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.

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.

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.

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.

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.

Splenectomy ablates endotoxin-induced IFNgamma response in rats.

The mechanism of liver injury in endotoxemia is unclear. Previous studies have shown that splenectomy protects the liver from endotoxin-induced injury. The purpose of this study was to determine the relationship of TNFalpha and IFNgamma release and endotoxin-induced liver injury in splenectomized and nonsplenectomized rats. Splenectomized and nonsplenectomized (Sham) rats with chronic catheters in the aorta and inferior vena cava (IVC) were parenterally infused with 10 to 5000 microg/kg endotoxin. TNFalpha, IFNgamma, and alanine aminotransferase (ALT), a marker of hepatocellular damage, were measured in aortic blood. Compared to sham controls, splenectomized animals demonstrated significantly reduced endotoxin-induced ALT concentrations at endotoxin doses >10 microg/kg. Peak endotoxin-induced TNFalpha concentrations were not significantly different between the splenectomized and sham groups. In contrast, peak endotoxin-induced IFNgamma concentrations were significantly decreased in the splenectomized group. These data suggest a relationship between endotoxin-induced IFNgamma and liver injury. We speculate that the spleen contributes to the endotoxin-induced liver injury by modulating release of IFNgamma.

Management of birth injuries.

Birth injuries are a significant cause of neonatal morbidity and mortality. Although they are frequently 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 encountered by health care providers caring for newborns.

The albumin controversy.

There are relatively few studies of albumin use in neonates and children, with most showing no consistent benefit compared with the use of crystalloid solutions. Certainly, albumin treatment is not indicated for treatment of hypoalbuminemia alone. Studies also show that albumin is not indicated in neonates for the initial treatment of hypotension, respiratory distress, or partial exchange transfusions. In adults, albumin is not considered to be the initial therapy for hypovolemia, burn injury, or nutritional supplementation. Based on the evidence, albumin should be used rarely in the neonatal ICU. Albumin may be indicated in the treatment of hypovolemia only after crystalloid infusion has failed. In patients with acute hemorrhagic shock, albumin may be used with crystalloids when blood products are not available immediately. Inpatients with acute or continuing losses of albumin and normal capillary permeability and lymphatic function, such as during persistent thoracostomy tube or surgical site drainage, albumin supplementation will prevent the development of hypoalbuminemia, and possibly edema formation. This has not been studied systematically, however. In patients with hypoalbuminemia and increased capillary permeability, albumin supplementation often leads to greater albumin leakage across the capillary membrane, contributing to edema formation without improvement in outcome. As the disease process improves and capillary permeability normalizes, albumin supplementation may accelerate recovery, but long-term benefits of albumin treatment usually cannot be demonstrated. These patients will recover whether or not albumin is administered.

Role of admission gas exchange measurement in predicting congenital diaphragmatic hernia survival in the era of gentle ventilation.

BACKGROUND/PURPOSE: Neonates with significant congenital diaphragmatic hernia (CDH) require cardiopulmonary support. Management has been characterized by progressive abandonment of hyperventilation. Ability to prognosticate outcomes using measures of ventilation and oxygenation with gentle ventilation remains unclear. We sought to determine whether assessment of gas exchange at the time of NICU admission is predictive of survival in this current era. METHODS: Neonates with CDH admitted to a Children's Hospital from 1995 to 2006 were evaluated for demographics, blood gas (ABG) measurements and ventilator settings for the first 48hours, and discharge outcome. RESULTS: One-hundred-and-nineteen CDH patients were admitted, 88 (74%) survived. Mean admission ABG pCO2 was higher in infants who died compared to survivors (86±48 versus 49±20, p≤0.001); positive predictive value (PPV) for mortality of pCO2≥80mmHg was 0.71. Mean first hour preductal oxygen saturation (preductalO2Sat) was lower in infants who died compared to survivors (81±17 versus 97±5, p<0.001); PPV for mortality of preductalO2Sat<85% was 0.82. Eleven patients met both pCO2 and preductalO2Sat criteria, and 10 (91%) died, PPV of 0.92. Within hours of admission, pCO2 and preductalO2Sat differences between survivors and nonsurvivors lost significance. CONCLUSION: Admission pCO2 and preductalO2Sat may be useful in predicting survival in neonatal CDH. The differential in gas exchange between survivors and nonsurvivors loses significance with contemporary neonatal care.

Strategies to prevent bacterial and fungal infection in the neonatal intensive care unit.

Hospital-acquired infections are one of the leading causes of preventable morbidity and mortality in neonatal intensive care units (NICUs). Device-related infections, such as catheter-associated blood stream infections (CABSIs) and ventilator-associated pneumonia (VAP), are the most common nosocomial infections. This review examines the pathogenesis of CABSIs and methods, widely accepted and novel, that can be used to help prevent them. Strategies to prevent fungal infections, which are often associated with the presence of a central venous catheter, are also reviewed. Finally, the dilemmas in the diagnosis and prevention of VAP in the NICU are discussed.

Optimizing growth in the preterm infant.

Most very low birth weight preterm infants experience postnatal growth failure in the neonatal ICU. In an attempt to minimize this phenomenon, the nutritional support of these infants has tended to become more aggressive in recent years and has become a focus of much study. Despite this attention, many questions remain unresolved. This article examines several of these issues, including the controversies regarding optimal postnatal growth velocity, early aggressive nutritional support, and the transition to enteral nutrition in preterm infants.

Endotoxin-induced hyperlactatemia results from decreased lactate clearance in hemodynamically stable rats.

OBJECTIVE: To determine whether endotoxin-induced hyperlactatemia in hemodynamically stable animals is due to increased lactate production or decreased lactate clearance by measuring lactate turnover rate in the vascular compartment (LTRvc). DESIGN: Prospective, controlled trial. SETTING: Research laboratory in a university hospital. SUBJECTS: Male Sprague-Dawley rats weighing 275-425 g with chronic vascular catheters. INTERVENTIONS: Chronically catheterized rats were treated with 6 microg/kg endotoxin or saline. LTRvc was determined from the specific activity of carbon-14 [14C]lactate in aortic blood during a constant infusion of [14C]lactate into the inferior vena cava. The role of the splanchnic organs in lipopolysaccharide-induced alterations in LTRvc was determined from the splanchnic first-pass clearance of [14C]lactate infused into the superior mesenteric artery and direct measurements of blood lactate concentration gradients across the splanchnic organs. MEASUREMENTS AND MAIN RESULTS: Despite a 260% increase in lactate concentrations after lipopolysaccharide treatment, the specific activity of [14C]lactate and the LTRvc did not change, indicating that lipopolysaccharide-induced hyperlactatemia is caused by decreased lactate clearance from the vascular compartment rather than increased lactate flux into the vascular compartment. In contrast, lactate clearance by the splanchnic system was increased. The specific activity of [14C]lactate in aortic blood decreased 33% after lipopolysaccharide treatment when the [14C]lactate was infused into the superior mesenteric artery, indicating increased first-pass clearance of [14C]lactate by the splanchnic organs. Furthermore, the hepatic venous-aortic concentration gradient of lactate became increasingly negative after lipopolysaccharide treatment, indicating increased vascular extraction of lactate by the splanchnic system (0.07 +/- 0.07 micromol/mL vs. -0.34 +/- 0.14 micromol/mL). CONCLUSIONS: Lipopolysaccharide-induced hyperlactatemia in hemodynamically stable rats is caused by a net decrease in lactate clearance from the vascular compartment despite the fact that the clearance of lactate by the splanchnic system remains intact.

Chronic Staphylococcal enterotoxin B and lipopolysaccharide induce a bimodal pattern of hepatic dysfunction and injury.

OBJECTIVE: To determine the effect of chronic exposure to endotoxin (lipopolysaccharide) and Staphylococcal enterotoxin B on hepatic injury and function. DESIGN: Prospective, controlled trial. SETTING: Research laboratory in a university hospital. SUBJECTS: Male Sprague-Dawley rats weighing 325-350 g with chronic vascular and bile catheters. INTERVENTIONS: Chronically catheterized rats were treated daily with saline, 50 microg/kg Staphylococcal enterotoxin B alone, 1000 microg/kg lipopolysaccharide alone, 1000 microg/kg lipopolysaccharide with 50 microg/kg Staphylococcal enterotoxin B, or 100 microg/kg lipopolysaccharide with 50 microg/kg Staphylococcal enterotoxin B for 10 days. Serum and biliary measures of hepatic injury and dysfunction were measured before and then 6 hrs and 1, 2, 3, 7, and 10 days after the start of treatment. The animals were killed at 10 days and the livers examined histologically. MEASUREMENTS AND MAIN RESULTS: Mean rates of bile flow, biliary indocyanine green excretion, and bile acid flux were significantly decreased immediately after treatment (6 hr, 1 and 2 days) and then at 10 days. Increases in biliary and serum gamma-glutamyltransferase and serum bile acids also occurred in a similar bimodal pattern. Animals treated with lipopolysaccharide or Staphylococcal enterotoxin B alone became tolerant and did not develop the bimodal pattern of hepatic dysfunction. Histologic examination of the liver at 10 days revealed periportal inflammation and fibrosis. CONCLUSIONS: The combination of lipopolysaccharide and Staphylococcal enterotoxin B leads to late liver injury, whereas either toxin alone does not. These data may explain the frequent development of liver dysfunction in patients exposed to multiple bacterial toxins such as in sepsis, multiple-system organ failure, and other diseases with altered intestinal permeability.

The effect of anesthesia and surgery on CYP3A activity in rats.

The purpose of this investigation was to examine the effects of surgery and anesthesia on in vivo CYP3A activity and portal venous blood flow. Midazolam, a CYP3A probe for both rats and humans, was administered orally (2.7 mg), intravenously (0.57 mg), or via the portal vein (0.57 mg) to rats 4 h after anesthesia with ketamine/xylazine and surgery for placement of indwelling vascular and duodenal catheters and 3 days after surgery (chronic). The systemic clearance of midazolam was 51 +/- 4 ml/min/kg in the chronic animals, and this was significantly decreased (29 +/- 1 ml/min/kg, P = 0.024) in acute rats studied 4 to 6 h after anesthesia and surgery. The hepatic availability (FH), directly determined from the aortic and hepatic venous concentration gradient, was significantly higher in the acute animals (0.57 +/- 0.05) compared with the chronic animals (0.33 +/- 0.07, P = 0.001). Hepatic availability was determined using a classical approach in which FH was calculated from the area under the plasma concentration versus time curve ratio after portal venous or intravenous administration. FH was higher in the acute rats (0.48) compared with the chronic animals (0.27 +/- 0.03). Portal venous blood flow was significantly lower in the acute animals (5.0 +/- 0.4 ml/min/100 g body weight) compared with the chronic animals (9.1 +/- 0.9 ml/min/100 g body weight, P = 0.015). The effect of surgery and anesthesia was confirmed using the indicator dye dilution method after infusion of [14C]polyethylene glycol 4000 into the superior mesenteric artery. Our data suggest that anesthesia and surgery decreases both hepatic CYP3A activity and hepatic blood flow in rats. Studies performed in rats within 3 days of surgery and anesthesia are conducted under nonphysiologic conditions and therefore provide inaccurate assessment of drug disposition, in particular, clearance and bioavailability.