for the development of clinically identifiable catheter-associated thrombosis (CT). STUDY DESIGN: We performed a retrospective cohort study of neonates in whom a central catheter was present. A total of 1,475 catheters were identified in 766 patients during a 36-month study period. The odds ratio (OR) of thrombi formation in catheterized neonates was modeled using simple (single predictor) and multiple (multiple predictors) logistic regressions as well as simple and multiple Cox's proportional hazard models. RESULT: The incidence of CT was 1.17 per 100 neonates. Unadjusted factors including age at insertion, history of surgery before or during line placement, cholestasis, femoral location, and line size significantly increased the OR or hazards ratio (HR) of developing thrombi formation. In multiple logistic and Cox's regression analyses, three factors continued to be significantly associated with OR or HR of thrombi formation: line size, femoral location, and cholestasis. CONCLUSION: We conclude that clinically identifiable CT is rare in the neonatal population. Furthermore, catheter-specific characteristics are predictive for CT and require further investigation.

Maternal opioid dose is associated with neonatal abstinence syndrome in children born to women with sickle cell disease.

The objective of this study was to test the hypothesis that higher daily opioid dose is associated with the presence and severity of neonatal abstinence syndrome (NAS) in pregnant women with sickle cell disease (SCD). This was a retrospective study of pregnant women with SCD who required opioids. NAS was evaluated using the Finnegan scoring system and classified as none, mild, and severe. Severe NAS was defined as a Finnegan score ≥ 8 on 3 consecutive tests. Thirty-four pregnancies were examined in 30 women with SCD. Higher daily morphine dose was associated with a higher percentage of days in the hospital during pregnancy (P < 0.001). Hospital days contributed disproportionately to daily morphine dose as larger amounts of opioids were administered in the hospital compared to home (P = 0.002). Median maternal oral morphine dose was 416 mg for infants with severe NAS compared with 139 mg for those with mild NAS (P = 0.04). For infants with no NAS, median maternal morphine was 4 mg, significantly less than those with mild NAS (P < 0.001). Infants born to women who used on average >200 mg/day of oral morphine equivalent in the last month of pregnancy had a 13-fold increased risk of severe NAS compared with those who used <200 mg/day. These data demonstrate that higher median daily opioid dose is associated with progressively more severe NAS in pregnant women with SCD. Strategies to decrease pain and avoid hospitalizations are needed to reduce opioid use and NAS.

Adverse Events in Young and Preterm Infants Receiving Topical Timolol for Infantile Hemangioma.

BACKGROUND: The success of oral propranolol for treatment of infantile hemangiomas (IHs) has led practitioners to use topical ß-blockers. In preterm infants, clinicians frequently turn to topical timolol, with the presumption that topical application will result in less systemic absorption. We used Holter monitoring to assess for drug-induced bradycardia in high-risk infants. METHODS: We retrospectively reviewed the charts of 22 at-risk infants who received a Holter monitor to assess for association between timolol administration and development of significant bradycardia. RESULTS: Four infants had episodic bradycardia detected by Holter monitoring. Two of these infants were full term; weighed more than 3,000 g; and had rare, brief, asymptomatic episodes unrelated to the timing of the timolol application. The other two infants had symptomatic bradycardia while on timolol and were the only two babies that weighed less than 2,500 g at initiation of therapy. Both were young (postmenstrual age [PMA] 34 and 37 wks) at initiation and had a timolol dose above the average exposure for the cohort. CONCLUSION: In this cohort of at-risk infants, topical timolol appeared to provide safe treatment for IHs in full-term infants receiving a dose of less than 0.2 mg/kg/day, but infants with a PMA of less than 44 weeks and weight at treatment initiation of less than 2,500 g may be at risk of adverse events, including bradycardia, hypotension, apnea, and hypothermia. We recommend close monitoring of temperature, blood pressure, and heart rate in premature and low-birthweight infants with IHs at initiation of and during therapy with topical timolol.

Migration of Central Venous Catheters in Neonates: A Radiographic Assessment.

Objective This study aims to determine the frequency that umbilical venous catheters (UVCs) and peripherally inserted central catheters (PICCs) migrate into the cardiothymic silhouette after initial verification of correct placement. Study Design This is a single-center, retrospective study in neonates in whom a PICC or UVC was placed. The frequency of catheter tip migration into the cardiothymic silhouette requiring catheter manipulation was determined radiographically at 1 and 24 hours, respectively, after insertion. Results At 1 and 24 hours, 36 and 23% of UVCs (n = 41) migrated into the cardiothymic silhouette, respectively. At 1 and 24 hours, 23 and 11% of PICCs (n = 63) migrated into the cardiothymic silhouette, respectively. Migration was not associated with birth weight, weight at insertion, or postnatal age at insertion. Conclusion UVCs and PICCs frequently migrate into the cardiothymic silhouette increase the risk for development of a pericardial effusion. Serial radiographic assessment of catheter tip location is needed to assess catheter migration within the first 24 hours of line placement.

Is there an alternative to continuous opioid infusion for neonatal pain control? A preliminary report of parent/nurse-controlled analgesia in the neonatal intensive care unit.

BACKGROUND: Continuous opioid infusion (COI) remains the mainstay of analgesic therapy in the neonatal intensive care unit (NICU). Parent/nurse-controlled analgesia (PNCA) has been accepted as safe and effective for pediatric patients, but few reports include use in neonates. This study sought to compare outcomes of PNCA and COI in postsurgical neonates and young infants. METHODS: Twenty infants treated with morphine PNCA were retrospectively compared with 13 infants treated with fentanyl COI in a Midwestern pediatric hospital in the United States. Outcome measures included opioid consumption, pain scores, frequency of adverse events, and subsequent methadone use. RESULTS: The PNCA group (median 6.4 µg · kg(-1) · h(-1) morphine equivalents, range 0.0-31.4) received significantly less opioid (P < 0.001) than the COI group (median 40.0 µg · kg(-1) · h(-1) morphine equivalents; range 20.0-153.3), across postoperative days 0-3. Average daily pain scores (based on 0-10 scale) were low for both groups, but median scores differed nonetheless (0.8 PNCA vs 0.3 COI, P < 0.05). There was no significant difference in the frequency of adverse events or methadone use. CONCLUSION: Results suggest PNCA may be a feasible and effective alternative to COI for pain management in postsurgical infants in the NICU. Results also suggest PNCA may provide more individualized care for this vulnerable population and in doing so, may potentially reduce opioid consumption; however, more studies are needed.

Intensive Care Associated Experiences of Extremely Premature Infants Who Die.

Objective: Pain and quality of death are important considerations in treatment choices for children. Our objective is to assess the intensive care-associated experiences of 22-25 weeks gestational age (GA) infants who die despite intensive care treatment. Study Design: In a 1:1 case-control study, medical records were screened for all inborn 22-25 weeks GA infants who received intensive care treatments between 2014 and 2020. Cases were all infants who died. Each case was matched by GA and birth weight to an infant who survived to discharge (control). Data was collected on cases and controls for a matched timeframe based on the case's duration of intensive care treatment. Information collected included intensive care-associated negative experiences (invasive procedures, surgeries, use of pain medication) and positive experiences (enteral feedings, being held by family). Results: The cases (n=20) survived for 0 to 93 days, with median (IQR) survival 8 (5, 24) days. The mean (SD) number of invasive procedures was higher for cases than controls, 34 (30) vs. 24 (22), p=0.004. Cases underwent 8 surgeries compared to 4 in the controls. Additionally, compared to controls, cases spent more time receiving pain medications (64% vs. 27%, p<0.001) and without being fed (54% vs. 39%, p<0.001). Half of cases were never held by parents until the day they died. Conclusion: Extremely premature infants who die despite intensive care face more treatment burdens than the survivors. Larger studies are needed to confirm these findings and gather information necessary for informed decisions about intensive care treatment of these infants.

Assessing growth of infants with chylothorax receiving fortified skimmed human breast milk.

LEARNING OUTCOME: To learn how skimmed human milk (SHM) can be used in infants with chylothorax to support adequate weight gain and nutrition while receiving human milk. BACKGROUND: Traditional nutrition management for chylothorax is to limit long-chain triglycerides (LCTs) and provide a diet high in medium-chain triglycerides (MCTs). Transition from human milk to formula has been required to provide the ratio of MCT to LCT required to stop the accumulation of chyle. Although SHM may provide the right fat content for a baby with chylothorax, previous studies have shown slow growth in infants receiving SHM. OBJECTIVE: To demonstrate that infants receiving SHM fortified with high-MCT infant formula will have age appropriate growth without re-accumulation of chyle. DESIGN/METHODS: Between 2017 and 2019, term infants with the diagnosis of chylothorax who were previously receiving human milk and transitioned to fortified SHM were monitored for growth and reaccumulation of chyle. RESULTS: The six infants who were prescribed fortified SHM with high-MCT infant formula using standardized recipes did not show reaccumulation of chyle and showed positive weight gain in five of the six study patients. The infants gained a mean weight of 30.5 g/day (±19.5), and their weight z scores improved by a mean of +0.29 (±0.33). CONCLUSIONS: Fortified SHM is a safe treatment option that can provide adequate nutrition for the infant with chylothorax to gain weight appropriately for age.

Predicting treatment of pulmonary hypertension at discharge in infants with congenital diaphragmatic hernia.

OBJECTIVE: To predict pulmonary hypertension (PH) therapy at discharge in a large multicenter cohort of infants with congenital diaphragmatic hernia (CDH). STUDY DESIGN: Six-year linked records from Children's Hospitals Neonatal Database and Pediatric Health Information System were used; patients whose diaphragmatic hernia was repaired before admission or referral, who were previously home before admission or referral, and non-survivors were excluded. The primary outcome was the use of PH medications at discharge and the secondary outcome was an inter-center variation of therapies during inpatient utilization. Clinical factors were used to develop a multivariable equation randomly applied to 80% cohort; validated in the remaining 20% infants. RESULTS: A total of 831 infants with CDH from 23 centers were analyzed. Overall, 11.6% of survivors were discharged on PH medication. Center, duration of mechanical ventilation, and duration of inhaled nitric oxide were associated with the use of PH medication at discharge. This model performed well in the validation cohort area under the receiver operating characteristic curve of 0.9, goodness-of-fit χ2, p = 0.17. CONCLUSIONS: Clinical variables can predict the need for long-term PH medication after NICU hospitalization in surviving infants with CDH. This information may be useful to educate families and guide the development of clinical guidelines.

Catch-down growth in infants born large for gestational age.

Infants born large for gestational age (LGA) not exhibiting catch-down growth (a decline of weight z-score by 1) have a higher likelihood of future obesity. We aimed to identify the term LGA infants in our neonatal intensive care unit (NICU) and document nutrition interventions that may influence growth. Our 10-year retrospective review identified 47 term LGA infants who had a NICU length of stay (LOS) ≥7 days. We obtained demographic data, nutrition interventions in the NICU, and data regarding growth patterns. Of the 47 infants, 31 (66%), demonstrated catch-down growth at discharge at ≥7 days. Overall, 39 of 47 patients (83%) received interventions during their NICU stay, including 32 (69%) who had nasogastric tubes placed, and 24 (51%) had formula fortification to augment weight gain. Among patients with LOS ≥14 days, 23 of 23 patients without catch-down growth and four of five patients with catch-down growth had nutrition interventions performed. Of the overall population, only 38% of those who did not demonstrate catch-down growth had an LOS of ≥14 days vs 77% of all infants that did exhibit catch-down growth (P = .01). Our data suggest that nutrition interventions in LGA infants are common in the NICU. Our study highlights the need for further clinical studies to help direct care in this population of infants.

Quality Improvement Approach to Reducing Admission Hypothermia Among Preterm and Term Infants.

BACKGROUND: Newborns, particularly premature newborns, are susceptible to hypothermia when transitioning from birth to admission to the NICU, potentially leading to increased mortality and morbidity. Despite attention to this issue, our rate of admission hypothermia was 39.8%. METHODS: We aimed to reduce the rate of admission hypothermia for all inborn infants admitted to our institution to <10%. We undertook a quality improvement effort that spanned from 2013 through 2019 in our level IV NICU. Current state analysis involved investigating patient risk factors for hypothermia and staff understanding of hypothermia prevention. Improvement cycles included auditing processes, an in-hospital relocation of our NICU, expanded use of chemical heat mattresses and polyethylene bags, and staff education. Improvement was evaluated by using Shewhart control charts. RESULTS: We demonstrated a reduction in admission hypothermia from 39.8% to 9.9%, which was temporally related to educational efforts and expanded use of chemical heat mattresses and polyethylene bags. There was not an increase in admission hyperthermia over this time period. We found that our group at highest risk of admission hypothermia was not our most premature cohort but those infants born between 33 and 36 6/7 weeks' gestation and those infants prenatally diagnosed with congenital anomalies. CONCLUSIONS: Expanded use of polyethylene bags and chemical heat mattresses can improve thermoregulation particularly when combined with staff education. Although premature infants have been the focus of many hypothermia prevention efforts, our data suggest that older infants, and those infants born with congenital anomalies, require additional attention.

Treatment of pulmonary hypertension during initial hospitalization in a multicenter cohort of infants with congenital diaphragmatic hernia (CDH).

OBJECTIVE: Describe inpatient pulmonary hypertension (PH) treatment and factors associated with therapy at discharge in a multicenter cohort of infants with CDH. METHODS: Six years linked records from Children's Hospitals Neonatal Database and Pediatric Health Information System were used to describe associations between prenatal/perinatal factors, clinical outcomes, echocardiographic findings and PH medications (PHM), during hospitalization and at discharge. RESULTS: Of 1106 CDH infants from 23 centers, 62.8% of infants received PHM, and 11.6% of survivors were discharged on PHM. Survivors discharged on PHM more frequently had intrathoracic liver, small for gestational age, and low 5 min APGARs compared with those discharged without PHM (p < 0.0001). Nearly one-third of infants discharged without PHM had PH on last inpatient echo. CONCLUSIONS: PH medication use is common in CDH. Identification of infants at risk for persistent PH may impact ongoing management. Post-discharge follow-up of all CDH infants with echocardiographic evidence of PH is warranted.

Antibiotic stewardship in the newborn surgical patient: A quality improvement project in the neonatal intensive care unit.

BACKGROUND: There is significant diversity in the utilization of antibiotics for neonates undergoing surgical procedures. Our institution standardized antibiotic administration for surgical neonates, in which no empiric antibiotics were given to infants with surgical conditions postnatally, and antibiotics are given no more than 72 hours perioperatively. METHODS: We compared the time periods before and after implementation of antibiotic protocol in an institution review board-approved, retrospective review of neonates with congenital surgical conditions who underwent surgical correction within 30 days after birth. Surgical site infection at 30 days was the primary outcome, and development of hospital-acquired infections or multidrug-resistant organism were secondary outcomes. RESULTS: One hundred forty-eight infants underwent surgical procedures pre-protocol, and 127 underwent procedures post-protocol implementation. Surgical site infection rates were similar pre- and post-protocol, 14% and 9% respectively, (P = .21.) The incidence of hospital-acquired infections (13.7% vs 8.7%, P = .205) and multidrug-resistant organism (4.7% vs 1.6%, P = .143) was similar between the 2 periods. CONCLUSION: Elimination of empiric postnatal antibiotics did not statistically change rates of surgical site infection, hospital-acquired infections, or multidrug-resistant organisms. Limiting the duration of perioperative antibiotic prophylaxis to no more than 72 hours after surgery did not increase the rate of surgical site infection, hospital-acquired infections, or multidrug-resistant organism. Median antibiotic days were decreased with antibiotic standardization for surgical neonates.

Outcomes of Infants With Home Tube Feeding: Comparing Nasogastric vs Gastrostomy Tubes.

BACKGROUND: The aim of this study was to determine the tube-related complications and feeding outcomes of infants discharged home from the neonatal intensive care unit (NICU) with nasogastric (NG) tube feeding or gastrostomy (G-tube) feeding. MATERIALS AND METHODS: We performed a chart review of 335 infants discharged from our NICU with home NG tube or G-tube feeding between January 2009 and December 2013. The primary outcome was the incidence of feeding tube-related complications requiring emergency department (ED) visits, hospitalizations, or deaths. Secondary outcome was feeding status at 6 months postdischarge. Univariate and multivariate analyses were conducted. RESULTS: There were 322 infants discharged with home enteral tube feeding (NG tube, n = 84; G-tube, n = 238), with available outpatient data for the 6-month postdischarge period. A total of 115 ED visits, 28 hospitalizations, and 2 deaths were due to a tube-related complication. The incidence of tube-related complications requiring an ED visit was significantly higher in the G-tube group compared with the NG tube group (33.6% vs 9.5%, P < .001). Two patients died due to a G-tube-related complication. By 6 months postdischarge, full oral feeding was achieved in 71.4% of infants in the NG tube group compared with 19.3% in the G-tube group ( P < .001). Type of feeding tube and percentage of oral feeding at discharge were significantly associated with continued tube feeding at 6 months postdischarge. CONCLUSION: Home NG tube feeding is associated with fewer ED visits for tube-related complications compared with home G-tube feeding. Some infants could benefit from a trial home NG tube feeding.

Anesthetic Management of an Infant With Postnatally Diagnosed Tracheal Agenesis Undergoing Tracheal Reconstruction: A Case Report.

A term infant born cyanotic failed multiple intubation attempts and tracheostomy placement. After esophageal intubation resulted in the ability to ventilate, he was presumed to have tracheal agenesis and distal bronchoesophageal fistula. He was transferred to our institution where he was diagnosed with Floyd Type II tracheal agenesis. He underwent staged tracheal reconstruction. He was discharged to home at 4 months of age with a tracheostomy collar, cervical spit fistula, and gastrostomy tube. He represents the sole survivor-to-discharge of tracheal agenesis in the United States. We describe the anesthetic considerations for a patient with tracheal agenesis undergoing reconstruction.

Management of birth injuries.

Birth injuries are a significant cause of neonatal morbidity and mortality. Although often associated with traumatic delivery, birth injuries often occur in normal spontaneous deliveries in the absence of any risk factors. This article discusses the diagnosis and management of the most common birth injuries that are encountered by health care providers who care for newborns.

Current concepts in acute respiratory support for neonates and children.

Current trends in mechanical respiratory support are evolving toward gentle approaches to avoid short- and long-term problems that are historically associated with mechanical ventilation. These ventilator-associated issues include the need for long-term sedation, muscle deconditioning, ventilator-associated lung injury (VALI), and ventilator-associated pneumonia (VAP). This article will describe recent trends of ventilatory support in neonates and children: (1) utilization of volume ventilation in infants, (2) synchrony and improving patient-ventilator interaction specifically using neurally adjusted ventilatory assist (NAVA), and (3) use of noninvasive ventilation techniques. When applicable, their uses in the surgical newborn and pediatric patients are described.

Differential induction of hepatic dysfunction after intraportal and intravenous challenge with endotoxin and Staphylococcal enterotoxin B.

We have previously shown that systemic infusion of the bacterial toxins Staphylococcal enterotoxin B (SEB) and endotoxin (LPS) induces hepatic dysfunction as measured by decreased biliary indocyanine green (ICG) excretion. In this study, we compare the effects of these bacterial toxins after infusion into the portal and systemic circulation and directly measure biliary bile acid excretion as a measure of cholestasis. We hypothesized that bacterial toxins infused into the portal vein would induce greater hepatic dysfunction than toxins infused into the systemic circulation. Using a chronically catheterized rat model, biliary bile acid excretion was directly measured after infusion of LPS at 10 and 100 microg/kg with and without 50 microg/kg SEB into the portal vein (IPV) or inferior vena cava (IV) at baseline, and at 6 and 24 h. We found that when LPS was infused alone, only IPV administration caused a significant decrease in bile acid excretion at 6 h. There was no change in bile acid excretion after IV administration of LPS. In contrast, when the combination of LPS and SEB was infused, both IV and IPV administration significantly decreased bile acid excretion at 6 and 24 h. At 6 h post-LPS and -SEB administration, the decrease in bile acid excretion was significantly greater after IPV than IV administration. There was no site-specific difference in IFN-gamma release after infusion of toxins. However, peak TNFalpha release was decreased in IPV-infused rats [10 microg/kg (P < 0.05) or 100 microg/kg (P = ns) LPS with SEB] compared with the same doses in IV-infused rats. These data question the role of systemic TNF-alpha and IFN-gamma in regulating hepatic dysfunction and suggest a differential functional response of the liver to systemic and gut-derived septic events. This study also further explains the frequent development of liver dysfunction in patients with sepsis, multisystem organ failure, and other diseases with altered intestinal permeability.