Ranitidine pharmacokinetics and adverse central nervous system reactions.

BACKGROUND: Treatment with histamine2-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.

Hypogammaglobulinemia in lung transplant recipients.

BACKGROUND: 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. METHODS: All lung transplant recipients followed at a single center between October 1996 and June 1999 underwent a posttransplant humoral immune status survey as part of routine posttransplant follow-up. This survey consists of total immunoglobulin levels (IgG, IgM, IgA), IgG subclasses (IgG1-4), and antibody titers to Pneumococcus, diphtheria, and tetanus. Since February 1997, this survey has been incorporated into the pretransplant evaluation as well. Humoral survey results for October 1996 through July 1999 were recorded, and clinical information on major infectious disease outcomes was obtained from chart reviews, discharge summaries, the Cleveland Clinic Unified Transplant Database, and review of all microbiological studies and pathology results for each patient. RESULTS: Of 67 patients with humoral immune surveys drawn posttransplant, 47 (70%) had IgG levels less than 600 mg/dl (normal 717-1410 mg/dl), of which 25 (37%) had IgG levels less than 400 mg/dl ("lowest IgG group") and 22 (33%) had IgG levels between 400 and 600 mg/dl ("moderately low IgG group"). A total of 20 patients (30%) had IgG levels of more than 600 mg/dl ("normal IgG group"). Infections that were significantly more common in the lowest IgG group, and more common in the moderately low IgG group than the normal IgG group, included: number of pneumonias (P=0.0006), bacteremias (P=0.02), total bacterial infections (P=0.002), tissue-invasive cytomegalovirus (P=0.01), invasive aspergillosis (P=0.001), total fungal infections (P=0.001), and total infections (P=0.006). Median hospital days per posttransplant year was significantly different in the three groups (11.0 vs. 7.4 vs. 2.8 days, P=0.0003.) Invasive aspergillosis occurred in 44% of the lowest IgG group, 9% of the moderately low IgG group, and 0% of the normal IgG group (P<0.001). Survival was poorest in the lowest IgG group and intermediate in the moderately low IgG group. IgG subclass deficiencies occurred in a variety of patterns. Hypogammaglobulinemic patients lacked protective responses to Pneumococcus in 14/47 (30%), diphtheria in 15%, and tetanus in 19%. In a group of 48 patients screened pretransplant, 90% had normal immunoglobulin levels. CONCLUSIONS: Hypogammaglobulinemia in lung transplant recipients is more common than has been previously recognized. An IgG level of less than 400 mg/dl identifies a group at extremely high risk of bacterial and fungal infections, tissue-invasive cytomegalovirus, and poorer survival. Immunoglobulin monitoring may offer an opportunity for intensive surveillance, tapering of immunosuppression, and preemptive therapy for infection.

Does the donor-recipient ABO blood group compatibility status predict subsequent lung transplantation outcomes?

BACKGROUND: The study was conducted to compare lung transplantation outcomes between ABO-identical (AI) and ABO-compatible (AC) recipients. METHODS: Charts of lung allograft recipients transplanted between February, 1990 and October, 1995 were reviewed. Standard triple-drug immunosuppression and general antimicrobial prophylaxis were provided. Surveillance spirometry was administered every three months. Flexible bronchoscopy (FB) with transbronchial biopsies (TBBs) were undertaken for clinical indications. Time to event analysis on acute (AR) and chronic (CR) rejection and actuarial survival were determined by Kaplan-Meier analysis. Cumulative curves were compared with a log rank test. Comparisons of age, maximum forced expiratory volume in one second (FEV1) in the single (SLT) and double (DLT) lung recipients, duration of intensive care unit and hospital stay were carried out using the Wilcoxon Rank Sum test. Gender, race, underlying diagnoses, cytomegalovirus (CMV) status and pulmonary reimplantation response (PRR) were compared by Chi-square or Fisher's exact test where appropriate. RESULTS: Of the 100 lung recipients (age = 42.5 +/- 13.4 years; M:F = 50:50), 64 were AI and 36 AC. Median follow-up was 22 (range = 0-78) months. Outcome did not differ significantly between the 2 groups in terms of intensive care unit and hospital stay, PRR incidence and grade, incidence and frequencies of AR, median time and grade of first AR, maximum FEV1 for SLT and DLT recipients, incidence of CR and survival at 12 months. CONCLUSIONS: As the donor supply remains limited, this could considerably simplify the logistics of future transplantation.

Central nervous system complications after lung transplantation.

PURPOSE: This study describes the central nervous system (CNS) events after lung transplantation. METHODS: A chart review of all lung transplant recipients (LTR) to collect the clinical and neuroimaging data for CNS events defined as seizures, severe headaches, confusion, or stroke. RESULTS: Twenty-six patients of 100 LTRs from 1990 through 1995 had a CNS event; more than one event occurred in 5 patients for a total of 32 events. Severe headache was most common, occurring in 14 patients, followed by seizures in 10, stroke in 5, and confusion in 3. The CNS event was related to infection in three of the 26 patients. Of all evaluations performed, magnetic resonance imaging (MRI) identified the most abnormalities, the most common being white matter changes consistent with cyclosporine toxicity. Cyclosporine levels were elevated in slightly more than half of the patients. Hypomagnesemia was present in three of 10 patients with seizures. Prognosis for recovery from these complications was good, with only five patients having ongoing problems with headaches, one requiring long term anticonvulsant therapy, three having minor or no limitations from stroke and no long-term problems with confusion. One patient with seizures resulting from an aspergilloma died. CONCLUSION: CNS events occur commonly in LTRs, mostly related to cyclosporine toxicity or infection. MRI identifies more abnormalities than computed tomography. These events were not consistently associated with documented high cyclosporine levels and hypomagnesemia. In spite of significantly abnormal MRIs, the functional outcome is favorable.

Intravenous azithromycin-induced ototoxicity.

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.

Cystic fibrosis patients with and without central nervous system complications following lung transplantation.

Central nervous system (CNS) complications occur more frequently in cystic fibrosis (CF) patients than other lung transplant recipients. The purpose of this study was to compare CF patients with and without CNS complications following lung transplantation, to identify risk factors for CNS events. Records of 21 patients with CF who underwent lung transplant between 1991-1996 were reviewed. Data were collected on multiple variables, including: age at transplant; gender; cytomegalovirus (CMV) status; cholesterol and triglyceride levels; sinusitis; percent ideal body weight (IBW); body mass index (BMI); augmented immunosuppression, acute lung rejection episodes (ALR); cyclosporine doses; electrolytes; magnesium, blood urea nitrogen (BUN), and creatinine levels; and 6-month survival. CNS complications identified were seizures, severe headaches (HA), strokes, or confusional episodes. Eleven of 21 patients (52%) with CF had CNS events: eight had seizures, five HA, three strokes, and one confusional episode. There was no difference in age at transplant, pretransplant percent IBW or BMI, cholesterol and triglyceride levels, or number of ALR. CMV mismatch and clinical sinusitis had no effect. Cyclosporine doses did not differ between groups at 30 days, or 3 or 6 months posttransplant. Both BUN and creatinine concentrations showed a rise over time that did not differ between groups. Potassium levels were within normal limits for both groups. While sodium levels did not differ between groups pretransplant, or at 30 days or 6 months posttransplant, a decrease in sodium values was seen at the time of CNS events. There was no difference in 6-month survival. We could not identify any pre- or posttransplant risk factors that predicted CNS events. It is likely that cyclosporine toxicity is the major cause of CNS complications. Despite the high rate of CNS events, the overall prognosis was good, and 6-month survival was not affected.

Total parenteral nutrition by a nutrition support team: improved quality of care.

Most of the studies that have examined the effect of nutrition support teams (NST) on the quality of total parenteral nutrition (TPN) have found reductions in the frequency of metabolic and central venous catheter related complications. Previous studies have not examined the patterns of nutrient delivery (eg, calories and protein) when TPN is provided either by a primary physician or by a NST. We compared the quality of TPN care provided by our NST or by primary physicians utilizing nonspecialized hospital personnel and resources. As expected, catheter complications were significantly less frequent in NST patients. Assessment of nutritional status and nutrient requirements as well as nitrogen balance were performed and documented significantly more often in NST patients. In addition, nutritional goals for calories and protein were achieved and positive nitrogen balance documented more often in NST patients. The need to consult the NST physician to utilize the NST was not well received by primary attending and resident physicians and resulted in nonuse of the team. In the future, modification of NST policies will be explored to encourage greater utilization of the NST without compromising the high standard of nutrition care delivered by the NST.

Reduction of diazepam serum half life and reversal of coma by activated charcoal in a patient with severe liver disease.

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 (t1/2) of diazepam was reduced from 195 to 18 hours during charcoal administration. We postulate that higher free (unbound) diazepam concentrations secondary to hypoalbuminemia, occurring 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.

Insulin antibodies and hypoglycemia in diabetic patients. Can a quantitative analysis of antibody binding predict the risk of hypoglycemia?

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 insulin-treated 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 x 10(-9) mol/L; binding capacity, 0.6-659 mU/L) and low-affinity with high capacity (Kd, 0.3 to 35.7 x 10(-7) mol/L; binding capacity; 202-113,680 mU/L). One NIDDM patient had only high-affinity antibodies (Kd, 22.9 x 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 afford 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.

The incidence of invasive aspergillosis among solid organ transplant recipients and implications for prophylaxis in lung transplants.

BACKGROUND: Invasive aspergillosis (IA) is associated with significant morbidity and mortality in solid organ transplant recipients but data on the incidence rates stratified by type of solid organ are limited. OBJECTIVE: To describe the attack rates and incidence of IA in solid organ transplant recipients, and the impact of universal Aspergillus prophylaxis (aerosolized amphotericin B or oral itraconazole) in lung transplant recipients. PATIENTS: The 2,046 patients who received solid organ transplants at the Cleveland Clinic Foundation from January 1990 through 1999 were studied. METHODS: Cases were ascertained through computerized records of microbiology, cytology, and pathology reports. Definite IA was defined as a positive culture and pathology showing septate hyphae. Probable IA was clinical disease and either a positive culture or histopathology. Disseminated IA was defined as involvement of two or more noncontiguous anatomic sites. RESULTS: We identified 33 cases of IA (28% disseminated) in 2,046 patients (attack rate = 1.6%) for an incidence of 4.8 cases per 1,000 patient-years (33 cases/6,813 pt-years). Both the attack and the incidence rates were significantly higher for lung transplant recipients vs. other transplant recipients: lung 12.8% (24 cases/188 patients) or 40.5 cases/1,000-pt year vs. heart 0.4% (3/686) or 1.4 per 1,000-pt year vs. liver 0.7% (3/439) or 2.1 per 1,000-pt year vs. renal 0.4% (3/733) or 1.2 per 1,000-pt year (P < 0.01). The incidence of IA was highest during the first year after transplantation for all categories, but cases occurred after the first year of transplantation only in lung transplant recipients. The attack rate of IA in lung transplant recipients was significantly lower after institution of routine Aspergillus prophylaxis (4.9% vs. 18.2%, P < 0.05). CONCLUSIONS: The highest incidence and attack rate of invasive aspergillosis among solid organ transplant recipients occurs in lung transplant recipients and supports the routine use of Aspergillus prophylaxis for at least one year after transplantation in this group.