An Fc-optimized CD133 antibody for induction of NK cell reactivity against myeloid leukemia.

Antibody-dependent cellular cytotoxicity (ADCC) of natural killer (NK) cells largely contributes to the success of monoclonal antibody (mAb) treatment in cancer. As no antibodies are clinically available for immunotherapy of myeloid leukemias (MLs), we aimed to develop an Fc-optimized CD133 mAb for induction of NK ADCC against MLs. When comparing different available CD133 mAbs, no difference was observed with regard to binding to primary chronic myeloid leukemia cells. However, clone 293C3 recognized acute myeloid leukemia (AML) cells in a substantially higher percentage of patient cases and was thus chosen to generate chimeric mAbs with either wild-type Fc part (293C3-WT) or a variant containing amino-acid exchanges (S239D/I332E) to enhance affinity to CD16 on NK cells (293C3-SDIE). In vitro, treatment with 293C3-SDIE significantly enhanced activation, degranulation and lysis of primary CD133-positive AML cells by allogeneic and autologous NK cells as compared with its wild-type counterpart. In line with the observed lower expression levels of CD133 on healthy cells compared with malignant hematopoietic cells, 293C3-SDIE caused no relevant toxicity towards committed hematopoietic progenitor cells. In a NOD.Cg-PrkdcscidIL2rgtmWjl/Sz xenotransplantation model, 293C3-SDIE facilitated elimination of patient AML cells by human NK cells. Thus, 293C3-SDIE constitutes an attractive immunotherapeutic compound, in particular for elimination of minimal residual disease in the context of allogeneic stem cell transplantation in AML.

Advances in Navy pharmacy information technology: accessing Micromedex via the Composite Healthcare Computer System and local area networks.

The pharmacy profession has long used technology to more effectively bring health care to the patient. Navy pharmacy has embraced technology advances in its daily operations, from computers to dispensing robots. Evolving from the traditional role of compounding and dispensing specialists, pharmacists are establishing themselves as vital team members in direct patient care: on the ward, in ambulatory clinics, in specialty clinics, and in other specialty patient care programs (e.g., smoking cessation). An important part of the evolution is the timely access to the most up-to-date information available. Micromedex, Inc. (Denver, Colorado), has developed a number of computer CD-ROM-based full-text pharmacy, toxicology, emergency medicine, and patient education products. Micromedex is a recognized leader with regard to total pharmaceutical information availability. This article discusses the implementation of Micromedex products within the established Composite Healthcare Computer System and the subsequent use by and effect on the international Navy pharmacy community.

Comparison of a portable capillary whole blood coagulation monitor and standard laboratory methods for determining international normalized ratio.

The international normalized ratio (INR) is the current standard for monitoring anticoagulation therapy. Although simple to determine, it normally requires venipuncture and extensive laboratory resources for specimen handling and analysis. The portable capillary whole blood coagulation monitor is an alternative to laboratory venipuncture. Its promoted advantages are: it obtains a blood sample by finger-stick versus venipuncture; rapid turnaround time for results; resultant dosage adjustments (as appropriate) performed in minutes versus hours or days after testing; relative ease of use by nonlaboratory personnel; and potential for home monitoring. This project compared the results of INRs obtained through the venipuncture/laboratory process to INRs obtained by the portable monitoring process at the National Naval Medical Center. A correlation coefficient of 0.97 was determined. The difference in the mean INR results of the two testing methods was not clinically significant (p = 0.269). The portable monitor was determined to be a viable alternative to laboratory testing.

Effects of long-term infusion of prostacyclin (epoprostenol) on echocardiographic measures of right ventricular structure and function in primary pulmonary hypertension. Primary Pulmonary Hypertension Study Group.

BACKGROUND: Right heart failure is an important cause of morbidity and mortality in primary pulmonary hypertension. In a recent prospective, randomized study of severely symptomatic patients, treatment with prostacyclin (epoprostenol) produced improvements in hemodynamics, quality of life, and survival. This article describes the echocardiographic characteristics of participants in this trial; the relationship of echocardiographic variables to hemodynamic parameters, exercise capacity, and quality of life; and the echocardiographic changes associated with prostacyclin therapy. METHODS AND RESULTS: The 81 patients enrolled in this multicenter trial were randomized to treatment with a long-term infusion of prostacyclin in addition to conventional therapy (n = 41) or conventional therapy alone (n = 40) for 12 weeks. Echocardiograms and assessments of hemodynamics, exercise capacity, and quality of life were performed before and after the treatment phase. On baseline evaluation, patients had marked right ventricular dilatation and dysfunction, abnormal septal curvature, and significant tricuspid regurgitation with a high regurgitant velocity. Pericardial effusions were common. More pronounced abnormalities in right heart structure and function were associated with higher pulmonary arterial and mean right atrial pressures, lower cardiac index, and impaired exercise capacity but had no predictable relationship to quality-of-life indicators. The 12-week infusion of prostacyclin had beneficial effects on right ventricular size, curvature of the interventricular septum, and maximal tricuspid regurgitant jet velocity. CONCLUSIONS: The echocardiographic manifestations of severe primary pulmonary hypertension reflect abnormalities in hemodynamics and exercise capacity. Prostacyclin has beneficial effects on right heart structure and function that may contribute to the clinical improvement and prolonged survival observed with this drug.

The implementation of Prime Vendor Europe and its successful impact on an overseas naval medical treatment facility.

Prime Vendor Europe (PVE) is the commercial pharmaceutical ordering and delivery program that is revolutionizing overseas health care delivery at military health care treatment facilities located in the European theater. Mirroring civilian programs already available and replacing the Federal Supply System, PVE offers many benefits never before realized at overseas military health care treatment facilities, including: diminished order turnaround times with resultant decreased Operating Target requirements; rapid order confirmation after order placement; lower carrying costs and inventory needs; better dating of pharmaceuticals received; redistribution and increased efficiency of the current manhours needed to operate a pharmacy supply system; order tracking capabilities; and enhancement of the present cooperative and constructive dichotomous relationship between medical logistics and pharmacy regarding pharmaceutical purchasing practices. This paper will explore the fundamentals, past performance, continuous quality improvement of logistical functions, frame-work establishment for PVE, implementation of PVE, and subsequent observed command benefits of PVE realization.

Gastric intramural pH in mechanically ventilated patients.

BACKGROUND: The hypothesis that gastric intramural pH (pHi) is predictive of outcome in haemodynamically stable, mechanically ventilated patients was tested in 25 patients on assisted mechanical ventilation for respiratory failure. METHODS: Simultaneous samples of arterial blood and gastric juice were obtained from patients on assist control, synchronised intermittent and pressure control ventilation during the first 48 hours of mechanical ventilation. Gastric pHi was calculated from the equation: pHi= 6.1 + log HCO3/(gastric PCO2 X 0.03). The outcome was survival or death due to respiratory or circulatory failure within 45 days of admission. RESULTS: Gastric pHi proved to be a better predictor of outcome than all presently utilised parameters. Although all patients included in this study were haemodynamically stable and were similar for all laboratory indices, the only variable capable of accurately predicting outcome was gastric pHi. Patients with a normal arterial pH but a gastric intramural pH of less than 7.25 had an observed mortality of 66%. Standard severity of illness scores grossly underestimated mortality rates. The sensitivity and specificity of a gastric pHi value of less than 7.25 in predicting death were 86% and 83%, respectively. A receiver operator curve for all variables exaggerates the superiority of gastric pHi as a predictor of outcome. CONCLUSION: Low gastric pHi, a marker of gastrointestinal ischaemia, may occur in the presence of normal haemodynamics and may be used to predict severity of illness and mortality accurately.

Delayed development of obliterative bronchiolitis syndrome with OKT3 after unilateral lung transplantation. A plea for multicenter immunosuppressive trials.

There is no consensus regarding the optimal induction immunosuppression regimen after lung transplantation (LT). In addition to the potential benefit of a reduced incidence of early acute allograft rejection, cytolytic induction immunosuppression may impact on long-term allograft function. We retrospectively assessed our incidence of obliterative bronchiolitis syndrome (OBS) stages Ia and IIa in LT survivors given two different cytolytic induction immunosuppression regimens: (between March 1989 and October 1990) OKT3 (5 mg/d)x10 to 14 days (n=11) vs (between November 1990 and April 1993) Minnesota antilymphocyte globulin (MALG) (10 to 15 mg/kgdx5 to 7 days. Cyclosporine (CSA) (whole blood polyclonal assay=600 to 800 ng/mL), azathioprine (1 to 2 mg/kg/d), and maintenance prednisone (0.2 mg/kg/d) were similar. Surveillance spirometry was performed monthly, in accordance with accepted American Thoracic Society criteria. Fiberoptic bronchoscopy with transbronchial biopsies (TBBs) were performed for clinical indications. Surveillance TBBs were not performed during the era of this study. As defined by the ISHLT "Working Formulation for the Standardization of Nomenclature and for Clinical Staging of Chronic Dysfunction in Lung Allografts," latencies to development of OBS stages Ia and IIa were determined by Kaplan-Meir analysis. Stepwise regression (Cox proportional hazards model) was performed for the variables: cytolytic induction regimen, episodes cytomegalovirus (CMV) pneumonitis, episodes CMV infection, serologic CMV donor (+): recipient (-) mismatch, prior pregnancy, HLA (A,B,DR +/- DQ) mismatches, episodes greater than grade A1 acute cellular rejection (ACR). We found that the OKT3 cohort experienced longer latencies for OBS stages Ia and IIa. Latencies to OBS stages Ia for OKT3 ve MALG were 962 +/- 65 vs 354 +/- 85 days (X +/- SEM) respectively. Brookmeyer-Crowley 95% confidence intervals for median latencies were 744 to 1,180 vs 266 to 510 days for OKT3 vs MALG, respectively. The Cox model was significant only for the variable of the induction cytolytic immunosuppression regimen (p=0.0015). By physiologic criteria, a longer course of OKT3 appeared superior to the short-course MALG protocol in delaying chronic lung allograft dysfunction. These effects may be related either to inherent differences in the antilymphocyte preparations or, alternatively, the difference in duration of treatment between groups. Surveillance TBB and treatment of detected occult ACR may serve to negate the observed differences in latencies for OBS.

A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension.

BACKGROUND: Primary pulmonary hypertension is a progressive disease for which no treatment has been shown in a prospective, randomized trial to improve survival. METHODS: We conducted a 12-week prospective, randomized, multicenter open trial comparing the effects of the continuous intravenous infusion of epoprostenol (formerly called prostacyclin) plus conventional therapy with those of conventional therapy alone in 81 patients with severe primary pulmonary hypertension (New York Heart Association functional class III or IV). RESULTS: Exercise capacity was improved in the 41 patients treated with epoprostenol (median distance walked in six minutes, 362 m at 12 weeks vs. 315 m at base line), but it decreased in the 40 patients treated with conventional therapy alone (204 m at 12 weeks vs. 270 m at base line; P < 0.002 for the comparison of the treatment groups). Indexes of the quality of life were improved only in the epoprostenol group (P < 0.01). Hemodynamics improved at 12 weeks in the epoprostenol-treated patients. The changes in mean pulmonary-artery pressure for the epoprostenol and control groups were -8 percent and +3 percent, respectively (difference in mean change, -6.7 mm Hg; 95 percent confidence interval, -10.7 to -2.6 mm Hg; P < 0.002), and the mean changes in pulmonary vascular resistance for the epoprostenol and control groups were -21 percent and +9 percent, respectively (difference in mean change, -4.9 mm Hg/liter/min; 95 percent confidence interval, -7.6 to -2.3 mm Hg/liter/min; P < 0.001). Eight patients died during the study, all of whom had been randomly assigned to conventional therapy (P = 0.003). Serious complications included four episodes of catheter-related sepsis and one thrombotic event. CONCLUSIONS: As compared with conventional therapy, the continuous intravenous infusion of epoprostenol produced symptomatic and hemodynamic improvement, as well as improved survival in patients with severe primary pulmonary hypertension.

Isogravitational heterogeneity of perfusion after unilateral lung transplantation.

1. Single-photon emission computerized tomography in both an intact canine model and man has demonstrated an aspect of pulmonary perfusion to be independent of gravitational forces. 2. Using technetium 99m-labelled macroaggregated albumin single-photon emission computerized tomographic imaging, we investigated normal human subjects (n = 5), stable unilateral lung transplant recipients (n = 6) and transplant recipients with chronic allograft dysfunction related to obliterative bronchiolitis (n = 5). 3. In coronal isogravitational sections, a 1 x 1 x N pixel strip (medial to lateral) was constructed through the 'core' pixel of maximal radioactive counts. The counts were measured for the 'core' pixel and at two mid-points (medial and lateral) between the core pixel and the lung edges. Coefficients of variation were computed for each isogravitational strip and compared between groups. Fractional whole-lung perfusion was determined for left versus right lungs of normal subjects and allograft versus native lungs of transplant recipients. 4. Using these indices, 'isogravitational heterogeneity' (i.e. increased 'core' versus peripheral perfusion) was observed in allografts and native diseased lungs after unilateral transplantation. Despite significantly increased fractional whole-lung perfusion directed to the allografts (84.8% +/- 3.0% and 75.8% + 12.1% for stable unilateral lung transplant recipients and patients with obliterative bronchiolitis respectively) compared with normal lungs (50.2% +/- 1.2% and 49.8% +/- 1.2% for left and right respectively), 'isogravitational flow heterogeneity' (i.e. increased 'core' versus peripheral perfusion) was preserved after transplantation. 5. These findings suggest that 'isogravitational heterogeneity' was maintained despite increased unilateral pulmonary perfusion and the presumed increase in pulmonary capillary recruitment and/or distension.

Bronchiolitis obliterans in single-lung transplant recipients.

The presentation and clinical course of bronchiolitis obliterans (BO) in single-lung transplant (SLT) recipients has thus far not been well described. We retrospectively analyzed the serial spirometry of 15 SLT patients with BO. All the patients fulfilled the criteria for BO syndrome, and 11 of the 15 had histologically documented BO. Based on serial FEV1 analysis, we identified three patterns of presentation and progression of BO. The first pattern (n = 6) was characterized by a rapid onset and a relentless progressive course; the second pattern (n = 5) was characterized by a similar rapid onset and initial rapid decline, but was followed by stabilization in lung function; the third pattern (n = 4) was characterized by an insidious onset and course. In all patients, a permanent reduction in the mean forced expiratory flow during the middle half of the forced vital capacity appeared to be an early sensitive index for the development of BO. An appreciation of these different modes of presentation and progression of BO is potentially important in the assessment of prognosis and management of the SLT recipient.

Differential soluble interleukin-2R levels in bilateral bronchoalveolar lavage after single lung transplantation.

Preliminary reports suggest that measurement of the soluble 55 kd subunit of the interleukin-2 receptor may facilitate the diagnosis of allograft rejection in solid organ transplants. Levels of soluble interleukin-2 receptor in serum or plasma have previously lacked sufficient sensitivity and specificity for the diagnosis of acute allograft rejection. Because single lung transplantation is preferentially performed for nonseptic end-stage pulmonary and cardiopulmonary maladies, we questioned whether the pattern of soluble interleukin-2 receptor recovery in bronchoalveolar lavage fluid obtained from both the native and transplanted lungs may enhance correct diagnosis. Fifty-three consecutive fiberoptic bronchoscopic procedures were performed with bilateral bronchoalveolar lavage fluid. Transbronchoscopic biopsies were histologically classified by the International Society for Heart Transplantation Working Formulation for Standardized Nomenclature. "Soluble interleukin-2 receptor index" was calculated as the quotient of soluble interleukin-2 receptor (in units per milliliter) by enzyme-linked immunosorbent assay, divided by protein (in milligrams per milliliter) to correct for differences in bronchoalveolar lavage fluid techniques and cellularity. Soluble interleukin-2 receptor indexes were significantly increased in the allograft bronchoalveolar lavage fluid during histologic grade A (acute rejection) versus normal transbronchoscopic biopsy specimens (3395 +/- 1298 U/mg versus 76 +/- 21 U/mg) associated with an increased transplanted/native lung ratio (69.9 +/- 46 versus 2 +/- 1 [mean +/- standard error of the mean]) (one-way analysis of variance, p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

The relationship between oxygen consumption and work rate in patients with airflow obstruction.

The oxygen cost of augmented ventilation is increased in patients with chronic obstructive pulmonary disease, either at rest or during exercise. Thus, if excessive demands are placed on the respiratory muscles during exercise in these patients, we postulate that the total oxygen consumption (VO2) may increase relative to the work rate compared to control subjects. The aim of this study was to examine the relationship between VO2 and work rate during exercise in patients with airflow obstruction. A retrospective analysis of data collected over 7 years was conducted. Patients with airflow obstruction (n = 131) were compared and contrasted with those in whom pulmonary function studies (spirometry, lung volumes) were normal (n = 199). Severity of airflow obstruction (ie, mild moderate, severe) was determined, using the 95 percent confidence limits for the ratio of FEV1 to FVC. Incremental exercise studies were performed on a cycle ergometer. Resting VO2 was not significantly different across the groups with airflow obstruction measured either directly or normalized for body weight. The VO2max was significantly reduced in the patients with severe airflow obstruction, compared with the normal group, as well as the patients with mild and moderate airflow obstruction. No differences were noted in the slope of VO2 plotted against work rate in the patients with airflow obstruction (regardless of the severity of the obstruction) and individuals in whom results of pulmonary function tests were normal. In addition, when gender was taken into account, there was essentially no difference in the slopes for either male or female subjects across all groups. Stepwise, linear regression failed to demonstrate any variable or variables that were strongly related to slope. We postulate that the maintenance of a normal slope of VO2 on work rate in patients with airflow obstruction, in whom the oxygen cost and work of breathing is likely increased, may mask a significant reduction in nonrespiratory VO2 (for example, to exercising skeletal muscles).

Obstructive flow-volume loop contours after single lung transplantation.

The development of spirometric airflow obstruction may be a diagnostic dilemma in recipients of single lung allografts. The contribution of bronchial anastomotic stenosis to the observed spirometric obstruction may be clinically difficult to distinguish from that of obliterative bronchiolitis. Similarly, differentiating the "normal" obstructive defect after single lung transplantation for emphysema from obliterative bronchiolitis may be clinically challenging. We retrospectively reviewed the maximum inspiratory and expiratory flow-volume loop contours of lung transplant recipients with either obliterative bronchiolitis (n = 7) or bronchoscopically diagnosed severe bronchial anastomotic stenosis (n = 3). Five patients underwent single lung transplantation for obstructive native lung diseases and underwent observation before and after development of obliterative bronchiolitis. Bronchial anastomotic stenosis-maximum inspiratory and expiratory flow-volume loops were analyzed both before and after correction of stenosis by niobium: yttrium-aluminum-garnet laser photoresection or endobronchial silicone stent placement. Measures of airflow derived from maximum inspiratory and expiratory flow-volume loops, such as peak expiratory flow, peak inspiratory flow, forced expiratory flow at 50% vital capacity, forced inspiratory flow at 50% vital capacity, and forced expiratory volume in 1 second/peak expiratory flow ratio could not differentiate patients with bronchial anastomotic stenosis versus obliterative bronchiolitis. The most clinically useful index was the maximum inspiratory and expiratory flow-volume contour, which was characterized by terminal plateaus during exhalation and inhalation in patients with bronchial anastomotic stenosis. This index was reflected in a lower forced inspiratory flow at 75% vital capacity and forced inspiratory flow at 75% vital capacity/peak inspiratory flow ratio in bronchial anastomotic stenosis that increased after elimination of the anastomotic obstruction.(ABSTRACT TRUNCATED AT 250 WORDS)

Utility of inhaled pentamidine prophylaxis in lung transplant recipients.

The incidence of Pneumocystis carinii pneumonia (PCP) has been shown to be high posttransplantation in the absence of prophylaxis. For this reason, lung transplant recipients routinely receive prophylaxis. We report on our results using aerosolized pentamidine prophylaxis in nine patients post-lung transplantation (eight single lung transplants, one double). The patients received monthly treatments of 300 mg of aerosolized pentamidine for a mean of 10.6 months (range, 4 to 21 months). Patients were routinely monitored with serial pulmonary function studies and bronchoscopy as clinically indicated. Two of the patients experienced bronchospasm in response to the therapy. None of the patients experienced any episodes of PCP during the period of inhaled pentamidine prophylaxis. Inhaled pentamidine is a safe and effective form of PCP prophylaxis and may be used instead of sulfamethoxazole-trimethoprim in patients who have a sulfa allergy or other untoward sulfa side effects.

Prediction of maximal exercise capacity in obstructive and restrictive pulmonary disease.

We evaluated the predictive value of resting pulmonary function tests (PFTs) in the determination of maximal exercise capacity in patients with obstructive and restrictive ventilatory disease. We performed resting PFTs and an incremental exercise study on a bicycle ergometer in 146 patients with chronic obstructive pulmonary disease (COPD) and 68 patients with restrictive disease. The patients with obstructive disease were further subdivided into mild, moderate, and severe based on the severity of their airway obstruction (mean +/- SD:FEV1, 2.78 +/- 0.77, 2.12 +/- 0.74, and 1.06 +/- 0.47, respectively). Correlation coefficients for PFTs vs VO2max and VEmax in restricted patients was generally low (DL = 0.67 and 0.34, IC = 0.58 and 0.35, FVC = 0.57 and 0.35, TLC = 0.35 and 0.18). In patients with COPD, the maximum voluntary ventilation (MVV) was the single best predictor of VO2 in all groups with correlation coefficients of 0.75, 0.69, and 0.89 in the mild, moderate, and severe subgroups, respectively. Similarly, the MVV was the best predictor of VEmax in all groups with correlation coefficients of 0.59, 0.64, and 0.89 in the three subgroups. The correlation with FEV1 was slightly less for both VO2max (0.69, 0.65, and 0.87) and VEmax (0.52, 0.64, 0.64) in the mild, moderate, and severe subgroups, respectively. Our findings show that PFTs are unreliable in predicting VEmax and VO2max in restricted patients. In patients with obstruction, the MVV is the single best predictor of VO2max and VEmax in all three categories, but was not significantly improved by stepwise multiple regression with additional PFT variables. Higher correlations were obtained in the severe group in whom the correlation with VO2max and VEmax was 0.89. However, the 95 percent confidence interval of the estimate for VO2 and VE was relatively large (+/- 0.16 L/min and +/- 6.6 L/min, respectively). We conclude that although several PFTs correlate significantly with maximum exercise, the large variance precludes their use to accurately predict maximum performance in individual patients with COPD.

Gastric intramural pH as a predictor of success or failure in weaning patients from mechanical ventilation.

OBJECTIVE: To determine whether gastric intramural pH (pHi), an indirect measure of gastric mucosal ischemia, can be used to predict the success of weaning from mechanical ventilation. Gastric mucosal ischemia (and, therefore, acidosis) may develop in patients during unsuccessful attempts to wean them from mechanical ventilation because blood flow from nonvital areas (for example, splanchnic bed) is diverted to meet the increased demands of respiratory muscles. DESIGN: Cohort study. SETTING: Intensive care unit. PATIENTS: Twenty-nine patients receiving assisted mechanical ventilation for respiratory failure who were thought by their physicians to be weanable from mechanical ventilation. MEASUREMENTS: Simultaneous samples of arterial blood and gastric juice were obtained from patients during assisted mechanical ventilation, as well as during weaning trials. The predictor variable, pHi, was calculated using the following equation: 6.1 + log HCO3/(gastric PCO2 x 0.0307). The outcome was success or failure of weaning, decided by physicians blinded to the study. RESULTS: Patients who could not be weaned from mechanical ventilation had a substantially reduced gastric pHi (7.36 during mechanical ventilation compared with 7.09 during weaning [difference, 0.27; 95% Cl, 0.12 to 0.42; P < 0.01]). Patients who were successfully weaned from mechanical ventilation showed no change in pHi (7.45 during mechanical ventilation compared with 7.46 during weaning [difference, 0.01; Cl, -0.01 to 0.03; P = 0.29]). The sensitivity and specificity of pHi in predicting weaning success or failure were both 100% (Cl, 81 to 100 and 72 to 100, respectively). CONCLUSION: Gastrointestinal acidosis may be an early sign of weaning failure. Measurement of pHi, which is simple and rapid, may be of practical value in predicting the likelihood of weaning success or failure during weaning trials.

Transesophageal echocardiographic assessment of pulmonary venous flow after single lung transplantation.

Transesophageal echocardiography was used to evaluate pulmonary venous flow velocity and pulmonary venous diameter of both the transplanted and native lungs in six single lung transplant recipients. Mean pulmonary venous velocity (50 +/- 10 versus 27 +/- 8 cm/sec) and pulmonary venous diameter (1.39 +/- 0.16 versus 0.98 +/- 0.18 cm) were significantly greater in the transplanted lung than in the native contralateral lung. An index of allograft perfusion, QD-transesophageal echocardiography (pulmonary venous velocity x pulmonary venous diameter), correlated highly with previously measured technetium 99m-labeled macroaggregated albumin quantitative lung perfusion studies (r = 0.94). A pressure gradient in pulmonary venous flow velocity across the left atrial anastomosis was detected in two patients (8 and 12 mm Hg). Analysis of previous resting supine and upright incremental hemodynamic exercise testing showed no significant differences in these two patients with respect to maximum oxygen uptake, mean pulmonary arterial pressure, pulmonary capillary wedge pressure, cardiac index, or pressure-flow relationships. Therefore these left atrial anastomotic gradients did not appear to adversely affect the pulmonary vascular response to incremental exercise. Transesophageal echocardiography may be an invaluable technique in the expedient evaluation of cardiac function and allograft perfusion after lung transplantation.

Regional distribution of lung perfusion and ventilation at rest and during steady-state exercise after unilateral lung transplantation.

Cardiopulmonary exercise testing has previously demonstrated a reduced maximum oxygen uptake and anaerobic threshold, as well as abnormal wasted ventilation fraction and gas exchange after unilateral lung transplantation. To further explain the mechanisms of these abnormalities, we assessed the regional distribution of pulmonary blood flow and ventilation at rest and during steady-state exercise in nine recipients of unilateral lung transplants. Krypton-81 (81mKr) aerosol and technetium-99m (99mTc) were utilized to assess lung ventilation (V) and perfusion (Q), respectively. The digitalized images were trisected to analyze apical, mid-, and basilar lung perfusion and ventilation in both the transplanted and native lung, both at rest and steady-state upright exercise. Results were compared with previously reported data obtained in normal subjects in our laboratory using the identical technique. At rest, 75 +/- 13 percent of perfusion was directed to the transplanted lung; however, the corresponding fractional ventilation was only 67 +/- 14 percent. During exercise, there was no significant change in fractional perfusion or ventilation. Resting apical perfusion in the transplanted lung was higher than normal in four patients and comparable to normal in five patients. In contrast to the augmentation of apical perfusion observed in normal subjects during upright exercise, none of our patients increased the regional perfusion to the apices during exercise in either transplanted or native lungs. These unexpected responses suggest either more maximal allograft apical recruitment at rest due to the increased allograft perfusion or an abnormality in the apical pulmonary vasculature after transplantation. Furthermore, the relative mismatch in ventilation and perfusion in transplanted and native lungs suggests regions of high V/Q in the native, and low V/Q in the transplanted lung. This mismatch is most pronounced in recipients of single lung transplants for pulmonary vascular disease.

Prediction of minimal pressure support during weaning from mechanical ventilation.

Our goal was to evaluate the accuracy of a prediction equation that estimates the minimal level of pressure support (PS) required to overcome the resistance of the ventilator circuit and the endotracheal tube during mechanical ventilation. We calculated the minimal PS (PSmin) by means of the relationship between airway resistance and peak inspiratory flow rate during mechanical ventilation. Measurements of breathing pattern, flow rates, work of breathing (WOB), pressure time product (PTP), and PEEPi were made during several modes of ventilation (PSmin, PSmin + 25 percent, PSmin-25 percent, flow by, CPAP 0 cm H2O) and while breathing through an endotracheal tube (ETT) and spontaneous breathing (EXT). The WOB was significantly higher during EXT than PSmin, PSmin-25 percent, and ETT (1.04 vs 0.45, 0.54, and 0.74 J/L, respectively, p < 0.05). An unexpected finding was a higher WOB and PTP during EXT as compared with ETT in six of seven of our patients (1.04 vs 0.74 J/L). Examination of breathing pattern and flow volume loops in these two breathing modes raises the possibility that the post-EXT pathology increases in WOB is related to upper airway abnormality. Because of this, our predicted PSmin underestimated the WOB required for spontaneous breathing immediately post EXT.

Hemodynamic responses to exercise after lung transplantation.

A reduced exercise tolerance, maximum oxygen uptake (VO2max), and anaerobic threshold have been reported after lung transplantation (LT). We prospectively assessed the hemodynamic responses to incremental cycle ergometry before and after LT in eight recipients. All recipients underwent a 6-week formal exercise training program. The VO2max increased after versus before LT (13.4 +/- 0.8 vs 9.2 +/- 0.8 ml/min/kg) (p < 0.01). No transition thresholds by analysis of arterial standard bicarbonate were discerned before LT, while the thresholds after LT were abnormally low (VO2 = 9.4 +/- 0.6 ml/min/kg or 35 +/- 3 percent of predicted maximum VO2). An early rise in arterial lactate was similarly observed after LT. Maximum stroke volume index increased in six of seven patients after versus before LT (51 +/- 4 vs 37 +/- 2 ml/beat/m2) (p < 0.05). Three patients demonstrated an increased mean pulmonary arterial pressure at rest, while pressures during exercise were elevated in six. Pulmonary vascular resistance was mildly elevated after LT but decreased appropriately during incremental exercise and was associated with normal cardiac output responses. We conclude that pulmonary vascular abnormalities occurred during hemodynamic exercise testing in the majority of LT recipients; however, exercise limitation was primarily attributed to cardiovascular limitation or to deconditioning in five of the recipients. In the remaining three, the exercise study was considered to be submaximal by virtue of low peak heart rates. A persistent state of deconditioning may have important implications with respect to exercise training regimens after LT.