Stuart D. Saal

Accumulation of Normeperidine, an Active Metabolite of Meperidine, in Patients with Renal Failure or Cancer

Concentrations of meperidine and its active metabolite, normeperidine, were measured in plasma of patients receiving the drug for analgesia. Meperidine levels in cancer patients were 0.10 to 0.55 microng/ml 1 h after a dose and were 0.05 to 0.14 in patients in the oliguric period after renal transplantation. Normeperidine levels were 0.05 to 0.28 microng/ml in the cancer patients and 0.13 to 0.36 in the renal failure patients. The ratio of normeperidine to meperidine levels was always higher in the renal failure patients than in the cancer patients. Additionally, two patients receiving multiple doses of meperidine had high normeperidine levels and very high normeperidine/meperidine ratios when they showed signs of central nervous system excitation. These data indicate that normeperidine can contribute to the excitatory effects seen after multiple doses of meperidine and suggest that patients with renal failure are particularly susceptible to this problem.

Low lipid concentrations in critical illness : Implications for preventing and treating endotoxemia

OBJECTIVES To determine the prevalence and clinical significance of hypolipidemia found in critically ill patients, and whether the addition of a reconstituted lipoprotein preparation could inhibit the generation of tumor necrosis factor-alpha (TNF-alpha) in acute-phase blood taken from these patients. SETTING Surgical intensive care unit (ICU) of a large urban university hospital. DESIGN Prospective case series. PATIENTS A total of 32 patients with a variety of critical illnesses had lipid and lipoprotein concentrations determined. Six patients and six age- and gender-matched control subjects had whole blood in vitro studies of the effect of lipoprotein on lipopolysaccharide mediated TNF-alpha production. INTERVENTIONS Blood samples were drawn on admission to the ICU and over a subsequent 8-day period. MEASUREMENTS AND MAIN RESULTS Mean serum lipid and lipoprotein values obtained from patients within 24 hrs of transfer to the surgical ICU were extremely low: mean total cholesterol was 117 mg/dL (3.03 mmol/L), low-density lipoprotein cholesterol 71 mg/dL (1.84 mmol/L), and high-density lipoprotein cholesterol 25 mg/dL (0.65 mmol/L). Only the mean triglyceride concentration of 105 mg/dL (1.19 mmol/L), and the mean lipoprotein(a) concentration of 25 mg/dL (0.25 g/L) were within the normal range. During the first 8 days following surgical ICU admission, there were trends toward increasing lipid and lipoprotein concentrations that were significant for triglycerides and apolipoprotein B. Survival did not correlate with the lipid or lipoprotein concentrations, but patients with infections had significantly lower (p = .008) high-density lipoprotein cholesterol concentrations compared with noninfected patients. Lipopolysaccharide-stimulated production of TNF-alpha in patient and control blood samples was completely suppressed by the addition of 2 mg/mL of a reconstituted high-density lipoprotein preparation. CONCLUSIONS Patients who are critically ill from a variety of causes have extremely low cholesterol and lipoprotein concentrations. Correction of the hypolipidemia by a reconstituted high-density lipoprotein preparation offers a new strategy for the prevention and treatment of endotoxemia.

Relationship of hypolipidemia to cytokine concentrations and outcomes in critically ill surgical patients.

ObjectiveTo determine the relationship of hypolipidemia to cytokine concentrations and clinical outcomes in critically ill surgical patients. DesignConsecutive, prospective case series. SettingSurgical intensive care unit of an urban university hospital. PatientsSubjects were 111 patients with a variety of critical illnesses, for whom serum lipid, lipoprotein, and cytokine concentrations were determined within 24 hrs of admission to a surgical intensive care unit. Controls were 32 healthy men and women for whom serum lipid, lipoprotein, and cytokine concentrations were determined. InterventionsBlood samples were drawn on admission to the intensive care unit. Predetermined clinical outcomes including death, infection subsequent to intensive care unit admission, length of intensive care unit stay, and magnitude of organ dysfunction were monitored prospectively. Measurements and Main Results Measurements included total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, apolipoproteins A-I and B, phospholipid, triglyceride, interleukin-6, interleukin-10, soluble interleukin-2 receptor, tumor necrosis factor-&agr;, and soluble tumor necrosis factor receptors p55 and p75. Mean serum lipid concentrations were extremely low: total cholesterol, 127 ± 52 mg/dL; low-density lipoprotein cholesterol, 75 ± 41 mg/dL; high-density lipoprotein cholesterol, 29 ± 15 mg/dL. Total, low-density lipoprotein, and high-density lipoprotein cholesterol concentrations and apolipoprotein concentrations inversely correlated with interleukin-6, soluble interleukin-2 receptor, and interleukin-10 concentrations, whereas the triglyceride concentration correlated positively with tumor necrosis factor soluble receptors p55 and p75. Clinical outcomes were related to whether the admission cholesterol concentration was above (n = 56) or below (n = 55) the median concentration of 120 mg/dL. Each of the clinical end points occurred between 1.9- and 3.5-fold more frequently in the very low cholesterol (<120 mg/dL) group. Nine patients (8%) died during the hospitalization. Seven of the nine patients who died had total cholesterol concentrations below the median concentration of 120 mg/dL. ConclusionsLow cholesterol and lipoprotein concentrations found in critically ill surgical patients correlate with interleukin-6, soluble interleukin-2 receptor, and interleukin-10 concentrations and predict clinical outcomes.

Long-term effects of low-density lipoprotein apheresis using an automated dextran sulfate cellulose adsorption system

Abstract The short-term effectiveness of low-density lipoprotein (LDL) apheresis using a dextran sulfate cellulose adsorption column technique was previously examined in a 9- center, 22-week controlled trial in 64 patients with familial hypercholesterolemia (FH) who did not adequately respond to diet and drug therapy. Forty-nine patients (40 treatment, 9 controls) subsequently received LDL apheresis procedures as part of an optional follow-up phase. This study reports on the long-term safety, lipid lowering, and clinical efficacy of LDL apheresis for the 5-year period that includes both the initial controlled study and follow-up phase. During this time, patients received a total of 3,902 treatments of which 3,314 treatments were given during the follow-up phase. Adverse events were infrequent, occurring in 142 procedures (3.6%). Immediate reduction in LDL cholesterol was 76% both in homozygotes and in heterozygotes. Patients with homozygous FH had a progressive decrease in pretreatment LDL cholesterol level along with an increase in high-density lipoprotein (HDL) cholesterol level. There was no appreciable change in pretreatment lipoprotein level over time in heterozygotes. The rate of cardiovascular events during therapy with LDL apheresis and lipid-lowering drugs was 3.5 events per 1,000 patient-months of treatment compared with 6.3 events per 1,000 patient-months for the 5 years before LDL apheresis therapy. These findings support the long-term safety and clinical efficacy of LDL apheresis in patients with heterozygous and homozygous FH who are inadequately controlled with drug therapy.

Removal of low-density lipoproteins in patients by extracorporeal immunoadsorption.

A new technique called LDL-pheresis was used in patients to lower low-density lipoprotein cholesterol levels. This procedure combines continuous extracorporeal plasma separation with immunoadsorption of low-density lipoprotein on columns containing monospecific antibody to human apolipoprotein B. Six patients underwent a total of 164 procedures without significant side effects or nonspecific protein depletion. Acutely, LDL-pheresis lowered plasma cholesterol levels by removing up to 82 percent of the circulating low-density lipoprotein. Weekly LDL-pheresis combined with a portacaval shunt in a patient with homozygous familial hypercholesterolemia resulted in normalization of plasma cholesterol levels and rapid regression of skin xanthomata. Three of four patients with atherosclerotic coronary artery disease have noted improvement in their angina. LDL-pheresis appears to be a promising new technique capable of safely and efficiently lowering plasma low-density lipoprotein cholesterol levels.

Pruritus in Dialysis Patients Treated with Parenteral Lidocaine

Pruritus is one of the most disturbing and poorly understood symptoms in patients on chronic hemodialysis,1 2 3 4 its reported prevalence varying from 15 to 86 per cent. Except for a few case repor...

Reversible “end-stage” lupus nephritis: Analysis of patients able to discontinue dialysis

Seventeen of 41 patients with lupus nephritis who underwent dialysis for renal failure recovered renal function and discontinued dialysis. Two of these 17 had confounding factors unrelated to lupus that contributed to renal dysfunction (one meningococcemia, one vigorous diuresis). Indications for dialysis were identical both in patients who discontinued dialysis (short-term) and in those who did not (long-term). The rate of progression to dialysis, measured as the slope of the reciprocal of the serum creatinine level versus time, was significantly more rapid in the short-term group (p less than 0.001). Patients who underwent short-term dialysis were more likely to have had lupus for less than two years (p = 0.015). Anti-DNA antibody binding values, total hemolytic complement levels, extent of extrarenal disease, and hypertension did not differentiate the short-term from long-term dialysis groups. Renal biopsy performed within three months of first dialysis did not demonstrate a consistent picture in the short-term dialysis group. Dialysis is not equivalent to irrevocable end-stage renal disease in patients with lupus nephritis. Thirteen of 22 patients (59 percent) with a 10 percent reduction time for renal function of less than three weeks were able to discontinue dialysis. Ten of these 13 were alive without need for dialysis six months later, with a mean follow-up serum creatinine level of 2.9 +/- 1.9 mg/dl.

Deceased-donor kidney transplantation: improvement in long-term survival

BACKGROUND Despite marked improvement in short-term renal allograft survival rates (GSR) in recent years, improvement in long-term GSR remained elusive. METHODS We analysed the kidney transplant experience at our centre accrued over four decades to evaluate how short-term and long-term GSR had changed and to identify risk factors affecting graft survival. The study included 1476 adult recipients of a deceased-donor kidney transplant who were transplanted between 1963 and 2006 and who had received one of five distinct immunosuppressive protocols. RESULTS Five-year actual GSR steadily improved over the years as immunosuppressive therapy evolved (22-86%, P < 0.001) in spite of an increasing trend in the transplantation of higher-risk donor-recipient pairings. For those whose grafts functioned for the first year, subsequent 4-year GSR (5-year conditional GSR) also improved significantly (63-92%, P < 0.001). Acute rejection and delayed graft function (DGF) were the most significant risk factors for actual graft survival, while acute rejection was the only significant risk factor for conditional GSR. Use of kidneys from expanded-criteria donors (ECD) was not a risk factor, compared to the use of standard-criteria donor kidneys for either 5-year actual or conditional GSR. There was an impressive decline in the incidence of acute rejection events (77.4-5.8%, P < 0.001). While the DGF rate had decreased, it still remained high (68.7-38.5%, P < 0.001). CONCLUSIONS We found a significant improvement in both short-term and long-term GSR of deceased-donor kidney transplants over the last four decades. These improvements are most likely related to the decreased incidence of acute rejection episodes. Minimizing acute rejection events and preventing DGF could result in further improvement in the GSR. Our experience in the judicious use of ECD kidneys suggests that this source of kidneys could be expanded further.

Advances in LDL-apheresis for the treatment of severe hypercholesterolemia.

LDL-apheresis is an extracorporeal plasma-perfusion method that selectively removes apolipoprotein B-containing lipoproteins from the blood. It is indicated for patients with homozygous and drug-resistant heterozygous familial hypercholesterolemia. Clinical and angiographic regression of coronary artery disease has been demonstrated in patients treated with cholesterol-lowering programs that include LDL-apheresis.

Current status of low density lipoprotein-apheresis for the therapy of severe hyperlipidemia.

The use of LDL-apheresis to treat patients with severe hypercholesterolemia has gained wider clinical acceptance during the past 2-3 years, particularly in patients with coronary artery disease. Systems utilizing immunoadsorption columns, dextran sulfate cellulose columns and heparin precipitation have been most commonly employed. New or improved technologies include whole-blood compatible columns, double-filtration plasmapheresis and lipoprotein (a)-apheresis. The mechanisms for clinical improvement extend beyond simple regression of atherosclerotic plaque.