John Popovich

A prospective, randomized, controlled evaluation of peripheral nerve stimulation versus standard clinical dosing of neuromuscular blocking agents in critically ill patients.

OBJECTIVESnTo determine if vecuronium doses individualized by peripheral nerve stimulation are lower than those doses chosen by standard clinical techniques; and to determine whether patients monitored by peripheral nerve stimulation exhibit shorter recovery times and less prolonged neuromuscular blockade after discontinuation of vecuronium than control patients.nnnDESIGNnA prospective, randomized, controlled, single-blind trial.nnnSETTINGnTwo ten-bed medical intensive care units of a 937-bed tertiary care, not-for-profit, teaching hospital and health system.nnnPATIENTSnMechanically ventilated patients requiring continuous neuromuscular blockade as part of their therapy.nnnINTERVENTIONSnAfter obtaining written, informed consent and baseline neurologic examinations, patients were randomized to treatment, where dosing was individualized by peripheral nerve stimulation or standard clinical assessment. Doses in the peripheral nerve stimulation group were adjusted to 90% blockade (Train-of-Four of 1/4). The standard clinical dosing group received doses individualized to clinical response by the medical team (blinded to Train-of-Four). Differences between groups were evaluated by Wilcoxon matched-pairs signed rank test.nnnMEASUREMENTS AND MAIN RESULTSnA total of 77 patients (35 standard clinical patients vs. 42 peripheral nerve stimulation patients) were enrolled in the study. Despite no difference in initial doses and time to reach 90% blockade or clinical response between groups, the peripheral nerve stimulation group used less drug than the standard clinical group (0.040 +/- 0.028 vs. 0.070 +/- 0.030 mg/kg/hr, respectively, p = .001). The total cumulative amount of vecuronium for the episode of paralysis was greater in the control group (285.8 +/- 246.6 vs. 137.1 +/- 106.4 mg, p = .001). The peripheral nerve stimulation group recovered neuromuscular function (relative risk of 1.85, with 95% confidence interval [CI] of 1.02-3.35, p = .039) and spontaneous ventilation (relative risk of 1.86, 95% CI 1.00-3.45, p = .047) faster than the control group. In patients, adjusting for renal dysfunction, the likelihood of a faster recovery in the peripheral nerve stimulation group increased for neuromuscular function (relative risk of 1.89, 95% CI of 1.07-3.32, p = .018) and spontaneous ventilation (relative risk of 2.27, 95% CI of 1.23-4.21, p = .019). Patients with combined renal and liver failure similarly demonstrated a faster recovery in the peripheral nerve stimulation group. The recovery was affected to a lesser extent by adjusting for concurrent aminoglycoside and corticosteroid administration.nnnCONCLUSIONSnUse of peripheral nerve stimulation for monitoring the degree of blockade and adjusting drug doses in continuously paralyzed critically ill medical patients results in lower doses of vecuronium to maintain a desired depth of paralysis, and allows a faster recovery of neuromuscular function and spontaneous ventilation.

Heterogeneity of familial risk in sarcoidosis.

Familial clustering of sarcoidosis and the higher prevalence and clinical severity of sarcoidosis in African Americans suggests etiologic heterogeneity. To test for heterogeneity in familial risk of sarcoidosis, we studied 3,395 siblings and parents of 558 index cases (361 African American, 197 Caucasian) diagnosed at Henry Ford Hospital between 1951 and 1994. Using the age‐ and sex‐specific cumulative incidence of sarcoidosis in our sample, we found a statistically significant heterogeneity in familial risk of disease (P < .001). To determine if this was due to a greater risk of sarcoidosis in African Americans, we recalculated disease probabilities using age‐, sex‐, and race‐specific disease cumulative incidence and found the same amount of heterogeneity in familial risk (P < .001). Index cases (n = 69) from high‐risk families were more likely to be African American (odds ratio [OR] = 3.24; 95% confidence interval (CI) = 1.71−6.14) and to have an offspring or second‐degree relative affected (OR = 6.21; 95% CI = 2.86−13.45).

GENETICS OF SARCOIDOSIS

Sarcoidosis likely results from an interplay of environmental and genetic factors. Despite a recent large multicenter study, A Case-Control Etiologic Study of Sarcoidosis (ACCESS), no single causative environmental agent has been identified. Family clustering and differences in racial incidence of sarcoidosis support an inherited susceptibility to sarcoidosis. Siblings of patients with sarcoidosis have about a fivefold increased risk of developing sarcoidosis. Certain human leukocyte antigen (HLA) alleles have been consistently associated with sarcoidosis susceptibility. Furthermore, HLA-DRB1*0301/DQB1*0201 has been associated with good prognosis in Löfgrens syndrome. Many candidate genes studied based on their potential function in immunopathogenesis have been evaluated in case-control studies, but few have been consistently associated with sarcoidosis across populations. Two genome scans have been reported in sarcoidosis. One in African Americans reporting linkage to chromosome 5 and the other in German families reporting linkage to chromosome 6. Follow-up studies on chromosome 6 identified the BTNL2 gene, a B7 family costimulatory molecule to be associated with sarcoidosis. Advances in genotyping and statistical analysis are helping to elucidate the genetics of sarcoidosis.

An official American Thoracic Society policy statement: pay-for-performance in pulmonary, critical care, and sleep medicine.

RATIONALEnPay-for-performance is a model for health care financing that seeks to link reimbursement to quality. The American Thoracic Society and its members have a significant stake in the development of pay-for-performance programs.nnnOBJECTIVESnTo develop an official ATS policy statement addressing the role of pay-for-performance in pulmonary, critical care and sleep medicine.nnnMETHODSnThe statement was developed by the ATS Health Policy Committee using an iterative consensus process including an expert workshop and review by ATS committees and assemblies.nnnMEASUREMENTS AND MAIN RESULTSnPay-for-performance is increasingly utilized by health care purchasers including the United States government. Published studies generally show that programs result in small but measurable gains in quality, although the data are heterogeneous. Pay-for-performance may result in several negative consequences, including the potential to increase costs, worsen health outcomes, and widen health disparities, among others. Future research should be directed at developing reliable and valid performance measures, increasing the efficacy of pay-for-performance programs, minimizing negative unintended consequences, and examining issues of costs and cost-effectiveness. The ATS and its members can play a key role in the design and evaluation of these programs by advancing the science of performance measurement, regularly developing quality metrics alongside clinical practice guidelines, and working with payors to make performance improvement a routine part of clinical practice.nnnCONCLUSIONSnPay-for-performance programs will expand in the coming years. Pulmonary, critical care and sleep practitioners can use these programs as an opportunity to partner with purchasers to improve health care quality.

TGF-β1 Variants in Chronic Beryllium Disease and Sarcoidosis

Evidence suggests a genetic predisposition to chronic beryllium disease (CBD) and sarcoidosis, which are clinically and pathologically similar granulomatous lung diseases. TGF-β1, a cytokine involved in mediating the fibrotic/Th1 response, has several genetic variants which might predispose individuals to these lung diseases. We examined whether certain TGF-β1 variants and haplotypes are found at higher rates in CBD and sarcoidosis cases compared with controls and are associated with disease severity indicators for both diseases. Using DNA from sarcoidosis cases/controls from A Case Control Etiologic Study of Sarcoidosis Group (ACCESS) and CBD cases/controls, TGF-β1 variants were analyzed by sequence-specific primer PCR. No significant differences were found between cases and controls for either disease in the TGF-β1 variants or haplotypes. The −509C and codon 10T were significantly associated with disease severity indicators in both CBD and sarcoidosis. Haplotypes that included the −509C and codon 10T were also associated with more severe disease, whereas one or more copies of the haplotype containing the −509T and codon 10C was protective against severe disease for both sarcoidosis and CBD. These studies suggest that the −509C and codon 10T, implicated in lower levels of TGF-β1 protein production, are shared susceptibility factors associated with more severe granulomatous disease in sarcoidosis and CBD. This association may be due to lack of down-regulation by TGF-β1, although future studies will be needed to correlate TGF-β1 protein levels with known TGF-β1 genotypes and assess whether there is a shared mechanisms for TGF-β1 in these two granulomatous diseases.

The influence of T cell receptor and cytokine genes on sarcoidosis susceptibility in African Americans

The pathogenesis of sarcoidosis, a multisystem granulomatous disorder, is mediated through immunoregulatory pathways. While sarcoidosis clusters in families, inherited risk factors remain undefined. In search of possible sarcoidosis susceptibility genes, we examined anonymous polymorphic genetic markers tightly linked to six different candidate gene regions on chromosomes 2q13, 5q31, 6p23-25, 7p14-15, 14q11 and 22q11. These candidate regions contain T cell receptor, interleukin (IL) and interferon regulatory factor (IRF) genes. Our study population consisted of 105 African-American sarcoidosis cases and 95 unrelated healthy controls. The allelic frequency distribution of two out of the six markers, IL-1 alpha marker (p = 0.010) on 2q13 and the F13A marker (p = 0.0006) on 6p23-25, was statistically significantly different in cases compared with controls. The two alleles most strongly associated with sarcoidosis were IL-1 alpha*137 (Odds Ratio (OR) = 2.60; 95% confidence interval (CI) = 1.36-4.98) and F13A*188 (OR = 2.42; 95% CI = 1.37-4.30). Individuals that had both of these alleles were at a six-fold increased risk for sarcoidosis (OR = 6.19; 95% CI = 2.54-15.10). Restricting the analysis to cases with at least one first or second-degree relative affected with sarcoidosis increased the OR to 15.38. IL-1 levels are elevated in sarcoidosis and the F13A marker is tightly linked to a gene that codes for a newly identified interferon regulatory factor protein (IRF-4), which is thought to play a role in T cell effector functions. Our results suggest genetic susceptibility to sarcoidosis may be conferred by more than one immune-related gene that act synergistically on disease risk.

Differential lung ventilation with a modified ventilator.

To achieve synchronized differential pulmonary ventilation, an Ohio 560 ventilator was modified through separation of the outputs of the deep breath bellows and the tidal volume bellows and providing independent volume, flow rate, PEEP, oxygen-humidification, and alarm systems. The described ventilator modification is simple, inexpensive, and does not alter the performance characteristics of the original unmodified ventilator. Differential lung ventilation may be more easily achieved with this modified ventilator than with the simultaneous use of two ventilators or external electronic synchronizers.