An Aggressive Case of Cryoglobulinemia and Membranoproliferative Glomerulonephritis: A Case Report.

This case report describes a 66-year-old female with membranoproliferative glomerulonephritis (MPGN) with pulmonary involvement presumed secondary to Hepatitis C virus (HCV)-associated with mixed cryoglobulinemia. In this condition, pulmonary involvement is uncommon, and aggressive lung involvement can be associated with poor outcomes. Within eight weeks, the patient was hospitalized twice with acute pulmonary presentations and presented at a third hospitalization with dyspnea, chest pain, abdominal pain, and edema. Imaging revealed persistent and historically evolving lung consolidation, as well as a renal biopsy showing MPGN associated with mixed cryoglobulinemia. A lung biopsy revealed inflammation. Bronchoalveolar lavage did not show hemosiderin-laden macrophages and did not grow infectious agents. Serology revealed negative ANCAs and rheumatoid factor positive at 476 IU/ml (upper limit normal 14 IU/ml). Qualitative cryoglobulins were positive at 2 %ppt (reference range: negative %ppt) and Type II mixed cryoglobulinemia with IgM kappa plus polyclonal IgG. The treatment involved steroids and rituximab. The patient's clinical status deteriorated, and she elected to change her resuscitation status to comfort care measures. This case emphasizes that cryoglobulinemia can present with aggressive manifestations on a wide spectrum. Pulmonary manifestations are rare and were evident in this case (although without clear evidence of diffuse alveolar hemorrhage) and led to a complicated disease course and an unfavorable outcome. Overall, this case underscores the complexity of mixed cryoglobulinemia presentations and the challenges of managing severe cases with multi-organ involvement.

Rationale and evidence for extended infusion of piperacillin-tazobactam.

PURPOSE: The pharmacodynamics and therapeutic effects of extended-infusion (EI) piperacillin-tazobactam therapy are reviewed, with an emphasis on growing evidence of its advantages over traditional infusion schemes. SUMMARY: EI ß-lactam therapy is now considered a key aspect of antimicrobial stewardship, and published evidence indicates that i.v. infusion of piperacillin-tazobactam over extended periods (e.g., four hours) instead of the traditionally recommended 30 minutes may offer several advantages, including reduced mortality and length of hospital stay and lower treatment cost. A substantial body of evidence from in vitro and animal studies indicates that EI enhances the pharmacodynamic profile of piperacillin-tazobactam, particularly by extending the time the free drug level remains above the minimum inhibitory concentration. In one published study comparing the use of EI and traditional piperacillin-tazobactam infusion schemes in critically ill patients with Pseudomonas aeruginosa infection, EI therapy was associated with significantly improved 14-day mortality and significantly shorter hospital stays; a few other studies have yielded less favorable results. Pharmacoeconomic evaluations indicate that EI can offer significant cost benefits. However, evidence of the benefits of EI in actual clinical practice remains relatively weak, highlighting the need for large, controlled clinical trials to define its optimal role in patient care. CONCLUSION: The pharmacodynamic profile of EI piperacillin-tazobactam therapy; evidence of its benefits over traditional 30-minute infusions in terms of mortality, duration of hospitalization, clinical and microbiological cure rates, and reduction of fever; and EI's lower total treatment cost suggest that EI may be the superior mode of administration.

Prolonged neuromuscular paralysis following rapid-sequence intubation with succinylcholine.

OBJECTIVE: To report a case of severely prolonged succinylcholine-induced neuromuscular paralysis in a patient with previously undiagnosed butyrylcholinesterase deficiency. CASE SUMMARY: A 54-year-old female was admitted for surgical drainage of a groin abscess. She was given propofol 200 mg and succinylcholine 160 mg (1 mg/kg) intravenously to induce sedation and paralysis for endotracheal intubation. Thirty minutes after the 19-minute procedure, the patient showed no evidence of spontaneous recovery of respiration. She was transferred to the intensive care unit and 11 hours later was successfully weaned from the ventilator and extubated. A butyrylcholinesterase level of 552 IU/L (reference range 2673-6592) confirmed butyrylcholinesterase deficiency. Six months later, in compliance with institutional review board/human subjects research requirements, the patient returned for a dibucaine inhibition test and second butyrylcholinesterase assay; the butyrylcholinesterase level in the second assay was 789 IU/L. The dibucaine inhibition test result was 61.1% (reference range 81.6-88.3), suggesting that the adverse drug effect had a pharmacogenetic basis. Use of the Naranjo probability scale indicated a probable relationship between the prolonged neuromuscular paralysis and succinylcholine therapy in this patient. DISCUSSION: Succinylcholine remains the drug of choice to facilitate rapid-sequence endotracheal intubation during induction of anesthesia and in patients undergoing emergency procedures who are at risk for gastroesophageal regurgitation. Its short duration of action is due to rapid hydrolysis by the endogenous enzyme butyrylcholinesterase. Rarely, patients with butyrylcholinesterase deficiency may show marked sensitivity to succinylcholine, manifested clinically by severely prolonged neuromuscular paralysis and apnea. CONCLUSIONS: Butyrylcholinesterase deficiency may go undiagnosed for decades until succinylcholine is used in a surgical procedure. When it does occur, a butyrylcholinesterase level should be obtained and a dibucaine inhibition test should be conducted to test for unrecognized hereditary butyrylcholinesterase deficiency. If a pharmacogenetic basis is confirmed, the patient should receive information about the condition, implications, inheritance, and need for family testing.

Endothelial NADPH oxidase: mechanism of activation by low-density lipoprotein.

Exposure to atherogenic levels of low-density lipoprotein (LDL) causes elevated reactive oxygen species (ROS) production by human endothelial cells (ECs). NADPH oxidase is thought to be the main source of ROS generated by LDL-activated ECs. The mechanism by which this lipoprotein activates endothelial NADPH oxidase is incompletely understood. To gain further insight into the signaling pathway, the authors have examined the effects of inhibitors to various signal transducing enzymes, including the G(i)-protein coupled receptor (pertussis toxin), Src tyrosine kinase (PP1), phospholipase C-gamma (U73122), phosphatidylinositol 3-kinase (LY294002), p42/p44 mitogen-activated protein kinase (MAPK) kinase (PD98059), p38 MAPK (SB203580), protein kinase C (Ro 318220, GF 109203X, Go 6976), and cytosolic phospholipase A(2) (AACOCF3), on the ROS-producing capacity ECs activated by LDL. Exposure of cultured ECs to LDL (0.45 mg protein/mL) stimulated ROS formation, as measured using a 6-carboxy-2',7'-dichlorodihydrofluorescein diacetate assay. This effect was partially inhibited by Ro 318220, GF 109203X, U73122, and SB203580, and blocked or nearly completely inhibited by PP1, pertussis toxin, LY294002, PD98059, and AACOCF3. Only a partial, minor inhibition occurred with the protein kinase C inhibitor, Go 6976. These results are most consistent with LDL activating endothelial NADPH oxidase, predominantly through a signaling pathway that leads to cytosolic phospholipase A(2) activation.

Inhibition of NADPH oxidase activation in endothelial cells by ortho-methoxy-substituted catechols.

NADPH oxidase is a major enzymatic source of oxygen free radicals in stimulated endothelial cells (ECs). The ortho-methoxy-substituted catechol, apocynin (4-hydroxy-3-methoxyacetophenone), isolated from the traditional medicinal plant Picrorhiza kurroa, inhibits the release of superoxide anion (O2*-) by this enzyme. The compound acts by blocking the assembly of a functional NADPH oxidase complex. The underlying chemistry of this inhibitory activity, and its physiological significance to EC proliferation, have been investigated. A critical event is the reaction of ortho-methoxy-substituted catechols with reactive oxygen species (ROS) and peroxidase. Analysis of this reaction reveals that apocynin is converted to a symmetrical dimer through the formation of a 5,5' carbon-carbon bond. Both reduced glutathione and L-cysteine inhibit this dimerization process. Catechols without the ortho-methoxy-substituted group do not undergo this chemical reaction. Superoxide production by an endothelial cell-free system incubated with apocynin was nearly completely inhibited after a lagtime for inhibition of ca. 2 min. Conversely, O2*- production was nearly completely inhibited, without a lagtime, by incubation with the dimeric form of apocynin. The apocynin dimer undergoes a two-electron transfer reaction with standard redox potentials of -0.75 and -1.34 V as determined by cyclic voltammetry. Inhibition of endothelial NADPH oxidase by apocynin caused a dose-dependent inhibition of cell proliferation. These findings identify a metabolite of an ortho-methoxy-substituted catechol, which may be the active compound formed within stimulated ECs that prevents NADPH oxidase complex assembly and activation.