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BackgroundCommunity-onset bacterial coinfection in adults hospitalized with coronavirus disease 2019 (COVID-19) is reportedly uncommon, though empiric antibiotic use has been high. However, data regarding empiric antibiotic use and bacterial coinfection in children with critical illness from COVID-19 are scarce.MethodsWe evaluated children and adolescents aged ResultsOf the 532 patients, 63.3% received empiric antibiotics, but only 7.1% had bacterial coinfection, and only 3.0% had respiratory bacterial coinfection. In multivariable analyses, empiric antibiotics were more likely to be prescribed for immunocompromised patients (adjusted relative risk [aRR], 1.34 [95% confidence interval {CI}, 1.01–1.79]), those requiring any respiratory support except mechanical ventilation (aRR, 1.41 [95% CI, 1.05–1.90]), or those requiring invasive mechanical ventilation (aRR, 1.83 [95% CI, 1.36–2.47]) (compared with no respiratory support). The presence of a pulmonary comorbidity other than asthma (aRR, 2.31 [95% CI, 1.15–4.62]) was associated with bacterial coinfection.ConclusionsCommunity-onset bacterial coinfection in children with critical COVID-19 is infrequent, but empiric antibiotics are commonly prescribed. These findings inform antimicrobial use and support rapid de-escalation when evaluation shows coinfection is unlikely.

Previous latent class analysis of adults with acute respiratory distress syndrome (ARDS) identified two phenotypes, distinguished by the degree of inflammation. We aimed to identify phenotypes in children with ARDS in whom developmental differences might be important, using a latent class analysis approach similar to that used in adults.This study was a secondary analysis of data aggregated from the Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) clinical trial and the Genetic Variation and Biomarkers in Children with Acute Lung Injury (BALI) ancillary study. We used latent class analysis, which included demographic, clinical, and plasma biomarker variables, to identify paediatric ARDS (PARDS) phenotypes within a cohort of children included in the RESTORE and BALI studies. The association of phenotypes with clinically relevant outcomes and the performance of paediatric data in adult ARDS classification algorithms were also assessed.304 children with PARDS were included in this secondary analysis. Using latent class analysis, a two-class model was a better fit for the cohort than a one-class model (p0·001). Latent class analysis identified two classes: class 1 (181 [60%] of 304 patients with PARDS) and class 2 (123 [40%] of 304 patients with PARDS), referred to as phenotype 1 and 2 hereafter. Phenotype 2 was characterised by higher concentrations of inflammatory biomarkers, a higher incidence of vasopressor use, and more frequent diagnosis of sepsis, consistent with the adult hyperinflammatory phenotype. All levels of severity of PARDS were observed across both phenotypes. Children with the hyperinflammatory phenotype (phenotype 2) had worse clinical outcomes than those with the hypoinflammatory phenotype (phenotype 1), with a longer duration of mechanical ventilation (median 10·0 days [IQR 6·3-21·0] for phenotype 2 vs 6·6 days [4·1-10·8] for phenotype 1, p0·0001), and higher incidence of mortality (17 [13·8%] of 123 patients vs four [2·2%] of 181 patients, p=0·0001). When using adult phenotype classification algorithms in children, the soluble tumour necrosis factor receptor-1 (sTNFr1), vasopressor use, and interleukin (IL)-6 variables gave an area under the curve (AUC) of 0·956, and the sTNFr1, vasopressor use, and IL-8 variables gave an AUC of 0·954, compared with the gold standard of latent class analysis.Latent class analysis identified two phenotypes in children with ARDS with characteristics similar to those in adults, including worse outcomes among patients with the hyperinflammatory phenotype. PARDS phenotypes should be considered in design and analysis of future clinical trials in children.US National Institutes of Health.

Previous studies of severe acute respiratory syndrome coronavirus 2 infection in infants have incompletely characterized factors associated with severe illness or focused on infants born to mothers with coronavirus disease 2019 (COVID-19). Here we highlight demographics, clinical characteristics and laboratory values that differ between infants with and without severe acute COVID-19.Active surveillance was performed by the Overcoming COVID-19 network to identify children and adolescents with severe acute respiratory syndrome coronavirus 2-related illness hospitalized at 62 sites in 31 states from March 15 to December 27, 2020. We analyzed patients7 days to1 year old hospitalized with symptomatic acute COVID-19.We report 232 infants7 days to1 year of age hospitalized with acute symptomatic COVID-19 from 37 US hospitals in our cohort from March 15 to December 27, 2020. Among 630 cases of severe COVID-19 in patients7 days to18 years old, 128 (20.3%) were infants. In infants with severe illness from the entire study period, the median age was 2 months, 66% were from racial and ethnic minority groups, 66% were previously healthy, 73% had respiratory complications, 13% received mechanical ventilation and1% died.Infants accounted for over a fifth of children18 years of age hospitalized for severe acute COVID-19, commonly manifesting with respiratory symptoms and complications. Although most infants hospitalized with COVID-19 did not suffer significant complications, longer term outcomes remain unclear. Notably, 75% of infants with severe disease were6 months of age in this cohort study period, which predated maternal COVID-19 vaccination, underscoring the importance of maternal vaccination for COVID-19 in protecting the mother and infant.

OBJECTIVES There is evidence that noninvasive ventilation decreases the need for invasive mechanical ventilation. However, children with pediatric acute respiratory distress syndrome who fail noninvasive ventilation may have worse outcomes than those who are intubated without exposure to noninvasive ventilation. Our objective was to evaluate the impact of preintubation noninvasive ventilation on children with pediatric acute respiratory distress syndrome. DESIGN Secondary analysis of data from the Randomized Evaluation of Sedation Titration for Respiratory Failure trial. SETTING Thirty-one PICUs in the United States. PATIENTS Children 2 weeks to 17 years old with pediatric acute respiratory distress syndrome receiving invasive mechanical ventilation, excluding those admitted with tracheostomies. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Of 2,427 subjects receiving invasive mechanical ventilation, preintubation noninvasive ventilation was used in 995 (41%). Compared with subjects without preintubation noninvasive ventilation use, subjects with preintubation noninvasive ventilation use were more likely to have a history of seizures (10% vs 8%; p = 0.04) or cancer (11% vs 6%; p < 0.001) and have moderate or severe pediatric acute respiratory distress syndrome by the end of their first full day of invasive mechanical ventilation (68% vs 60%; p < 0.001). Adjusting for age, severity of illness on PICU admission, and baseline functional status, preintubation noninvasive ventilation use resulted in longer invasive mechanical ventilation duration (median 7.0 vs 6.0 d), longer PICU (10.8 vs 8.9 d), and hospital (17 vs 14 d) lengths of stay, and higher 28-day (5% vs 4%) and 90-day (8% vs 5%) inhospital mortalities (all comparisons p < 0.001). Longer duration of noninvasive ventilation before intubation was associated with worse outcomes. CONCLUSIONS In children with pediatric acute respiratory distress syndrome, preintubation noninvasive ventilation use is associated with worse outcomes when compared with no preintubation noninvasive ventilation use. These data can be used to inform the design of clinical studies to evaluate best noninvasive ventilation practices in children with pediatric acute respiratory distress syndrome.

Rationale: Racial disparities in pain management have been previously reported for children receiving emergency care. Objectives: To determine whether patient race or ethnicity is associated with the broader goal of pain management and sedation among pediatric patients mechanically ventilated for acute respiratory failure. Methods: Planned secondary analysis of RESTORE (Randomized Evaluation of Sedation Titration for Respiratory Failure). RESTORE, a cluster-randomized clinical trial conducted in 31 U.S. pediatric intensive care units, compared protocolized sedation management (intervention arm) with usual care (control arm). Participants included 2,271 children identified as non-Hispanic white (white, n = 1,233), non-Hispanic Black (Black, n = 502), or Hispanic of any race (Hispanic, n = 536). Results: Within each treatment arm, neither opioid nor benzodiazepine selection, nor cumulative dosing, differed significantly among race and ethnicity groups. Black patients experienced fewer days with an episode of pain (compared with white patients in the control arm and with Hispanic patients in the intervention arm) and experienced less iatrogenic withdrawal syndrome (compared with white patients in either arm or with Hispanic patients in the intervention arm). The percentage of days awake and calm while intubated was not significantly different in pairwise comparisons by race and ethnicity groups in either the control arm (median: white, 75%; Black, 71%; Hispanic, 75%) or the intervention arm (white, 86%; Black, 88%; Hispanic, 85%). Conclusions: Across multiple measures, our study found scattered differences in sedation management among critically ill Black, Hispanic, and white children that did not consistently favor any group. However, racial disparities related to implicit bias cannot be completely ruled out. Clinical trial registered with clinicaltrials.gov (NCT 00814099).

Clinical differences between critical illness from influenza infection versus coronavirus disease 2019 (COVID-19) have not been well characterized in pediatric patients.We compared U.S. children (8 months to 17 years) admitted to the intensive care or high acuity unit with influenza (17 hospitals, 12/19/2019-3/9/2020) or COVID-19 (52 hospitals, 3/15/2020-12/31/2020). We compared demographics, underlying conditions, clinical presentation, severity, and outcomes. Using mixed-effects models, we assessed the odds of death or requiring life-support for influenza versus COVID-19 after adjustment for age, sex, race and Hispanic origin, and underlying conditions including obesity.Children with influenza (n = 179) were younger than those with COVID-19 (n = 381; median 5.2 vs. 13.8 years), less likely to be non-Hispanic black (14.5% vs. 27.6%) or Hispanic (24.0% vs. 36.2%), and less likely to have ≥1 underlying condition (66.4% vs. 78.5%) or be obese (21.4% vs. 42.2%). They were similarly likely to require invasive mechanical ventilation (both 30.2%), vasopressor support (19.6% and 19.9%), or extracorporeal membrane oxygenation (2.2% and 2.9%). Four children with influenza (2.2%) and 11 children with COVID-19 (2.9%) died. The odds of death or requiring life-support in children with influenza vs. COVID-19 were similar (adjusted odds ratio, 1.30 [95% CI: 0.78-2.15; P = 0.32]). Median duration of hospital stay was shorter for influenza than COVID-19 (5 versus 7 days).Despite differences in demographics and clinical characteristics of children with influenza or COVID-19, the frequency of life-threatening complications was similar. Our findings highlight the importance of implementing prevention measures to reduce transmission and disease severity of influenza and COVID-19.

Background: Multisystem inflammatory syndrome in children (MIS-C) consensus criteria were designed for maximal sensitivity and therefore capture patients with acute COVID-19 pneumonia. Methods: We performed unsupervised clustering on data from 1,526 patients (684 labeled MIS-C by clinicians)

Background The assessment of real-world effectiveness of immunomodulatory medications for multisystem inflammatory syndrome in children (MIS-C) may guide therapy. Methods We analyzed surveillance data on inpatients younger than 21 years of age who had MIS-C and were admitted to 1 of 58 U.S. hospitals between March 15 and October 31, 2020. The effectiveness of initial immunomodulatory therapy (day 0, indicating the first day any such therapy for MIS-C was given) with intravenous immune globulin (IVIG) plus glucocorticoids, as compared with IVIG alone, was evaluated with propensity-score matching and inverse probability weighting, with adjustment for baseline MIS-C severity and demographic characteristics. The primary outcome was cardiovascular dysfunction (a composite of left ventricular dysfunction or shock resulting in the use of vasopressors) on or after day 2. Secondary outcomes included the components of the primary outcome, the receipt of adjunctive treatment (glucocorticoids in patients not already receiving glucocorticoids on day 0, a biologic, or a second dose of IVIG) on or after day 1, and persistent or recurrent fever on or after day 2. Results A total of 518 patients with MIS-C (median age, 8.7 years) received at least one immunomodulatory therapy; 75% had been previously healthy, and 9 died. In the propensity-score–matched analysis, initial treatment with IVIG plus glucocorticoids (103 patients) was associated with a lower risk of cardiovascular dysfunction on or after day 2 than IVIG alone (103 patients) (17% vs. 31%; risk ratio, 0.56; 95% confidence interval [CI], 0.34 to 0.94). The risks of the components of the composite outcome were also lower among those who received IVIG plus glucocorticoids: left ventricular dysfunction occurred in 8% and 17% of the patients, respectively (risk ratio, 0.46; 95% CI, 0.19 to 1.15), and shock resulting in vasopressor use in 13% and 24% (risk ratio, 0.54; 95% CI, 0.29 to 1.00). The use of adjunctive therapy was lower among patients who received IVIG plus glucocorticoids than among those who received IVIG alone (34% vs. 70%; risk ratio, 0.49; 95% CI, 0.36 to 0.65), but the risk of fever was unaffected (31% and 40%, respectively; risk ratio, 0.78; 95% CI, 0.53 to 1.13). The inverse-probability-weighted analysis confirmed the results of the propensity-score–matched analysis. Conclusions Among children and adolescents with MIS-C, initial treatment with IVIG plus glucocorticoids was associated with a lower risk of new or persistent cardiovascular dysfunction than IVIG alone. (Funded by the Centers for Disease Control and Prevention.)

Background It is unclear how acute coronavirus disease 2019 (COVID-19)-directed therapies are used in children with life-threatening COVID-19 in US hospitals. We described characteristics of children hospitalized in the intensive care unit or step-down unit (ICU/SDU) who received COVID-19-directed therapies and the specific therapies administered. Methods Between March 15, 2020 and December 27, 2020, children, No therapies for acute coronavirus disease 2019 (COVID-19) have been tested in children to establish effectiveness. Despite this, across 48 hospitals, 235/424 children (55%) admitted to the intensive care or step-down unit with COVID-19 received directed therapies. Systemic steroids and remdesivir were most commonly administered, with use rising from March 2020 to December 2020.

IMPORTANCE: Refinement of criteria for multisystem inflammatory syndrome in children (MIS-C) may inform efforts to improve health outcomes. OBJECTIVE: To compare clinical characteristics and outcomes of children and adolescents with MIS-C vs those with severe coronavirus disease 2019 (COVID-19). SETTING, DESIGN, AND PARTICIPANTS: Case series of 1116 patients aged younger than 21 years hospitalized between March 15 and October 31, 2020, at 66 US hospitals in 31 states. Final date of follow-up was January 5, 2021. Patients with MIS-C had fever, inflammation, multisystem involvement, and positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcriptase–polymerase chain reaction (RT-PCR) or antibody test results or recent exposure with no alternate diagnosis. Patients with COVID-19 had positive RT-PCR test results and severe organ system involvement. EXPOSURE: SARS-CoV-2. MAIN OUTCOMES AND MEASURES: Presenting symptoms, organ system complications, laboratory biomarkers, interventions, and clinical outcomes. Multivariable regression was used to compute adjusted risk ratios (aRRs) of factors associated with MIS-C vs COVID-19. RESULTS: Of 1116 patients (median age, 9.7 years; 45% female), 539 (48%) were diagnosed with MIS-C and 577 (52%) with COVID-19. Compared with patients with COVID-19, patients with MIS-C were more likely to be 6 to 12 years old (40.8% vs 19.4%; absolute risk difference [RD], 21.4% [95% CI, 16.1%-26.7%]; aRR, 1.51 [95% CI, 1.33-1.72] vs 0-5 years) and non-Hispanic Black (32.3% vs 21.5%; RD, 10.8% [95% CI, 5.6%-16.0%]; aRR, 1.43 [95% CI, 1.17-1.76] vs White). Compared with patients with COVID-19, patients with MIS-C were more likely to have cardiorespiratory involvement (56.0% vs 8.8%; RD, 47.2% [95% CI, 42.4%-52.0%]; aRR, 2.99 [95% CI, 2.55-3.50] vs respiratory involvement), cardiovascular without respiratory involvement (10.6% vs 2.9%; RD, 7.7% [95% CI, 4.7%-10.6%]; aRR, 2.49 [95% CI, 2.05-3.02] vs respiratory involvement), and mucocutaneous without cardiorespiratory involvement (7.1% vs 2.3%; RD, 4.8% [95% CI, 2.3%-7.3%]; aRR, 2.29 [95% CI, 1.84-2.85] vs respiratory involvement). Patients with MIS-C had higher neutrophil to lymphocyte ratio (median, 6.4 vs 2.7, P

Elevated surfactant protein D (SP-D) is a relatively specific indicator of lung injury and is associated with both acute and chronic lung disease in adults and respiratory distress syndrome in premature infants. The relationship between plasma SP-D and lung injury in children with acute respiratory failure is unclear.Is plasma SP-D associated with lung injury or outcome in children with acute respiratory failure?This was a prospective cohort study in children 2 weeks to 17 years of age with acute respiratory failure who participated in the BALI multi-center study. Analyses were done using SP-D levels in plasma from the first sample taken on either the day of intubation or one of the following 2 days. SP-D level was measured by enzyme-linked immunosorbent assay.Plasma samples from 350 patients were used in the analysis; 233 had pediatric ARDS (PARDS). SP-D levels varied across primary diagnoses (P .001). Elevated SP-D levels were associated with severe PARDS after adjusting for age, pediatric risk of mortality III (PRISM-III), and primary diagnosis (OR = 1.02; CI = 1.01-1.04; P = .011). Multivariable analyses also indicated that elevated SP-D levels were associated with death (OR = 1.02; CI = 1.01-1.04; P = .004), duration of mechanical ventilation (P = .012), PICU length of stay (P = .019), and highest oxygenation index (P = .040). SP-D levels also correlated with age (rElevated plasma SP-D levels are associated with severe PARDS and poor outcomes in children with acute respiratory failure. Future studies will determine whether SP-D can be used to predict the degree of lung injury or response to treatment and whether SP-D is useful in identifying PARDS endotypes.

Background: Mannose-binding lectin (MBL) is an innate immune protein with strong biologic plausibility for protecting against influenza virus-related sepsis and bacterial co-infection. In an autopsy cohort of 105 influenza-infected young people, carriage of the deleterious MBL gene MBL2_Gly54Asp(“B”) mutation was identified in 5 of 8 individuals that died from influenza-methicillin-resistant Staphylococcus aureus (MRSA) co-infection. We evaluated MBL2 variants known to influence MBL levels with pediatric influenza-related critical illness susceptibility and/or severity including with bacterial co-infections. Methods: We enrolled children and adolescents with laboratory-confirmed influenza infection across 38 pediatric intensive care units from November 2008 to June 2016. We sequenced MBL2 “low-producer” variants rs11003125(“H/L”), rs7096206(“Y/X”), rs1800450Gly54Asp(“B”), rs1800451Gly57Glu(“C”), rs5030737Arg52Cys(“D”) in patients and biologic parents. We measured serum levels and compared complement activity in low-producing homozygotes (“B/B,” “C/C”) to HYA/HYA controls. We used a population control of 1,142 healthy children and also analyzed family trios (PBAT/HBAT) to evaluate disease susceptibility, and nested case-control analyses to evaluate severity. Results: We genotyped 420 patients with confirmed influenza-related sepsis: 159 (38%) had acute lung injury (ALI), 165 (39%) septic shock, and 30 (7%) died. Although bacterial co-infection was diagnosed in 133 patients (32%), only MRSA co-infection (n = 33, 8% overall) was associated with death (p < 0.0001), present in 11 of 30 children that died (37%). MBL2 variants predicted serum levels and complement activation as expected. We found no association between influenza-related critical illness susceptibility and MBL2 variants using family trios (633 biologic parents) or compared to population controls. MBL2 variants were not associated with admission illness severity, septic shock, ALI, or bacterial co-infection diagnosis. Carriage of low-MBL producing MBL2 variants was not a risk factor for mortality, but children that died did have higher carriage of one or more B alleles (OR 2.3; p = 0.007), including 7 of 11 with influenza MRSA-related death (vs. 2 of 22 survivors: OR 14.5, p = 0.0002). Conclusions: MBL2 variants that decrease MBL levels were not associated with susceptibility to pediatric influenza-related critical illness or with multiple measures of critical illness severity. We confirmed a prior report of higher B allele carriage in a relatively small number of young individuals with influenza-MRSA associated death.

IMPORTANCE: Coronavirus disease 2019 (COVID-19) affects the nervous system in adult patients. The spectrum of neurologic involvement in children and adolescents is unclear. OBJECTIVE: To understand the range and severity of neurologic involvement among children and adolescents associated with COVID-19. SETTING, DESIGN, AND PARTICIPANTS: Case series of patients (age

To compare current analgesia and sedation management practices between critically ill children with pre-existing cognitive impairment and critically ill neurotypical children, including possible indicators of therapeutic efficacy.This study used secondary analysis of prospective data from the RESTORE clinical trial, with 2449 children admitted to the pediatric intensive care unit and receiving mechanical ventilation for acute respiratory failure. Subjects with a baseline Pediatric Cerebral Performance Category ≥3 were defined as subjects with cognitive impairment, and differences between groups were explored using regression methods accounting for pediatric intensive care unit as a cluster variable.This study identified 412 subjects (17%) with cognitive impairment. Compared with neurotypical subjects, subjects with cognitive impairment were older (median, years, 6.2 vs 1.4; P .001) with more severe pediatric acute respiratory distress syndrome (40% vs 33%; P = .009). They received significantly lower cumulative doses of opioids (median, mg/kg, 14.2 vs 16.2; P .001) and benzodiazepines (10.6 vs 14.4; P .001). Three nonverbal subjects with cognitive impairment received no analgesia or sedation. Subjects with cognitive impairment were assessed as having more study days awake and calm and fewer study days with an episode of pain. They were less likely to be assessed as having inadequate pain/sedation management or unplanned endotracheal/invasive tube removal. Subjects with cognitive impairment had more documented iatrogenic withdrawal symptoms than neurotypical subjects.Subjects with cognitive impairment in this study received less medication, but it is unclear whether they have authentically lower analgesic and/or sedative requirements or are vulnerable to inadequate assessment of discomfort because of the lack of validated assessment tools. We recommend the development of pain and sedation assessment tools specific to this patient population.

Background Interferon-induced transmembrane protein 3 (IFITM3) restricts endocytic fusion of influenza virus. IFITM3 rs12252_C, a putative alternate splice site, has been associated with influenza severity in adults. IFITM3 has not been evaluated in pediatric influenza. Methods The Pediatric Influenza (PICFLU) study enrolled children with suspected influenza infection across 38 pediatric intensive care units during November 2008 to April 2016. IFITM3 was sequenced in patients and parents were genotyped for specific variants for family-based association testing. rs12252 was genotyped in 54 African-American pediatric outpatients with influenza (FLU09), included in the population-based comparisons with 1000 genomes. Splice site analysis of rs12252_C was performed using PICFLU and FLU09 patient RNA. Results In PICFLU, 358 children had influenza infection. We identified 22 rs12252_C homozygotes in 185 white non-Hispanic children. rs12252_C was not associated with influenza infection in population or family-based analyses. We did not identify the Δ21 IFITM3 isoform in RNAseq data. The rs12252 genotype was not associated with IFITM3 expression levels, nor with critical illness severity. No novel rare IFITM3 functional variants were identified. Conclusions rs12252 was not associated with susceptibility to influenza-related critical illness in children or with critical illness severity. Our data also do not support it being a splice site.

Central line associated bloodstream infections in pediatric intensive care units extend the intensive care unit length of stay and increase the cost of hospitalization. These infections, once thought to be an accepted complication of central vascular access, are now known to be preventable. Despite using hand hygiene, full barrier protection, and proper skin disinfection with 70% isopropyl alcohol/20% chlorhexidine gluconate for pediatric central venous catheter insertion, our catheter associated bloodstream infection rate remained high. We instituted a new practice involving scrubbing the catheter hub and performing dressing changes with 70% isopropyl alcohol/20% chlorhexidine gluconate in a combined pediatric intensive care and pediatric cardiac intensive care unit. We removed alternative products from the bedside thereby making it easier for the staff to follow procedure and reducing the need for training and monitoring. This change reduced our catheter associated bloodstream infection rate from 7.1 episodes per 1000 line days to 1.5 episodes per 1000 line days. We describe the barriers we encountered in instituting this practice change, evaluating the impact of the change with limited resources, and in eventually implementing the change in other units system-wide. The most commonly encountered obstacle to change was not a lack of resources, but the insistence by the medical staff that the incidence of these infections was a result of differences in patient populations and not differences in compliance with standardized procedure.

Purpose: The transition of care between hospitalists and primary care providers (PCPs) is a vulnerable step in the journey of hospitalized patients and their families, reliant on the communication at discharge. While discharge summaries (DS) using electronic medical record could be an ideal tool of sharing information, prior studies have shown inconsistent content and timeliness, lack of standardization, and differing expectations between hospitalists and PCPs. In our tertiary care academic institution, we implemented a discharge bundle aiming to achieve a timely completion and transmission of …

Objective: To describe a single-center experience of pediatric intestinal transplantation (Itx) and to provide an overview of the children who underwent this procedure along with their outcomes. Background Data: Pediatric Itx presents multiple challenges because of the very young ages at which patients require transplantation and their higher susceptibility to infectious complications. Methods: We have performed 141 Itx in 123 children with a median age of 1.37 years. Primary grafts included isolated intestine (n = 28), liver and intestine (n = 27), multivisceral (n = 61), and multivisceral without the liver (n = 7). Two protocol modifications were introduced in 1998: daclizumab induction and frequent rejection surveillance. In 2001, indications for multivisceral transplantation were expanded, and induction with Campath-lH was introduced. Results: Actuarial patient survival at 1 and 3 years for group 1 (January 1994 to December 1997, n = 25), group 2 (January 1998 to March 2001, n = 29), group 3a (April 2001 to present, daclizumab, n = 51), and group 3b (April 2001 to present, Campath-lH, n = 18) was 44%/32%, 52%/38%, 83%/60%, and 44%/44%, respectively (P = 0.0003 in favor of group 3a). Severe rejection implied a dismal prognosis (65% mortality at 6 months). Observed incidence of severe rejection in groups 1, 2, 3a, and 3b was 32%, 24%, 14%, and 11%, respectively. In multivariable analysis, use of a multivisceral (with or without liver) transplant (P = 0.002), induction with daclizumab (P = 0.005), patient at home prior to transplant (P = 0.007), and age at transplant ≥ 1 year (P = 0.02) favorably influenced patient survival. Multivisceral transplant was protective with respect to the mortality rate due to rejection, while an older age at transplant was associated with both a lower incidence rate of developing respiratory infection and lower risk of mortality following the respiratory infection. Survivors are off parenteral nutrition and have demonstrated significant growth catch-up. Conclusions: Itx in children still is a high-risk procedure but has now become a viable option for children who otherwise have no hope for survival. Control of respiratory infection is of particular importance in the younger children.

Background. Calcineurin inhibitors induce renal vasoconstriction and oliguria during acute toxicity. We previously demonstrated that the nonspecific adenosine receptor antagonist theophylline improved glomerular filtration rate (GFR) and renal blood flow in the setting of acute tacrolimus (TAC) toxicity. This study was undertaken to determine which of the known adenosine receptor subtypes is responsible for the observed effect of theophylline. Methods. The GFR was measured by clearance of 51 Cr-EDTA in anaesthetized, instrumented Sprague– Dawley rats at three time points: at baseline, 60 min after intravenous administration of TAC (0.05 mg/kg) or vehicle (V) and at 100 min after TAC or V. Either DMSO (n ¼ 5) or one of the three available specific adenosine receptor subtype antagonists 1,3-dipropyl-8cyclopentylxanthine (DPCPX, 2 mg/kg, n ¼ 5), a selective A1 receptor antagonist, 8-(3-chlorostyryl) caffeine (CSC, 2 mg/kg, n ¼ 4), a selective A2a receptor antagonist and 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-dihydropyridine-3,5 dicarboxylate (MRS1191, 1 mg/kg, n ¼ 5), a selective A3 receptor antagonist, was administered intra-peritoneally prior to the final GFR measurement. Repeated measures analysis of variance was used to detect differences between groups (P

To understand the utility of open lung biopsy (OLB) in the evaluation of respiratory failure in pediatric abdominal organ transplant we reviewed the records of nine children in this patient population who underwent an OLB. Eight of nine patients had undergone a previous non-diagnostic bronchoalveolar lavage. Biopsies were performed at the bedside in the pediatric intensive care unit and tissue was processed by the Department of Pathology with special stains for infectious agents. There were no significant complications of OLB. A specific treatable etiology was identified in four patients (respiratory syncytial virus, adenovirus, graft-vs.-host disease and post-transplant lymphoproliferative disease), leading to a change in therapy and survival in two. Overall survival was 44%. Given the low morbidity, OLB as performed in this study appears appropriate in this patient population.

Intestinal/multivisceral transplantation has evolved from an experimental procedure to the treatment of choice for patients with irreversible intestinal failure and serious complications related to long-term parenteral nutrition. Children who are likely to suffer permanent intestinal failure and benefit from intestinal transplantation include those with a remaining small bowel length of less than 30–40 cm, absence of the ileocecal valve, colonic resection and malabsorptive syndromes. Indications for transplant include frequent severe bouts of catheter associated sepsis, threatened loss of vascular access and the development of liver cirrhosis from cholestasis. Children who are more likely to experience cholestasis from total parenteral nutrition include those who experience persistent hyperbilirubinemia (greater than 6 mg/dl despite enteral nutrition), those with recurrent sepsis and/or bacterial overgrowth and those with minimal tolerance of any enteral feeds in the first few months post resection. The 1 year survival rate after intestinal transplantation has markedly improved over the last several years but long term survival rates have remained unchanged. The improved short term survival rates have led to an increased prevalence of this patient population in intensive care units. Management of intestinal and multivisceral transplant recipients is uniquely challenging because of complications arising from the high incidence of transplant rejection and its treatment. In the ICU, the complexity of medical care for the transplant recipient requires a multidisciplinary approach with coordination by an intensivist in collaboration with the transplant surgeon, gastroenterologist, and other specialists.

OBJECTIVE: To test the hypothesis that cerebral and other regional organ blood flow would be maintained during partial liquid ventilation (PLV) in an animal model of acute lung injury during different ventilation strategies. DESIGN: A prospective, randomized study. SETTING: Animal research facility. SUBJECTS: Sixteen piglets, 2 to 4 wks of age. INTERVENTIONS: Severe lung injury was induced in infant piglets by repeated saline lavage and high tidal volume ventilation. Animals were then randomized to either conventional volume-controlled ventilation or PLV. MEASUREMENTS AND MAIN RESULTS: Organ blood flow was determined in both groups using radiolabeled microspheres under four conditions: high mean airway pressure, Paw; high Paco(2), high Paw; normal Paco(2); low Paw, high Paco(2); low Paw, normal Paco(2). There were no differences in cerebral blood flow during conventional ventilation and PLV, regardless of ventilation strategy. CONCLUSIONS: These results suggest in an acute lung injury model, PLV does not affect cerebral blood flow or other regional organ blood flow over a range of airway pressures.

The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-activated chloride channel critical to intestinal anion secretion. In addition to phosphorylation, vesicle traffic regulates CFTR in some epithelial cells. Studies of cultured intestinal cells are conflicting regarding the role of cAMP-dependent vesicle traffic in regulating chloride transport. Whether CFTR is present in vesicular compartments within chloride secretory cells in the intestine is unknown and the role of cAMP-dependent vesicle insertion in regulating CFTR and intestinal fluid secretion remains unclear. The purpose of this study was to: (1) examine and quantify the subcellular distribution for CFTR in rat intestine, (2) further define the ultrastructure of the previously identified CFTR High Expresser (CHE) cell, and (3) examine the cellular distribution of CFTR following cAMP stimulation in vivo. Using the sensitive techniques of cryoimmunogold electron microscopy we identified CFTR in subapical vesicles and on the apical plasma membrane in crypt, Brunner glands, and CHE cells. cAMP stimulation in rat proximal small intestine produced a fluid secretory response and was associated with an apical redistribution of CFTR, supporting a physiologic role for cAMP-dependent CFTR vesicle insertion in regulating CFTR in the intestine.

Since Campath 1H (C1H) has been successfully used in adult liver transplant recipients since 2001 in our program, we started to use it in children. Patients and Methods C1H induction was employed in 10 children with autoimmune hepatitis (AIH) ( n = 6), primary sclerosing cholangitis (PSC) ( n = 1), biliary atresia ( n = 1), glycogen storage disease ( n = 1), and Wilson’s disease. Eight were primary transplants, and two retransplants. Patients ages ranged from 5 to 17 years. C1H was administered at a dose of 0.3 mg/kg on days 0, 4, and 7. Tacrolimus level was maintained at 5 to 10 ng/mL. No patient received maintenance steroids posttransplantation except two who were on steroid therapy at the time transplant. They were prescribed small doses of maintenance steroids. Median follow-up of C1H recipients was 679 days (range 115–1143). Results Postoperative courses were mostly uneventful except for one retransplant recipient who required prolonged hospitalization (40 days) for rehabilitation. Median hospital stay was 12 days (range 7–40 days). All 10 patients in the C1H group are currently alive and well with stable graft function. No opportunistic infection was observed in these patients to date. We compared six patients with AIH who received C1H to the historic control of 10 recipients with AIH who received conventional immunosuppression (tacrolimus + steroid). The patients treated with C1H showed significantly prolonged rejection-free survival. Conclusion In our preliminary experience, C1H induction was well tolerated in pediatric liver recipients. Rejections-free survival was prolonged among recipients with AIH despite a low level of maintenance immunosuppression.

Data were gathered from the records of 51 children of median age 1.5 years who survived more than 6 months after intestinal transplantation. Abnormal liver function tests (LFTs) were defined as serum aspartate aminotransferase (AST) greater than 100 IU/L or total bilirubin greater than 2.0 g/dL lasting more than 3 days. Temporary elevation was defined when LFTs returned to normal without graft loss or death. LFT elevation at the time of transplantation was not included as a temporary LFT elevation. Median follow-up was 36 months. In multivisceral transplant recipients, all patients (n = 34) showed abnormal LFTs at transplantation that normalized within a median period of 2 days. Temporary LFT elevations were seen in 20 of 34 (59%) in multivisceral transplantation and 5 of 17 (29%) in isolated intestinal transplantation. Median length of elevation was 14 days in multivisceral transplantation and 12 days in isolated intestinal transplantation. Peak AST was 353 +/- 190 IU/dL in multivisceral transplantation and 839 +/- 605 IU/dL in isolated intestinal transplantation (P = .0059). Events associated with temporary LFT elevations in multivisceral transplantation were total parental nutrition (TPN) (n = 8), dehydration (n = 2), viral infection (n = 2), others (n = 3), and nonspecific (n = 5). Events in isolated intestinal transplantation were posttransplant lymphoproliferative disorder (n = 2), TPN (n = 1), and nonspecific (n = 2). Temporary LFT elevations were commonly seen among pediatric intestinal recipients, which correlated with events other than rejection. Approximately half of the temporary LFT elevations were associated with no significant clinical events. They resolved spontaneously. Interestingly, the peak AST value was higher in isolated intestinal transplantation compared to multivisceral transplantation.

Data were analyzed from 44 patients who survived more than 2 years after intestinal transplantation performed between 1994 and 2002. Median age was 1.7 years. Tacrolimus level was defined as average tacrolimus level over 6 months. Kidney function was evaluated using a 6-month average serum creatinine. Glomerular filtration rate (GFR) was calculated with the Schwartz formula. The procedures were: isolated intestinal transplantation (n = 11), liver and intestinal transplantation (n = 9), multivisceral transplantation (n = 22), and modified multivisceral transplantation (n = 2). Forty-four patients were followed for a mean of 3.6 years on tacrolimus. Tacrolimus levels ranged between 3.5 and 19.9 ng/mL (median 14.6 ng/mL) at 0 to 6 months and 6.0 to 18.9 ng/mL (median 13.2 ng/mL) at 0 to 12 months. Pretransplant kidney function as mean GFR was 138 +/- 42 mL/min/1.73 m(2) (n = 44), posttransplant kidney function at 18 to 24 month as mean GFR was 102+/-35 mL/min/1.73 m(2) (n = 44), a value that was 81% of the pretransplant GFR (P < .0001). In an analysis of tacrolimus level versus renal function, a value greater than 13.5 ng/mL during the first 12 months was a significant predictor for impaired renal function at 2 years after transplantation (defined as average GFR less than 90 mL/min/1.73 m(2) at 18 to 24 months; P = .001). Only age among age, sex, diagnosis, transplant type, and rejection episodes showed a correlation with renal function. Renal function dropped significantly at 2 years after pediatric intestinal transplantation to 81% of the pretransplantation value. Tacrolimus level for the first 12 months seemed to predict subsequent development of renal impairment at 2 years.

Respiratory viral infections are a major cause of morbidity and mortality in solid organ transplant recipients. Early detection of a viral etiology of a LRTI in a febrile transplant recipient can theoretically reduce the use of antibiotics, trigger modification of immunosuppression and prompt appropriate isolation procedures to reduce nosocomial infections. We retrospectively evaluated pediatric abdominal organ transplant recipients hospitalized with respiratory illnesses to determine the viral pathogens identified by various methods including multiplex RT‐PCR performed on nasopharyngeal or endotracheal aspirates. Among 30 symptomatic subjects (median age, 2.5 yr) evaluated using this methodology, 25 (83%) were positive for at least one virus. Rhinovirus was the most frequently identified virus (14 subjects). RSV was identified in five subjects with associated mortality of 40%. Parainfluenza, influenza, metapneumovirus, and adenovirus were also identified. This study indicates that rhinovirus is a significant cause of morbidity in this single center cohort of pediatric abdominal organ transplant recipients.

The medical records of patients with acquired immunodeficiency syndrome were reviewed to evaluate the effect of our adoption to the pediatric population of the National Institutes of Health recommendation for adjunctive corticosteroid therapy in adults with Pneumocystis carinii pneumonia. In 21 episodes of P. carinii-related respiratory failure, only adjunctive corticosteroids were associated with a significant improvement in survival to successful removal of the tracheal tube, from a historical rate of 11% to 91%.

Exertional heat stroke (EHS) results in a constellation of systemic inflammatory responses resulting in multiorgan failure and an extremely high mortality. We present the case of an 11-year-old obese male who suffered EHS with rhabdomyolysis and concurrent renal, pulmonary, and hepatic failure. Conventional therapies including continuous veno-venous hemodiafiltration (CVVHDF) were ineffective in preventing ongoing deterioration in clinical status. Liver biopsy was reported as “extensive hepatocyte ballooning” and liver-kidney transplantation was tentatively planned. The addition of therapeutic plasma exchange using the Prismaflex® system (Gambro, Lakewood, CO, USA) resulted in a reversal of the inflammatory process and recovery from multiorgan failure. Liver biopsy was not a reliable indicator of irreversible hepatic injury.

Intestinal and multivisceral transplantation has evolved from an experimental procedure to the treatment of choice for patients with irreversible intestinal failure and serious complications related to long-term parenteral nutrition. Increased numbers of transplant recipients and improved survival rates have led to an increased prevalence of this patient population in intensive care units. Management of intestinal and multivisceral transplant recipients is uniquely challenging because of complications arising from the high incidence of transplant rejection and its treatment. Long-term comorbidities, such as diabetes, hypertension, chronic kidney failure, and neurological sequelae, also develop in this patient population as survival improves. This article is intended for intensivists who provide care to critically ill recipients of intestinal and multivisceral transplants. As perioperative care of intestinal/multivisceral transplant recipients has been described elsewhere, this review focuses on common nonsurgical complications with which one should be familiar in order to provide optimal care. The article is both a review of the current literature on multivisceral and isolated intestinal transplantation as well as a reflection of our own experience at the University of Miami.

OBJECTIVE To determine if a new class of agents, the 21-aminosteroids, which are reportedly potent inhibitors of iron-dependent lipid peroxidation, could protect rats from bleomycin-induced pulmonary fibrosis. SUBJECTS Fifty-five adult male Sprague-Dawley rats. DESIGN Prospective, randomized, blinded, controlled trial. INTERVENTIONS The rats were subjected to intratracheal bleomycin (or saline vehicle), and were then treated with the 21-aminosteroid, U74389F (20 mg/kg/day), or vehicle, for the next 7 days. MEASUREMENTS AND MAIN RESULTS At 21 days after bleomycin administration, pulmonary fibrosis was assessed histologically as percent of lung fields with evidence of fibrosis. Pulmonary fibrosis was assessed biochemically by measuring pulmonary elastin and hydroxyproline content. To determine if a protective effect of U74389F was linked to the 21-aminosteroid's ability to suppress lipid peroxidation, two products of lipid peroxidation were assayed in the lungs at 7 and 14 days after bleomycin exposure. By histologic assessment, the 21-aminosteroid-treated, bleomycin-exposed animals were found to have significantly decreased the extent of pulmonary fibrosis when compared with the bleomycin control group (mean 48.6 +/- 20.0 [SD] % [n = 9] vs. 68.4 +/- 19.6% [n = 11]; p < .05). In addition, lung elastin was decreased by approximately 75% (p < .05) and hydroxyproline was decreased by approximately 50% (NS) in the 21-aminosteroid-treated group when compared with the bleomycin control group. At 7 and 14 days after bleomycin exposure, all bleomycin-exposed animals had evidence of increased lipid peroxidation (conjugated dienes and thiobarbituric acid-reactive substances), but the 21-aminosteroid-treated, bleomycin-exposed animals had significantly decreased evidence of lipid peroxidation when compared with bleomycin controls. CONCLUSIONS The 21-aminosteroid can substantially protect animals from bleomycin-induced pulmonary fibrosis and may prove useful in other lung diseases where iron-dependent, free-radical reactions and/or lipid peroxidation are presumed mechanisms of toxicity.

Normal lung development involves septation of the large air saccules present at birth to form smaller diameter alveoli with a much increased surface area for respiratory exchange. This process in the newborn animal is markedly inhibited by hyperoxia, and the altered lung morphology that results may be permanent. We tested whether treatment of neonatal rats with the new 21-ami-nosteroid (21-AS) drug, U-74389F (15 mg/kg/d), could protect against O2-induced inhibition of normal lung development. By morphometric analysis after 10 d in >95% O2, the lungs of the animals treated with this potent iron chelator and inhibitor of lipid peroxidation showed a substantial protective effect—with reduced mean air space diameter and significantly increased internal surface area compared with O2 control pups. [Air control mean air space diameter = 47.4 μm, internal surface area = 1014 cm2; O2 controls = 61.0 μm (↑29%), 769 cm2 (↓24%); O2 21-AS = 53.4 μm (↑13%), 919 cm2 (↓9%); p < 0.05 between O2 groups.] Similarly, inhibition of lung elastin deposition (involved in septation process) during hyperoxia was significantly ameliorated by 21-AS treatment. In addition, follow-up studies of young adult rats demonstrated permanently enlarged lung alveoli and reduced surface area after neonatal high O2 exposure. These chronic morphologic effects were also significantly reduced by neonatal 21-AS treatment. The right ventricle hypertrophy (2° to pulmonary hypertension) in the O2 controls reaching adulthood [right ventricle/left ventricle + septum weight = 0.496 (f55% versus air control value = 0.320)] was markedly reduced in the adult 21-AS animals exposed to hyperoxia as neonates [0.382 (↑19%)]. Thus, 21-AS treatment had a substantial protective effect against both the acute and chronic lung as well as cardiac morphologic changes that early life exposure to hyperoxia can produce.

Most previous studies in isolated perfused lungs have utilized measurements of solute flow from alveolar to vascular space to characterize the barrier and transport properties of the alveolar epithelium. In this study, we measured flux of a series of nonionic hydrophilic solutes and sodium across the alveolar epithelium of the isolated rat lung from perfusate to airspace (P-->A), as well as from airspace to perfusate (A-->P). Apparent permeability-surface area products (PS) were calculated from the rates of isotope appearance downstream in either the airspace or the perfusate. Equivalent pore analysis of data for P-->A solute flow demonstrated a small pore population with radius 0.6 nm occupying 85% of the total pore area and a large pore population with radius 3.8 nm occupying 15% of the total area. Similar analysis of A-->P solute flux demonstrated a small pore population of 0.6 nm occupying 86% of the total pore area and a large pore population with radius 2.9 nm occupying 14% of total pore area. The ratio (R) of PSP-->A divided by PSA-->P was 0.8 for the nonionic hydrophilic solutes, while R for sodium was 0.5. In the presence of amiloride and ouabain, R for sucrose was unchanged while R for sodium increased to 0.8 due to a fall in PSA-->P. The difference between R for sodium and R for the passively transported solutes, and the reduction in this difference in the presence of sodium transport inhibitors, are consistent with active sodium reabsorption by the intact alveolar epithelium. Differences in measured unidirectional passive solute fluxes probably result from unequal effective surface areas for diffusion from vascular space to airspace and vice versa in the anatomically complex mammalian lung.

Fifty-five children with liver and intestinal failure have been transplanted at our center under daclizumab induction therapy since 1998. Of those, 19 received five multiviceral transplantation (MVT), 12 liver-intestine-pancreas transplants, and 2 noncomposite liver and intestine transplants (NCLIT) before 2001 (group 1). During this period, MVT was only used in children with gastric dysmotility. After 2001, we expanded the use of MVT. Therefore, 36 children in this period (group 2) received MVT except for two who received NCLIT. Median age was 1.08 in group 1 and 1.06 in group 2. Median recipient weight was 8.2 kg in group 1 and 7.5 kg in group 2. Six-month, 1-, and 2-year patient survivals were 54%, 37%, and 32% in group 1 and 94%, 91%, and 71% in group 2 (P = .00037). A statistically significant difference was observed in freedom from rejection between the two groups with group 2 being favorable (P = .0019). A statistically significant difference was observed in freedom from rejection between the two groups with group 2 being favorable (P = .0019) Four died of rejection in group 1 (21%); none died of rejection in group 2. There have been two esophago-gastrostomy strictures (one in each group) and a serious reflux of this anastomosis (group 2). Strictures were treated with balloon dilatation, and the reflux was surgically corrected. In 24 recent cases, gastro-gastric anastomosis was used in MVT with no complications to date. No pancreatic rejection was seen. Small children tolerated MVT with improved survival rates and reduced rates of rejection. Use of MVT may be considered as an alternative to liver-intestine-pancreas transplant.

Background Acute tacrolimus toxicity is manifest by oliguria and elevated serum creatinine. Various vasoregulatory molecules have been implicated in calcineurin inhibitor-mediated nephrotoxicity, including calcium, adenosine and endothelin. Theophylline (THEO), a non-specific adenosine-receptor antagonist prevents renal dysfunction from various nephrotoxins which mediate vasoconstriction. In the setting of acute tacrolimus toxicity, we demonstrated that administration of THEO along with a loop diuretic (LD) enhanced diuresis. This randomized, controlled trial was undertaken to confirm these earlier findings under more rigorous conditions. Methods Children with non-renal visceral transplant(s) and evidence of tacrolimus nephrotoxicity oliguria with a 25% increase in serum creatinine concentration from baseline, a whole blood tacrolimus concentration >20 ng/dl and oliguria resistant to therapy with a LD were randomized to receive either THEO (n = 10) or normal saline placebo (n = 8). Using pre and post (6 h) timed urine collections and coincident plasma concentrations the following were measured or calculated: urine flow rate, net fluid balance, creatinine clearance, fractional excretion of chloride, free water clearance and distal delivery of chloride. Results These patients had markedly impaired creatinine clearance at the onset of tacrolimus toxicity. Urine flow increased in the LD + THEO group by 110% over baseline, but was unchanged in the LD + NS group. An increase in creatinine clearance did not reach statistical significance (P = 0.09). Fractional excretion of chloride and distal solute delivery increased after THEO treatment. Conclusions THEO induced a solute diuresis during furosemide-resistant oliguric tacrolimus toxicity in paediatric patients with a trend towards improved renal function.

We performed 124 intestinal transplants on 108 children (median age, 1.5 years) since 1994. Initial graft types included isolated intestine (I) (n=26), liver and intestine (LI) (n=26), multivisceral (MV) (n=50), and multivisceral without liver (MMV) (n=6). Four groups were defined by type of induction therapy: none, OKT3, or cyclophosphamide (August 1994-December 1997, n=25), early experience with daclizumab (January 1998-December 2000, n=26), recent experience with daclizumab (January 2001-April 2004, n=40), and Campath-1H (January 2001-April 2004, n=17). Actuarial patient survival at 1 year for groups 1-4 was 44%+/-10%, 54%+/-10%, 83%+/-6%, and 41%+/-12%, respectively, with group 3 having the most favorable survival (P=0.0004). Using Cox stepwise regression, the hazard rate of developing severe rejection was significantly higher in patients with transplant type I or LI (P=0.0002), with no difference between these groups (P=0.24) but a significantly higher rate for LI versus MV (P=0.005). Three factors associated with improved patient survival were recipient of MV or MMV (P=0.008), age at transplantation greater than 1 year (P=0.01), and use of daclizumab (P=0.0006). Cause-specific hazard analysis revealed a decreased rate of rejection-related mortality for recipients of MV or MMV (P=0.0007), whereas age greater than 1 year indicated a lower rate of infection-related mortality (P=0.0009). Pediatric intestinal transplantation provides an increasingly realistic chance of survival, particularly with the more recent use of daclizumab and multivisceral transplantation. A protective effect of multivisceral transplantation appears to exist with respect to the development of severe rejection.

OBJECTIVE To determine whether theophylline, a nonselective adenosine receptor antagonist and phosphodiesterase inhibitor, reverses the acute declines in renal blood flow and glomerular filtration rate induced by high-dose tacrolimus in rats. DESIGN Prospective, randomized, placebo-controlled experimental study. SETTING University-based basic science research laboratory. SUBJECTS Adult male Sprague-Dawley rats. INTERVENTIONS After mechanical ventilation and instrumentation under isoflurane and nitrous oxide anesthesia, animals received either tacrolimus 0.5 mg/kg intravenously or vehicle and 1 hr later either theophylline 4 mg/kg intravenously or vehicle. MEASUREMENTS AND MAIN RESULTS By using radiolabeled microspheres, renal blood flow was measured in three groups: control (n = 5), tacrolimus plus vehicle (n = 6), and tacrolimus plus theophylline (n = 6) at four time points-baseline and 60, 75, and 90 mins after tacrolimus or vehicle (the latter two time points being 15 and 30 mins after theophylline or vehicle, respectively). Whole blood tacrolimus and serum theophylline concentrations were measured. In a separate group of animals, by using (51)Cr-EDTA, glomerular filtration rate was measured in two groups: tacrolimus plus vehicle (n = 5) and tacrolimus plus theophylline (n = 5) at baseline and over two consecutive 20-min time periods beginning 61 mins posttacrolimus. Urine flow rate also was measured. Following tacrolimus, both renal blood flow and glomerular filtration rate declined in parallel by approximately 33% and 50% from baseline after 75 and 90 mins, respectively (p

OBJECTIVE: The most severe form of generalized junctional epidermolysis bullosa, the Herlitz variant, is associated with a number of extracutaneous manifestations. We report on a 45-day-old infant with laryngotracheobronchial mucosa involvement who underwent successful tracheal extubation after 10 days of orotracheal intubation and mechanical ventilatory support. Issues regarding airway management and mechanical ventilatory support in the pediatric intensive care unit are discussed.