Caffeine pharmacokinetics following umbilical vein injection during delayed cord clamping in preterm lambs.

BACKGROUND: Spontaneous breathing during and after delayed cord clamping (DCC) stabilizes cardiopulmonary transition at birth. Caffeine stimulates breathing and decreases apnea in premature newborns. We evaluated the pharmacokinetics and physiological effects of early caffeine administration-direct injection into the umbilical vein (UV) during DCC or administered through a UV catheter (UVC) after delivery. METHODS: Eighteen extremely premature lambs (125-127d, term gestation 145d) were exteriorized and instrumented. Lambs received caffeine-citrate at high (40 mg/kg) or standard-dose (20 mg/kg) via direct UV (DUV) injection during DCC, or via the UVC. RESULTS: Mean peak plasma caffeine concentrations were lower with high-dose DUV compared to UVC (18 ± 4.3 vs. 46 ± 12 mg/L, p < 0.05). With standard-dose caffeine, mean peak plasma levels were 7.48 ± 2.6 with DUV and 28.73 ± 9.4 mg/L with UVC. The volume of distribution was higher in the DUV group compared to UVC (2.5 ± 1.0 vs. 0.69 ± 0.15 L/kg) with an estimated 39 ± 18% entering the maternal circulation. Maternal peak concentrations were 0.79 ± 0.71 and 1.43 ± 0.74 mg/L with standard and high-dose DUV, respectively. CONCLUSIONS: Caffeine injected directly into the UV during DCC is feasible but achieves lower concentrations due to high volume of distribution including maternal circulation. Further trials evaluating DUV caffeine injection should use higher caffeine doses. IMPACT: Respiratory stimulation with early caffeine may reduce the need for intubation in preterm infants. In the preterm lambs, caffeine injection directly into the umbilical vein during delayed cord clamping is feasible. Plasma caffeine concentrations are less than half when administered directly into the umbilical vein during delayed cord clamping compared to administration via an umbilical venous catheter following birth likely attributed to a larger volume of distribution or injection site leak. There were no significant hemodynamic alterations following caffeine injection.

Neonatal resuscitation with continuous chest compressions and high frequency percussive ventilation in preterm lambs.

BACKGROUND: Cerebral oxygen delivery (cDO2) is low during chest compressions (CC). We hypothesized that gas exchange and cDO2 are better with continuous CC with high frequency percussive ventilation (CCC + HFPV) compared to conventional 3:1 compressions-to-ventilation (C:V) resuscitation during neonatal resuscitation in preterm lambs with cardiac arrest induced by umbilical cord compression. METHODS: Fourteen lambs in cardiac arrest were randomized to 3:1 C:V resuscitation (90CC + 30 breaths/min) per the Neonatal Resuscitation Program guidelines or CCC + HFPV (120CC + HFPV continuously). Intravenous epinephrine was given every 3 min until return of spontaneous circulation (ROSC). RESULTS: There was no difference in the incidence and time to ROSC between both groups. Median (IQR) PaCO2 was significantly lower with CCC + HFPV during CC, at ROSC and 15 min post-ROSC-[104 (99-112), 83 (77-99), and 43 (40-64)], respectively compared to 3:1 C:V-[149 (139-167), 153 (143-168), and 153 (138-178) mmHg. PaO2 and cDO2 were higher with CCC + HFPV during CC and at ROSC. PaO2 was similar 15 min post-ROSC with a lower FiO2 in the CCC + HFPV group 0.4 (0.4-0.5) vs. 1 (0.6-1). CONCLUSION: In preterm lambs with perinatal cardiac-arrest, continuous chest compressions with HFPV does not improve ROSC but enhances gas exchange and increases cerebral oxygen delivery compared to 3:1 C:V during neonatal resuscitation. IMPACT STATEMENT: Ventilation is the most important intervention in newborn resuscitation. Currently recommended 3:1 compression-to-ventilation ratio is associated with hypercarbia and poor oxygen delivery to the brain. Providing uninterrupted continuous chest compressions during high frequency percussive ventilation is feasible in a lamb model of perinatal cardiac arrest, and demonstrates improved gas exchange and oxygen delivery to the brain. This is the first study in premature lambs evaluating high frequency percussive ventilation with asynchronous chest compressions and lays the groundwork for future clinical studies to optimize gas exchange and hemodynamics during chest compressions in newborns.

Intestinal Dysbiosis in the Infant and the Future of Lacto-Engineering to Shape the Developing Intestinal Microbiome.

PURPOSE: The goal of this study was to review the role of human milk in shaping the infant intestinal microbiota and the potential of human milk bioactive molecules to reverse trends of increasing intestinal dysbiosis and dysbiosis-associated diseases. METHODS: This narrative review was based on recent and historic literature. FINDINGS: Human milk immunoglobulins, oligosaccharides, lactoferrin, lysozyme, milk fat globule membranes, and bile salt-stimulating lipase are complex multifunctional bioactive molecules that, among other important functions, shape the composition of the infant intestinal microbiota. IMPLICATIONS: The co-evolution of human milk components and human milk-consuming commensal anaerobes many thousands of years ago resulted in a stable low-diversity infant microbiota. Over the past century, the introduction of antibiotics and modern hygiene practices plus changes in the care of newborns have led to significant alterations in the intestinal microbiota, with associated increases in risk of dysbiosis-associated disease. A better understanding of mechanisms by which human milk shapes the intestinal microbiota of the infant during a vulnerable period of development of the immune system is needed to alter the current trajectory and decrease intestinal dysbiosis and associated diseases.

Effect of a Larger Flush Volume on Bioavailability and Efficacy of Umbilical Venous Epinephrine during Neonatal Resuscitation in Ovine Asphyxial Arrest.

The 7th edition of the Textbook of Neonatal Resuscitation recommends administration of epinephrine via an umbilical venous catheter (UVC) inserted 2-4 cm below the skin, followed by a 0.5-mL to 1-mL flush for severe bradycardia despite effective ventilation and chest compressions (CC). This volume of flush may not be adequate to push epinephrine to the right atrium in the absence of intrinsic cardiac activity during CC. The objective of our study was to evaluate the effect of 1-mL and 2.5-mL flush volumes after UVC epinephrine administration on the incidence and time to achieve return of spontaneous circulation (ROSC) in a near-term ovine model of perinatal asphyxia induced cardiac arrest. After 5 min of asystole, lambs were resuscitated per Neonatal Resuscitation Program (NRP) guidelines. During resuscitation, lambs received epinephrine through a UVC followed by 1-mL or 2.5-mL normal saline flush. Hemodynamics and plasma epinephrine concentrations were monitored. Three out of seven (43%) and 12/15 (80%) lambs achieved ROSC after the first dose of epinephrine with 1-mL and 2.5-mL flush respectively (p = 0.08). Median time to ROSC and cumulative epinephrine dose required were not different. Plasma epinephrine concentrations at 1 min after epinephrine administration were not different. From our pilot study, higher flush volume after first dose of epinephrine may be of benefit during neonatal resuscitation. More translational and clinical trials are needed.

Non-invasive carbon dioxide monitoring in neonates: methods, benefits, and pitfalls.

Wide fluctuations in partial pressure of carbon dioxide (PaCO2) can potentially be associated with neurological and lung injury in neonates. Blood gas measurement is the gold standard for assessing gas exchange but is intermittent, invasive, and contributes to iatrogenic blood loss. Non-invasive carbon dioxide (CO2) monitoring has become ubiquitous in anesthesia and critical care and is being increasingly used in neonates. Two common methods of non-invasive CO2 monitoring are end-tidal and transcutaneous. A colorimetric CO2 detector (a modified end-tidal CO2 detector) is recommended by the International Liaison Committee on Resuscitation (ILCOR) and the American Academy of Pediatrics to confirm endotracheal tube placement. Continuous CO2 monitoring is helpful in trending PaCO2 in critically ill neonates on respiratory support and can potentially lead to early detection and minimization of fluctuations in PaCO2. This review includes a description of the various types of CO2 monitoring and their applications, benefits, and limitations in neonates.

Glucose Levels during the First 24 Hours following Perinatal Hypoxia.

OBJECTIVE: Hypoglycemia is a significant risk factor for perinatal brain injury and adverse outcomes, particularly in infants requiring resuscitation following hypoxic ischemic (HI) insult. We aimed to study blood glucose (BG) levels in physiologically stressed infants in the presence or absence of epinephrine (Epi) administration at resuscitation in the first 24 hours after birth. STUDY DESIGN: A retrospective chart review of all infants with heart rate (HR) < 100/min at 1 minute requiring positive pressure ventilation (PPV) at birth was performed. Infants were classified into two groups as follows: (1) PPV group: infants' HR improved with PPV only at resuscitation, and Epi group: infants received Epi at resuscitation for persistent bradycardia. Serial measurements of BG levels collected and glucose infusion rate (GIR) calculated at 24 hours. RESULTS: By design, infants in the Epi group had lower cord pH and higher base deficit. BG was significantly lower overtime in premature infants ≤32 weeks of gestation in the Epi group. The BG was markedly higher in near-term and term infants in the Epi group compared with the PPV group. Hypoglycemia was more common despite administration of higher GIR in premature infants ≤32 weeks of gestation. CONCLUSION: In the presence of physiological stress, premature infants are more at risk for hypoglycemia than term infants.

Down Syndrome and Postoperative Complications in Children Undergoing Intestinal Operations.

OBJECTIVE: This paper intends to evaluate the association between Down Syndrome (DS) and postoperative medical and surgical complications and inpatient postoperative mortality in pediatric patients undergoing intestinal operations. METHODS: The 2012 Kids' Inpatient Database was queried to compare short-term postoperative medical and surgical complications and in-patient mortality among patients with DS undergoing intestinal operations to a cohort without DS using inverse probability weighting. Subset analysis was performed for patients undergoing intestinal operations exclusive of gastrostomy placement. Adverse treatment effects were calculated for the outcomes of interest. RESULTS: Of 17,026 pediatric patients undergoing intestinal operations, 444 had DS. In unadjusted analysis, medical complications (urinary tract infection, deep venous thrombosis, sepsis, pneumonia) occurred in 7.9% of patients with DS, compared to 14.1% of those without (p < 0.001). Surgical complications (wound disruption, hemorrhage, superficial or deep wound infection) occurred in 3.5% of patients with DS, compared to 4.6% of those without (p = 0.34), and in-patient mortality occurred in 0.3% of patients with DS, compared to 2.7% of those without (p = 0.009). Adverse treatment effects (ATE) calculated after inverse probability weighting demonstrated no difference for medical or surgical complications but a significantly decreased mortality with DS. CONCLUSIONS: Contrary to common perception and data extrapolated from the adult literature, pediatric patients with DS have neither higher medical nor surgical complication rates after intestinal operations. Similar to patients undergoing congenital heart surgery, pediatric patients with DS have a lower postoperative inpatient mortality after these general operations compared to those without DS. Mechanisms influencing risks in DS patient remain unknown. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Yield of Echocardiogram and Predictors of Positive Yield in Pediatric Patients: A Study in an Urban, Community-Based Outpatient Pediatric Cardiology Clinic.

The yield of outpatient echocardiograms varies based on the indication for the echocardiogram and the age of the patient. The purpose of this study was to determine the cumulative yield of outpatient echocardiograms by age group and reason for the test. A secondary aim was to determine the predictors of a positive echocardiogram in an outpatient cardiology clinic at a large community teaching hospital. We retrospectively reviewed the charts of 891 patients who had a first-time echocardiogram between 2011 and 2015. Positive yield was defined as echocardiographic findings that explained the reason for the echocardiogram. The overall positive yield was 8.2%. Children between birth and 3 months of age had the highest yield (34.2%), and children between 12 and 18 years of age had the lowest yield (1%). Patients with murmurs (18.1%) had the highest yield compared with patients with other signs or symptoms. By age group and reason, the highest yields were as follows: 0 to 3 months of age, murmur (39.2%); 4 to 11 months of age, >1 symptom (50%); and 1 to 5 years of age, shortness of breath (66.7%). Based on our study, the overall yield of echocardiograms in the outpatient pediatric setting is low. Age and symptoms should be considered before ordering an echocardiogram.

Relation between HER-2 gene expression and Gleason score in patients with prostate cancer.

INTRODUCTION: HER-2 is a proto-oncogene of the tyrosine kinase receptor family on chromosome 17. Overexpression of this gene affects the growth and prognosis of some tumors. This study was performed to evaluate the expression of the HER-2 gene in patients with prostate cancer and its relation with the Gleason score. MATERIALS AND METHODS: Pathology specimens of all men with prostate cancer who had undergone radical prostatectomy without any supportive treatment were studied. The Gleason scores of the specimens and the expression of HER-2 gene were examined. The expression of HER-2 was scored between zero and 3+ in accordance with the HercepTest method. Patients with scores of 2+ and 3+ were considered to be positive for HER-2 overexpression. RESULTS: Of 150 cancerous prostate specimens evaluated, 20 (13.3%) were positive for HER-2 gene overexpression. A weakly positive HER-2 overexpression (2+) was seen in 15 of them (75%) and the remaining 5 (25%) were strongly positive. The Gleason score was not different between the HER-2-positive and HER-2-negative patients (P = .08). Fourteen out of 97 patients (14.4%) with a Gleason score less than 7 and 6 out of 53 (11.3%) with scores of 7 or greater were positive for HER-2 overexpression. CONCLUSION: The frequency of HER-2 gene overexpression is not very high in our patients with prostate cancer, and we failed to show any association of HER-2 expression and the Gleason score.