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Background Although antibody-mediated rejection (AMR) is described in other solid organ transplant populations, the literature describing the management following lung transplantation is limited.Objective The purpose of this study is to evaluate the management strategies of AMR in lung transplant recipients.Methods This single-center, retrospective study described the management of AMR in adult lung transplant recipients who received treatment with rabbit antithymocyte globulin, bortezomib, rituximab, intravenous immune globulin (IVIG), and/or plasmapheresis between September 2015 and June 2019.Results A total of 270 medication orders for 55 patient admissions were included in the primary outcome analysis. The most commonly used regimen consisted of IVIG, plasmapheresis, and rituximab (49.1%; n = 27), followed by IVIG and plasmapheresis alone (27.3%, n = 15). A total of 51 patients (93%) received plasmapheresis as part of their AMR treatment, with a median of 4 [3, 5] sessions per encounter; 86% of patients with positive donor-specific antibodies (DSAs) had a reduction in DSAs following AMR treatment. Overall, 23.5% of patients had noted allograft failure or need for retransplantation. A total of 10 patients died during the AMR treatment hospital admission, and an additional 11 patients died within 1 year of the initial encounter.Conclusion and Relevance This represents the largest report describing management strategies of AMR in lung transplant recipients. Although practice varied, the most commonly used regimen consisted of plasmapheresis, IVIG, and rituximab.

Background--Treatment with [histamine.sub.2]-receptor antagonists has been associated with adverse central nervous system reactions (CNS-ADRs). Previous studies of cimetidine have shown an association between CNS-ADRs and high cimetidine drug levels. While case reports of ranitidine CNS-ADRs have appeared, we wanted to study a series of patients, some of whom were critically ill, for the presence of CNS-ADRs and to correlate these with ranitidine pharmacokinetics. Methods.--A prospective, observational, open study included 163 consecutive patients, of whom 41 met entry criteria. A nonlinear least-squares regression analysis was used to establish a ranitidine pharmacokinetic dosing model. Ranitidine levels were determined by a high-performance liquid chromatographic assay. Individual ranitidine pharmacokinetics were determined by means of a bayesian model. Observations on 13 possible CNS-ADRs were recorded. The CNS-ADRs were evaluated by the Naranjo rating system. Results.--Ranitidine-associated CNS-ADRs, particularly lethargy, confusion, somnolence, and disorientation, occurred more frequently in patients with renal function impairment, and these were associated with higher peak concentrations, average plasma concentrations, and area under the curve. Conclusions.--Ranitidine, when given in conventional doses, can cause CNS-ADRs, particularly in older patients who have substantial renal function impairment. These CNS-ADRs occur as a consequence of altered ranitidine disposition. Ranitidine doses should be reduced when renal function impairment is present, and patients should be carefully observed for CNS-ADRs. (Arch Intern Med. 1992;152:2325-2329)

Using a rat model of laryngeal transplantation, we sought to define the relationships between acute laryngeal rejection grade (RG) and cyclosporin A (CSA) concentration and CSA dosage. Five recipient Lewis rat groups (N = 10 per group) were administered intramuscular CSA doses of 1.0 (group 1), 2.5 (group 2), 5.0 (group 3), 7.5 (group 4), and 10 mg/kg per day (group 5) for 14 days. Immediately before sacrifice, 5 mL of whole blood was obtained to assay CSA trough levels by high-performance liquid chromatography. The specimens were graded microscopically by blinded reviewers by day of RG, 0 to 14 days after transplantation, as described in earlier reports. Despite high intragroup variability in CSA levels, significantly different mean CSA concentrations were achieved among all CSA dosage groups: 1,2,3,4, and 5 (.0001 < p < .02). The mean laryngeal RGs did not test significantly different from each other with groups 3, 4, and 5 (RG, 2.3 ± 1.3 versus 1.9 ± 1.1 versus 1.7 ±0.3, respectively, .2 < p < .6). The RG for group 1 was significantly greater than those for groups 2 through 5 (p < .001), and the group 2 RG was greater (p < .02) than those for groups 3, 4, and 5. Polynomial fitting was used to determine the continuous relationship between each individual specimen's CSA concentration and the RG. Significant pathological allograft rejection correlated with CSA concentrations below 250 ng/mL.

Adding oral prednisone or in vitro organ irradiation to an immunosuppressive regimen for laryngeal transplantation may allow cyclosporine dosage to be decreased without compromising organ rejection rates. Using an established rat laryngeal transplant model, we sought to determine whether combined immunosuppressive regimens decreased rejection rates. Twenty-two treatment groups of 10 animals each were studied. Cyclosporine was administered at 2 different historically low dosages (1.5 and 2 mg/kg per day) alone, in combination with prednisone, and with in vitro irradiation of the harvested larynx. At 15 days after transplantation, cyclosporine combined with prednisone did not significantly alter the mean severity of rejection. At 30 days after transplantation, rats treated with a combination of cyclosporine 2 mg/kg and prednisone 1 mg/kg showed the least amount of rejection. Rejection rates were significantly higher with 2 mg/kg cyclosporine alone (p < .00024). Irradiation did not significantly decrease the severity of rejection. These results demonstrate that at 1 month after transplantation, a combined steroid and cyclosporine regimen reduces the severity of rejection after laryngeal transplantation in an animal model. Our findings suggest that laryngeal transplant patients may be treated with low cyclosporine doses without experiencing organ rejection if steroids are added to the immunosuppressive regimen.

Infectious complications continue to represent a significant source of morbidity and mortality in lung transplant recipients.Identifying specific, remediable immune defects is of potential value. After one lung transplant patient with recurrent infections was noted to be severely hypogammaglobulinemic, a screening program for humoral immune defects was instituted. The objectives were to define the prevalence of hypogammaglobulinemia in lung transplant recipients, assess levels of antibody to specific pathogens, and correlate infectious disease outcomes and survival with immunoglobulin levels.

Intravenous azithromycin is increasingly administered for treatment of hospitalized patients with community‐acquired pneumonia. Macrolide antibiotics cause ototoxicity, which occurs most frequently when high serum concentrations are achieved. Current dosing guidelines for intravenous azithromycin can result in much higher serum concentrations than is seen with oral administration. We describe a 47‐year‐old woman who developed complete deafness after receiving 8 days of intravenous azithromycin.

In response to the letter by McIsaac regarding our study of ranitidine-associated central nervous system adverse drug reactions (CNS-ADRs),1 first of all, it is important to focus on the questions and issues examined by our studies dealing with complex problems in patients hospitalized in an intensive care unit, as contrasted with the use of ranitidine in an outpatient setting in otherwise healthy patients. It is clear that ranitidine is associated with CNS-ADRs.2 In contrast to their data on file concerning general use of ranitidine, our study, in addition, documents a much higher incidence of CNS-ADRs while patients are receiving ranitidine and are hospitalized in an intensive care unit, and further, that the occurrence is related to the level of renal function.This was a clinical study, of known high-risk patients in whom we evaluated and carefully documented CNS-ADRs. An estimate of patient numbers necessary for valid statistical evaluation

Abstract: We report a noninsulin-dependent diabetes mellitus (NIDDM) patient with spontaneous, severe hypoglycemic reactions and the presence of insulin antibodies. He had a remote antecedent history of beef-pork insulin therapy as well as exposure to hydralazine. Detailed insulin binding kinetic studies were performed in this patient as well as in six other insulintreated diabetic patients with anti-insulin antibodies (three with and three without an obvious cause of hypoglycemia). Sera from the current patient and five of the six other diabetic patients (one NIDDM, four IDDM) revealed two types of binding sites: high-affinity with low capacity (Kd′, 0.4–12.4×10−9 mol/L; binding capacity, 0.6–659 mU/L) and low-affinity with high capacity (K d′, 0.3 to 35.7×10−7 mol/L; binding capacity; 202–113,680 mU/L). One NIDDM patient had only high-affinity antibodies (K d′ 22.9 ×10−9 mol/L; binding capacity of 78 mU/L). Type of diabetes mellitus, insulin antibody titers or their binding capacities, insulin levels (total, bound, or free), and bioavailable insulin were not related to hypoglycemic reactions. Two calculated values by the method described tended to discriminate patients with and without hypoglycemia. The calculated amount of low-affinity antibody bound insulin ranged from 69.4–2090 mU/L vs <4–70.6 mU/L in patients with and without hypoglycemia, respectively. The best discrimination was afforded by the percent saturation of low-affinity binding sites; values were clearly higher in the patients with hypoglycemia (2.5–34.4 %) than in those without hypoglycemia (not detectable, 0.06, 0.15 %). Consideration of the possible drug-associated insulin antibody formation in insulin-treated diabetics and the novel quantitative analysis of the antibody binding kinetics should prove, helpful in evaluating patients with high insulin antibody titers and assessing the risk of hypoglycemia.

We report a case of prolonged coma (7 days) which arose as a complication of the treatment of alcohol withdrawal seizures and delirium with intravenous phenobarbital and diazepam. In an attempt to enhance the elimination of diazepam and its active metabolites, as well as phenobarbital, 40 grams activated charcoal was given every 4 hours (6 doses). Coma was completely reversed within 12 hours; serum half life (tl/2) of diazepam was reduced from 195 to 18 hours during charcoal administration. We postulate that higher free (unbound) diazepam concentrations secondary to hypoalbuminemia, occuring as a result of liver disease, may have increased the depth of our patient's coma, but paradoxically, by making more drug available for diffusion across the gastrointestinal membrane barrier, may have enhanced the ability of activated charcoal to adsorb diazepam and, therefore, decrease its t1/2.