Gut-associated biomarkers L-FABP, I-FABP, and TFF3 and LIT score for diagnosis of surgical necrotizing enterocolitis in preterm infants.

OBJECTIVES: To evaluate the use of gut barrier proteins, liver-fatty acid binding protein (L-FABP), intestinal-fatty acid binding protein (I-FABP), and trefoil factor 3 (TFF3), as biomarkers for differentiating necrotizing enterocolitis (NEC) from septicemic/control infants and to identify the most severely affected surgical NEC from nonsurgical NEC infants. BACKGROUND: Clinical features and routine radiologic investigations have low diagnostic utilities in identifying surgical NEC patients. METHODS: The diagnostic utilities of individual biomarkers and the combination of biomarkers, the LIT score, were assessed among the NEC (n = 20), septicemia (n = 40), and control groups (n = 40) in a case-control study for the identification of proven NEC and surgical NEC infants. RESULTS: Plasma concentrations of all gut barrier biomarkers and the LIT score were significantly higher in the NEC than in the septicemia or control group (P < 0.01). Using median values of biomarkers and the LIT score in the NEC group as cutoff values for identifying NEC from septicemic/control cases, all had specificities of 95% or more and sensitivities of 50%. Significantly higher levels of biomarkers and the LIT score were found in infants with surgical NEC than in nonsurgical NEC cases (P ≤ 0.02). The median LIT score of 4.5 identified surgical NEC cases with sensitivity and specificity of 83% and 100%%, respectively. A high LIT score of 6 identified nonsurvivors of NEC with sensitivity and specificity of 78% and 91%, respectively. CONCLUSIONS: The LIT score can effectively differentiate surgical NEC from nonsurgical NEC infants and nonsurvivors of NEC from survivors at the onset of clinical presentation. Frontline neonatologists and surgeons may, therefore, target NEC infants who are most in need of close monitoring and those who may benefit from early surgical intervention.

Spiritual and cultural influences on end-of-life care and decision-making in NICU.

Understanding and respecting the spiritual beliefs, ethnic roots, cultural norms and customs of individual families is essential for neonatologists to provide clinically appropriate and humane end-of-life care. This review describes the religious/philosophical principles, cultural-related practices/rituals, and traditions in end-of-life care in major spiritual groups of today's multi-cultural, multi-faith societies. The spiritual groups include Christians, Muslims, Jewish Judaism believers and Asian religious/philosophy followers such as Buddhists, Hindus, Taoists, Confucianism devotees and ancestral worshippers. It is vital to understand that substantial variation in views and practices may exist even within the same religion and culture in different geographic locations. Ethical views and cultural practices are not static elements in life but behave in a fluidic and dynamic manner that could change with time. Interestingly, an evolving pattern has been observed in some Asian and Middle East countries that more parents and/or religious groups are beginning to accept a form of redirection of care most compatible with their spiritual belief and culture. Thus, every family must be assessed and counseled individually for end-of-life decision-making. Also, every effort should be made to comply with parents' requests and to treat infants/parents of different religions and cultures with utmost dignity so that they have no regret for their irreversible decisions.

A prospective longitudinal study to estimate the "adjusted cortisol percentile" in preterm infants.

The normal range of serum cortisol concentrations and the appropriate levels of circulating cortisol in different clinical situations in preterm infants are not well defined. This study aimed to evaluate the impact of perinatal factors on circulating cortisol levels in preterm infants and to create a quantitative model that could estimate the "adjusted cortisol percentile." Serial serum cortisol concentrations were measured in 209 infants ≤ 32 wk gestation on d 1, 4, 7, 14, and 21 of life. Seven perinatal factors or conditions that could affect circulating cortisol level were identified. Serum cortisol levels were higher on d 4 (p = 0.007) and d 7 (p = 0.007) but lower on d 21 (p = 0.001) compared with d 1. Serum cortisol was also higher in infants on nasal continuous positive airway pressure (p = 0.003); requiring a second vasopressor (p < 0.001); with intraventricular hemorrhage (≥ grade 3; p < 0.001); with histologic chorioamnionitis (p = 0.007); with severe lung disease (p = 0.046); and with decreasing GA (p < 0.001). A mathematical equation was proposed based on factors derived in this preliminary study for estimating the adjusted cortisol percentile. Frontline neonatologists could now access the equation on our Web site (http://www.sta.cuhk.edu.hk/pswong/ACortP.html) to calculate the adjusted cortisol percentile, which could potentially improve the interpretation of circulating cortisol in different clinical situations.

Use of prokinetics in the preterm infant.

PURPOSE OF REVIEW: Functional gastrointestinal dysmotility is a common condition that affects premature infants. Delay in achievement of full enteral nutrition results in dependence on prolonged parenteral nutrition, predisposing to adverse outcomes. Studies in recent years show apparently conflicting results regarding the use of prokinetic agents in preterm infants. This review aims to evaluate these studies to determine whether use of these agents in premature infants is beneficial and justified. RECENT FINDINGS: Randomized controlled trials in recent years have been performed to investigate the effectiveness of erythromycin in the treatment of nonobstructive gastrointestinal dysmotility in preterm infants. Overall, neither low-dose regimes nor prophylactic trials have been shown to be useful. High-dose regimes used as rescue therapy of infants with established gastrointestinal dysmotility have consistently shown clinical benefit. Theoretical risks of prolonged antibiotic use, such as emergence of antibiotic resistance and abnormal intestinal microbiota, have not been fully evaluated. SUMMARY: Judicious use of high-dose erythromycin in premature infants as rescue therapy is probably justifiable. Further research in this area is warranted to develop newer prokinetic agents which may improve the safety profile of therapy.

Influenza or not influenza: analysis of a case of high fever that happened 2000 years ago in Biblical time.

The Bible describes the case of a woman with high fever cured by our Lord Jesus Christ. Based on the information provided by the gospels of Mark, Matthew and Luke, the diagnosis and the possible etiology of the febrile illness is discussed. Infectious diseases continue to be a threat to humanity, and influenza has been with us since the dawn of human history. If the postulation is indeed correct, the woman with fever in the Bible is among one of the very early description of human influenza disease. Infectious diseases continue to be a threat to humanity, and influenza has been with us since the dawn of human history. We analysed a case of high fever that happened 2000 years ago in Biblical time and discussed possible etiologies.

Rapid identification and differentiation of Gram-negative and Gram-positive bacterial bloodstream infections by quantitative polymerase chain reaction in preterm infants.

OBJECTIVE: To evaluate the usefulness of the Gram-specific probe-based quantitative polymerase chain reaction test for rapid detection and differentiation of Gram-negative and Gram-positive bacterial bloodstream infection in preterm infants. DESIGN: Cross-sectional study. SETTING: University-affiliated Level III neonatal intensive care unit. PATIENTS: Preterm infants with clinical features suggestive of late-onset infection. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In addition to the full sepsis screen, 0.5 mL of EDTA blood was collected aseptically for Gram-specific quantitative polymerase chain reaction evaluation. The results were analyzed with respect to outcomes of bacterial culture in blood and other body fluids, including peritoneal and cerebrospinal fluids. The diagnostic utilities of the quantitative polymerase chain reaction were determined. A total of 218 suspected infection episodes were investigated, of which 42 episodes were culture positive and 176 were culture negative. For Gram-negative infection, the quantitative polymerase chain reaction test correctly identified 19 of 22 episodes, and the sensitivity and specificity were 86.4% and 99.0%, respectively. For Gram-positive infection, the test correctly identified 14/19 episodes, and the sensitivity and specificity were 73.7% and 98.5%. The remaining one episode was Candida albicans septicemia. None of the episodes with positive quantitative polymerase chain reaction test were classified into the wrong Gram stain category. More importantly, despite negative blood culture in five infants suffering from intra-abdominal sepsis (peritonitis [n = 4] and hepatosplenic abscess [n = 1]), the quantitative polymerase chain reaction test could detect the Gram-specific category of causative organisms in blood. CONCLUSIONS: The Gram-specific quantitative polymerase chain reaction test is reliable and highly specific for rapid identification and differentiation of Gram-negative and Gram-positive bloodstream and intra-abdominal infections. The result could be made available within 5 hrs after the specimen reaches the laboratory. A positive test is able to "rule in" bacterial bloodstream infection before blood culture results become available, and serves as a guide to predict the virulence of the causative organism according to its Gram-specific category so that critical patients can be targeted for intensive treatment.

Transient increase in intraocular pressure during a dose-tapering regime of systemic dexamethasone in preterm infants.

PURPOSE: To determine the intraocular pressure (IOP) profile during and after systemic dexamethasone treatment in preterm very low birth weight (VLBW; <1500 g) infants. DESIGN: A cohort study at a university-affiliated tertiary neonatal center. PARTICIPANTS: Twenty-seven VLBW infants who received a 3-week dose-tapering course of systemic dexamethasone for treatment of bronchopulmonary dysplasia were consecutively enrolled over a period of 32 months. METHODS: Intraocular pressure was assessed using a handheld tonometer immediately before (week 0), during (weeks 1 and 3), and after (weeks 5, 7, and 9) commencement of the dexamethasone course. The mixed-effects models were used to evaluate the longitudinal IOP measurements at different time points. MAIN OUTCOME MEASURES: To assess the magnitude and duration of increase in IOP during systemic corticosteroid treatment. RESULTS: The IOP at week 1, while the infants were receiving the maximum dose of dexamethasone (0.6 mg/kg/day), was significantly higher than (1) the pretreatment IOP at week 0 (mean [+/- standard deviation]: 19.7 [+/-3.7] vs. 16.4 [+/-3.7] mmHg, respectively) (P<0.0001), (2) the IOP when the infants were receiving the minimum dose of dexamethasone (0.15 mg/kg/day) at week 3 (19.7 [+/-3.7] vs. 15.8 [+/-4.3] mmHg) (P<0.0001), and (3) the IOP after the dexamethasone course had been stopped between week 5 and week 9 (19.7 [+/-3.7] vs. 16.0 [+/-4.0], 15.3 [+/-3.5], and 14.5 [+/-3.3] mmHg for weeks 5, 7, and 9, respectively) (P<0.0001 for all comparisons). In contrast, there was no significant difference between the pretreatment IOP (week 0) and IOP at week 3, 5, 7, or 9 (P = 0.07-0.62) and in the IOP between week 3 and week 5, 7, or 9 (P = 0.27-0.75). CONCLUSIONS: The use of a dose-tapering regime of dexamethasone is associated with transient increase of IOP. As IOP was significantly raised during the high-dose but not the low-dose treatment period, we speculate that the physiologic or stress dose of corticosteroids commonly advocated for treatment of serious neonatal conditions should be safe and unlikely to cause significant ocular hypertension in preterm infants.

C-reactive protein in children with obstructive sleep apnea and the effects of treatment.

OBJECTIVE: To evaluate C-reactive protein (CRP) concentration in children with OSA and to determine the effects of treatment for OSA on its serum concentration. METHODS: Consecutive children with habitual snoring and symptoms suggestive of OSA were recruited. They completed a sleep apnea symptom questionnaire, underwent physical examination and an overnight polysomnography (PSG). Fasting serum CRP and lipid profile were taken after overnight PSG. OSA was diagnosed if obstructive apnea index (OAI)>1. RESULTS: One hundred forty-one children with a median (IQR) age of 10.8 (8.5-12.8) years were recruited. There were 96 boys and the commonest presenting symptoms were nocturnal mouth breathing, prone sleeping position and poor attention at school. Forty-five children were found to have OSA and those with moderate disease (OAI>5) had significantly higher CRP levels compared to their non-OSA counterparts [1.3 (0.8-3.6) vs. 0.7 (0.2-2.0), P=0.01]. Stepwise linear multiple regression analysis indicated that OAI was independently associated with CRP (beta coefficient=0.013, P=0.001). Sixteen children underwent treatment and there was significant reduction in their serum CRP after intervention [pre vs. post-CRP, 1.3 (0.6-4.1) vs. 0.4 (0.2-1.3), P=0.033]. A significant correlation was also demonstrated between change in CRP and change in OAI (r=0.593, P=0.042) following treatment for OSA. CONCLUSION: Children with OSA may have associated systemic inflammation as reflected by a raised CRP that decreased significantly following treatment.

Biochemical markers of neonatal sepsis.

The use of biochemical markers in neonatal infection has remained an important area of research in the past decades. Many infection markers are components of the inflammatory cascade and reflect the host's immunological status and response to infection. Cytokines and chemokines such as interleukin (IL)-6 and IL-8 have been demonstrated to have good diagnostic utilities as early phase markers, while acute phase reactants such as C-reactive protein and procalcitonin have superior diagnostic properties during the later phases. Other markers, including inter-alpha-inhibitor proteins, IL-10 and regulated upon activation normal T cells expressed and secreted (RANTES) have been demonstrated to yield important prognostic information and may help the clinician identify infants who will develop fulminant infection from the outset of presentation. The advent of flow cytometry and molecular techniques have made crucial contributions to the field and promise to further improve the diagnostic accuracy and clinical management of infected infants.

Unusual loss of body hair in childhood: Trichotillomania or alopecia.

Hair loss (alopecia) is a relatively common problem in childhood and the underlying pathophysiology and manifestations are diverse. We report four cases of hair loss with unusual distributions and discuss the outcome of their management. One child had alopecia with unilateral loss of hair over the eyebrow. He received topical corticosteroids and tacrolimus and his condition resolved. A girl had scalp alopecia which evolved to alopecia universalis. The mother and the child were non-compliant with treatment. A boy had alopecia totalis not responsive to Western or alternative treatment. The fourth child had trichotillomania and bizarre loss of scalp hair. Mother and child received psychological counselling and the child's hair loss improved. It is important to differentiate between alopecia and trichotillomania as the management is very different. Diagnosis and treatment are based on clinical assessment, evaluation of coexisting psychosocial factors and exclusion of autoimmune and other underlying disorders. In alopecia totalis or universalis, alternative therapy is often sought and tried for prolonged periods but efficacy has remained unproven. These cases serve to illustrate the principles of management of children with unusual patterns of hair loss.

Fetal methylmercury exposure as measured by cord blood mercury concentrations in a mother-infant cohort in Hong Kong.

This study was designed to examine newborn infants in Hong Kong prenatally exposed to levels of methylmercury considered to increase risk of neurotoxic effects and to examine subject characteristics that modify the degree of prenatal mercury exposure. Mercury concentrations in 1057 sets of maternal and cord blood samples and 96 randomly selected maternal hair samples were measured. Subject characteristics were measured or collected by questionnaire. Of the 1057 cord blood samples collected only 21.6% had mercury concentrations less than 29 nmol/L (5.8 micro g/L). Median maternal hair mercury concentration was 1.7 ppm. The geometric mean cord to maternal blood mercury ratio was 1.79 to 1. Increasing maternal fish consumption and maternal age were found to be associated with increased cord blood mercury concentrations. Marine fish consumption increased cord blood mercury concentrations more than freshwater fish (5.09%/kg vs 2.86%/kg). Female babies, maternal alcohol consumption and increasing maternal height were associated with decreased cord blood mercury concentrations. Pregnant women in Hong Kong consume large amounts of fish and as a result, most of their offspring have been prenatally exposed to moderately high levels of mercury. In this population, pregnant women should choose freshwater over marine fish and limit fish consumption.

Persistent Staphylococcus capitis septicemia in a preterm infant.

A preterm infant had persistent Staphylococcus capitis septicemia with 11 consecutive positive blood cultures over a period of 33 days. The clinical evidence suggested that the source of infection probably originated from the gastrointestinal tract. The combination of rifampin and linezolid treatment, together with prolonged stoppage of enteral feeding, successfully terminated the infection. Rifampin and linezolid should be considered as alternative antimicrobial agents when glycopeptides fail to eradicate Gram-positive pathogens from the host.

Bronchodilator effect of salbutamol from two different spacer devices.

Our aim was to compare the bronchodilator effect of salbutamol delivered via a new holding chamber (Volumatic Soft, VS) with that of an established device (Volumatic, V) in asthmatic children. Children with stable asthma were recruited. They inhaled 100 microg, and 10 min later, 300 microg of salbutamol aerosol delivered via VS or V on day 1, and vice versa on day 2. Spirometry was measured at baseline, 10 min after 100 microg, and 15 min after 300 microg of salbutamol were given. The preference for either device was assessed by visual analogue score. Forty-four children with a median age of 9.2 years (interquartile range, 8.0-10.7) completed the study. There were significant improvements in forced expired volume in 1 sec (FEV1) with time throughout the study period for both V and VS (linear and quadratic trend P < 0.001). There was a statistically significant difference in postbronchodilator FEV1 between V and VS (P = 0.013). VS gave an overall greater change in FEV1 than V, by 1.8%. The preference scores for V and VS were 7.0 (IQR 5.0-8.0) and 9.0 (IQR 8.0-10.0) (p < 0.0005), respectively. In conclusion, comparable clinical efficacy was found for V and VS with respect to changes in FEV1 after salbutamol. Patients also showed a strong preference for the new device.

Life-Threatening Hemolytic Anemia after Intrapleural Instillation of OK-432 for Treatment of Congenital Chylothorax.

Recent reports have advocated treatment of congenital chylothorax with chemical pleurodesis via intrapleural administration of OK-432. Severe complications have not been reported, but recently we have encountered a life-threatening case of massive hemolysis after the procedure. The hemoglobin of the infant decreased from 8.7 to 3.1 g/dl within 48 h, with concomitant severe hyperbilirubinemia (472 µmol/l) requiring exchange transfusion. Frontline neonatologists should be aware of this rare but potentially life-threatening adverse reaction. In addition, it is possible that a longer indwelling time (3.5 vs. 0.5 h) for OK-432 pleurodesis may alter the therapeutic response.

End-of-life decision-making for newborns: a 12-year experience in Hong Kong.

SETTING: Neonatal end-of-life decisions could be influenced by cultural and ethnic backgrounds. These practices have been well described in the West but have not been systematically studied in an Asian population. OBJECTIVES: To determine: (1) different modes of neonatal death and changes over the past 12 years and (2) factors influencing end-of-life decision-making in Hong Kong. DESIGN: A retrospective study was conducted to review all death cases from 2002 to 2013 in the busiest neonatal unit in Hong Kong. Modes of death, demographical data, diagnoses, counselling and circumstances around the time of death, were collected and compared between groups. RESULTS: Of the 166 deaths, 46% occurred despite active resuscitation (group 1); 35% resulted from treatment withdrawal (group 2) and 19% occurred from withholding treatment (group 3). A rising trend towards treatment withdrawal was observed, from 20% to 47% over the 12-year period. Similar number of parents chose extubation (n=44, 27%) compared with other modalities of treatment limitation (n=45, 27%). Significantly more parents chose to withdraw rather than to withhold treatment if clinical conditions were 'stable' (p=0.03), whereas more parents chose withholding therapy if treatment was considered futile (p=0.03). CONCLUSION: In Hong Kong, a larger proportion of neonatal deaths occurred despite active resuscitation compared with Western data. Treatment withdrawal is, however, becoming increasingly more common. Unlike Western practice, similar percentages of parents chose other modalities of treatment limitation compared with direct extubation. Cultural variance could be a reason for the different end-of-life practice adopted in Hong Kong.

Clinical, virologic and immunologic profiles of a young infant with severe acute respiratory syndrome.

The clinical findings, plasma viral load, cytokines and chemokines of a 4-month-old infant with severe acute respiratory syndrome (SARS) were assessed at different phases of the disease. Ribavirin failed to inhibit SARS coronavirus (SARS-CoV) replication. One-step real time reverse transcription-polymerase chain reaction for plasma SARS-CoV RNA quantification was useful for early diagnosis and monitoring viremia.

Are your hands clean enough for point-of-care electrolyte analysis?

AIM: To investigate clinically significant analytical interference in point-of-care electrolyte analysis caused by contamination of blood specimens with hand disinfectant. METHODS: Six different hand hygiene products were added separately to heparinised blood samples in varying amounts as contaminant. The contaminated samples were analysed by three different blood gas and electrolyte analysers for assessing interference on measured whole blood sodium and potassium concentrations. RESULTS: There were significant analytical interferences caused by hand hygiene product contamination that varied depending on the combination of disinfectant and analyser. Small amounts of Microshield Antibacterial Hand Gel contamination caused large increases in measured sodium concentration. Such effect was much greater compared with the other five products tested, and started to occur at much lower levels of contamination. There was a trend towards lower sodium results in blood samples contaminated with Hexol Antiseptic Lotion (Hexol), the hand hygiene product that we used initially. Apart from AiE Hand Sanitizer, all the other hand disinfectants, especially Hexol, significantly elevated the measured potassium concentration, particularly when a direct ion-selective electrode method was used for measurement. CONCLUSIONS: Hand disinfectant products can significantly interfere with blood electrolyte analysis. Proper precautions must be taken against contamination since the resultant errors can adversely affect the clinical management of patients.

A double-blind randomised controlled trial of fish oil-based versus soy-based lipid preparations in the treatment of infants with parenteral nutrition-associated cholestasis.

BACKGROUND: Infants receiving prolonged parenteral nutrition (PN) are at risk of PN-associated cholestasis (PNAC). This can progress to hepatic failure and death if PN cannot be discontinued. Fish oil-based parenteral lipid preparation (FOLP) has been shown to be beneficial in case studies. OBJECTIVES: (1) To evaluate whether FOLP could halt or reverse the progression of PNAC compared with soy-based parenteral lipid preparation (SLP) and (2) to assess the effects of FOLP on liver function and physical growth. DESIGN: double-blind randomised controlled trial. SETTING: level III neonatal intensive care unit. PARTICIPANTS: infants with PNAC (plasma-conjugated bilirubin concentration ≥ 34 µmol/l or 2 mg/dl) expected to be PN-dependent for >2 weeks. INTERVENTION: to receive either FOLP or SLP at 1.5 g/kg/day. PRIMARY OUTCOME MEASURE: reversal of PNAC within 4 months after commencement of lipid treatment; secondary outcomes: rate of change of weekly liver function tests, infant growth parameters, blood lipid profile and episodes of late-onset sepsis. RESULTS: A total of 9 infants were randomised to the FOLP group and 7 to the SLP group. There was no significant difference in reversal of PNAC at 4 months between groups. Rates of increase of plasma-conjugated bilirubin and alanine aminotransferase in the SLP group were significantly greater than the FOLP group (13.5 vs. 0.6 µmol/l per week and 9.1 vs. 1.1 IU/l per week, respectively, p = 0.03). Increased enteral nutrition was associated with significant improvement of PNAC in infants receiving FOLP compared with SLP (-8.5 vs. -1.6 µmol/l per 10% increase in enteral nutrition, respectively). The study was terminated prematurely. CONCLUSIONS: progression of PNAC in PN-dependent infants can be halted by replacing SLP with FOLP and reversed by increasing the proportion of enteral nutrition in infants receiving FOLP. Replacement of SLP with FOLP in PN-dependent infants who develop PNAC may be considered.

Biomarkers for prediction and diagnosis of necrotizing enterocolitis.

This article summarizes the commonly used biomarkers currently available for diagnosis of necrotizing enterocolitis. The most exciting advances in diagnostic tests were the use of new nucleic acid sequencing techniques (eg, next-generation sequencing) and molecular screening methods (eg, proteomics and microarray analysis) for the discovery of novel biomarkers. The new technology platform coupled with stringent protocols of biomarker discovery and validation would enable neonatologists to study biologic systems at a level never before possible and discover unique biomarkers for specific organ injury and/or disease entity.