Virtual reality bronchoscopy simulation: a revolution in procedural training.

BACKGROUND: In the airline industry, training is costly and operator error must be avoided. Therefore, virtual reality (VR) is routinely used to learn manual and technical skills through simulation before pilots assume flight responsibilities. In the field of medicine, manual and technical skills must also be acquired to competently perform invasive procedures such as flexible fiberoptic bronchoscopy (FFB). Until recently, training in FFB and other endoscopic procedures has occurred on the job in real patients. We hypothesized that novice trainees using a VR skill center could rapidly acquire basic skills, and that results would compare favorably with those of senior trainees trained in the conventional manner. METHODS: We prospectively studied five novice bronchoscopists entering a pulmonary and critical care medicine training program. They were taught to perform inspection flexible bronchoscopy using a VR bronchoscopy skill center; dexterity, speed, and accuracy were tested using the skill center and an inanimate airway model before and after 4 h of group instruction and 4 h of individual unsupervised practice. Results were compared to those of a control group of four skilled physicians who had performed at least 200 bronchoscopies during 2 years of training. Student's t tests were used to compare mean scores of study and control groups for the inanimate model and VR bronchoscopy simulator. Before-training and after-training test scores were compared using paired t tests. For comparisons between after-training novice and skilled physician scores, unpaired two-sample t tests were used. RESULTS: Novices significantly improved their dexterity and accuracy in both models. They missed fewer segments after training than before training, and had fewer contacts with the bronchial wall. There was no statistically significant improvement in speed or total time spent not visualizing airway anatomy. After training, novice performance equaled or surpassed that of the skilled physicians. Novices performed more thorough examinations and missed significantly fewer segments in both the inanimate and virtual simulation models. CONCLUSION: A short, focused course of instruction and unsupervised practice using a virtual bronchoscopy simulator enabled novice trainees to attain a level of manual and technical skill at performing diagnostic bronchoscopic inspection similar to those of colleagues with several years of experience. These skills were readily reproducible in a conventional inanimate airway-training model, suggesting they would also be translatable to direct patient care.

Phase 1 evaluation of the respiratory syncytial virus-specific monoclonal antibody palivizumab in recipients of hematopoietic stem cell transplants.

Intravenous palivizumab (15 mg/kg) was investigated in 2 phase 1 studies among recipients of hematopoietic stem cell transplants (HSCTs). Study 1 included 6 HSCT patients without active respiratory syncytial virus (RSV) infection. Study 2 included 15 HSCT patients with RSV upper respiratory tract infection (URTI; n=3) or RSV interstitial pneumonia (IP; n=12), all of whom also received aerosolized ribavirin. Peak serum concentrations of palivizumab in the 2 studies were similar. The mean serum half-life was 22.4 days in study 1, which mainly included autologous HSCT recipients, and 10.7 days in study 2, which mainly included allogeneic HSCT recipients. No antibodies to palivizumab were detected in study 1. No adverse events were attributed to palivizumab in the 2 studies. In study 2, all 3 patients with RSV URTI recovered without progression to lower respiratory tract disease, and 10 (83%) of the 12 patients with RSV IP survived the 28-day study period. Thus, palivizumab appears to be safe and well tolerated in HSCT recipients.

Stroke after bone marrow transplantation: frequency, aetiology and outcome.

Few data exist on the frequency, aetiology and outcome of cerebrovascular complications of bone marrow transplantation (BMT). We reviewed all patients undergoing BMT at the Fred Hutchinson Cancer Research Center, Seattle, Wash., USA (a large referral institution) over 3 years. We reviewed ICD-9 (International Classification of Diseases) codes for ischaemic stroke, seizure, intracranial haemorrhage and brain infection. Using standardized forms, we paid detailed attention to clinical features and demographics, oncological diagnosis, conditioning regimens, neurological history, comorbidities, time from BMT to ictus, stroke subtype, radiological and pathological features, and outcomes. We identified 36 patients with stroke from 1245 patients who had BMT (2.9%) over 3 years. These patients' median age was 35 (range 5-60, interquartile range 25-45) years. The most common causes of stroke were intracranial haemorrhage related to thrombocytopenia (38.9%) and infarction or haemorrhage secondary to fungal infection (30.6%). Twenty-five patients (69.4%) died from their stroke; none survived without disability. Using a logistic regression model, we found that neither demographic (e.g. age, gender) nor clinical (e.g. oncological diagnosis, type of BMT, time of stroke after BMT) factors predicted outcome. Stroke occurs relatively frequently (incidence almost 3%) after BMT, has a relatively high frequency of infection-triggered events, has a neurological outcome not easily predicted from available data and is often fatal.

Outcome of children who require mechanical ventilatory support after bone marrow transplantation.

OBJECTIVE: To identify clinically measurable factors that could predict outcome for pediatric patients undergoing mechanical ventilatory support after bone marrow transplant. DESIGN: Cohort study. SETTING: A referral center for bone marrow transplant patients in Seattle, Washington. PATIENTS: Children <17 yrs old who received a bone marrow transplant and subsequently required mechanical ventilatory support for > or =24 hrs between 1983 and 1996. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data were abstracted from the charts of 121 pediatric patients who received a bone marrow transplant and subsequently required mechanical ventilatory support. A total of 19 patients (16%) survived to be extubated and survived for > or =30 days postextubation. Major risk factors for death included respiratory failure as the reason for endotracheal intubation (4% survival), the presence of pulmonary infection (6% survival), and impairment of more than one organ system (2% survival if more than one organ system was dysfunctional on day 7 postintubation). CONCLUSIONS: Although the prognosis generally is poor among pediatric bone marrow transplant recipients who subsequently require mechanical ventilatory support, there appear to be some groups within this population in whom the likelihood of survival is close to 0. Because the chance of survival was so small for children with dysfunction of more than one organ system on day 7 after intubation, a recommendation to limit medical support for these children could be considered pending the results of other studies.

High rates of Pneumocystis carinii pneumonia in allogeneic blood and marrow transplant recipients receiving dapsone prophylaxis.

Chemoprophylaxis for Pneumocystis carinii pneumonia (PCP) is routinely given after allogeneic blood or marrow transplantation. We evaluated the effectiveness of dapsone prophylaxis (50 mg orally twice daily, 3 times per week) compared with twice-weekly trimethoprim-sulfamethoxazole (TMP-SMZ) in preventing PCP after allogeneic blood or marrow transplantation. Patients included all (n=646) who received allogeneic blood or marrow transplants between 1 September 1993 and 31 December 1996 who survived at least 100 days after transplantation. A cohort of 111 dapsone recipients was compared with the remaining 535 who received TMP-SMZ. Ten patients developed PCP; 8 were taking dapsone. PCP incidence in the TMP-SMZ cohort was 0.37% versus 7.2% for dapsone. The relative risk for PCP associated with dapsone use was 18.8 (P<.001) and was not accounted for by age, clinical extensive chronic graft-versus-host disease, donor source, or malignant relapse. Dapsone prophylaxis at this dosage is associated with significantly higher rates of PCP than is TMP-SMZ after allogeneic marrow transplantation. We advise caution in prescribing alternatives to TMP-SMZ prophylaxis in this setting.

Idiopathic pneumonia after bone marrow transplantation: cytokine activation and lipopolysaccharide amplification in the bronchoalveolar compartment.

OBJECTIVE: To determine whether idiopathic pneumonia syndrome (IPS), a form of noninfectious lung injury that follows bone marrow transplantation, is associated with cytokine activation and increased susceptibility to lipopolysaccharide (LPS). DESIGN: Case series. SETTING: Tertiary referral center for marrow transplantation. PATIENTS: Recipients with biopsy-confirmed IPS; normal volunteers and marrow transplant recipients without IPS were analyzed as controls. MEASUREMENTS AND MAIN RESULTS: Levels of lymphocyte and macrophage-derived cytokines as well as components of the LPS, LPS-binding protein (LBP), and CD14 system in bronchoalveolar lavage (BAL) fluid were determined. We found evidence of increased vascular permeability (BAL protein) and inflammatory cytokine activation (interleukin-1, interleukin-2, interleukin-6, and tumor necrosis factor-alpha) in patients with IPS. Patients without IPS had BAL fluid cytokine and protein levels that were similar to levels in BAL fluid from normal volunteers. Moreover, components of the LPS amplification system (LBP and soluble CD14) were increased in patients with IPS but not in patients without IPS. CONCLUSIONS: These results provide direct evidence for proinflammatory cytokine activation in IPS and suggest that these patients might be at increased risk for LPS-mediated injury through the LBP amplification pathway.

Noninfectious lung disease in the immunocompromised host.

Patients with compromised immune function suffer a wide variety of lung insults. Infections are the most common causes of both acute and chronic lung diseases, but many noninfectious conditions affect the lungs. The clinical presentation of these noninfectious conditions often mimic infections, thus causing diagnostic dilemmas. The spectrum of noninfectious lung injury and response in the immunosuppressed host includes interstitial edema, interstitial fibrosis, diffuse idiopathic pneumonia, acute respiratory distress syndrome, and obliterative bronchiolitis. Alveolar hemorrhage may complicate any of these conditions. Lung injury in the immunosuppressed host is associated with a diversity of etiologies: sepsis, irradiation, graft rejection, reperfusion injury, graft-versus-host disease, and chemotherapeutic agents and other drug reactions. These injuries most often present as diffuse pulmonary infiltrates on chest radiograph. Establishing a specific diagnosis and etiology for the injury is often problematic. From a pragmatic standpoint, excluding the possibility of infection is the principal aim of diagnostic testing.

Association of pulmonary function testing abnormalities and severe veno-occlusive disease of the liver after marrow transplantation.

We investigated an association between pulmonary function testing (PFT) before bone marrow transplantation and the development of severe veno-occlusive disease (VOD) of the liver. We previously noted that reductions in diffusing capacity of the lung for carbon monoxide (corrected for hemoglobin) (D(L)COc) were associated with mortality after transplantation, but this was not caused by respiratory failure. We performed a case-series review of prospectively collected data from 307 marrow recipients who underwent PFT within 2 weeks of transplantation. Of these, 170 (56%) developed VOD; 39 (13%) mild, 81 (26%) moderate, and 50 (16%) severe or fatal. Both total lung capacity (TLC) and D(L)COc were associated with severe VOD in univariate analysis (P = 0.006 for each). However, D(L)COc entered logistic regression models that contained variables for all known risk factors for severe VOD, while TLC did not contribute additional predictive information. The odds ratio (OR) associated with a D(L)COc below the lower limits of normal (70% of predicted) was 2.4 (95 % CI, 1.0 to 5.4; P = 0.04). We conclude that reduced diffusion capacity of the lung measured before marrow transplantation is an independent risk for severe hepatic VOD. We speculate that the decreased D(l)COc indicates pre-existing systemic endothelial cell damage and a susceptibility to severe hepatic injury from chemotherapy.

Using outcomes research to improve the management of blood and marrow transplant recipients in the intensive care unit.

The practice of medicine is shaped by prior experiences. I believe that "outcomes research" involves studies that answer questions you need to resolve in order to more effectively practice medicine. Review of the outcomes of interventions is required to assess the effectiveness of our interventions. The major management problem of blood and marrow transplantation (BMT) recipients is the overwhelmingly high mortality with critical illness. A series of studies about these outcomes forms the basis of the present management strategies and decision-making after BMT. The questions involve survival after life support and the ability to identify survivors and nonsurvivors preemptively. The incidence of mechanical ventilation is associated with the characteristics of the recipients. Older age, receipt of an HLA-nonidentical graft, and malignancy in relapse at time of transplantation are associated with respiratory failure. These data are of limited value in predicting survival. It is extremely difficult to identify the small percentage of patients who will survive these episodes. However, experience suggests that patients can be identified who will not survive. Preliminary evidence suggests that physicians do not effectively utilize this mortality data in decisions about withdrawal of life support.

Idiopathic pneumonia syndrome: changing spectrum of lung injury after marrow transplantation.

BACKGROUND: The aim of our study was to describe the incidence, clinical course, and risk factors for the idiopathic pneumonia syndrome (IPS), compared with those previously described for "idiopathic pneumonia," after bone marrow transplantation (BMT). METHODS: Our study design was a case-series review with determination of risk by comparison with unaffected controls by log-rank or Fisher's exact (two-tailed) test and logistic regression analyses. The study group comprised 1165 consecutive marrow recipients at a single center from 1988 to 1991. RESULTS: IPS was documented in 85 BMT recipients (7.3%) by bronchoalveolar lavage (n=68), open lung biopsy (n=3), or autopsy (n=14). The calculated actuarial incidence for IPS within 120 days after BMT was 7.7%. Median time to onset was 21 days (mean 34+/-30). Hospital mortality was 74%, and 53 BMT recipients (62%) died with progressive respiratory failure. IPS resolved in 22 patients (26%); 18 patients (21%) survived to discharge. Mechanical ventilation was required by 59 BMT recipients (69%), within a median of 2 days of onset of infiltrates. Two of these 59 recipients (3%) survived to discharge. Pulmonary infection (predominantly fungal) was noted in 7 of 25 (28%) BMT recipients who had an autopsy. Potential risk factors for IPS were assessed in univariate and multivariate logistic regression analyses. Although the incidence was not significantly different between autologous (5.7%) and allogeneic marrow recipients (7.6%), risks were identified only for the latter: malignancy other than leukemia (odds ratio=6.5 compared with aplastic anemia), and grade 4 graft-versus-host disease (odds ratio=5.4 compared with lower grades). No factors were associated with recovery. CONCLUSIONS: The incidence of idiopathic lung injury seems lower, the onset earlier, and the risk factors different from those previously reported. The major risks seem to be regimen-related toxicity and multi-organ dysfunction associated with alloreactive processes.

Phase I study of intravenous ribavirin treatment of respiratory syncytial virus pneumonia after marrow transplantation.

Respiratory syncytial virus (RSV) pneumonia in marrow transplant recipients is associated with significant mortality. Ribavirin is a nucleoside analog with activity against RSV and in its aerosolized formulation is the only drug approved for treatment of RSV pneumonia in the United States. The clinical use of aerosolized ribavirin has been limited by caregivers' concerns about drug exposure and potential teratogenic effects. Since there is lack of proven efficacy and safety of the aerosolized ribavirin in this setting, we performed a phase I study of intravenous ribavirin treatment. Between November 1993 and May 1994, 10 patients with clinically significant RSV pneumonia at the Fred Hutchinson Cancer Research Center were enrolled. Only 2 of the 10 survived (20%; 95% CI, 3-56). Two of the 10 patients developed acute hemolysis that necessitated discontinuation of the medication. In conclusion, treatment of marrow transplant recipients with RSV pneumonia with intravenous ribavirin did not improve mortality compared with historical controls treated with the aerosolized drug.

Withdrawing life support from mechanically ventilated recipients of bone marrow transplants: a case for evidence-based guidelines.

BACKGROUND: Mechanical ventilation after bone marrow transplantation is associated with a high mortality rate. The available literature provides conflicting predictors of outcome in relatively small study groups. OBJECTIVE: To identify predictors of death and mortality trends in mechanically ventilated transplant recipients. DESIGN: Nested case-control study. SETTING: The Fred Hutchinson Cancer Research Center in Seattle, Washington, which specializes in bone marrow transplantation. PATIENTS: All survivors (cases, n = 53) and a group of patients matched for year of transplantation who did not survive (controls, n = 106) were selected from all mechanically ventilated patients (n = 865) who received a bone marrow transplant between January 1980 and July 1992. Patients who received mechanical ventilation for less than 24 hours after a procedure or who received mechanical ventilation after a second bone marrow transplantation were excluded. MEASUREMENTS: Surviving patients were defined as those who were alive 30 days after extubation and who were discharged from the hospital. Daily laboratory, physiologic, and treatment variables were collected. RESULTS: Survival was statistically associated with younger age, lower score on the Acute Physiology and Chronic Health Evaluation III, and a shorter time from transplantation to intubation. There were no survivors among an estimated 398 patients who had lung injury and either required more than 4 hours of vasopressor support or had sustained hepatic and renal failure. Through the use of these factors, an accurate prediction of death could have been made in the first 4 days of mechanical ventilation for more than half of the patients who did not survive. During the past 5 years, survival rate has changed from 5% to 16% (P = 0.008), an increase that was not explained by changes in the age of the patients, the rate or timing of intubation, or the percentage of allogeneic transplants that were not HLA-identical. CONCLUSION: Of the patients who required mechanical ventilation after bone marrow transplantation, no one survived with lung injury combined with either hemodynamic instability or hepatic and renal failure. However, survival after mechanical ventilation seems to be improving.

Allogeneic marrow transplantation for aplastic anaemia associated with dyskeratosis congenita.

Eight patients with aplastic anaemia associated with dyskeratosis congenita received allogeneic marrow grafts from either HLA-identical siblings (six patients) or HLA-matched unrelated donors (two patients). Patients who received marrow from HLA-identical siblings were conditioned with cyclophosphamide (140-200 mg/kg), with or without antithymocyte globulin. Patients who received unrelated donor marrow were conditioned with cyclophosphamide (120 mg/kg) and total body irradiation (1200 cGy). The six patients who survived for >2 weeks following transplant all had haematological evidence of engraftment, and all three patients who survived for at least a year following transplant recovered normal haematological function. Three patients died with respiratory failure and pulmonary fibrosis at 70 d. 8 years and 20 years posttransplant; three patients died during the neutropenic period of invasive fungal infections; one patient died on day 44 of refractory acute graft-versus-host disease; and one patient remains alive 463 d following transplant. The surviving patient recently underwent surgical resection of a Dukes' stage C rectal carcinoma diagnosed 14 months posttransplant. The aplastic anaemia associated with dyskeratosis congenita can be successfully treated by allogeneic bone marrow transplantation; however, this approach does not reverse the other systemic manifestations of the syndrome. The pathogenesis of the intestinal lung disease observed in dyskeratosis congenita patients following marrow transplantation is not understood.

A controlled trial of long-term administration of intravenous immunoglobulin to prevent late infection and chronic graft-vs.-host disease after marrow transplantation: clinical outcome and effect on subsequent immune recovery.

To determine whether intravenous immunoglobulin (IVIg) given monthly from day 90 to day 360 posttransplantation decreased the incidence of late infection, chronic graft-vs.-host disease (GVHD), and obliterative bronchiolitis after marrow transplantation, patients were assigned randomly to receive either IVIg (500 mg/kg/month) or no IVIg prophylaxis. Participants were registered before transplantation, and 250 patients (123 IVIg and 127 control) were evaluable for events after day 100. The two groups were balanced for age, marrow source, cytomegalovirus (CMV) seropositivity, pretransplantation conditioning, and prophylaxis for infection and GVHD. Between days 100 and 365 posttransplantation, the incidence of bacteremia or septicemia per 100 patient-days of risk was 0.10 in the IVIg group and 0.12 in the controls (p = not significant). During the same period, the incidence of localized infection was marginally higher in control patients than in IVIg recipients (0.44 vs. 0.24, respectively; relative risk [RR] 1.46, p < 0.07). Administration of IVIg prophylaxis had no effect on survival, the incidence of obliterative bronchiolitis, severity of airflow obstruction, or the incidence or mortality of chronic GVHD. After discontinuing IVIg prophylaxis at day 360, subsequent recovery of endogeneous humoral immunity was impaired (serum IgG1 and IgA levels were significantly lower than controls at day 730), and total infections were less common in the second year in control patients than in former IVIg recipients (0.12 vs 0.19, respectively; RR 0.61, p = 0.03). We conclude that in the absence of hypogammaglobulinemia, monthly administration of IVIg given from day 90 to 360 does not reduce late complications and may impair long-term humoral immune recovery after marrow transplantation.

Abnormalities of pulmonary function tests after marrow transplantation predict nonrelapse mortality.

To determine whether pulmonary function test (PFT) results after marrow transplantation were predictive of nonrelapse mortality, a review was made of prospective, nonrandomized PFT results for association with nonrelapse mortality by log-rank test and Cox proportional hazards modeling. The setting was a tertiary referral center. The patients were all marrow recipients who performed PFT between Days 60 and 120 after marrow transplantation between July 1, 1983 and December 31, 1990 (n = 906). At 3 mo after transplantation, the mean values for total lung capacity (TLC) and diffusing capacity decreased, and restrictive ventilatory defects (TLC < 80% of predicted) were noted in 34% of the cohort. Airflow rates (FEV1/FVC) were unchanged. A restrictive lung defect at 3 mo after transplant or a significant decline (> or = 15%) in TLC from baseline despite remaining within the normal range was associated with a twofold increased risk of nonrelapse mortality. Neither airflow obstruction nor impairment in diffusing capacity was associated with an increased risk. Abnormalities of the TLC at 3 mo after transplant were associated with death with respiratory failure, but not with an increased risk of chronic graft-versus-host disease (GVHD). There is an increase in the nonrelapse mortality rate associated with either the presence of a restrictive defect 3 mo after marrow transplantation or a significant decline in lung volume compared with baseline. This effect is most pronounced more than 1 yr after marrow transplant and appears to be a result of an increase in the rate of death with respiratory failure, not chronic GVHD.(ABSTRACT TRUNCATED AT 250 WORDS)

Respiratory infections following organ transplantation.

Successful organ transplantation often is limited by infection. The early transplant period is predominated by bacterial and fungal infections related to surgery and neutropenia, whereas opportunistic infections occur later due to long-term immunosuppression therapy. Despite technical differences between various types of organ transplants, the diagnostic approaches to lung disease are similar and rely largely on fiberoptic bronchoscopy. Whereas better antibacterial prophylaxis is available, fungal infections are emerging as significant problems. Lipid suspension formulations of amphotericin B and itraconazole offer new treatment options for fungal pulmonary infection. These formulations appear to have improved pharmacologic safety, but relative efficacy is unclear. Cytomegalovirus infections continue to plague transplant recipients. Improved understanding of the risk factors (especially the role of screened blood products) and improved prophylactic strategies with ganciclovir and immunoglobulin are decreasing the incidence of fatal infection. Surveillance for viremia and antigenemia now permit early identification of patients at significant risk for clinical disease, and responses to prompt administration of ganciclovir are encouraging, especially among solid organ recipients.

Use of the Hickman-Crawford critical care catheter in marrow transplant recipients: a pulmonary artery catheter-adaptable central venous access.

OBJECTIVE: To describe the use of a modified 15.5-Fr double-lumen, tunneled right atrial catheter (Hickman-Crawford catheter) in adult bone marrow transplant recipients, that permits passage of a 5-Fr pulmonary artery catheter through the larger of the catheter's lumens. DESIGN: A case series review of the clinical experience with a modification of the existing central venous catheter design. SETTING: A bone marrow transplantation center. PATIENTS: Fourteen patients (weighing at least 50 kg body weight) undergoing bone marrow transplantation. Ages ranged from 18 to 64 yrs (median 40). There were nine male and five female patients. All patients, except for three who were receiving autologous marrow transplants, underwent allogeneic transplants. MEASUREMENTS AND MAIN RESULTS: Sixteen catheters were inserted into the subclavian vein in 14 patients. The catheters remained in place for a mean of 44 days (median 30; range 6 to 107) and 56% remained functional until removed an average of 60 days later at the time of death (n = 5) or discharge to home (n = 4). One catheter was accidentally dislodged by the patient and six catheters (38%) were electively removed, two because of infection and four because of mechanical occlusion or damage. The Hickman-Crawford catheter was used as venous access for insertion of 21 pulmonary artery catheters in 12 patients (twice in seven patients). Ninety percent of these insertions (19 of 21) were done without difficulty; use of a guidewire was required in the remaining two cases. No complications of pulmonary artery catheterization were seen. CONCLUSIONS: This experience illustrates that a tunneled right atrial catheter for long-term use can be employed safely and repeatedly for insertion of pulmonary artery catheters for central hemodynamic monitoring.

Bronchiolitis associated with bone marrow transplantation.

New onset airflow obstruction after BMT is a relatively common complication and may be seen in as many as 11% of long-term survivors of allogeneic BMT with chronic GVHD. Bronchiolitis and, occasionally, obliterative bronchiolitis is seen in the majority of cases in which histopathology is available. The primary risk factors recognized are the presence of clinical chronic GVHD, administration of methotrexate as an immunosuppressive, and older recipient age. Improved control of chronic GVHD with effective agents such as cyclosporine likely will decrease the incidence of this airway disorder. The causes probably are multifactorial and donor cytotoxic T-lymphocyte interaction with host cells is a likely contributor in many cases. The clinical course is variable, but the process usually is fatal in cases with rapidly progressive or severe obstruction. Interventions are directed at immune suppression and at diagnosing and treating infections that frequently occur in association with the airflow obstruction.