Mark R. Rigby

Guidelines for the use of an insulin infusion for the management of hyperglycemia in critically ill patients.

Objective:To evaluate the literature and identify important aspects of insulin therapy that facilitate safe and effective infusion therapy for a defined glycemic end point. Methods:Where available, the literature was evaluated using Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) methodology to assess the impact of insulin infusions on outcome for general intensive care unit patients and those in specific subsets of neurologic injury, traumatic injury, and cardiovascular surgery. Elements that contribute to safe and effective insulin infusion therapy were determined through literature review and expert opinion. The majority of the literature supporting the use of insulin infusion therapy for critically ill patients lacks adequate strength to support more than weak recommendations, termed suggestions, such that the difference between desirable and undesirable effect of a given intervention is not always clear. Recommendations:The article is focused on a suggested glycemic control end point such that a blood glucose ≥150 mg/dL triggers interventions to maintain blood glucose below that level and absolutely <180 mg/dL. There is a slight reduction in mortality with this treatment end point for general intensive care unit patients and reductions in morbidity for perioperative patients, postoperative cardiac surgery patients, post-traumatic injury patients, and neurologic injury patients. We suggest that the insulin regimen and monitoring system be designed to avoid and detect hypoglycemia (blood glucose ⩽70 mg/dL) and to minimize glycemic variability.Important processes of care for insulin therapy include use of a reliable insulin infusion protocol, frequent blood glucose monitoring, and avoidance of finger-stick glucose testing through the use of arterial or venous glucose samples. The essential components of an insulin infusion system include use of a validated insulin titration program, availability of appropriate staffing resources, accurate monitoring technology, and standardized approaches to infusion preparation, provision of consistent carbohydrate calories and nutritional support, and dextrose replacement for hypoglycemia prevention and treatment. Quality improvement of glycemic management programs should include analysis of hypoglycemia rates, run charts of glucose values <150 and 180 mg/dL. The literature is inadequate to support recommendations regarding glycemic control in pediatric patients. Conclusions:While the benefits of tight glycemic control have not been definitive, there are patients who will receive insulin infusion therapy, and the suggestions in this article provide the structure for safe and effective use of this therapy.

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.

Heterogeneous expression of four MAP kinase isoforms in human tissues

Mitogen‐activated protein kinases (MAP kinases) are a group of closely related enzymes implicated in signal transduction pathways. We report the molecular cloning of four human proteins (p40 mapk , p41 mapk , p44 mapk and p63 mapk , with high homology to members of the MAP kinase family. Sequence analysis demonstrated that p44 mapk and p63 mapk were the products of distinct genes. However, the p40 mapk and p41 mapk were found to be related, and are likely to result from alternative processing of transcripts from a single gene. The heterogeneous expression of these human MAP kinase isoforms in different tissues may reflect the diversity of signal transduction pathways in differentiated cells.

Value of postprocedural chest radiographs in the adult intensive care unit

ObjectiveTo evaluate the necessity for post-procedural chest radiographs after catheterization of central veins, insertion of pulmonary artery catheters, and placement of endotracheal tubes. DesignProspective, controlled study. SettingTwo academic tertiary adult ICUs. PatientsConsecutive patients (n = 316) requiring central vein cannulation or endotracheal intubation in the ICUs. InterventionAfter each invasive procedure, the physician was instructed to complete a detailed evaluation sheet. Criteria based on the details of the procedure and immediate postprocedural clinical evaluation of the patient were used to determine the likelihood of a radiologically detectable complication. Actual radiologic findings were subsequently compared against clinical predictions. Main Outcome MeasurementsAbility of housestaff to correctly predict the absence of radiologically detectable postprocedural complications (predictive negatives). ResultsAbility to predict the absence of complications after cordis catheter insertions via the subclavian vein or internal jugular vein was very high (151/152; p < .001). Unsuspected complications were more frequent with central vein multilumen catheter insertions (3/24; p < .001). Ability to predict uncomplicated pulmonary artery catheterization was also high (110/111; p < .001). Physicians were unable to predict the majority of complications associated with endotracheal intubations (28/32; p > .50). ConclusionsThe use of a protocol that includes an evaluation of the characteristics of the procedure and postprocedural physical examination can greatly reduce the need for routine chest radiographs after subclavian and internal jugular vein cordis catheterizations and pulmonary artery catheter placement. Chest radiographs should be performed after endotracheal intubation and multilumen catheter insertion.

Targeting of memory T cells with alefacept in new-onset type 1 diabetes (T1DAL study): 12 month results of a randomised, double-blind, placebo-controlled phase 2 trial

BACKGROUND Type 1 diabetes results from autoimmune targeting of the pancreatic β cells, likely mediated by effector memory T (Tem) cells. CD2, a T cell surface protein highly expressed on Tem cells, is targeted by the fusion protein alefacept, depleting Tem cells and central memory T (Tcm) cells. We postulated that alefacept would arrest autoimmunity and preserve residual β cells in patients newly diagnosed with type 1 diabetes. METHODS The T1DAL study is a phase 2, double-blind, placebo-controlled trial in patients with type 1 diabetes, aged 12-35 years who, within 100 days of diagnosis, were enrolled at 14 US sites. Patients were randomly assigned (2:1) to receive alefacept (two 12-week courses of 15 mg intramuscularly per week, separated by a 12-week pause) or a placebo. Randomisation was stratified by site, and was computer-generated with permuted blocks of three patients per block. All participants and site personnel were masked to treatment assignment. The primary endpoint was the change from baseline in mean 2 h C-peptide area under the curve (AUC) at 12 months. Secondary endpoints at 12 months were the change from baseline in the 4 h C-peptide AUC, insulin use, major hypoglycaemic events, and HbA1c concentrations. This trial is registered with ClinicalTrials.gov, number NCT00965458. FINDINGS Of 73 patients assessed for eligibility, 33 were randomly assigned to receive alefacept and 16 to receive placebo. The mean 2 h C-peptide AUC at 12 months increased by 0.015 nmol/L (95% CI -0.080 to 0.110) in the alefacept group and decreased by 0.115 nmol/L (-0.278 to 0.047) in the placebo group, and the difference between groups was not significant (p=0.065). However, key secondary endpoints were met: the mean 4 h C-peptide AUC was significantly higher (mean increase of 0.015 nmol/L [95% CI -0.076 to 0.106] vs decrease of -0.156 nmol/L [-0.305 to -0.006]; p=0.019), and daily insulin use (0.48 units per kg per day for placebo vs 0.36 units per kg per day for alefacept; p=0.02) and the rate of hypoglycaemic events (mean of 10.9 events per person per year for alefacept vs 17.3 events for placebo; p<0.0001) was significantly lower at 12 months in the alefacept group than in the placebo group. Mean HbA1c concentrations at week 52 were not different between treatment groups (p=0.75). So far, no serious adverse events were reported and all patients had at least one adverse event. In the alefacept group, 29 (88%) participants had an adverse event related to study drug versus 15 (94%) participants in the placebo group. In the alefacept group, 14 (42%) participants had grade 3 or 4 adverse events compared with nine (56%) participants in the placebo group; no deaths occurred. INTERPRETATION Although the primary outcome was not met, at 12 months, alefacept preserved the 4 h C-peptide AUC, lowered insulin use, and reduced hypoglycaemic events, suggesting efficacy. Safety and tolerability were similar in the alefacept and placebo groups. Alefacept could be useful to preserve β-cell function in patients with new-onset type 1 diabetes.Background Type 1 diabetes (T1D) results from autoimmune targeting of the pancreatic beta cells, likely mediated by effector memory T cells (Tems). CD2, a T cell surface protein highly expressed on Tems, is targeted by the fusion protein alefacept, depleting Tems and central memory T cells (Tcms). We hypothesized that alefacept would arrest autoimmunity and preserve residual beta cells in newly diagnosed T1D.

Antithymocyte globulin treatment for patients with recent-onset type 1 diabetes: 12-month results of a randomised, placebo-controlled, phase 2 trial

BACKGROUND Type 1 diabetes results from T-cell-mediated destruction of β cells. Findings from preclinical studies and pilot clinical trials suggest that antithymocyte globulin (ATG) might be effective for reducing this autoimmune response. We assessed the safety and efficacy of rabbit ATG in preserving islet function in participants with recent-onset type 1 diabetes, and report here our 12-month results. METHODS For this phase 2, randomised, placebo-controlled, clinical trial, we enrolled patients with recent-onset type 1 diabetes, aged 12-35 years, and with a peak C-peptide of 0.4 nM or greater on mixed meal tolerance test from 11 sites in the USA. We used a computer generated randomisation sequence to randomly assign patients (2:1, with permuted-blocks of size three or six and stratified by study site) to receive either 6.5 mg/kg ATG or placebo over a course of four days. All participants were masked and initially managed by an unmasked drug management team, which managed all aspects of the study until month 3. Thereafter, to maintain masking for diabetes management throughout the remainder of the study, participants received diabetes management from an independent, masked study physician and nurse educator. The primary endpoint was the baseline-adjusted change in 2-h area under the curve C-peptide response to mixed meal tolerance test from baseline to 12 months. Analyses were by intention to treat. This is a planned interim analysis of an on-going trial that will run for 24 months of follow-up. This study is registered with ClinicalTrials.gov, number NCT00515099. FINDINGS Between Sept 10, 2007, and June 1, 2011, we screened 154 individuals, randomly allocating 38 to ATG and 20 to placebo. We recorded no between-group difference in the primary endpoint: participants in the ATG group had a mean change in C-peptide area under the curve of -0.195 pmol/mL (95% CI -0.292 to -0.098) and those in the placebo group had a mean change of -0.239 pmol/mL (-0.361 to -0.118) in the placebo group (p=0.591). All except one participant in the ATG group had both cytokine release syndrome and serum sickness, which was associated with a transient rise in interleukin-6 and acute-phase proteins. Acute T cell depletion occurred in the ATG group, with slow reconstitution over 12 months. However, effector memory T cells were not depleted, and the ratio of regulatory to effector memory T cells declined in the first 6 months and stabilised thereafter. ATG-treated patients had 159 grade 3-4 adverse events, many associated with T-cell depletion, compared with 13 in the placebo group, but we detected no between-group difference in incidence of infectious diseases. INTERPRETATION Our findings suggest that a brief course of ATG does not result in preservation of β-cell function 12 months later in patients with new-onset type 1 diabetes. Generalised T-cell depletion in the absence of specific depletion of effector memory T cells and preservation of regulatory T cells seems to be an ineffective treatment for type 1 diabetes.

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.

Continuous glucose monitors prove highly accurate in critically ill children.

IntroductionHyperglycemia 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.MethodsWe 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.ResultsForty-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.ConclusionsIn 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.

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.

Targeting Regulatory T Cells in the Treatment of Type 1 Diabetes Mellitus

Type 1 diabetes mellitus (T1DM) is a T cell-mediated autoimmune disease resulting in islet β cell destruction, hypoinsulinemia, and severely altered glucose homeostasis. T1DM has classically been attributed to the pathogenic actions of auto-reactive effector T cells(Teffs) on the β cell. Recent literature now suggests that a failure of a second T cell subtype, known as regulatory T cells (Tregs), plays a critical role in the development of T1DM. During immune homeostasis, Tregs counterbalance the actions of autoreactive Teff cells, thereby participating in peripheral tolerance. An imbalance in the activity between Teff and Tregs may be crucial in the breakdown of peripheral tolerance, leading to the development of T1DM. In this review, we summarize our current understanding of Treg function in health and in T1DM, and examine the effect of experimental therapies for T1DM on Treg cell number and function in both mice and humans.