Evaluating Osteoarthritis Management Programs: outcome domain recommendations from the OARSI Joint Effort Initiative.

OBJECTIVE: To develop sets of core and optional recommended domains for describing and evaluating Osteoarthritis Management Programs (OAMPs), with a focus on hip and knee Osteoarthritis (OA). DESIGN: We conducted a 3-round modified Delphi survey involving an international group of researchers, health professionals, health administrators and people with OA. In Round 1, participants ranked the importance of 75 outcome and descriptive domains in five categories: patient impacts, implementation outcomes, and characteristics of the OAMP and its participants and clinicians. Domains ranked as "important" or "essential" by ≥80% of participants were retained, and participants could suggest additional domains. In Round 2, participants rated their level of agreement that each domain was essential for evaluating OAMPs: 0 = strongly disagree to 10 = strongly agree. A domain was retained if ≥80% rated it ≥6. In Round 3, participants rated remaining domains using same scale as in Round 2; a domain was recommended as "core" if ≥80% of participants rated it ≥9 and as "optional" if ≥80% rated it ≥7. RESULTS: A total of 178 individuals from 26 countries participated; 85 completed all survey rounds. Only one domain, "ability to participate in daily activities", met criteria for a core domain; 25 domains met criteria for an optional recommendation: 8 Patient Impacts, 5 Implementation Outcomes, 5 Participant Characteristics, 3 OAMP Characteristics and 4 Clinician Characteristics. CONCLUSION: The ability of patients with OA to participate in daily activities should be evaluated in all OAMPs. Teams evaluating OAMPs should consider including domains from the optional recommended set, with representation from all five categories and based on stakeholder priorities in their local context.

Biomarkers and longitudinal changes in lumbar spine degeneration and low back pain: the Johnston County Osteoarthritis Project.

OBJECTIVE: To determine if baseline biomarkers are associated with longitudinal changes in the worsening of disc space narrowing (DSN), vertebral osteophytes (OST), and low back pain (LBP). DESIGN: Paired baseline (2003-2004) and follow-up (2006-2010) lumbar spine radiographs from the Johnston County Osteoarthritis Project were graded for severity of DSN and OST. LBP severity was self-reported. Concentrations of analytes (cytokines, proteoglycans, and neuropeptides) were quantified by immunoassay. Pressure-pain threshold (PPT), a marker of sensitivity to pressure pain, was measured with a standard dolorimeter. Binary logistic regression models were used to estimate odd ratios (OR) and 95% confidence intervals (CI) of biomarker levels with DSN, OST, or LBP. Interactions were tested between biomarker levels and the number of affected lumbar spine levels or LBP. RESULTS: We included participants (n = 723) with biospecimens, PPT, and paired lumbar spine radiographic data. Baseline Lumican, a proteoglycan reflective of extracellular matrix changes, was associated with longitudinal changes in DSN worsening (OR = 3.19 [95% CI 1.22, 8.01]). Baseline brain-derived neuropathic factor, a neuropeptide, (OR = 1.80 [95% CI 1.03, 3.16]) was associated with longitudinal changes in OST worsening, which may reflect osteoclast genesis. Baseline hyaluronic acid (OR = 1.31 [95% CI 1.01, 1.71]), indicative of systemic inflammation, and PPT (OR = 1.56 [95% CI 1.02, 2.31]) were associated with longitudinal increases in LBP severity. CONCLUSION: These findings suggest that baseline biomarkers are associated with longitudinal changes occurring in structures of the lumbar spine (DSN vs OST). Markers of inflammation and perceived pressure pain sensitivity were associated with longitudinal worsening of LBP.

The association between walking speed from short- and standard-distance tests with the risk of all-cause mortality among adults with radiographic knee osteoarthritis: data from three large United States cohort studies.

OBJECTIVE: Adults with radiographic knee OA (rKOA) are at increased risk of mortality and walking difficulty may modify this relation. Little is known about specific aspects of walking difficulty that increase mortality risk. We investigated the association of walking speed (objective measure of walking difficulty) with mortality and examined the threshold that best discriminated this risk in adults with rKOA. METHODS: Participants with rKOA from the Johnston County Osteoarthritis Project (JoCoOA, longitudinal population-based cohort), Osteoarthritis Initiative and Multicenter Osteoarthritis Study (OAI and MOST, cohorts of individuals with or at high risk of knee OA) were included. Baseline speed was measured via 2.4-meter (m) walk test (short-distance) in JoCoOA and 20-m walk test (standard-distance) in OAI and MOST. To examine the association of walking speed with mortality risk over 9 years, hazard ratios (HR) and 95% confidence intervals (CI) were calculated from Cox regression models adjusted for potential confounders. A Maximal Likelihood Ratio Chi-square Approach was utilized to identify an optimal threshold of walking speed predictive of mortality. RESULTS: Deaths after 9 years of follow-up occurred in 23.3% (290/1244) of JoCoOA and 5.9% (249/4215) of OAI + MOST. Walking 0.2 m/s slower during short- and standard-distance walk tests was associated with 23% (aHR [95%CI]; 1.23 [1.10, 1.39]) and 25% (1.25 [1.09, 1.43]) higher mortality risk, respectively. Walking <0.5 m/s on short-distance and <1.2 m/s standard-distance walk tests, best discriminated those with and without mortality risk. CONCLUSION: Slower walking speed measured via short- and standard-distance walk tests was associated with increased mortality risk in adults with rKOA.

Hip symptoms are associated with premature mortality: the Johnston County Osteoarthritis Project.

OBJECTIVE: To investigate the impact of hip osteoarthritis (OA) and/or hip symptoms on excess mortality. DESIGN: We analyzed data from 3,919 individuals in a community-based prospective cohort of African Americans and Caucasians age ≥45 years. Women ≥50 years of age and all men underwent supine anteroposterior pelvic radiography at baseline, with the participant's feet in 15 degrees of internal rotation. Hip radiographic (rOA) was defined as a Kellgren-Lawrence grade of ≥2 in at least one hip. Participants completed questionnaires at baseline to determine presence of hip symptoms and covariate status. Participants with symptomatic hip rOA (SxOA) are a subset of individuals with hip rOA and symptoms in the same hip. Multiple imputation was used to impute missing values of covariates. Mortality was determined through 2015 and follow-up time was calculated from baseline assessment until death or censoring which took place when a participant was lost to follow-up or reached the end of study period. Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI). We carried out additional analyses stratified by sex, race, age and obesity. RESULTS: Mean follow-up time was 14.2 years during which 1762 deaths occurred. There were 29.9% participants in our population with hip rOA at baseline. Compared to those with neither hip rOA nor hip symptoms, we observed an increased risk of all-cause mortality in participants with hip symptoms alone (HR = 1.28, 95% CI = 1.13-1.46), but no association for hip rOA either with or without symptoms. In stratified analyses we observed increased associations for hip symptoms alone and hip sxOA in those <65 years (43% and 39% increase, respectively) and in Caucasians (34% and 21% increase, respectively). CONCLUSIONS: Individuals who had hip symptoms without hip rOA had an increased risk of mortality. These effects were particularly strong for those who were <65 years of age and Caucasians. Effective interventions to identify those with hip pain in order to lessen it could reduce premature mortality.

Evaluation of the self-directed format of Walk With Ease in patients with systemic lupus erythematosus: the Walk-SLE Pilot Study.

OBJECTIVE: To conduct a proof-of-concept pilot evaluation of the self-directed format of Walk With Ease (WWE), a 6-week walking program developed for adults with arthritis, in patients with systemic lupus erythematosus (SLE). METHODS: This was a single arm, 6-week pre- and post-evaluation of the self-directed WWE program to assess feasibility, tolerability, safety, acceptability, and effectiveness. Adult patients with physician-diagnosed SLE were recruited to participate during regularly scheduled visits to an academic rheumatology clinic. Self-reported outcomes of pain, stiffness, and fatigue were assessed by visual analog scales (VAS) and the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-fatigue) scale at baseline and at completion of the 6-week program. Patients also completed a satisfaction survey at the end of the program. Multivariate linear regression models were used to calculate mean changes between baseline and 6-week follow-up scores, adjusting for covariates. Mean change scores were used to estimate effect sizes (ES). RESULTS: At 6 weeks, 48 of the 75 recruited participants completed the WWE program. Participants experienced modest improvements in stiffness and fatigue (ES = 0.12 and ES = 0.23, respectively, for VAS scores; ES = 0.16 for FACIT-fatigue score) following the intervention. The majority of participants reported satisfaction with the program (98%) and benefitted from the workbook (96%). CONCLUSIONS: The self-directed format of WWE appears to reduce stiffness and fatigue in patients with SLE. It also seems to be a feasible and acceptable exercise program to patients with SLE. Larger studies are needed to confirm these findings.

A machine learning approach to knee osteoarthritis phenotyping: data from the FNIH Biomarkers Consortium.

OBJECTIVE: Knee osteoarthritis (KOA) is a heterogeneous condition representing a variety of potentially distinct phenotypes. The purpose of this study was to apply innovative machine learning approaches to KOA phenotyping in order to define progression phenotypes that are potentially more responsive to interventions. DESIGN: We used publicly available data from the Foundation for the National Institutes of Health (FNIH) osteoarthritis (OA) Biomarkers Consortium, where radiographic (medial joint space narrowing of ≥0.7 mm), and pain progression (increase of ≥9 Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC] points) were defined at 48 months, as four mutually exclusive outcome groups (none, both, pain only, radiographic only), along with an extensive set of covariates. We applied distance weighted discrimination (DWD), direction-projection-permutation (DiProPerm) testing, and clustering methods to focus on the contrast (z-scores) between those progressing by both criteria ("progressors") and those progressing by neither ("non-progressors"). RESULTS: Using all observations (597 individuals, 59% women, mean age 62 years and BMI 31 kg/m2) and all 73 baseline variables available in the dataset, there was a clear separation among progressors and non-progressors (z = 10.1). Higher z-scores were seen for the magnetic resonance imaging (MRI)-based variables than for demographic/clinical variables or biochemical markers. Baseline variables with the greatest contribution to non-progression at 48 months included WOMAC pain, lateral meniscal extrusion, and serum N-terminal pro-peptide of collagen IIA (PIIANP), while those contributing to progression included bone marrow lesions, osteophytes, medial meniscal extrusion, and urine C-terminal crosslinked telopeptide type II collagen (CTX-II). CONCLUSIONS: Using methods that provide a way to assess numerous variables of different types and scalings simultaneously in relation to an outcome of interest enabled a data-driven approach that identified key variables associated with a progression phenotype.

The impact of painful knee osteoarthritis on mortality: a community-based cohort study with over 24 years of follow-up.

OBJECTIVE: To investigate the impact of knee osteoarthritis (OA) and/or knee pain on excess mortality. METHOD: We analyzed data from 4,182 participants in a community-based prospective cohort study of African American and Caucasian men and women aged ≥45 years. Participants completed knee radiographs and questionnaires at baseline and at up to three follow-ups to determine knee OA (rOA), knee pain and covariate status. Mortality was determined through 2015. We used Cox proportional hazards regression with time-varying covariates (TVC) to estimate hazard ratios (HR) and 95% confidence intervals (CI). Additional analyses stratified by sex, race and age were carried out. RESULTS: Median follow-up time was 14.6 years during which 1822 deaths occurred. Baseline knee radiographic osteoarthritis (rOA) was 27.7%, 38.8% at first follow-up, 52.6% at second follow-up and 61.9% at the third follow-up. Knee rOA with pain and knee pain alone were both associated with a >15% increase in premature all-cause mortality. In analyses stratified by sex, race and age, associations between knee pain, with or without knee rOA, and all-cause death were found among women, Caucasians, those ≤65 years of age, and those with a body mass index (BMI)≥30, with observed increased risks of death between 21% and 65%. We observed similar, somewhat attenuated, results for cardiovascular disease (CVD) deaths. CONCLUSION: In models taking into account variables that change over time, individuals who had knee pain, alone or with knee rOA, had increased mortality. These effects were particularly strong among those obese. Effective interventions to reduce knee pain, particularly those including weight management and prevention of comorbidities, could reduce mortality.

Osteoarthritis induced by destabilization of the medial meniscus is reduced in germ-free mice.

OBJECTIVE: To determine the contribution of the gut microbiota to the development of injury-induced osteoarthritis (OA). DESIGN: OA was induced using the destabilized medial meniscus (DMM) model in 20 germ-free (GF) C57BL/6J male mice housed in a gnotobiotic facility and 23 strain-matched specific pathogen free (SPF) mice in 2 age groups -13.5 weeks avg age at DMM (17 SPF and 15 GF) and 43 weeks avg age at DMM (6 SPF and 5 GF). OA severity was measured using scores for articular cartilage structure (ACS), loss of safranin O (SafO) staining, osteophyte size, and synovial hyperplasia. Microbiome analysis by 16S rRNA amplicon sequencing was performed on stool samples and LPS and LPS binding protein (LBP) were measured in plasma. RESULTS: Compared to the SPF DMM mice, the maximum (MAX) ACS score per joint was 28% lower (p = 0.036) in GF DMM mice while the SafO sum score of all sections evaluated per joint was decreased by 31% (p = 0.009). The differences between SPF and GF mice in these scores were greater when only the younger mice were included in the analysis. The younger GF DMM mice also had significant reductions in osteophyte size (36%, P = 0.0119) and LBP (27%, P = 0.007) but not synovial scores or LPS. Differences in relative abundance of a number of Operational Taxonomic Units (OTUs) were noted between SPF mice with high vs low maximum ACS scores. CONCLUSIONS: These results suggest factors related to the gut microbiota promote the development of OA after joint injury.

Polymorphisms of genes coding for insulin-like growth factor 1 and its major binding proteins, circulating levels of IGF-I and IGFBP-3 and breast cancer risk: results from the EPIC study.

Insulin-like growth factor I (IGF-I) stimulates cell proliferation and can enhance the development of tumours in different organs. Epidemiological studies have shown that an elevated level of circulating IGF-I is associated with increased risk of breast cancer, as well as of other cancers. Most of circulating IGF-I is bound to an acid-labile subunit and to one of six insulin-like growth factor binding proteins (IGFBPs), among which the most important are IGFBP-3 and IGFBP-1. Polymorphisms of the IGF1 gene and of genes encoding for the major IGF-I carriers may predict circulating levels of IGF-I and have an impact on cancer risk. We tested this hypothesis with a case-control study of 807 breast cancer patients and 1588 matched control subjects, nested within the European Prospective Investigation into Cancer and Nutrition. We genotyped 23 common single nucleotide polymorphisms in IGF1, IGFBP1, IGFBP3 and IGFALS, and measured serum levels of IGF-I and IGFBP-3 in samples of cases and controls. We found a weak but significant association of polymorphisms at the 5' end of the IGF1 gene with breast cancer risk, particularly among women younger than 55 years, and a strong association of polymorphisms located in the 5' end of IGFBP3 with circulating levels of IGFBP-3, which confirms previous findings. Common genetic variation in these candidate genes does not play a major role in altering breast cancer risk in Caucasians.

Association of recall rates with sensitivity and positive predictive values of screening mammography.

OBJECTIVE: The performance of screening mammography is measured mainly by its sensitivity, positive predictive value, and cancer detection rate. Recall rates are also suggested as a surrogate measure. The main objective of this study was to measure the effect on sensitivity and positive predictive value as recall rates increase in the community practice of mammography. MATERIALS AND METHODS: Mammography and pathology data are linked in the Carolina Mammography Registry, a population-based registry of screening mammography. Our mammography database is created from prospectively collected data from mammography facilities; the data include information on the woman and the imaging studies. Our pathology database is created from prospectively collected breast pathology data received from pathology sites and the Central Cancer Registry. Women in the registry who were 40 years old and older and who underwent screening mammography between January 1994 and June 1998 were included. "Recall rate" was defined as the percentage of screening studies for which further workup was recommended by the radiologist. RESULTS: The study included 215,665 screening mammograms. The mean age of the women was 56 years. The recall rates of the average practice ranged from 1.9% to 13.4%. Sensitivity rose from a mean of 65% in the lowest recall rates to 80.2% at the highest level of recall rates. The positive predictive value of screening decreased from 7.2% in the lowest level of recall to 3.3% in the highest. As recall rates increased, sensitivity increased very little beyond a recall rate of 4.8%, and positive predictive value began decreasing significantly at a recall rate of 5.9%. CONCLUSION: Practices with recall rates between 4.9% and 5.5% achieve the best trade-off of sensitivity and positive predictive value.

Repair of coarctation of the aorta during infancy minimizes the risk of late hypertension.

BACKGROUND: Recent surgical reports on coarctation of the aorta have primarily focused on the relative merits of various operative techniques. However, appropriate timing for elective repair remains unclear. METHODS: In a retrospective analysis we examined the surgical outcomes in 176 consecutive patients undergoing repair of coarctation of the aorta in our institution over a 25-year period. Ninety-nine percent of the patients had follow-up for a median of 7.5 years. RESULTS: A total of 13 patients have died (7.4% overall mortality). Nine of these patients had associated complex intracardiac anomalies. There was no mortality in the 113 patients with isolated coarctation. Residual or recurrent coarctation occurred in 27 patients (15.3%). The age at operation and the type of surgical repair did not have an effect on the incidence of recurrence. Persistent or late hypertension was identified in 18 of the 107 patients who have been followed up for more than 5 years (16.8%). A total of 48 patients operated on during infancy have been followed up for more than 5 years. Only 2 have developed late hypertension (4.2%). Both of these patients had recurrence. In contrast, 16 of the 59 patients operated on after a year of age had late hypertension (27.1%). CONCLUSIONS: To minimize the risk of persistent hypertension, elective repair of coarctation should be performed within the first year of life.

Planning, development, and execution of an international training program in laparoscopic surgery.

In the late 1980s, minimally invasive surgery experienced unprecedented growth. Centers appeared worldwide, providing a variety of training opportunities and laboratory experiences. Because standard surgical training varies greatly from country to country, it became apparent that this variety was even more pronounced in the area of minimally invasive and laparoscopic surgery, posing significant credentialling difficulties for professional standards committees wishing to certify surgical staff who submit unevaluable credentials from all over the world. In January 1993, the Center for Minimally Invasive Surgery at New England Medical Center and Tufts University School of Medicine was asked to plan and execute a program of education, training, and credentialling for a multispecialty surgical staff in the Eastern province of Saudi Arabia. A four-stage program was designed and developed to provide credentialling from the technician level through the instructor surgeon level. A multidisciplinary course was developed and a team placed on site for 1 month to execute the program. This program began with an 8-h didactic/video session in basic laparoscopy, covering areas common to the involved subspecialties: surgery, urology, and gynecology. This session was followed by hands-on training sessions in general surgery and urology and credentialling in gynecology. Physicians who successfully completed the examination in basic laparoscopy were later eligible for credentialling at one of three clinical specialty levels: basic clinical laparoscopy, advanced clinical laparoscopy, or instructor in clinical laparoscopy. Education and credentialling in minimally invasive surgery can be accomplished by executing a program of basic science and clinical training for physicians, technicians, and nurses that accommodates a wide range of experience of participants, from novice to master surgeon. Support from the hospital administrators and department chairs was instrumental in the program's success. Among the goals we accomplished was identification of persons in an institution who could serve as future instructors and certifiers for the hospital's self-sustaining program as well as providing a relationship in which international institutions can serve as a resource for further continuing medical education and clinical and laboratory training. This program may well serve as the model template for international credential standards of the future.

Granulocyte sequestration and early failure in the autoperfused heart-lung preparation.

We investigated the role of pulmonary granulocyte sequestration in the development of early failure of the autoperfused working heart-lung preparation. A significant decline in the total circulating leukocyte count in 21 preparations at 60 minutes of perfusion (5.0 to 1.4 x 10(3)/microL; 28% of baseline; p less than 0.001) was observed. Differential cell counts in 14 of these preparations revealed a predominant decrease in granulocyte count (8.7% of baseline) and a moderate decline in lymphocyte count (46% of baseline). In study I, indium 111-labeled autologous granulocytes were injected intravenously into 10 adult New Zealand White rabbits. In group I (n = 5), an autoperfused working heart-lung preparation was harvested and perfused for 60 minutes. In group II (controls, n = 5), the heart-lung block was harvested following 60 minutes of in situ perfusion. Organ blocks were imaged before and after saline flush. There was a significant decline in granulocyte counts at 60 minutes of perfusion in group I versus no change in group II (I, 2.3 +/- 0.4 to 0.3 +/- 0.1; p less than 0.01; II, 1.7 +/- 0.2 to 2.3 +/- 0.5; not significant; x 10(3)/microL +/- standard error of the mean). Postflush lung activity was significantly increased in group I versus group II (I, 3,751 +/- 566; II, 1,867 +/- 532; p less than 0.05; counts +/- standard error of the mean). In study II, 15 autoperfused preparations were divided into two groups. Group I (n = 10) preparations were controls. Group II (n = 5) animals were depleted of leukocytes by pretreating with nitrogen mustard. Group I (controls) produced a bimodal survival distribution (Ia, 8.2 +/- 1.0; Ib, 26.4 +/- 2.0; hours +/- standard error of the mean). Group II survival was significantly longer than that of group Ia and similar to that of group Ib (II, 25.3 +/- 2.2; p less than 0.01 versus group Ia, not significant versus group Ib; hours +/- standard error of the mean). Hemodynamic profiles for group II closely paralleled those of group Ib. In conclusion, pulmonary sequestration of granulocytes occurs early in the autoperfused working heart-lung preparation (within 60 minutes of autoperfusion), and preoperative leukocyte depletion prolongs survival of the autoperfused working heart-lung preparation by eliminating the subset group Ia (short survivors) seen in untreated preparations.

Spinal cord protection during aortic occlusion: efficacy of intrathecal tetracaine.

Spinal cord ischemia and resultant paraplegia are devastating sequelae in up to 40% of patients undergoing repair of thoracoabdominal aneurysms. We investigated the effect of intrathecal tetracaine on the neurological sequelae of spinal cord ischemia and reperfusion with aortic occlusion. Cocaine-derived anesthetics (lidocaine and its analogues) have been shown to decrease neuronal cell metabolism and also have specific neuronal membrane stabilizing effects. New Zealand white rabbits were anesthetized and spinal cord ischemia was then induced by infrarenal aortic occlusion. Animals were divided into six treatment groups. Tetracaine (groups 2 and 4) or normal saline solution (group 5) was administered intrathecally before aortic cross-clamping. Groups 1 and 3 functioned as controls. Group 6 animals received intravenous thiopental. Rabbits were classified as either neurologically normal or injured (paralyzed or paretic). Among controls, 25 minutes of aortic occlusion produced varied neurological sequelae (group 1, 3/6 injured, 50%) whereas 30 minutes resulted in more consistent injury (group 3, 5/6 injured, 83%). All rabbits that received intrathecal saline solution were paralyzed (group 5, 4/4 injured, 100%). Animals treated with intrathecal tetracaine and aortic occlusion of 30 minutes (group 4) showed significantly better preservation of neurological function (6/7 normal, 86%) than controls and saline-treated animals (groups 3 and 5). All animals treated with intrathecal tetracaine and aortic occlusion for 25 minutes (group 2) showed no signs of injury (5/5 normal, 100%), but this was not significant versus controls (group 1). Intravenous thiopental (group 6, 5/5 injured, 100%) had no beneficial effect. Intrathecal tetracaine significantly and dramatically abrogated the neurological injury secondary to spinal cord ischemia and reperfusion after aortic occlusion at 30 minutes in the rabbit model.

Patch aortotomy for aortic valve replacement after previous coronary artery bypass grafting.

Exposure for aortic valve operations after previous coronary artery bypass grafting may be technically difficult owing to the presence of patent vein grafts on the proximal aorta. A patch or "island" aortotomy technique that allows excellent exposure of the aortic valve is presented here. In select patients this approach may facilitate cardioplegia administration.

Leukocyte redistribution and eicosanoid changes during the autoperfused working heart-lung preparation.

We studied the role of leukocyte redistribution and eicosanoid changes in the early stages of instituting 16 rabbit autoperfused working heart-lung preparations (AWHLP). Physiological changes occurring during the transition from the intact animal to the AWHLP may determine the survival and viability of the organ blocks for transplantation. White blood cell (WBC) count decreased from 5,160/microL to 1430/microL (P less than .01) at 60 min of autoperfusion. Differential WBC counts performed in ten of these AWHLP revealed a 63% decrease in lymphocyte count and an 88% decrease in the granulocyte count at 60 min. Thus, the predominant leukocyte remaining in the circulation was the lymphocyte. Blood samples were collected from the intact animal and from the AWHLP for assay of the stable metabolites of thromboxane A2 (TxA2) and prostacyclin (PGI2). Transition from the in situ heart-lung block to the in vitro AWHLP stage caused significant changes in these metabolites. The PGI2 metabolite 6-ketoprostaglandin F1a (6KPGF1a) increased from 2680 +/- 487 to 4339 +/- 478 (pg/mL), P less than .05, while the TxA2 metabolite, thromboxane B2 (TxB2) decreased from 618 +/- 105 to 289 +/- 63 (pg/mL). However, assays of 11-dehydro-TxB2 (11-DHT), a longer lived metabolite of TxA2 (n = 7) increased (668.4 +/- 84.6 to 946.4 +/- 43.7, P less than .05). The transition from the in situ heart-lung block of the intact animal to the AWHLP involves significant physiological changes. Redistribution of leukocytes occurs with a predominant decrease in the granulocyte count, while levels of bioactive lipid mediators show a distinct large rise in the PGI2 metabolites and a lesser increase in TxA2 metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)

Rapid in-line blood warming using microwave energy: preliminary studies.

The management of massive blood loss resulting from trauma or surgery necessitates rapid transfusion capability. Hypothermia secondary to shock, transfusion, and prolonged surgical procedures significantly increases morbidity and mortality in these patients. Transfusion at high flow rates frequently exceeds the warming capacity of conventional blood-warming devices, whose inherent resistance also limits the maximal flow rates. Microwave ovens are capable of blood warming, but have been associated with unacceptable hemolysis. We have investigated the possibility of using microwave energy to provide rapid in-line blood warming. Fresh blood from 10 human subjects was warmed from an average of 18 degrees C to temperatures ranging from 37 to 39 degrees C at flow rates from 250 to 500 mL/min. Laboratory analysis of free plasma hemoglobin, haptoglobin, hematocrit, hemoglobin, and electrolytes showed no difference between heated and control samples. LDH was elevated in those samples warmed repeatedly, but remained within the normal range. These data indicate the potential for further investigation utilizing properly controlled microwave energy for in-line blood and fluid warming.

Extended ex vivo preservation of the heart and lungs. Effects of acellular oxygen-carrying perfusates and indomethacin on the autoperfused working heart-lung preparation.

The autoperfused working heart-lung preparation has been proposed as a method for long-term heart-lung preservation. We investigated the effects of acellular oxygen-carrying perfusates (study 1) and the effect of donor pretreatment with indomethacin (study 2) on the working ex vivo heart-lung block. In study 1 perfusion with stroma-fee hemoglobin resulted in significantly reduced survival (118 +/- 46 minutes) compared with autologous blood (561 +/- 125 minutes, p less than 0.05) or perfluorocarbon (438 +/- 114 minutes, p less than 0.05). Decrease in survival with stroma-free hemoglobin perfusate is associated with a marked decrease in left ventricular performance and a significant increase in pulmonary vascular resistance. Perfusion with autologous blood is associated with a significant increase in pulmonary vascular resistance after 240 minutes of explantation, which is significantly delayed by perfusion with perfluorocarbon. Perfusion for 6 hours with blood pretreated with indomethacin (study 2) resulted in a decrease in the concentration of prostacyclin and thromboxane A2 metabolites but an increase in the prostaglandin/thromboxane A2 metabolite ratio. This is associated with abrogation of the increase in pulmonary vascular resistance (12,787 +/- 1682 dynes/sec/cm-5, T = 0; 13,134 +/- 2654 dynes/sec/cm-5, T = 360 minutes) observed in preparations perfused with autologous blood (13,194 +/- 1942 dynes/sec/cm-5, T = 0; 24,768 +/- 3325 dynes/sec/cm-5, T = 360 minutes, p less than 0.05). We conclude that alteration of the cellular and humoral components of autologous blood may prove advantageous for increasing the utility of the autoperfused working heart-lung preparation as a preservation technique.

Total lymphoid irradiation and discordant cardiac xenografts.

Total lymphoid irradiation can prolong concordant cardiac xenografts. The effects of total lymphoid irradiation in a discordant xenograft model (guinea pig to rat) were studied with and without adjuvant pharmacologic immunosuppression. Inbred Lewis rats were randomly allocated to one of four groups. Group 1 (n = 6) served as a control group and rats received no immunosuppression. Group 2 (n = 5) received triple-drug therapy that consisted of intraperitoneal azathioprine (2 mg/kg), cyclosporine (20 mg/kg), and methylprednisolone (1 mg/kg) for 1 week before transplantation. Group 3 animals (n = 5) received 15 Gy of total lymphoid irradiation in 12 divided doses over a 3-week period. Group 4 (n = 6) received both triple-drug therapy and total lymphoid irradiation as described for groups 2 and 3. Complement-dependent cytotoxicity assay was performed to determine if a correlation between complement-dependent cytotoxicity and rejection-free interval existed. Rejection was defined as cessation of graft pulsation and was confirmed by histologic test results. Only groups 1 and 2 showed a difference in survival (group 1, 6.9 +/- 1.0 minutes; group 2, 14.2 +/- 2.7 minutes, p = 0.02). Although total lymphoid irradiation did decrease complement-dependent cytotoxicity, linear regression revealed no correlation between complement-dependent cytotoxicity and graft survival (coefficient of correlation, 0.30). Unlike concordant cardiac xenografts, total lymphoid irradiation with or without triple-drug therapy does not prolong graft survival.

Clinical and hemodynamic performance of the Ionescu-Shiley valve in the small aortic root. Results in 117 patients with 17 and 19 mm valves.

The Ionescu-Shiley pericardial valve was our bioprosthetic valve of choice between 1981 and 1985 for patients in whom the aortic anulus could not accept a valve larger than 19 mm in outer diameter or in whom the avoidance of warfarin sodium (Coumadin) was important. A series of 117 consecutive patients who received 17 or 19 mm valves for isolated aortic valve replacement or aortic valve replacement combined with coronary artery bypass grafting or other valvular procedures was analyzed. Overall, 74% of the patients were female, with a mean age of 70.9 years and a body surface area of 1.67 +/- 0.19 m2; 92.3% were in New York Heart Association class III-IV, and the operation was urgent or emergent in 46%. The operative mortality rate was 7.7%, with no deaths in patients undergoing isolated elective first-time aortic valve replacement. Mean follow-up for survivors was 2.5 years (10 to 62 months). There were 20 late deaths, of which three were valve related, three were due to sudden death or arrhythmias, and two were due to persistent heart failure. The actuarial survival rate at 5 years was 68%. Clinical follow-up revealed a low incidence of valve-related complications, and 96.4% of survivors were in class I-II. Postoperative echocardiography before hospital discharge revealed a maximum instantaneous gradient of 18.4 +/- 3.0 mm Hg in five patients having a 17 mm valve and 31.3 +/- 12.7 mm Hg in 20 patients having a 19 mm valve. Doppler echocardiography was performed in 22 patients at a mean follow-up of 39.3 +/- 11.7 months. The maximum instantaneous gradient was 25 +/- 17.2 mm Hg for 17 mm and 17.41 +/- 5.4 mm Hg for 19 mm valves at late follow-up. The effective orifice area was 0.85 +/- 0.1 cm2 for 17 mm and 1.21 +/- 0.21 cm2 for 19 mm valves. This study defines the normal range of Doppler echocardiographic transprosthetic gradients for the Ionescu-Shiley valve and confirms that low operative mortality and excellent clinical improvement can result from the use of small Ionescu-Shiley valves in elderly patients despite moderate postoperative transvalvular gradients.