Golimumab and Beta-Cell Function in Youth with New-Onset Type 1 Diabetes.

BACKGROUND: Type 1 diabetes is an autoimmune disease characterized by progressive loss of pancreatic beta cells. Golimumab is a human monoclonal antibody specific for tumor necrosis factor α that has already been approved for the treatment of several autoimmune conditions in adults and children. Whether golimumab could preserve beta-cell function in youth with newly diagnosed overt (stage 3) type 1 diabetes is unknown. METHODS: In this phase 2, multicenter, placebo-controlled, double-blind, parallel-group trial, we randomly assigned, in a 2:1 ratio, children and young adults (age range, 6 to 21 years) with newly diagnosed overt type 1 diabetes to receive subcutaneous golimumab or placebo for 52 weeks. The primary end point was endogenous insulin production, as assessed according to the area under the concentration-time curve for C-peptide level in response to a 4-hour mixed-meal tolerance test (4-hour C-peptide AUC) at week 52. Secondary and additional end points included insulin use, the glycated hemoglobin level, the number of hypoglycemic events, the ratio of fasting proinsulin to C-peptide over time, and response profile. RESULTS: A total of 84 participants underwent randomization - 56 were assigned to the golimumab group and 28 to the placebo group. The mean (±SD) 4-hour C-peptide AUC at week 52 differed significantly between the golimumab group and the placebo group (0.64±0.42 pmol per milliliter vs. 0.43±0.39 pmol per milliliter, P<0.001). A treat-to-target approach led to good glycemic control in both groups, and there was no significant difference between the groups in glycated hemoglobin level. Insulin use was lower with golimumab than with placebo. A partial-remission response (defined as an insulin dose-adjusted glycated hemoglobin level score [calculated as the glycated hemoglobin level plus 4 times the insulin dose] of ≤9) was observed in 43% of participants in the golimumab group and in 7% of those in the placebo group (difference, 36 percentage points; 95% CI, 22 to 55). The mean number of hypoglycemic events did not differ between the trial groups. Hypoglycemic events that were recorded as adverse events at the discretion of investigators were reported in 13 participants (23%) in the golimumab group and in 2 (7%) of those in the placebo group. Antibodies to golimumab were detected in 30 participants who received the drug; 29 had antibody titers lower than 1:1000, of whom 12 had positive results for neutralizing antibodies. CONCLUSIONS: Among children and young adults with newly diagnosed overt type 1 diabetes, golimumab resulted in better endogenous insulin production and less exogenous insulin use than placebo. (Funded by Janssen Research and Development; T1GER ClinicalTrials.gov number, NCT02846545.).

Targeting memory T cells in type 1 diabetes.

Type 1 diabetes (T1D) is a chronic autoimmune disease that leads to progressive destruction of pancreatic beta cells. Compared to healthy controls, a characteristic feature of patients with T1D is the presence of self-reactive T cells with a memory phenotype. These autoreactive memory T cells in both the CD4(+) and CD8(+) compartments are likely to be long-lived, strongly responsive to antigenic stimulation with less dependence on costimulation for activation and clonal expansion, and comparatively resistant to suppression by regulatory T cells (Tregs) or downregulation by immune-modulating agents. Persistence of autoreactive memory T cells likely contributes to the difficulty in preventing disease progression in new-onset T1D and maintaining allogeneic islet transplants by regular immunosuppressive regimens. The majority of immune interventions that have demonstrated some success in preserving beta cell function in the new-onset period have been shown to deplete or modulate memory T cells. Based on these and other considerations, preservation of residual beta cells early after diagnosis or restoration of beta cell mass by use of stem cell or transplantation technology will require a successful strategy to control the autoreactive memory T cell compartment, which could include depletion, inhibition of homeostatic cytokines, induction of hyporesponsiveness, or a combination of these approaches.

Inconsistencies in care of the pediatric hematopoietic stem cell transplant recipient with respiratory failure: opportunity for standardization and improved outcome.

There is variability in critical care outcome of the HSCT recipient. One potential reason may be due to the inconsistent ventilation approaches. To quantitate this variability, we conducted a survey to assess self-reported use of ventilation and adjunctive strategies for the HSCT recipient. Electronic survey, open from June 2012 through January 201, distributed through the Pediatric Acute Lung Injury and Sepsis Investigators network electronic mailing list. Ninety-four individual responses were from 36 different institutions. The majority indicated that HSCT recipients requiring critical care were admitted to the general PICU. The vast majority (89%) endorsed routine practice of low-tidal-volume ventilation strategies. More than half stated that pressure-regulated volume control is the starting mode of choice. Eighty-three percent felt their group practiced early initiation of lung protective strategies. Eleven percent encouraged "early transition" to HFOV. Inhaled nitric oxide and milrinone were reported at the highest frequencies, but the majority used these empirically. Opinions regarding variables that affect outcomes of the HSCT were diverse. The estimated mortality of HSCT patients with respiratory was highly variable. Strategies for ventilation and oxygenation, use of HFOV, and adjunctive therapies are variable among pediatric intensivists.

Vasovagal syncope and severe bradycardia following intranasal dexmedetomidine for pediatric procedural sedation.

We report syncope and bradycardia in an 11-year-old girl following administration of intranasal dexmedetomidine for sedation for a voiding cystourethrogram. Following successful completion of VCUG and a 60-min recovery period, the patient's level of consciousness and vital signs returned to presedation levels. Upon leaving the sedation area, the patient collapsed, with no apparent inciting event. The patient quickly regained consciousness and no injury occurred. The primary abnormality found was persistent bradycardia, and she was admitted to the hospital for telemetric observation. The bradycardia lasted ~2 h, and further cardiac workup revealed no underlying abnormality. Unanticipated and previously unreported outcomes may be witnessed as we expand the use of certain sedatives to alternative routes of administration.

Successful use of intravenous dexmedetomidine for magnetic resonance imaging sedation in autistic children.

OBJECTIVES: Autism and autism spectrum disorders (A/ASD) represent a family of neurodevelopmental conditions that are associated with overactive, difficult-to-control behaviors. Sedating these patients for magnetic resonance imaging (MRI) poses challenges. Children with A/ASD were examined against clinical controls to determine the effectiveness and safety of intravenous (IV) dexmedetomidine for deep sedation. METHODS: The quality assurance data on all of the children who received IV dexmedetomidine sedation for MRI between July 2007 and December 2012 were reviewed. Patients in both groups were sedated by an intensivist-based team with a standard plan of 2 µg/kg IV dexmedetomidine administered for 10 minutes followed by an infusion of 1 µg · kg(-1)· hour(-1). The amount of IV dexmedetomidine was titrated to the deep level of sedation. A total of 56 patients in the A/ASD group and 107 in the control group were sedated with no reported sedation failures. Sedation parameters were compared between the A/ASD and control groups using analysis of covariance models, controlling for age, sex, and weight. RESULTS: Children in the A/ASD group were predominantly male (73%) and older (6.1 ± 0.3 years) than children in the control group (56%; 5.0 ± 0.2 years; P < 0.05 for both). Procedure time was significantly shorter for patients in the A/ASD group than in control patients (34.6 ± 2.4 vs 44.3 ± 1.6 minutes; P < 0.05). The A/ASD and control groups required a similar IV bolus of dexmedetomidine (2.6 µg/kg ± 0.1 vs 2.4 µg/kg ± 0.10; P = 0.29), with a significantly lower infusion dose in the A/ASD group (0.74 µg/kg ± 0.05 vs 0.89 µg/kg ± 0.03; P < 0.05). Heart rates were similar in the A/ASD group and the control group (67.0 beats per minute ± 1.6 vs 69.3 ± 1.1 beats per minute; P = 0.250). There were no complications. Recovery time was approximately 7 minutes longer in the A/ASD group than in the control group, but this was nonsignificant (101.2 ± 3.5 minutes vs 94.2 ± 2.4 minutes; P = 0.12). Analyses were performed using analysis of covariance methods and generalized linear models to control for age, sex, and weight. CONCLUSIONS: Children with A/ASD can be successfully sedated for MRIs with IV dexmedetomidine without complications.

Safe and effective use of a glycemic control protocol for neonates in a cardiac ICU.

OBJECTIVE: To investigate the safety and efficacy of a hyperglycemia protocol in neonates with critical cardiac illness. Neonates are often regarded as high risk for hypoglycemia while receiving continuous insulin infusions and thus have been excluded from some clinical trials. DESIGN: A retrospective review. SETTING: A pediatric cardiac ICU in a tertiary academic center. INTERVENTIONS: Neonates with critical cardiac illness who developed hyperglycemia were placed on an insulin-hyperglycemia protocol at the attending physician's discretion. Insulin infusions were titrated based on frequent blood glucose monitoring. MEASUREMENTS: Critical illness hyperglycemia was defined as a blood glucose less than 140 mg/dL. Hypoglycemia was defined as moderate (≤ 60 mg/dL) or severe (≤ 40 mg/dL). Initiating blood glucose, lowest blood glucose during insulin infusion, doses of insulin, duration of insulin, and time to blood glucose greater than 140 mg/dL were evaluated. MAIN RESULTS: A total of 44 patients were placed on the protocol between January 2009 and October 2011. The majority of insulin infusions were initiated in the early postoperative period (33 of 44, 75%). Moderate hypoglycemia occurred in two patients (4.5%), with blood glucose levels of 49 and 53 mg/dL. No episodes of severe hypoglycemia occurred. A total of 345 discrete blood glucose levels were analyzed; two of these being greater than 60 mg/dL (0.58%). Mean blood glucose prior to starting insulin was 252 ± 45 mg/dL and time until euglycemia was 6.1 ± 3.9 hours. The mean duration of insulin infusion was 24.6 ± 38.7 hours, mean peak dose was 0.10 ± 0.05 units/kg/hour, and mean insulin dose was 0.06 ± 0.02 units/kg/hour. For postoperative patients, mean time after bypass until onset of hyperglycemia was 2.2 ± 2.6 hours. CONCLUSIONS: A glycemic control protocol can safely and effectively be applied to neonates with critical cardiac disease. Neonates with critical cardiac illness should be included in clinical trials evaluating the benefits of glycemic control.

Two-Year Follow-up From the T1GER Study: Continued Off-Therapy Metabolic Improvements in Children and Young Adults With New-Onset T1D Treated With Golimumab and Characterization of Responders.

OBJECTIVE: The T1GER (A Study of SIMPONI to Arrest ß-Cell Loss in Type 1 Diabetes) study showed many metabolic benefits of the tumor necrosis factor-α blocker golimumab in children and young adults with type 1 diabetes (T1D). Off-therapy effects are reported. RESEARCH DESIGNS AND METHODS: T1GER was a phase 2, placebo-controlled, randomized trial in which golimumab or placebo was administered for 52 weeks to participants 6-21 years old diagnosed with T1D within 100 days of randomization. Assessments occurred during the 52-week on-therapy and 52-week off-therapy periods. RESULTS: After treatment was stopped, C-peptide area under the curve (AUC) remained greater in the treatment versus control group. At weeks 78 and 104, the golimumab group had lower reductions in the 4-h C-peptide AUC baseline than the placebo group, where specifically the golimumab group had reductions of 0.31 and 0.41 nmol/L, and the placebo group had reductions of 0.64 and 0.74 nmol/L. There were also trends in less insulin use, higher peak C-peptide levels and those in partial remission, and higher peak C-peptide levels in the golimumab group. Golimumab responders, defined as having an increase or minimal loss of C-peptide AUC and/or being in partial remission at week 52, showed even greater improvements in most metabolic parameters on and off therapy and had less hypoglycemia during the off-therapy period versus placebo. Adverse events, including infections, were similar between the groups during all time periods of the study. CONCLUSIONS: In children and young adults with new-onset T1D, golimumab preserved endogenous ß-cell function and resulted in other favorable metabolic parameters on and off therapy. A subpopulation had disease stabilization while on therapy, with improved metabolic parameters off therapy.

A disparity between physician attitudes and practice regarding hyperglycemia in pediatric intensive care units in the United States: a survey on actual practice habits.

INTRODUCTION: Hyperglycemia is common in critically ill patients and is associated with increased morbidity and mortality. Strict glycemic control improves outcomes in some adult populations and may have similar effects in children. While glycemic control has become standard care in adults, little is known regarding hyperglycemia management strategies used by pediatric critical care practitioners. We sought to assess both the beliefs and practice habits regarding glycemic control in pediatric intensive care units (ICUs) in the United States (US). METHODS: We surveyed 30 US pediatric ICUs from January to May 2009. Surveys were conducted by phone between the investigators and participating centers and consisted of a 22-point questionnaire devised to assess physician perceptions and center-specific management strategies regarding glycemic control. RESULTS: ICUs included a cross section of centers throughout the US. Fourteen out of 30 centers believe all critically ill hyperglycemic adults should be treated, while 3/30 believe all critically ill children should be treated. Twenty-nine of 30 believe some subsets of adults with hyperglycemia should be treated, while 20/30 believe some subsets of children should receive glycemic control. A total of 70%, 73%, 80%, 27%, and 40% of centers believe hyperglycemia adversely affects outcomes in cardiac, trauma, traumatic brain injury, general medical, and general surgical pediatric patients, respectively. However, only six centers use a standard, uniform approach to treat hyperglycemia at their institution. Sixty percent of centers believe hypoglycemia is more dangerous than hyperglycemia. Seventy percent listed fear of management-induced hypoglycemia as a barrier to glycemic control at their center. CONCLUSIONS: Considerable disparity exists between physician beliefs and actual practice habits regarding glycemic control among pediatric practitioners, with few centers reporting the use of any consistent standard approach to screening and management. Physicians wishing to practice glycemic control in their critically ill pediatric patients may want to consider adopting center-wide uniform approaches to improve safety and efficacy of treatment.

Continuous glucose monitors prove highly accurate in critically ill children.

INTRODUCTION: Hyperglycemia is associated with increased morbidity and mortality in critically ill patients and strict glycemic control has become standard care for adults. Recent studies have questioned the optimal targets for such management and reported increased rates of iatrogenic hypoglycemia in both critically ill children and adults. The ability to provide accurate, real-time continuous glucose monitoring would improve the efficacy and safety of this practice in critically ill patients. The aim of our study is to determine if a continuous, interstitial glucose monitor will correlate with blood glucose values in critically ill children. METHODS: We evaluated 50 critically ill children age 6 weeks to 16 years old with a commercially available continuous glucose monitor (CGM; Medtronic Guardian®). CGM values and standard blood glucose (BG) values were compared. During the study, no changes in patient management were made based on CGM readings alone. RESULTS: Forty-seven patients had analyzable CGM data. A total of 1,555 CGM and routine BG measurements were compared using Clarke error grid and Bland-Altman analysis. For all readings, 97.9% were within clinically acceptable agreement. The mean absolute relative difference between CGM and BG readings was 15.3%. For the 1,555 paired CGM and BG measurements, there is a statistically significant linear relationship between CGM values and BG (P < .0001). A high degree of clinical agreement existed in three subpopulation analyses based on age, illness severity, and support measures. This included some of our smallest patients (that is, < 12 months old), those who required vasopressors, and those who were treated for critical illness hyperglycemia. CONCLUSIONS: In one of the largest studies to date, in a highly vulnerable ICU population, CGM values have a clinically acceptable correlation with the BG values now used diagnostically and therapeutically. Our data contest the theoretical concerns posed by some regarding CGM use in the ICU. The existing medical evidence may now support a role for CGM devices in the identification and management of hyperglycemia in diverse ICU settings.

Ultrasound-guided central venous catheter placement decreases complications and decreases placement attempts compared with the landmark technique in patients in a pediatric intensive care unit.

OBJECTIVE: To determine whether ultrasound (US) increases successful central venous catheter (CVC) placement, decreases site attempts, and decreases CVC placement complications. DESIGN AND SETTING: A prospective observational cohort study evaluating a transition by the Pediatric Critical Care Medicine service to US-guided CVC placement. Medical and surgical patients in a 21-bed quaternary multidisciplinary pediatric intensive care unit had CVCs placed by attendings, fellows, residents, and a nurse practitioner. PATIENTS: Ninety-three patients were prospectively enrolled into the landmark (LM) group and 119 into the US group. INTERVENTIONS: : After collection of prospective LM data, training with US guidance was provided. CVCs were subsequently placed with US guidance. MEASUREMENTS AND MAIN RESULTS: Operator information, disease process, emergent/routine, sites attempted, and complications were recorded. Procedure time was from initial skin puncture to guidewire placement. There was no difference overall in success rates (88.2% LM vs. 90.8% US, p = 0.54) or time to successful placement (median seconds 269 LM vs. 150 US, p = 0.14) between the two groups. Median number of attempts were fewer with US for all CVCs attempted (3 vs. 1, p < 0.001) as were attempts at >1 anatomical site (20.7% LM vs. 5.9% US, p = 0.001). Use of US was associated with fewer inadvertent artery punctures (8.5% vs. 19.4%, p = 0.03). Time to successful placement by residents was decreased with US (median 919 seconds vs. 405 seconds, p = 0.02). More internal jugular CVCs were placed during the US period than during the LM period (13.4% vs. 2.1%). CONCLUSIONS: US-guided CVC placement in children is associated with decreased number of anatomical sites attempted and decreased number of attempts to gain placement. Time to placement by residents was decreased with US, but not the time to placement by other operators. US guidance increased the use of internal jugular catheter placement and decreased artery punctures. US guidance did not improve success rates.

Pediatric critical illness hyperglycemia: risk factors associated with development and severity of hyperglycemia in critically ill children.

OBJECTIVE: To determine which children are susceptible to critical illness hyperglycemia (CIH) and whether CIH severity and duration correlate with diagnosis or illness severity. STUDY DESIGN: We developed a standard approach to identify and treat CIH in our medical/surgical pediatric intensive care unit. We define CIH as persistent blood glucose (BG) >140 mg/dL and titrate infused insulin to maintain BG 80 to 140 mg/dL. We conducted a retrospective analysis of patients with hyperglycemia from June 2006 through May 2007. Main outcomes were risk of development of CIH in different patient subgroups and CIH severity and duration. RESULTS: Average peak BG, CIH duration, and peak insulin requirements were 199 mg/dL, 6.3 days, and 0.09 units/kg/h, respectively, in patients with CIH. CIH severity and duration were highest in neurosurgical and patients with sepsis, those requiring mechanical ventilation and vasopressors, extracorporeal support, and those with highest illness severity scores. CONCLUSIONS: CIH severity and duration correlate with diagnosis and illness severity. Certain "risk factors" may be predictive of who develops CIH.

Hyperglycaemia results from beta-cell dysfunction in critically ill children with respiratory and cardiovascular failure: a prospective observational study.

INTRODUCTION: Hyperglycaemia is common in critical illness and associated with poor outcome. Glycaemic control using insulin may decrease morbidity and mortality. Many questions remain about the cause of critical illness hyperglycaemia (CIH). Our objective was to investigate the endocrinological basis of paediatric CIH. METHODS: C-peptide and blood glucose (BG) levels were assessed in 41 children aged 2 to 18 years old who were admitted to our paediatric intensive care unit (PICU). Patients who developed CIH, defined as persistent BG above 7.7 mmol/L, were treated with insulin infusion to achieve BG levels between 4.4 and 7.7 mmol/L. C-peptide levels were compared with respect to CIH development and degree of organ failure in all patients. Respiratory and cardiovascular failure were defined as need for mechanical ventilation and need for vasoactive infusions, respectively. Clinical and laboratory parameters, including c-peptide levels, were assessed. RESULTS: Of 41 children enrolled, 18 had respiratory failure only, 11 had both respiratory and cardiovascular failure, and 12 had neither respiratory or cardiovascular failure. Nine patients with respiratory failure only, 10 with both respiratory and cardiovascular failure, and none with no respiratory or cardiovascular failure developed CIH. Patients with CIH and respiratory and cardiovascular failure (n = 10) had very low c-peptide levels (4.4 ng/mL) despite significantly elevated mean BG levels (10.8 mmol/L), while those with CIH and respiratory failure only had very high c-peptide levels (11.5 ng/mL) with mean BG of 9.9 mmol/L. Low endogenous insulin production in those with respiratory and cardiovascular failure was associated with rapid onset of CIH, illness severity, higher insulin requirement and longer mechanical ventilation days, PICU length of stay and CIH duration. CONCLUSIONS: Primary beta-cell dysfunction as defined by low endogenous c-peptide production appears to be prevalent in critically ill children with both respiratory and cardiovascular failure who develop CIH, whereas elevated insulin resistance appears to be the prominent cause of CIH in children with respiratory failure only. Our finding that beta-cell dysfunction is present in a subset of critically ill children with CIH challenges the assertion from adult studies that CIH is primarily the result of elevated insulin resistance.

Neuroendocrine dysfunction in pediatric critical illness.

BACKGROUND: The extent of neuroendocrine dysfunction (NED) has not been well defined in critically ill children and likely varies significantly from that in adults. We sought to define the prevalence of neuroendocrine dysfunction in a group of children in a multidisciplinary pediatric intensive care unit and determine the relationship of neuroendocrine dysfunction with severity of illness and presence of sepsis. METHODS: Prospective observational study in a pediatric intensive care unit at a referral childrens hospital. Blood samples were evaluated within 12 hrs of admission for serum cortisol, thyroid stimulating hormone, total triiodothyronine (T3), reverse triiodothyroine (rT3), free thyroxine, and arginine vasopressin. Pediatric risk of mortality, pediatric logistic organ dysfunction scores, and length of stay were calculated. RESULTS: Seventy-three children were enrolled over a 13-month period. Median patient age was 72 months (range, 3-228 months). Overall prevalence of absolute adrenal insufficiency ranged from 7% to 58% based on cortisol cutoff chosen. Presence of absolute adrenal insufficiency, low T3 syndrome (LT3S), or vasopressin insufficiency did not differ between septic or nonseptic patients. NED did not correlate with pediatric logistic organ dysfunction, Pediatric Risk of Mortality Score III, length of stay, or mortality. Prevalence of multiple NED was 62% (28 of 45 children), where 62% had 2 neurohormonal deficiencies and 24% had 3 neurohormonal deficiencies. CONCLUSION: NED is common in both septic and nonseptic critically ill children in a single pediatric intensive care unit. Larger scale studies are necessary to determine whether presence of NED, or specific combinations of neurohormonal dysfunction, is important in predicting outcomes or benefit of early hormonal replacement therapies in critically ill children.

Glycemic control for postoperative pediatric cardiac patients.

This study aimed to determine the prevalence of hyperglycemia among pediatric postoperative cardiac patients, its impact on outcomes, and whether hyperglycemia can be controlled effectively in this population. A retrospective chart review of 100 postoperative patients admitted to the authors' pediatric cardiac intensive care unit (ICU) was conducted. Patients were evaluated for incidence of hyperglycemia, defined as blood glucose (BG) level exceeding 7.7 mmol/l (140 mg/dl), and outcomes. The evaluation also included 20 different postoperative patients with a BG level exceeding 7.7 mmol/l (140 mg/dl) who received management with insulin via the authors' pediatric-specific glycemic control protocol. The BG control and hypoglycemic rates in this cohort were assessed. The prevalence of hyperglycemia was 84%. The hyperglycemic patients had higher inotrope scores, longer hospital stays, more mechanical ventilation days, and higher mortality rates than those without hyperglycemia. For the patients with hyperglycemia managed via the authors' pediatric-specific glycemic control protocol, 62% of all BG values were within the authors' goal range, and less than 4% of BG values were less than 3.3 mmol/l (60 mg/dl). No patient had a BG level lower than 2.2 mmol/l (40 mg/dl) during glycemic management. Severe hyperglycemia is prevalent among postoperative pediatric cardiac patients and correlates with morbidity and mortality. Hyperglycemia may be controlled effectively in these patients using a pediatric-specific glycemic control protocol without increasing the incidence of hypoglycemia.

Pediatric procedural sedation by a dedicated nonanesthesiology pediatric sedation service using propofol.

OBJECTIVES: To evaluate the success and dosing requirements of propofol in children for prolonged procedural sedation by a nonanesthesiology-based sedation service. METHODS: The pediatric sedation service at this institution uses propofol as its preferred sedative, and the local guideline suggests using 3 mg/kg for induction and 5 mg kg(-1) h(-1) for maintenance sedation. Doses can be adjusted as needed to individualize successful sedation. A retrospective analysis of patients sedated for 30 minutes or longer was conducted. Patients were stratified into 4 cohorts based on age (<1 year [n = 16], 1-2 years [n = 85], 3-7 years [n = 54], and >7 years [n = 55]) and dosing patterns, success, and adverse effects were investigated. RESULTS: Two hundred forty-nine patients met the inclusion criteria. Mean age was 4.8 years (SD, 4.1). The mean induction dose was 3.2 mg/kg (range, 0.9-9.7), and the mean maintenance infusion was 5.2 mg kg(-1) h(-1) (range, 0.14-21.3). No differences were seen in the induction doses in the different age cohorts, yet the SD was largest in the youngest cohort compared to any other. Although no differences were seen in maintenance rates by age, the greatest SD for dosing was seen in the oldest cohort. For all ages, all sedations were successful (100%) and unanticipated adverse effects rare (<1%). CONCLUSIONS: Although it seems that the mean dosing of propofol does not vary significantly with age, there is greater variability in induction dosage for those younger than 1 year and in maintenance dosing for those 7 years or older. The results and general dosing parameters may assist pediatric subspecialists in using propofol for prolonged procedural sedation.

A protocolized approach to identify and manage hyperglycemia in a pediatric critical care unit.

INTRODUCTION: Hyperglycemia is a risk factor for poor outcome in critically ill patients, and glycemic control may decrease morbidity and mortality in adults. There is limited information regarding hyperglycemia and its control in pediatric intensive care. OBJECTIVE: To determine prevalence and risk factors for hyperglycemia and evaluate our approach to glycemic control in critically ill children. DESIGN, SETTING, PATIENTS, AND MAIN OUTCOMES: A pediatric-specific protocol to identify and manage hyperglycemia was developed and instituted as standard practice in our pediatric intensive care unit, and was applicable to patients >6 months and >5 kg, without end-stage liver disease or type 1 diabetes mellitus. Triggers for routine blood glucose assessment were based on supportive measures including mechanical ventilation, vasopressor/inotrope infusions, and antihypertensive infusions. Hyperglycemic patients, defined by two consecutive blood glucose readings of >140 mg/dL (7.7 mmol/L), were treated with infused insulin to maintain blood glucose levels 80-140 mg/dL (4.4-7.7 mmol/L). We performed retrospective analysis 6 months after instituting this approach. Main outcomes were prevalence and risk factors for hyperglycemia, and effectiveness of our approach to achieve glycemic control. INTERVENTIONS: None. MEASUREMENTS/MAIN RESULTS: One hundred forty-five of 477 patients had blood glucose actively assessed, and 74 developed hyperglycemia and were managed with insulin. This approach to identify patients with hyperglycemia had a positive predictive value of 51% and negative predictive value of 94%. Hyperglycemia prevalence was 20%. Mechanical ventilation, vasopressor/inotropic infusion, continuous renal replacement therapy, high illness severity scores, and longer lengths of stay were associated with hyperglycemia. The average blood glucose of patients with hyperglycemia was 200 mg/dL (11 mmol/L), and on average, patients were treated with insulin for 6.3 days with 2.4 units/kg/day. Blood glucose levels were <160 mg/dL (8.8 mmol/L) in 70% of insulin-treated days, 80-140 mg/dL (4.4-7.7 mmol/L) in 49% of insulin-treated days, and 4% of insulin-treated patients had any blood glucose measurements <40 mg/dL (2.2 mmol/L). CONCLUSIONS: Hyperglycemia is prevalent in pediatric intensive care units and may be effectively identified and managed using a protocolized approach.

Endocrine issues in the pediatric intensive care unit.

This article reviews selected issues of endocrine concerns in the pediatric intensive care unit, exclusive of diabetic ketoacidosis. The sympathoadrenergic arm of the neuroendocrine stress response is described, followed by discussions of two topics of particular current concern: critical illness hyperglycemia and relative adrenal insufficiency. A selected set of common scenarios encountered in the daily practice of intensive care follows.

Infusion of stably immature monocyte-derived dendritic cells plus CTLA4Ig modulates alloimmune reactivity in rhesus macaques.

BACKGROUND: Immature dendritic cells (DC) can promote long-term transplant survival in rodents. We assessed the impact of stably immature, donor-derived DC on alloimmune reactivity in rhesus macaques. METHODS: CD14 monocytes isolated from leukapheresis products of Macacca mulatta were cultured in granulocyte-macrophage colony stimulating factor plus interleukin (IL)-4+/-vitamin (vit) D3, and IL-10. Major histocompatibility complex class II and cosignaling molecule expression was determined on CD11c cells by flow cytometry. T-cell allostimulatory capacity of the DC, including DC exposed to proinflammatory cytokines, was determined in mixed leukocyte reaction. To test their influence in vivo, purified DC were infused intravenously into allogeneic recipients, either alone or followed by CTLA4Ig, 24 hr later. Proliferative responses of recipient CFSE-labeled T cells to donor or third party DC, cytokine production by stimulated T cells, and circulating alloantibody levels were determined by flow cytometry, up to 100 days postinfusion. RESULTS: VitD3/IL-10-conditioned, monocyte-derived DC were resistant to maturation and failed to induce allogeneic T cell proliferation in vitro. After their infusion, an increase in anti-donor and anti-third party T-cell reactivity was observed, that subsequently subsided to fall significantly below pretreatment levels (by day 56) only in animals also given CTLA4Ig. No increase in circulating immunoglobulin (Ig) M or IgG anti-donor alloantibody titers compared with pretreatment values was detected. With DC+CTLA4Ig infusion, alloreactive IL-10-producing T cells were prevalent in the circulation after day 28. CONCLUSIONS: Maturation-resistant rhesus DC infusion is well-tolerated. DC+CTLA4Ig infusion modulates allogeneic T-cell responses and results in hyporesponsiveness to donor and third party alloantigens.