Simulation as a set-up for technical proficiency: can a virtual warm-up improve live fibre-optic intubation?

BACKGROUND: Fibre-optic intubation (FOI) is an advanced technical skill, which anaesthesia residents must frequently perform under pressure. In surgical subspecialties, a virtual 'warm-up' has been used to prime a practitioner's skill set immediately before performance of challenging procedures. This study examined whether a virtual warm-up improved the performance of elective live patient FOI by anaesthesia residents. METHODS: Clinical anaesthesia yr 1 and 2 (CA1 and CA2) residents were recruited to perform elective asleep oral FOI. Residents either underwent a 5 min, guided warm-up (using a bronchoscopy simulator) immediately before live FOI on patients with predicted normal airways or performed live FOI on similar patients without the warm-up. Subjects were timed performing FOI (from scope passing teeth to viewing the carina) and were graded on a 45-point skill scale by attending anaesthetists. After a washout period, all subjects were resampled as members of the opposite cohort. Multivariate analysis was performed to control for variations in previous FOI experience of the residents. RESULTS: Thirty-three anaesthesia residents were recruited, of whom 22 were CA1 and 11 were CA2. Virtual warm-up conferred a 37% reduction in time for CA1s (mean 35.8 (SD 3.2) s vs. 57 (SD 3.2) s, P<0.0002) and a 26% decrease for CA2s (mean 23 (SD 1.7) s vs. 31 (SD 1.7) s, P=0.0118). Global skill score increased with warm-up by 4.8 points for CA1s (mean 32.8 (SD 1.2) vs. 37.6 (SD 1.2), P=0.0079) and 5.1 points for CA2s (37.7 (SD 1.1) vs. 42.8 (SD 1.1), P=0.0125). Crossover period and sequence did not show a statistically significant association with performance. CONCLUSIONS: Virtual warm-up significantly improved performance by residents of FOI in live patients with normal airway anatomy, as measured both by speed and by a scaled evaluation of skills.

De novo immunosuppression with sirolimus and tacrolimus in heart transplant recipients compared with cyclosporine and mycophenolate mofetil: a one-year follow-up analysis.

BACKGROUND: Limited data exist regarding the safety and efficacy of sirolimus in combination with a calcineurin inhibitor in heart transplant recipients. METHODS: From January 2001 to June 2002, 31 de novo heart transplant recipients (treatment group) received a combination of sirolimus, tacrolimus, low-dose rabbit antithymocyte globulin, and glucocorticoids. Outcomes, such as actuarial survival, rate of rejection, incidence of infection, probability of developing diabetes mellitus, renal function, platelet and white blood cell counts, and incidence of coronary artery disease at 1 year, were compared with a cohort of 25 patients (control group) who underwent transplantation primarily in 2000 and in early 2002 treated with cyclosporine, mycophenolate mofetil, and glucocorticoids. All patients were followed up for at least 12 months. RESULTS: Kaplan-Meier actuarial 1-year survival rates were equivalent between groups (97% for the treatment group and 88% for the control group), as was freedom from allograft rejection (48% and 42% for treatment and control groups, respectively). No cases of transplant arteriopathy were noted within the first posttransplantation year. Renal function was not significantly affected in either group. There was a striking increased incidence of mediastinitis in the treatment group (19%) versus 0% in the control group (P = .02). Tacrolimus-sirolimus therapy was associated with a nearly 11-fold increased incidence of new-onset diabetes mellitus as well (P = .004). CONCLUSION: Tacrolimus, sirolimus, and steroids (following low-dose rabbit antithymocyte globulin) were associated with an increased incidence of mediastinitis and posttransplantation diabetes mellitus. No obvious long-term benefit on survival, arteriopathy, or renal function was noted.

Engagement of OX40 enhances antigen-specific CD4(+) T cell mobilization/memory development and humoral immunity: comparison of alphaOX-40 with alphaCTLA-4.

Increasing the long-term survival of memory T cells after immunization is key to a successful vaccine. In the past, the generation of large numbers of memory T cells in vivo has been difficult because Ag-stimulated T cells are susceptible to activation-induced cell death. Previously, we reported that OX40 engagement resulted in a 60-fold increase in the number of Ag-specific CD4(+) memory T cells that persisted 60 days postimmunization. In this report, we used the D011.10 adoptive transfer model to examine the kinetics of Ag-specific T cell entry into the peripheral blood, the optimal route of administration of Ag and alphaOX40, and the Ag-specific Ab response after immunization with soluble OVA and alphaOX40. Finally, we compared the adjuvant properties of alphaOX40 to those of alphaCTLA-4. Engagement of OX-40 in vivo was most effective when the Ag was administered s.c. Time course studies revealed that it was crucial for alphaOX40 to be delivered within 24-48 h after Ag exposure. Examination of anti-OVA Ab titers revealed a 10-fold increase in mice that received alphaOX40 compared with mice that received OVA alone. Both alphaOX40 and alphaCTLA-4 increased the percentage of OVA-specific CD4(+) T cells early after immunization (day 4), but alphaOX40-treated mice had much higher percentages of OVA-specific memory CD4(+) T cells from days 11 to 29. These studies demonstrate that OX40 engagement early after immunization with soluble Ag enhances long-term T cell and humoral immunity in a manner distinct from that provided by blocking CTLA-4.

Augmentation versus inhibition: effects of conjunctional OX-40 receptor monoclonal antibody and IL-2 treatment on adoptive immunotherapy of advanced tumor.

Therapeutic efficacy of adoptive immunotherapy of malignancies is proportional to the number of effector T cells transferred. Traditionally, exogenous IL-2 treatment has been used to promote the survival and function of transferred cells. Recently, we described the therapeutic effects of in vivo ligation of the costimulatory receptor, OX-40R, on activated T cells during early tumor growth. In this study, we examined the effects of IL-2 and OX-40R mAb on adoptive immunotherapy of advanced tumors. For treatment of 10-day 3-methylcholanthrene 205 pulmonary metastases, systemic transfer of 50 x 10(6) activated tumor-draining lymph node T cells resulted in >99% reduction of metastatic nodules. With either IL-2 or OX-40R mAb conjunctional treatment, only 20 x 10(6) cells were required. Advanced 10-day 3-methylcholanthrene 205 intracranial tumors could be cured by the transfer of 15 x 10(6) L-selectin(low) T cells derived from draining lymph nodes. In this situation, IL-2 administration inhibited therapeutic effects of the transferred cells. By contrast, 5 x 10(6) T cells were sufficient to cure all mice if OX-40R mAb was administrated. Studies on trafficking of systemically transferred T cells revealed that IL-2, but not OX-40R mAb, impeded tumor infiltration by T cells. Tumor regression required participation of both CD4 and CD8 T cells. Because only CD4 T cells expressed OX-40R at cell transfer, direct CD4 T cell activation is possible. Alternatively, OX-40R might be up-regulated on transferred T cells at the tumor site, rendering them reactive to the mAb. Our study suggests OX-40R mAb to be a reagent of choice to augment T cell adoptive immunotherapy in clinical trials.

A comparison of consecutive off-pump versus conventional coronary artery bypass.

BACKGROUND: Coronary revascularization on the beating heart is an attractive alternative to conventional coronary artery bypass grafts (CCABG), but remains controversial. Our study compares the outcomes of consecutive patients undergoing off-pump CABG (OPCABG) with a group of similar patients undergoing consecutive CCABG. METHODS: A retrospective analysis of 268 patients who underwent elective CABG between July 1998 and July 1999 at St. Michael's Medical Center yielded 134 consecutive patients who underwent OPCABG and 134 consecutive patients who had CCABG. Patients' medical charts were reviewed for age, preoperative risk factors, operative findings, postoperative complications, and length of stay (LOS). RESULTS: The two cohorts were well matched, with similar ages (66.4 +/- 11.2 for OPCABG vs. 65.8 +/- 10 for CCABG, p = 0.66) and preoperative ejection fractions (EF) (44 +/- 13 vs. 44 +/- 12, p = 0.85). There were no hospital mortalities, and there were five conversions to cardiopulmonary bypass. The OPCABG group had a significantly shorter ICU and postoperative LOS. CONCLUSIONS: Our data suggests that a fair number of patients are potential candidates for OPCABG, the only contraindications being technical limitations or the surgeon's comfort level. Six- to twelve-month follow-up indicates that OPCABG can be performed safely with a decrease in LOS, and should be part of the surgeon's armamentarium.

Induction of anti-mammary cancer immunity by engaging the OX-40 receptor in vivo.

The OX-40 receptor (OX-40R) is a member of the tumor necrosis factor receptor (TNF-R) superfamily that is expressed on activated CD4+ T cells. The OX-40R is a costimulatory molecule that induces CD4+ T cell activation when engaged by its ligand (OX-40 L; found on antigen presenting cells). In human and murine tumors, we have shown upregulation of the OX-40R on CD4+ T cells from tumor-infiltrating lymphocytes (TIL) and tumor-draining lymph node cells (TDLNC) but not on systemic CD4+ T cells, such as peripheral blood lymphocytes (PBL) or splenocytes. In order to examine potentially heightened anti-tumor immunity through enhanced costimulation when engaging OX-40R in vivo, we inoculated mice with a murine mammary cancer cell line (SM1) and then treated with a soluble form of the OX-40 L. Mice injected with a lethal inoculum of SM1 cells were given two intraperitoneal injections (days 3 and 7 post-inoculation) of 100 microg soluble OX-40 L. Seven of 28 treated mice survived the lethal tumor inoculum, as compared to one of 28 control mice, demonstrating a significant survival benefit with treatment (p = 0.0136, log rank analysis). Mice that did not develop tumor by day 90 were rechallenged; all remained tumor-free. Mice were also injected with a second mammary tumor line (4T1) and treated with OX-40L:Ig with similar therapeutic results. Activation of OX-40R+ CD4+ T cells during mammary cancer priming stimulated an antitumor immune response resulting in enhanced survival and protective anti-tumor immunity. These results should have practical applications for treatment modalities for patients with breast cancer.

Long-term outcomes after cardiac transplantation: an experience based on different eras of immunosuppressive therapy.

BACKGROUND: Constantly changing practices in heart transplantation have improved posttransplant survival in patients with end-stage heart disease. The objective of this study was to evaluate long-term outcomes in different eras of immunosuppressive therapy after cardiac transplantation at a single center during a two-decade period. METHODS: A retrospective review of 1,086 consecutive cardiac allograft recipients who underwent transplantation between 1977 to 1999 was performed. Patients were divided into four eras based on type of immunosuppressive therapy: era 1 = steroids, azathioprine (n = 26, February 1977 to March 1983), era II = steroids, cyclosporine (n = 43, April 1983 to April 1985), era III = cyclosporine, steroids, azathioprine (n = 752, April 1985 to December 1995), era IV = cyclosporine, steroids, mycophenolate mofetil (n = 315, January 1996 to October 1999). RESULTS: The actuarial survival of the entire cohort of 1,086 patients undergoing cardiac transplantation was 79%, 66%, and 49% at 1, 5, and 10 years, respectively. There were significant trends in recipient age and gender distribution among the four eras with increasing proportion of older age (> 60 years) and female recipients in eras III and IV (p = 0.001 and 0.02). Early mortality and long-term survival improved significantly over all eras (p < 0.001). Rejection as a cause of death decreased over time (era I, 24%; era II, 21%; era III, 15%; era IV, 9%; p = 0.02), whereas the contribution of transplant coronary artery disease as a cause of death remained unchanged. CONCLUSIONS: Cardiac transplantation provides satisfactory long-term survival for patients with end-stage heart failure. The improving outcomes in survival correlate with improved immunosuppressive therapy in each era. Although the reasons for improvement in survival over time are multifactorial, we believe that changes in immunosuppressive therapy have had a major impact on survival as evidenced by the decreasing number of deaths due to rejection.

OX40 ligation enhances cell cycle turnover of Ag-activated CD4 T cells in vivo.

OX40 costimulates T cells, increases activated T cell longevity, and promotes memory acquisition. T cells activated in vivo with agonist anti-OX40 and ovalbumin have a unique pattern of survival and cell division compared to control cells, but are able to respond to recall Ag equally well. BrdU incorporation shows that early cellular division rates of the anti-OX40-treated and the control groups are similar. Nevertheless, more BrdU(+) Ag-specific T cells accumulate in lymphoid tissue upon anti-OX40 administration. Thus, OX40 ligation does not necessarily lead to increased cell cycle entry, but promotes the accumulation of dividing cells. However, CFSE staining shows that OX40 ligation allows cells to progress through more cellular division cycles, while control cells stall or die. Moreover, OX40 ligation leads to a proportional decrease in apoptotic Ag-specific T cells. Thus, OX40 ligation boosts immunity by promoting an increase in the number cell cycles completed, thereby increasing the life span of Ag-activated CD4 T cells.

Optimal timing of revascularization: transmural versus nontransmural acute myocardial infarction.

BACKGROUND: Higher mortality for emergency coronary artery bypass grafting (CABG) after an acute myocardial infarction (AMI) is well established. Whether it applies to both transmural and nontransmural AMI is unclear. This information may have different therapeutic implications for each cohort of patients. METHODS: A retrospective multicenter analysis of 44,365 patients who underwent CABG after myocardial infarction between 1993 and 1996 by 179 surgeons at 32 hospitals in New York State was performed. RESULTS: Overall hospital mortality for all patients with or without AMI was 2.5% versus 3.1% for patients who underwent CABG with history of myocardial infarction. Hospital mortality decreased with increasing time interval between CABG and AMI; 11.8%, 9.5%, and 2.8% (p < 0.001 for all values) for less than 6 hours, 6 hours to 1 day, and greater than 1 day, respectively. Patients with transmural and nontransmural AMI had identical mortality of 3.1%. However, different patterns emerged when comparing these two groups of patients with respect to time of operation. Mortality was higher in the transmural group if CABG was performed within 7 days after AMI. Multivariate analysis confirmed that CABG within 1 day and 6 hours of AMI are independent risk factors for mortality in the transmural and nontransmural groups, respectively. CONCLUSIONS: Early operation after transmural AMI has a significantly higher risk, and surgeons should be prepared to provide aggressive cardiac support including left ventricular assist devices in this ailing population. Waiting in some may be warranted.

Influence of donor and recipient HLA locus mismatching on development of obliterative bronchiolitis after lung transplantation.

Obliterative bronchiolitis (OB) after lung transplantation is the end result of multiple immunologic, virologic, genetic, and environmental effects on the transplanted lung. In this study, we first analyzed risk factors for OB in a single-center population of 152 lung transplant recipients. We then examined the influence of donor and recipient HLA mismatching on progression to OB, and on the identified risk factors for OB. The median time to onset of OB for the entire study population was 2.7 yr. The significant risk factors for OB by multivariate analyses were grade A2 or A3 acute rejection (p = 0.0126) and cytomegalovirus (CMV) pneumonitis (p = 0.0358). The only significant HLA risk factor for OB was mismatching at the HLA-A locus (p = 0.0144). On the basis of Cox proportional hazards modeling, a predictive formula was derived to estimate the risk of OB after lung transplantation. Although mismatching at the HLA-DR locus was a significant risk factor for CMV pneumonitis in recipients exposed to CMV before transplantation (p = 0.0199), and protected against acute rejection, it did not independently protect against OB. These results indicate that HLA mismatches between donors and recipients significantly influence the development of OB both directly, and indirectly, by influencing the major risk factors for OB.

Factors affecting long-term survival (>10 years) after cardiac transplantation in the cyclosporine era.

OBJECTIVES: The aim of this study was to determine long-term survival (>10 years) after cardiac transplantation in the cyclosporine era and identify risk factors influencing long-term survival. BACKGROUND: Despite the availability of newer modalities for heart failure, cardiac transplantation remains the treatment of choice for end-stage heart disease. METHODS: Between 1983 and 1988, 195 patients underwent heart transplantation at a single center for the treatment of end-stage heart disease. Multivariable logistic regression analysis of pretransplant risk factors affecting long-term survival after cardiac transplantation included various recipient and donor demographic, immunologic and peritransplant variables. RESULTS: Among the group of 195 cardiac transplant recipients, actuarial survival was 72%, 58% and 39% at 1, 5 and 10 years respectively. In the 65 patients who survived >10 years, mean cardiac index was 2.91/m2 and mean ejection fraction was 58%. Transplant-related coronary artery disease (TRCAD) was detected in only 14 of the 65 patients (22%). By multivariable analysis, the only risk factor found to adversely affect long-term survival was a pretransplant diagnosis of ischemic cardiomyopathy (p = 0.04). CONCLUSIONS: Long-term survivors maintain normal hemodynamic function of their allografts with a low prevalence of TRCAD. It is possible that similar risk factors that lead to coronary artery disease in native vessels continue to operate in the post-transplant period, thereby contributing to adverse outcomes after cardiac transplantation. Aggressive preventive and therapeutic measures are essential to limit the risk factors for development of coronary atherosclerosis and enable long-term survival after cardiac transplantation.

Quantitative analysis of reproducible changes in high-voltage electrophotography.

OBJECTIVES: The existence of electromagnetic fields not generated by neuronal action or muscle stimulation remains controversial especially because they are difficulty to detect. We attempted to investigate the existence of electromagnetic fields associated with biologic systems using new image analysis techniques to analyze high-voltage electrophotography. DESIGN/SUBJECTS: Five energy practitioners (three males and two females) and five control subjects (four males and one female) participated in the study. Each practitioner had studied a formal training curriculum and was a professional energy practitioner. Images representing attempts of both energy practitioners and controls to elicit a change in electromagnetic emissions were captured by electrophotographic means. A statistical analysis on the comparison of "ON" vs. "OFF" states for the controls and practitioners in the study was made via digital representation of analogue images. RESULTS: Our interest was threefold: (1) to determine whether corona discharge patterns could be obtained and photographed and be reproducible; (2) to quantify some of the qualitative properties of the coronas; and (3) to determine if individuals can alter, at will, their electrophotographic images. We found a correlation between a change in the electromagnetic emissions for the body and the conscious desire of an energy practitioner to change this state. Analyses of individual finger coronas demonstrate statistically significant differences as analyzed by overall color changes and via analysis of individual sections of the various colors dominating the field. Control subjects were unable to produce statistically significant changes that were reproducible. Physiologic processes, such as changes in skin resistance, sweating, and surface blood constriction, have been suggested as an explanation of the colors and patterns that appear on the film in previous studies, but were not observed in this investigation. CONCLUSIONS: After controlling for the above variables and identifying reproducible and statistically significant changes, we believe the images created in our study represent the interaction of biologically generated electromagnetic fields interacting with the corona discharge created by the electrophotographic device.

The OX40 costimulatory receptor determines the development of CD4 memory by regulating primary clonal expansion.

The costimulatory receptor OX40 has recently been shown to be involved in primary CD4 responses to several defined Ags. However, to date there has been little information regarding the mechanism of action of OX40, such as whether it regulates T cell numbers, reactivity, or both, and whether it contributes to induction of long-term T cell responses. With an agonist Ab to OX40, and by tracking Ag-specific TCR transgenic T cells in vivo, we show that ligation of OX40 induces clonal expansion and survival of CD4 cells during primary responses, and results in the accumulation of greater numbers of memory cells with time. Significantly, OX40-deficient T cells, from mice generated by gene targeting, secrete IL-2 and proliferate normally during the initial period of activation, but cannot sustain this during the latter phases of the primary response, exhibiting decreased survival over time. Mice lacking OX40 develop only low frequencies of Ag-specific CD4 cells late in primary responses in vivo and generate dramatically lower frequencies of surviving memory cells. These results demonstrate that OX40-OX40L interactions control primary T cell expansion and the ability to retain high numbers of Ag-specific T cells. In this way, OX40 signals promote survival of greater numbers of T cells with time and control the size of the memory T cell pool.

Impact of current management practices on early and late death in more than 500 consecutive cardiac transplant recipients.

OBJECTIVE: To study risk factors for early and late death after heart transplantation in the current era. SUMMARY BACKGROUND DATA: The current cardiac transplant population differs from earlier periods in that an increasing number of sicker patients, such as those with ventricular assist device (LVAD) support, prior cardiac allotransplantation, and pulmonary hypertension, are undergoing transplantation. In addition, sensitized patients constitute a greater proportion of the transplanted population. Emphasis has been placed on therapies to prevent early graft loss, such as the use of nitric oxide and improved immunosuppression, in addition to newer therapies. METHODS: Five hundred thirty-six patients undergoing heart transplantation between 1993 and 1999 at a single center were evaluated (464 adults and 72 children; 109 had received prior LVAD support and 24 underwent retransplantation). The mean patient age at transplantation was 44.9 years. Logistic regression and Cox proportional hazard models were used to evaluate the following risk factors on survival: donor and recipient demographics, ischemic time, LVAD, retransplantation, pretransplant pulmonary vascular resistance, and immunologic variables (ABO, HLA matching, and pretransplant anti-HLA antibodies). RESULTS: The rate of early death (less than 30 days) was 8.5% in adults and 8.8% in children. The actuarial survival rate of the 536 patients was 83%, 77%, and 71% at 1, 3, and 5 years, respectively, by Kaplan Meier analysis. Risk factors adversely affecting survival included the year of transplant, donor age, and donor-recipient gender mismatching. Neither early nor late death was influenced by elevated pulmonary vascular resistance, sensitization, prior LVAD support, or prior cardiac allotransplantation. CONCLUSIONS: Previously identified risk factors did not adversely affect short- or long-term survival of heart transplant recipients in the current era. The steady improvement in survival during this period argues that advances in transplantation have offset the increasing acuity of transplant recipients.

Hypoplastic left heart syndrome: valuing the survival.

OBJECTIVE: To examine the survival, developmental status, quality of life, and direct medical costs of children with hypoplastic left heart syndrome who have undergone stage I, II, and III reconstructive surgery. METHODS: A total of 106 children underwent staged repair for classic hypoplastic left heart syndrome between February 1990 and March 1999 (stage I: 106; stage II: 49; stage III: 25; 4 converted to heart transplantation). Survival was analyzed by the Kaplan-Meier method. In a cross-sectional study, parents assessed quality of life by completing the Infant/Toddler Child Health Questionnaire or Child Health Questionnaire Parent Format-28; they assessed developmental progress by completing the Ages and Stages Questionnaire. The ratio-of-costs-to-charges method was used to derive hospital costs, and payments were used to capture physician time and wholesale pricing for outpatient medications. RESULTS: Institutional 1-year and 5-year actuarial survivals were 58% and 54%. Birth weight, the need for preoperative inotropic drugs, and surgical experience were predictors of survival. Norwood I patients achieved fewer developmental benchmarks than those who survived to subsequent stages. Child Health Questionnaire Parent Format-28 mean summary scores for physical and psychosocial health were 48.5 +/- 6.3 and 42.8 +/- 9.9. The median inpatient costs for stage I, II, and III repairs were $51,000, $33,892, and $52,183, respectively. Monthly outpatient and readmission costs were less than 10% of total costs. CONCLUSION: A prospective, large-scale study of the comprehensive outcomes of staged repair and transplantation is needed. This study will need to address the longer-term developmental and quality-of-life outcomes, as well as the long-term cost effectiveness of these procedures.

Multicenter review of preoperative risk factors for stroke after coronary artery bypass grafting.

BACKGROUND: Stroke complicates the postoperative course in 1% to 6% of patients undergoing coronary revascularization. There has been no large scale mandatory database reporting on the incidence of stroke after coronary revascularization. METHODS: A multicenter regional database from the Bureau of Health Care Research Information Services, New York State Department of Health, on 19,224 patients who underwent coronary revascularization in 31 hospitals within New York State during 1995 was analyzed to determine the risk factors for postoperative stroke. RESULTS: The incidence of postoperative stroke was 1.4% (n = 270). Hospital mortality for patients who had a stroke was 24.8%, compared with 2.0% for the rest of the patient population. Postoperative stroke increased the hospital length of stay threefold (27.9+/-1.9 versus 9.1+/-0.9 days, p<0.0001). Multivariable logistic regression identified the following variables to be significantly associated with a postoperative stroke: calcified aorta (p<0.0001; odds ratio [OR], 3.013), prior stroke (p = 0.0003; OR, 1.909), age (p<0.0001; OR, 1.522 per 10 years), carotid arterial disease (p = 0.002; OR, 1.590), duration of cardiopulmonary bypass (p = 0.0004; OR, 1.27 per 60 minutes), renal failure (p = 0.0062; OR, 2.032), peripheral vascular disease (p = 0.0157; OR, 1.62), cigarette smoking (p = 0.0197; OR, 1.621), and diabetes mellitus (p = 0.0158; OR, 1.373). CONCLUSIONS: Postoperative stroke increases mortality and length of stay after coronary revascularization. Several risk factors can be identified, and some of these factors are potentially amenable to intervention, either before or during coronary revascularization, and should also influence patient selection.