Anti-insulin antibodies are a cause of hypoglycemia following pancreas transplantation.

OBJECTIVE: Hypoglycemic symptoms have been reported by more than half of pancreas transplantation (PTX) recipients. To better understand the mechanism for the hypoglycemia documented in some of these patients, we studied the glucose and pancreatic hormone response to Sustacal in patients with and without hypoglycemia following PTX. RESEARCH DESIGN AND METHODS: Twelve patients with established, repeated episodes of hypoglycemia following PTX (hypo) were case-matched to PTX recipients without hypoglycemic symptoms (control; n = 7). On the day of the study, fasting glucose, free and total immunoreactive insulin (IRI), C-peptide, proinsulin, and glucagon were drawn (time 0); Sustacal was administered; and glucose, free and total IRI, and C-peptide were assayed at 15, 30, 45, 75, 120, 150, 180, and 240 min. Based on the glucose response to Sustacal, the hypo group was further divided into those whose glucose rose after Sustacal (hypo-high; n = 7) and those with no increase in glucose from baseline concentration (hypo-flat; n = 5). RESULTS: Before the administration of Sustacal, the hypo-high group had a lower fasting free/total IRI (0.26 +/- 0.06, mean +/- SE) than the hypo-flat (0.51 +/- 0.02) or control (0.52 +/- 0.04) groups (both P < 0.05 compared with hypo-high). The glucose response to Sustacal was greatest in the hypo-high group as defined. Area under the curve (AUC) for total IRI following Sustacal was also greatest in the hypo-high group (P < 0.05 compared with both control and hypo-flat groups), but there was no significant difference in free IRI AUC following Sustacal between the three groups. Two individuals developed hypoglycemia during the Sustacal challenge, both in the hypo-high group. CONCLUSIONS: The lower fasting free/total IRI ratio and greater increase in glucose and total IRI in response to Sustacal in the hypo-high group compared with either the hypo-flat or control groups are consistent with the presence of significant quantities of anti-insulin antibodies in the hypo-high group. Because anti-insulin antibodies are, in turn, an established cause of episodic hypoglycemia, this study provides the first data to support the hypothesis that significant quantities of anti-insulin antibodies are a cause of symptomatic hypoglycemia following PTX in some recipients.

Pharmacokinetics of antithrombin concentrate during autologous hematopoietic stem cell transplantation.

Antithrombin is a naturally-occurring anticoagulant protein. Congenital deficiency of this protein predisposes to thrombotic complications. Acquired deficiency of antithrombin occurs in a variety of clinical circumstances, including hematopoietic stem cell transplantation (HSCT), and is associated with multiorgan failure and death in these situations. Normalization of antithrombin levels by infusion of concentrates of this protein has been found to be beneficial in many of these situations, but has not been routinely used in HSCT. Before antithrombin concentrates can be widely recommended in HSCT, its pharmacokinetics at various phases of the transplant process must be defined to allow estimation of the proper dose and dosing interval. To this end, the recovery and half-life of antithrombin concentrate was determined prior to and 7, 14 and 28 days after beginning the preparative regimen in nine patients with lymphoma undergoing HSCT. The recovery of the infused material was constant during the transplant hospitalization, averaging 2.0% per unit/kg. The half-life, however, dropped significantly during the latter half of the transplant procedure. The half-lives pre-chemotherapy and on day 7 were similar and averaged 20.4 h. On days 14 and 21 the the half-lives were significantly lower at 12.2 and 15.5 h, respectively. The drop in half-life during the transplant process will require antithrombin concentrate to be given more frequently during this time to maintain constant antithrombin levels.

Results of liver transplantation in diabetic recipients.

BACKGROUND: The results of orthotopic liver transplantation (OLTx) in patients with diabetes mellitus (DM) are not well defined. METHODS: Between 1985 and 1991, 45 adult patients with pretransplantation DM (5 type I, 40 type II) underwent OLTx at our center as identified by retrospective chart review. We compared this diabetic recipient group to a case-control nondiabetic group matched for age, gender, primary liver disease, weight, and timing of OLTx. A total of 30 variables were collected and analyzed with McNemar's test for categorical data, paired t tests for continuous data, and survival and repeated measures analysis for longitudinal data. RESULTS: No differences between diabetic and nondiabetic recipients were noted in patient or graft survival, the incidence or severity of rejection, blood transfusions, operative complications, readmissions, major infections, or number of hospital days after OLTx. However, the incidence of minor bacterial (p = 0.046) and minor fungal (p = 0.035) infections were higher in the DM group. Serum blood urea nitrogen (p = 0.02) and creatinine (p = 0.03) levels were also higher in patients with diabetes versus control patients during the first year after OLTx. CONCLUSIONS: In carefully selected patients with pretransplantation DM, OLTx can be accomplished with results similar to nondiabetic recipients in spite of a higher incidence of minor infections and renal dysfunction.

Cardiovascular stability during carotid endarterectomy: endotracheal intubation versus laryngeal mask airway.

STUDY OBJECTIVE: To compare cardiovascular stability during carotid endarterectomy in groups managed either with laryngeal mask airway (LMA) or endotracheal intubation. DESIGN: Randomized, retrospective, blinded study. SETTING: Teaching hospital. PATIENTS: 61 ASA physical status II, III, and IV unpremedicated adult males scheduled for carotid endarterectomy. INTERVENTIONS: Following standardized anesthetic technique, including intravenous (i.v.) induction with thiopental sodium 3 to 4 mg/kg, fentanyl 2 to 3 microg/kg), and isoflurane, standard intraoperative cardiovascular monitoring plus direct arterial blood pressure measurements were instituted. Patients were randomly assigned to an endotracheal intubation or LMA group. MEASUREMENTS AND MAIN RESULTS: Distinct intraoperative episodes of +/- 25% increase or decrease of mean arterial blood pressure (MABP) and heart rate (HR) when compared with preinduction baseline values, and the number of such episodes requiring interventional therapy were recorded from a blinded anesthesia record retrospectively. Mean end-tidal isoflurane determination and total case duration enabled calculation of minimum alveolar concentration (MAC) hours of isoflurane administered. The LMA group had a significantly (p < 0.05) lower incidence of increased MABP and HR episodes and such episodes requiring drug therapy than did the endotracheal intubation group. No difference was found in the length of surgery, mean end-tidal isoflurane concentration, or the total number of MAC hours of isoflurane administered. CONCLUSIONS: During carotid endarterectomy, a reduced incidence of hypertensive and tachycardic episodes, as well as such episodes requiring interventional drug therapy, was found in the group whose airway is managed by LMA when compared with endotracheal intubation.

Attitudes and expectations of 1995 gastroenterology graduates about gastroenterology.

OBJECTIVE: To learn more about current attitudes and expectations of recent (June 1995) graduates of gastroenterology fellowship programs, why they chose either a private practice or academic career, and what impact managed care or health care reform had in their decision. METHODS: Between April and June 1995, and 8-page, 35-question survey questionnaire was mailed to graduating fellows and returned for evaluation. RESULTS: Graduates believed managed care had an impact on job availability, but it was not a factor in their job choice. Forty percent of the respondents reported that finding a job was either difficult or very difficult. The majority of respondents (67%) are pursuing a career in private practice. Most private practice physicians (PP) trained in 2-yr programs whereas academic physicians (AC) trained for the most part in 3-yr programs. The principal criteria on which decisions regarding job selection were based were similar between the two groups: co-workers, geographic location, access to patient care, and ability to perform endoscopy. Respondents in PP and AC expected to work 50-70 h/wk, care for patients with similar diseases, and have ample time for family. They would choose GI again as a career and believed that there is a future in GI. Salary expectations varied markedly between the two groups, and AC physicians were more concerned about their future financial needs. Twenty percent of PP physicians and 71% of AC physicians plan to participate in clinical research. CONCLUSIONS: Recent graduates of gastroenterology fellowship programs continue to have high expectations of their future careers. Although some had difficulty finding a job and stated that, although managed care had an impact on the job market, it had not yet become a major factor in their job selection.

Influenza vaccination following liver transplantation in children.

Our objective was to determine the immunologic response to two influenza vaccine doses in 39 children who had undergone liver transplantation. Patients received two doses of trivalent inactivated influenza vaccine 4 weeks apart. Sera were collected 4 weeks after each dose and analyzed by a hemagglutination inhibition assay (HAI) for evidence of antibody response to the antigens A/Taiwan/1/86 (H1N1), A/Beijing/32/92 (H3N2), and B/Panama/45/95. Patients with HAI titers of 1:40 or greater were considered to have protective titers. Twenty-six (67%) patients showed a 1:40 or greater titer response to A/Beijing/32/92 1 month after the first vaccination. Only two additional patients were found to have similar titers after the second dose. A higher proportion of patients with protective titers were on smaller amounts of prednisone for body weight or alternate day low dose (< 10 mg/day) prednisone compared to patients on daily low dose or daily high dose prednisone. Patients with protective titers were significantly older (9.0 +/- 2.8 years) than those without protective titers (4.2 +/- 3.4 years, p = .002) following the first inoculation of the A/Beijing/32/92 vaccine component. Similar results were found for the second vaccination and with the H1N1 antigen. Cyclosporine level, gender, and body mass index were not associated with any outcome measures. We conclude that most liver transplant recipients had a protective antibody titer after a single influenza inoculation, but little further advantage was gained after an additional dose. Vaccination of household contacts of younger patients and those patients on daily prednisone or patient chemoprophylaxis may offer greater benefit in prevention of influenza in liver transplant recipients than multiple vaccine doses with current vaccine preparations.

Introduction of 6-mercaptopurine in Crohn's disease patients during the perioperative period: a preliminary evaluation of recurrence of disease.

BACKGROUND: Recurrence of Crohn's disease after surgery is a common occurrence, pointing to the need for a strategy to prevent recurrent disease. We report the postoperative course of 10 patients who required intestinal resections for complications related to Crohn's disease. METHODS: All patients had a Pediatric Crohn's Disease Activity Index score of 10 or greater. Among these patients, 5 began treatment with 6-mercaptopurine in the perioperative period. All 10 had received various combinations of prednisone and salicylate compounds. Patients who were given 6-mercaptopurine did not discontinue the medication until 2 years after the surgery. RESULTS: To date, none of the five patients who were placed on 6-mercaptopurine have had recurrence of their Crohn's disease (mean disease-free period 32.6 +/- 18.4 months). Among those five patients not receiving 6-mercaptopurine there have been three relapses (mean time to relapse 3.7 +/- 1.2 months). Log-rank sum analyses of Kaplan-Meier survival curves show benefit to patients receiving 6-mercaptopurine in preventing relapses after intestinal resection (p < 0.05). CONCLUSIONS: Although the underlying pathophysiologic reasons leading to the high relapse rate after intestinal surgery in Crohn's disease are unknown, we conclude that treatment with 6-mercaptopurine in the perioperative period may be warranted to help prevent the recurrence of Crohn's disease after surgery.

Multiple organ dysfunction syndrome in bone marrow transplantation.

OBJECTIVE: To define the frequency and outcome of organ dysfunction in bone marrow transplantation (BMT) and to determine if patients with organ dysfunction have lower levels of protein C (PC) and/or antithrombin III (ATIII) than those without organ dysfunction. DESIGN: Inception cohort of patients undergoing BMT, followed for 28 days, until hospital dismissal, or until death. SETTING: Bone marrow transplant department of a university hospital. PATIENTS: A total of 199 consecutive patients admitted for BMT. INTERVENTIONS: Standard supportive care was given to all patients. MAIN OUTCOME MEASURES: Definitions of organ dysfunction were arrived at prior to beginning the study. They include pulmonary, central nervous system (CNS), hepatic, and renal dysfunction. Protein C and ATIII levels were measured prior to beginning the preparative regimen and weekly thereafter. RESULTS: Single organ dysfunction, manifesting as pulmonary, CNS, or hepatic dysfunction, occurred in 93 (48.5%) of the 199 patients and was a strong predictor of multiple organ dysfunction syndrome (MODS) and death. Death occurred in 14 (7.0%) of the patients. Cause of death was precisely identified in only four patients. Low levels of either PC or ATIII were associated with death and pulmonary, CNS, and hepatic dysfunction. Multivariate analysis showed ATIII and PC levels were associated with single organ dysfunction independent of the type of transplant, the type of preparative regimen, and the presence of bacteremia. CONCLUSIONS: Single organ dysfunction during BMT is a marker for a systemic abnormality that has a high likelihood of progressing to MODS, similar to that seen in other critically ill patient populations. MODS is the leading cause of death in series of BMT patients. Low levels of ATIII and PC are markers of and may be involved in the pathogenesis of MODS in BMT.

Prognostic value of cellular proliferation and histologic grade in follicular lymphoma.

The clinical usefulness of histologic grading in follicular lymphoma (FL) is controversial and is further compromised by the subjective nature and poor reproducibility of most systems in current use. Therefore, we decided to objectively evaluate the importance of cellular proliferation in FL, along with the current grading systems. We studied 106 patients with FL who were uniformly staged and aggressively treated. A proliferative index (PI) was determined quantitatively using an automated image analyzer and a new Ki-67 antibody that stains archival paraffin tissues. The cases were also subclassified according to the Berard, Rappaport, Luke-Collins, and Jaffe methods, and survival analysis was performed. Patients with a low PI (< 40%) had a significantly longer overall survival (OS) than those with a high PI (> or = 40%), but the PI did not predict failure-free survival (FFS). The mean PI correlated well with the subgroups in each of the various classifications. All four of the classification methods were predictive of OS, but only the Berard method appeared to predict FFS and suggest that a proportion of patients with FL may be curable. In multivariate analysis, histologic classification was the only independent predictor of OS (Berard method: relative risk, 3.1) and the International Prognostic Index was the only independent predictor of FFS (relative risk, 2.3). We conclude that the Berard method for grading of FL is clinically useful and, along with the International Prognostic Index, should be included in future clinical studies of FL. The measurement of cellular proliferation does not appear to add additional useful information in FL.

The role of high-dose therapy and autologous hematopoietic stem cell transplantation for mantle cell lymphoma.

BACKGROUND: Although mantle cell lymphoma (MCL) is a distinct disease entity with well described clinical and pathological features, little information exists regarding its therapy. This paper will evaluate patients with MCL receiving either induction therapy with an anthracycline or high-dose chemotherapy and autologous hematopoietic stem cell transplantation for relapsed disease. PATIENTS AND METHODS: The cases of 14 previously untreated patients with MCL who received an anthracycline-containing combination chemotherapy regimen on Nebraska Lymphoma Study Group protocols from 3/83 to 2/92 were reviewed. During the same time period, a different set of nine patients with recurrent MCL were referred for high-dose chemoradiotherapy and autologous stem cell rescue as salvage therapy. RESULTS: The five year overall (OS) and failure-free (FFS) survivals from the initiation of chemotherapy for the patients receiving an induction therapy with an anthracycline containing regimen were 23% and 8%, respectively. At the time of this analysis, three of the nine transplant patients remain progression-free 7, 12, and 25 months post-transplant. Two year overall and FFS for all nine patients was 34%. CONCLUSIONS: Longer follow-up of greater patient numbers is required to determine whether high-dose therapy can overcome the chemoresistance and increase the cure rate of MCL. Since most patients with this disease have minimal chance of cure with standard chemotherapy, the optimal timing for high dose therapy may be as part of front-line treatment. Further clinical trials are required to investigate the potential benefits of high-dose therapy for patients with MCL.

A prospective randomized double-blind trial of antithrombin III concentrate in the treatment of multiple-organ dysfunction syndrome during hematopoietic stem cell transplantation.

Many of the complications of high-dose therapy with hematopoietic stem cells are caused by or lead to the multiple-organ dysfunction syndrome (MODS). In hematopoietic stem cell transplantation (HSCT), acquired antithrombin III (ATIII) deficiency is independently associated with MODS to the exclusion of transplant type, preparative regimen, and bacteremia. In experimental settings, replacement of ATIII can ameliorate the severity of MODS that develops in response to a variety of pathologic stimuli, suggesting that ATIII supplementation might improve the clinical course of MODS in patients undergoing HSCT. We performed a study to determine if ATIII can improve the morbidity of MODS in HSCT. Forty-nine patients undergoing HSCT, who developed pulmonary dysfunction (oxygen saturation of <90%), central nervous system dysfunction (drop of >4 points in the mini-mental status exam), or hepatic dysfunction (bilirubin >34 micromol/L [2.0 mg%], weight gain of >5% over baseline, and abdominal pain, possibly of hepatic origin) with a concomitant ATIII activity of <84% were double-blind randomized to receive ATIII concentrate, 70 units/kg within 24 hours of recognition of initial organ dysfunction followed by 50 units/kg 8, 16, 48, and 72 hours later, or albumin placebo. The group randomized to ATIII had a lower severity-of-illness score (15.7 +/- 19.2 vs. 28.6 +/- 25.2, p = 0.03), shorter duration of hospitalization (14.9 +/- 16.7 vs. 25.7 /- 17.9 days, p = 0.03), and lower hospital charges ($138,700 +/- $23,500 vs. $206,400 +/- $34,000). ATIII concentrate was associated with improved morbidity of MODS in patients undergoing HSCT when given early in the evolution of the syndrome.

Correlation of mucosal disaccharidase activities with histology in evaluation of rejection following intestinal transplantation.

Following intestinal transplantation, we have found that recovery from severe rejection may be difficult to identify. In this study we sought to ascertain whether concurrent determination of mucosal disaccharidase activities and histologic assessment improves the accuracy of diagnosis of rejection. Histologic changes were graded blindly using a standard set of diagnostic criteria, and these changes were compared over time to maltase, sucrase, lactase, and palatinase activities in four pediatric patients under treatment for severe rejection. The histologic criteria, which included magnitude of enterocyte loss, degree of granulation tissue, severity of villus atrophy, and frequency of apoptosis and cryptitis, were found to correlate with one another over time irrespective of outcome (r = 0.72 to r = 0.85). Enzyme activities were also correlated with each other over time (r = 0.64 to r = 0.80). However, the correlation between histologic diagnosis and enzyme activity was weaker (r = -0.48 to r = -0.57). Furthermore, neither histologic nor enzyme evaluation early in the course of rejection predicted ultimate clinical outcome. The results of this investigation show that determination of mucosal disaccharidase activity provides no additional useful information concerning efficacy of anti-rejection therapy as compared to histologic analysis alone.

Morbidity in patients with posttransplant diabetes mellitus following orthotopic liver transplantation.

It is not well understood whether posttransplant diabetes mellitus (PTDM) following orthotopic liver transplantation (OLTx) alters postoperative morbidity. This study was designed to evaluate this question. All adult patients who received an OLTx between July 1985 and March 1993 (n = 497) were evaluated by retrospective chart review for evidence of PTDM after OLTx. The patients identified with PTDM (n = 26) were case matched with nondiabetic OLTx recipients based on primary liver disease diagnosis, age, gender, date of first OLTx, and survival. Liver synthetic function, number and severity of rejection episodes, graft survival, total number of hospital days within the first year post-OLTx, renal function, and number and type of infection episodes were analyzed to assess differences in morbidity between the PTDM and control patients after OLTx. Of the 497 adult patients who underwent OLTx, 26 (5.2%) were identified as having PTDM within 1 month of discharge. Factors which identified individuals at higher risk for DM after OLTx included higher pre-OLTx fasting blood glucose (P = .04); lower body mass index after OLTx (P = .02); and cyclosporine rather than OKT3 induction (P = .009). Graft survival, synthetic function, and the total number of rejection episodes during the first year were not different between the two groups. The morbidity variables of total number of days in the hospital during the first 12 months, renal function, and type and number of infections were also similar between the two groups. In summary, 5.2% of adult patients developed DM within 1 month of OLTx. Pre-existing insulin resistance, postoperative stress, and immunosuppression medications all likely contribute to the development of overt hyperglycemia after OLTx. Although PTDM can be a consequence of OLTx, it does not have a significant impact on patient outcome in the first year after OLTx.