Early extubation (EE) of children after surgery (occurring within the operating room or <= 6hours postadmission) for congenital heart disease (CHD) has been advocated to improve postoperative care. The objective of this study is to compare outcomes of neonates undergoing EE following CHD surgical repair with those extubated more than 6hours after surgery. Retrospective cohort study utilizes data from the Virtual Pediatric Systems database. Data from neonates undergoing surgical repair for six common CHD lesions and admitted to 57 pediatric intensive care units (ICUs) between July 1, 2010, and June 30, 2015, were analyzed. A total of 1,274 neonates were analyzed; 100 (7.8%) had EE, and 146 (11.5%) were extubated>6hours but <= 24hours. Most patients (80.4%) were extubated>24hours. The EE group had higher (p <0.001) failed extubation rate than patients extubated at any other time; a multivariate analysis of linear regression showed no advantage in length of stay (LOS) of EE compared with those subjects who were extubated in the first 24hours (p-value: 0.178). Extubation failure was found to impact ICU LOS in this analysis. The ICU LOS was increased by 3.5 days for every failed extubation attempt (p-value: <0.001, 95% confidence interval: 1.6-5.5 days). EE after CHD surgery is possible. Though it appears as an attractive option to decrease potential mechanical ventilation complications, this study of neonates shows that EE might result in worse outcomes than when performing extubation between 6 and 24hours postoperatively.

OBJECTIVE The pharmacokinetics of β-lactam antibiotics favor administration via an extended infusion. Although literature to support extended infusion β-lactams exists for adults, few data are available in pediatrics, especially among patients with bacteremia. The purpose of this study was to compare clinical outcomes between extended and standard infusions in children with Gram-negative bacteremia. METHODS This retrospective chart analysis included hospitalized patients ages 0 to 18 years who received at least 72 hours of cefepime, meropenem, or piperacillin-tazobactam between January 1, 2013 and July 30, 2021. Clinical outcomes included duration of antibiotic therapy, hospital length of stay, readmission within 30 days, all-cause mortality, time to blood culture clearance, and time to normalization of inflammatory markers. RESULTS A total of 124 patients (51 extended infusion, 73 standard infusion) met criteria for evaluation. Duration of antibiotic therapy was shorter in the extended infusion group (6.6 days versus 10.2 days; p = 0.01). There were no differences in hospital length of stay, readmission rates, all-cause mortality, time to normalization of inflammatory markers, or time to blood culture clearance. CONCLUSIONS Use of extended infusion β-lactam antibiotics in children with Gram-negative bacteremia was associated with shorter durations of therapy and should be the preferred method of administration when feasible.

Objectives The heterogeneity of sepsis makes it difficult to predict outcomes using existing severity of illness tools. The vasoactive-inotrope score (VIS) is a quantitative measure of the amount of vasoactive support required by patients. We sought to determine if a higher aggregate VIS over the first 96 h of vasoactive medication initiation is associated with increased resource utilization and worsened clinical outcomes in pediatric patients with severe sepsis. Design Retrospective cohort study. Setting Single-center at Children's Wisconsin in Milwaukee, WI. Patients One hundred ninety-nine pediatric patients, age less than 18 years old, diagnosed with severe sepsis, receiving vasoactive medications between January 2017 and July 2019. Interventions Retrospective data obtained from the electronic medical record, calculating VIS at 2 h intervals from 0–12 h and at 4 h intervals from 12–96 h from Time 0. Measurements Aggregate VIS derived from the hourly VIS area under the curve (AUC) calculation based on the trapezoidal rule. Data were analyzed using Pearson's correlations, Mann-Whitney test, Wilcoxon signed rank test, and classification, and regression tree (CART) analyses. Main Results Higher aggregate VIS is associated with longer hospital LOS (p < 0.0001), PICU LOS (p < 0.0001), MV days (p = 0.018), increased in-hospital mortality (p < 0.0001), in-hospital cardiac arrest (p = 0.006), need for ECMO (p < 0.0001), and need for CRRT (p < 0.0001). CART analyses found that aggregate VIS >20 is an independent predictor for in-hospital mortality (p < 0.0001) and aggregate VIS >16 for ECMO use (p < 0.0001). Conclusions There is a statistically significant association between aggregate VIS and many clinical outcomes, allowing clinicians to utilize aggregate VIS as a physiologic indicator to more accurately predict disease severity/trajectory in pediatric sepsis.

The effect of positive fluid balance (FB) on extracorporeal membrane oxygenation (ECMO) outcomes in pediatric patients remains unknown. We sought to evaluate if positive FB in pediatric intensive care unit (PICU) patients with respiratory and/or cardiac failure necessitating ECMO was associated with increased morbidity or mortality. This was a multicenter retrospective cohort study of data from the deidentified PEDiatric ECMO Outcomes Registry (PEDECOR). Patients entered into the database from 2014 to 2017, who received ECMO support, were included. A total of 168 subjects met the study criteria. Univariate analysis showed no significant difference in total FB on ECMO days 1–5 between survivors and non-survivors [median 90 ml/kg (IQR 18–208.5) for survivors vs. median 139.7 ml/kg (IQR 11.2–300.6) for non-survivors, p = 0.334]. There was also no difference in total FB on ECMO days 1–5 in patients with no change in functional outcome as reflected by the Pediatric Outcome Performance Category (POPC) score vs. those who had worsening in POPC score ≥2 at hospital discharge [median 98 ml/kg (IQR 18–267) vs. median 130 ml/kg (IQR 13–252), p = 0.91]. Subjects that required 50 ml/kg or more of blood products over the initial 5 days of ECMO support had an increased rate of mortality with an odds ratio of 5.8 (95% confidence interval of 2.7–12.3; p = 0.048). Our study showed no association of the noted FB with survival after ECMO cannulation. This FB trend was also not associated with POPC at hospital discharge, MV duration, or ECMO duration. The amount of blood product administered was found to be a significant predictor of mortality.

OBJECTIVE:The pharmacokinetics of beta-lactam antibiotics favor administration via an extended infusion. Although literature supporting extended infusion beta-lactams exists in adults, few data are available to guide the practice in pediatrics. The purpose of this study was to compare clinical outcomes between extended and standard infusions in children.METHODS:This retrospective chart analysis included hospitalized patients 0 to 18 years old who received at least 72 hours of cefepime, piperacillin-tazobactam, or meropenem between October 1, 2017, and March 31, 2019. Clinical outcomes of care included hospital length of stay, readmission within 30 days, and all-cause mortality.RESULTS:A total of 551 patients (258 extended infusion, 293 standard infusion) met criteria for evaluation. Clinical outcomes among the entire population were similar. A subanalysis of select populations demonstrated decreased mortality in critical care patients (2.1% vs 19.6%, p = 0.006) and decreased 30-day readmission rates in bone marrow transplant patients (0% vs 50%, p = 0.012) who received the extended infusion compared with a standard infusion.CONCLUSIONS:Outcomes were similar between extended and standard infusions in children. Subgroup analyses suggest a possible mortality benefit in the critically ill and decreased readmission rate in bone marrow transplant patients.

In pediatrics, an increasing need for transplantable organs exists. This study aimed to describe the epidemiology of pediatric deceased donors in the United States. This retrospective observational study utilized data from the Organ Procurement and Transplantation Network (OPTN) from 2000 to 2015. Patients were stratified based on method of organ donation. Demographic variables and mechanism of death were then compared. A total of 14,481 deceased pediatric organ donors, donation after brain death (DBD) and donation after circulatory death (DCD), were included in the study, of which 8% were DCD donors. A significant difference (p<0.001) existed between the two donor groups with respect to ethnicity and mechanism of death. The annual trend of DCD and DBD donors showed an inverse relationship. During the 15-year study period the number of DBD donors decreased from 985 to 785 per year while DCD donors increased from 15 to 146 per year. As well, overall organs transplanted per year decreased from 3,475 to 3,117 over the 15-year study period. Significant differences exist between pediatric DBD donors and DCD donors, specifically with respect to ethnicity and mechanism of death. The number of pediatric DBD donors is decreasing while the number of pediatric DCD is slowly rising, making it increasingly important to be able to characterize these donors to better identify eligible DCD donors to optimize organ utilization.

BACKGROUND:Mortality after stage 1 palliation of hypoplastic left heart syndrome remains significant. Both cardiac output (CO) and systemic vascular resistance (SVR) contribute to hemodynamic vulnerability. Simultaneous measures of mean arterial pressure and somatic regional near infrared spectroscopy saturation can classify complex hemodynamics into 4 distinct states, with a low-CO state of higher risk. We sought to identify interventions associated with low-CO state occupancy and transition. METHODS:Perioperative data were prospectively collected in an institutional review board-approved database. Hemodynamic state was classified as high CO, high SVR, low SVR, and low CO using bivariate analysis. Associations of static and dynamic support levels and state classifications over 48 postoperative hours were tested between states and across transitions using mixed regression methods in a quasi-experimental design. RESULTS:Data from 10,272 hours in 214 patients were analyzed. A low-CO state was observed in 142 patients for 1107 hours. Both low CO and extracorporeal membrane oxygenation had increased mortality risk. The low-CO state was characterized by lower milrinone but higher catecholamine dose. Successful transition out of low CO was associated with increased milrinone dose and hemoglobin concentration. Increasing milrinone and hemoglobin levels predicted reduced risk of low CO in future states. CONCLUSIONS:Bivariate classification objectively defines hemodynamic states and transitions with distinct support profiles. Maintaining or increasing inodilator and hemoglobin levels were associated with improved hemodynamic conditions and were predictive of successful future transitions from the low-CO state.

Objectives: The use and outcomes of nasotracheal intubation in pediatric patients requiring mechanical ventilation have not been quantified. Our goal is to identify prevalence of use, associated factors, and outcomes of nasotracheal versus orotracheal intubation in patients requiring mechanical ventilation. Design: Retrospective cohort study using deidentified data from the Virtual Pediatric Systems database. Data from PICU admissions from January 1, 2015, to December 31, 2016 were analyzed. Setting: One hundred twenty-one PICUs located within the United States. Patients: PICU admissions requiring an endotracheal tube—either nasotracheal or orotracheal—were included. Those with a tracheostomy tube present at admission were excluded from the study. Interventions: Not applicable. Measurements and Main Results: Among the 121 PICUs included in the study, 64 PICUs (53%) had zero nasotracheal intubations during the reviewed time period. There were 12,088 endotracheal intubations analyzed, and 680 of them (5.6%) were nasotracheal. Of those patients nasotracheally intubated, most were under 2 years old (88.1%), and 82.2% of them were classified as a cardiac patient. Among these young cardiac patients, the rate of unplanned extubation was 0% in the nasotracheal intubated versus 2.1% in the orotracheal intubated group (p < 0.001) Conclusions: Nasotracheal intubation is used in a minority of U.S. PICUs and mainly among young cardiac patients. Nasotracheal intubation is associated with a lower rate of unplanned extubations in this patient population. Future prospective studies analyzing the benefits and complications of nasotracheal versus orotracheal intubation in pediatric patients requiring mechanical ventilation are indicated.

We describe the case of a 10-year-old male with a history of repaired Tetralogy of Fallot and known intramural right coronary artery (RCA) who presented for bioprosthetic pulmonary valve replacement. The operation was complicated by postoperative ventricular fibrillation arrest. Selective coronary angiography revealed external compression of the mid-RCA by a mediastinal chest tube that improved immediately upon removal of the tube. Ultimately, the patient required additional unroofing of the intramural coronary for full recovery. This case highlights the need to thoroughly investigate malignant ventricular dysrhythmias following pediatric cardiac surgery and to rule out coronary insufficiency, which may be due to both extrinsic and/or intrinsic lesions.

Objectives: Opioids are routinely used in the PICU. Methadone is an effective method of preventing and treating iatrogenic opioid withdrawal; however, it carries an Food and Drug Administration Boxed Warning due to the potential to prolong the corrected QT interval and potentially lead to life-threatening arrhythmias. Guidelines on the safe use of methadone have limited applicability to children since their cardiac intervals differ from those of adults. There is little data on the electrophysiologic effects in the pediatric population. We set out to describe the safety of methadone use in the PICU, hypothesizing that methadone does not cause a significant change in corrected QT interval from baseline. Design: Retrospective cohort study. Setting: Children’s Hospital of Wisconsin, Milwaukee, WI. Patients: Fifty-one patients, age less than or equal to 18 years old, initiated on methadone during PICU admission, over an 11-month period, for the prevention or treatment of opioid withdrawal. Interventions: Retrospective data queried from the electronic health record and stored telemetry waveforms obtained from an automated real-time patient data acquisition software system (BedMasterEx; Anandic Medical Systems AG, Feuerthalen, Switzerland). Measurements and Main Results: Corrected QT intervals were not significantly different at 12 hours, 96 hours, or PICU discharge (p values: 0.57, 0.54, and 0.34) when compared to baseline. The median change in corrected QT from baseline to 12 hours after the first dose of methadone was 5 ms (interquartile range, –12 to 11 ms), 0 ms to steady state (interquartile range, –18 to 18 ms), and 5 ms from baseline to 12 hours after the highest dose of methadone (interquartile range, –14 to 16 ms). The most common primary diagnosis was structural heart disease (29% of subjects) in our cohort and every subject that experienced an increase in corrected QT interval greater than or equal to 40 ms had some form of structural heart disease. Conclusions: Methadone did not significantly prolong the corrected QT interval in a population of critically ill children, suggesting that it can be safely used in this population, although patients with structural heart disease may warrant closer monitoring.

Background. Arginine vasopressin is a nonapeptide hormone with effects on intracellular water transport and arterial tone that is used in distributive shock and following cardiopulmonary bypass. We sought to evaluate the safety and efficacy of vasopressin infusion on hemodynamics and fluid balance in the early postoperative period after Fontan completion. Methods. We conducted a randomized, double blinded, placebo-controlled study of vasopressin infusion for 24 hours after cardiopulmonary bypass for Fontan completion. Patient characteristics, hospital outcomes, and measures of hemodynamic parameters, urine output, chest tube drainage, fluid balance, laboratory data, and plasma arginine vasopressin concentrations were collected at baseline and for 48 postoperative hours. Data were analyzed using mixed-effect regressions. Results. Twenty patients were randomized, 10 to vasopressin and 10 to placebo. Transpulmonary gradient (6.4 +/- 0.5 vs 8.3 +/- 0.5 mm Hg, P =.011) and chest tube drainage (23 +/- 20 vs 40 +/- 20 mL/kg, P =.028) for 48 hours after surgery were significantly lower in the vasopressin arm compared to placebo. Arginine vasopressin concentrations were elevated above baseline after surgery until 4 hours post cardiac intensive care unit admission in both arms, and higher in the vasopressin arm during postoperative infusion. No differences in sodium concentration, liver function, or renal function were noted between groups. Conclusions. Vasopressin infusion after Fontan completion appears safe and was associated with reduced transpulmonary gradient and chest tube drainage in the early postoperative period. A larger multiinstitutional study may show further outcome benefit. (C) 2019 by The Society of Thoracic Surgeons

We describe the case of a 4-year-old male with a past medical history significant for nephrotic syndrome, short-bowel syndrome and fulminant hepatic failure status post (s/p) liver transplant (LT) who developed early post-transplant allograft dysfunction (hyperbilirubinemia, coagulopathy) and septic shock requiring central extracorporeal membrane oxygenation (ECMO). He remained on ECMO for 85 hours before he was decannulated without event and later underwent repeat LT. This case highlights the potential of central ECMO to provide the circulatory output necessary to reverse distributive shock physiology in patients with sepsis and hepatic dysfunction following LT. Furthermore, this is the first documented example of central ECMO as a bridge to recovery for repeat LT.

Results Background The prevalence of respiratory-technology dependent children is increasing although for most children the goal is liberation from technology. Liberation from home mechanical ventilation (HMV) and decannulation strategies vary due to the lack of clinical practice standards. The primary objective of this study was to describe our practice utilizing a polysomnography (PSG) in the liberation from respiratory-technology process. Methods Retrospective study of tracheostomized children with and without HMV who underwent an evaluation for decannulation between January 2006 and June 2016. Patient demographics, indication for tracheostomy, indication for PSG, PSG results and interventions performed after the PSG were collected. We identified 153 decannulation attempts in 148 children. Ninety-nine children had a tracheostomy only and 49 children had a tracheostomy with HMV. There were 190 PSGs performed. Almost two-thirds of the children (N=92) had at least one PSG, 37 children (25%) had two and 19 children (13%) had more than 2 PSGs. Children with tracheostomy and HMV had more PSGs compared to children with tracheostomy only. PSGs were performed at four points: (1) prior to tracheostomy placement (N=23); (2) to titrate HMV (N=19); (3) off-HMV support (N=43); and with a capped tracheostomy (N=101). Most of the off-HMV PSGs (N=39) were favorable for discontinuing HMV. About two-thirds of the capped PSGs (N=73) were favorable for decannulation; of the unfavorable capped PSGs (N=28), thirteen required airway surgeries following the unfavorable PSG. Conclusion: Overnight PSG provides useful information to the liberation process, particularly when determining readiness for discontinuing HMV and decannulation.

Study Objective To describe our experience with voriconazole in three patients younger than 2 years using an optimized dosing strategy for voriconazole that incorporates intensive therapeutic drug monitoring ( TDM ). Design Case series. Setting Large pediatric hospital. Patients Three patients younger than 2 years who received voriconazole therapy and had serum trough concentrations measured between January 1, 2010, and October 31, 2015. Measurements and Main Results A clinical practice guideline developed at our institution was used to standardize initial dosing, appropriate use and timing of TDM , and dosage modifications based on TDM . TDM was used to guide dosing to achieve a target voriconazole serum trough concentration of 2–6 μg/ml. Voriconazole samples were assayed by using a high‐performance liquid chromatography analytical method with solid‐phase extraction. Initial dosages for the three patients were 9 mg/kg intravenously every 12 hours (one patient) and 9 mg/kg enterally twice/day (two patients). Multiple dose escalations and a more frequent dosing interval were required to achieve trough concentrations within the target range. The final dosages were 12 mg/kg intravenously every 8 hours, 17.7 mg/kg enterally 3 times/day, and 8.5 mg/kg enterally 3 times/day, respectively. In addition to voriconazole trough concentrations, TDM included evaluations for drug toxicities. Visual, neurologic, or hepatic adverse effects were not encountered in the three patients. Conclusion Our data support higher initial doses and perhaps a 3 times/day dosing schedule to achieve voriconazole serum concentrations in the target range for children younger than 2 years. Implementation of a clinical practice guideline with the participation of pharmacists specializing in pharmacokinetics allows for effective use of voriconazole in young children.

Copyright © 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Background: Recombinant activated factor VII (rFVIIa; NovoSeven® RT, Novo Nordisk, Bagsvaerd, Denmark) is a synthetic pro-coagulation factor derived from hamster kidney cells. Objectives: The purpose of this study was to evaluate the prescribing patterns of recombinant factor VIIa (rFVIIa) at a single, tertiary care pediatric hospital by indication of usage and dose administered. Materials and Methods: Retrospective data was queried from the centralized pharmacy medication computer system. All patients receiving rFVIIa between September 2009 and September 2012 were included in the analysis. Results: Over the three year period 887 doses of rFVIIa were administered to 186 patients. Only 4% of patients received rFVIIa for an FDA approved indication. The most common indication for off-label usage was refactory bleeding either during or following cardiothoracic surgery, accounting for 83% of all doses administered off-label. Despite being only a small portion of all patients receiving rFVIIa, the group receiving rFVIIa for an FDA approved indication received the majority of doses dispensed (72.6% of all doses). A significant difference (P < 0.0001) was noted in the dose administered to patients in the on-label versus off-label groups. Patients in the on-label group received a median dose of 113.6 mcg/kg (IQR 54.5 mcg/kg - 172.7 mcg/kg) versus a median dose of 74.4 mcg/kg (IQR 20.0 mcg/kg - 128.8 mcg/kg) in the off-label group. Conclusions: Prospective pediatric studies are needed to evaluate rFVIIa efficacy and safety in populations receiving the medication for off-label indications given increasing concerns involving the potential adverse effect profile of the medication as well as to develop evidence based dosing parameters for these indications.

Renal tubules process large amounts of NaCl that other investigators indicate increases tubular generation of nitric oxide. We questioned whether medullary or superficial cortical tubules would have the greater increase in nitric oxide concentration, [NO], when stressed by sodium and if the sodium/calcium exchanger was involved. Sodium stress in proximal tubules is due to the large amount of sodium absorbed and medullary tubules exist in a hypertonic sodium environment. To sodium stress the tissue, mouse kidney slices were exposed to monensin to allow passive entry of sodium ions from isotonic media and in separate studies, 400 and 600mOsm NaCl was used. [NO] was measured with microelectrodes. Monensin (10μM) caused a sustained increase in medullary and cortical [NO] to ∼180% of control and 400mOsm NaCl caused a similar initial increase in [NO] that then subsided. 600mOsm NaCl caused a more sustained increase in [NO] of >250% of control. L-NAME strongly attenuated the increased [NO] during sodium stress. The increase in [NO] during NaCl elevation was due to sodium ions because mannitol hyperosmolarity caused ∼20% of the increase in [NO]. Entry of sodium during NaCl hyperosmolarity was through bumetanide sensitive channels because the drug suppressed increased [NO]. Blockade of the sodium/calcium ion exchanger strongly suppressed the increased [NO] during monensin, to increase sodium entry into cells, and the elevated NaCl concentration. The data support a sodium–NO linkage that increased NO signaling in proportion to sodium stress by cortical tubules and was highly dependent upon sodium–calcium exchange.

Renal cortex tubules contain eNOS that may be used to generate nitric oxide (NO) when cells are challenged. We propose sodium stress could lead to increased NO production through a calcium linked mechanism. NO was measured with microelectrodes at 400 or 600 mOsm NaCl in the tissue bath over 150–200 um slices of mouse kidney. Resting NO of cortical tubules was 350–400 nM compared to 75–120 nM for papilla tubules. 400 mOsm NaCl caused a transient increase in NO of 39% and a larger transient increase of 124% in NO during isotonic recovery. 600 mOsm NaCl caused a sustained increase in NO of 265% with a transient overshoot of 308% during isotonic recovery. Tubules of the papilla responded minimally to hypertonic NaCl. To separate the effect of hyperosmolarity from sodium ion stress, the cortical tubules were exposed to media made hypertonic to 400 and 600 mOsm with mannitol. The NO response to mannitol was about one-fourth that of NaCl hyperosmolarity. To determine the mechanism linking sodium stress to increased NO production, we investigated if intracellular sodium used in osmotic equilibration was exchanged for calcium ions using the sodium/calcium exchanger blocker KB-R7943. After blockade, the basal NO was reduced to 57% of control and the NO response to 600 mOsm NaCl was about 20% of normal. The data indicate sodium accumulation by cortical tubules can initiate a large increase in NO generation as sodium ions are exchanged for calcium ions. With 400 mOsm NaCl, the NO response is transient as the cell adapts to hyperosmolarity. As isotonicity is restored, a large transient increase in reflects removal of sodium ions used for osmotic equilibration for a transient increase in intracellular calcium that activates NO production. (Supported by NIH Grant HL-20605 and American Heart Association Grant-In-Aid)