Best-practice IgM- and IgA-enriched immunoglobulin use in patients with sepsis

Background: Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Despite treatment being in line with current guidelines, mortality remains high in those with septic shock. Intravenous immunoglobulins represent a promising therapy to modulate both the pro- and anti-inflammatory processes and can contribute to the elimination of pathogens. In this context, there is evidence of the benefits of immunoglobulin M (IgM)- and immunoglobulin A (IgA)-enriched immunoglobulin therapy for sepsis. This manuscript aims to summarize current relevant data to provide expert opinions on best practice for the use of an IgM- and IgA-enriched immunoglobulin (Pentaglobin) in adult patients with sepsis. Main text: Sepsis patients with hyperinflammation and patients with immunosuppression may benefit most from treatment with IgM- and IgA-enriched immunoglobulin (Pentaglobin). Patients with hyperinflammation present with phenotypes that manifest throughout the body, whilst the clinical characteristics of immunosuppression are less clear. Potential biomarkers for hyperinflammation include elevated procalcitonin, interleukin-6, endotoxin activity and C-reactive protein, although thresholds for these are not well-defined. Convenient biomarkers for identifying patients in a stage of immune-paralysis are still matter of debate, though human leukocyte antigen–antigen D related expression on monocytes, lymphocyte count and viral reactivation have been proposed. The timing of treatment is potentially more critical for treatment efficacy in patients with hyperinflammation compared with patients who are in an immunosuppressed stage. Due to the lack of evidence, definitive dosage recommendations for either population cannot be made, though we suggest that patients with hyperinflammation should receive an initial bolus at a rate of up to 0.6 mL (30 mg)/kg/h for 6 h followed by a continuous maintenance rate of 0.2 mL (10 mg)/kg/hour for ≥ 72 h (total dose ≥ 0.9 g/kg). For immunosuppressed patients, dosage is more conservative (0.2 mL [10 mg]/kg/h) for ≥ 72 h, without an initial bolus (total dose ≥ 0.72 g/kg). Conclusions: Two distinct populations that may benefit most from Pentaglobin therapy are described in this review. However, further clinical evidence is required to strengthen support for the recommendations given here regarding timing, duration and dosage of treatment

Insulin adsorption to catheter materials used for intensive insulin therapy in critically ill patients: Polyethylene versus polyurethane - possible cause of variation in glucose control?

Introduction: Restoring and maintaining normoglycemia by intensified insulin therapy in critically ill patients is a matter of ongoing debate since the risk of hypoglycemia may outweigh positive effects on morbidity and mortality. In this context, adsorption of insulin to different catheter materials may contribute to instability of glucose control. We studied the adsorption of insulin to different tubing materials in vitro and the effects on glycemic control in vivo. Materials and Methods: In vitro experiments: A syringe pump was filled with 50 IU insulin diluted to 50 ml saline. A flow of 2 ml/h was perfused through polyethylene (PET) or polyurethane (PUR) tubing. Insulin concentrations were measured at the end of the tube for 24 hours using Bradford's protein assay. In vivo study: In a randomized double-blinded cross-over design, 10 intensive care patients received insulin via PET and PUR tubes for 24 hours each, targeting blood glucose levels of 80-150 mg/dl. We measured blood glucose levels, the insulin dose required to maintain target levels, and serum insulin and C-peptide levels. Results: In vitro experiments: After the start of the insulin infusion, only 20% (median, IQR 20-27) (PET) and 22% (IQR 16-27) (PUR) of the prepared insulin concentration were measured at the end of the 2 meter tubing. Using PET, after one hour infusion the concentration increased to 34% (IQR 29-36) and did not increase significantly during the next 24 hours (39% (IQR 39-40)). Using PUR, higher concentrations were detected than for PET at every measurement from 1 hour (82% (IQR 70-86)) to 24 hours (79% (IQR 64-87)). In vivo study: Glycemic control was effective and not different between groups. Significantly higher volumes of insulin solution had to be infused with PET compared to PUR (median PET 70.0 (IQR 56-82) ml vs. PUR 42 (IQR 31-63) ml; p=0.0015). Serum insulin concentrations did not decrease significantly one hour after changing to PET or PUR tubing. Conclusion: Polyurethane tubing systems allow application of insulin with significantly lower adsorption rates than polyethylene tubing systems. As a consequence, less insulin solution has to be infused to patients for effective blood glucose control. Tubing material of the insulin infusion may be crucial for safe and effective glycemic control in critically ill patients

Recurrent early filter clotting during continuous veno-venous hemodialysis with regional citrate anticoagulation is linked to systemic thrombin generation and heparin induced thrombocytopenia type II: a retrospective analysis

OBJECTIVE: Regional citrate anticoagulation (RCA) for continuous renal replacement therapy (CRRT) is widely used and leads to an excellent clottingfree filter survival. Despite strict adherence to protocols, in some cases recurrent early filter-clotting occurs. The aim of this observational study was to evaluate the underlying causes and the efficacy of interventions in patients with early recurrent filter-clotting during RCA. METHODS: In a retrospective analysis of a cohort of 1183 patients treated with RCA-CRRT we detected 12 patients with early filter-clotting unrelated to protocol violation or any obvious technical or medical reason. RESULTS: All patients were systemically anticoagulated with low molecular weight or unfractionated heparin for at least 24h before initiation of Continuous Veno-Venous Hemodialysis with RCA (RCA-CVVHD). During RCA, all postfilter ionized calcium concentrations were in the target range (mean 0.33±0.05 mmol/L). At the time of the first clotting event, thrombocyte counts were 168±66/ nL. After the clotting events, the systemic anticoagulation was switched to argatroban in all patients. With systemic anticoagulation using argatroban filter lifetime of RCA-CVVHD increased significantly (p<0.001) and clotting-events decreased from 0.61 to 0.10 per 24h. All patients were tested for HIT and 5/12 (42%) had a positive test for hep-PF4-antibodies. Application of argatroban significantly reduced early filter-clotting both in HIT-positive patients as well as in HIT-negative patients. At the time of the first clotting event, no patient had clinical signs of thrombosis or thromboembolism. However, during follow up a thromboembolic event occurred in three patients. CONCLUSION: In patients with recurrent early filter-clotting despite strict adherence to the citrate protocol undetected HIT or other causes of thrombin activation may be present. Therefore, patients with recurrent early filter clotting in RCA-CVVHD should be screened for HIT or other conditions that may activate thrombin. A significant improvement of filter run-time can be achieved by systemic administration of a thrombin inhibitor both in patients with and without HIT

The DOse REsponse Multicentre International Collaborative Initiative (DO‐RE‐MI)

Contrib Nephrol. 2007;156:434-43. The DOse REsponse Multicentre International Collaborative Initiative (DO-RE-MI). Monti G, Herrera M, Kindgen-Milles D, Marinho A, Cruz D, Mariano F, Gigliola G, Moretti E, Alessandri E, Robert R, Ronco C; Dose Response Multicentre International Collaborative Initiative Scientific Committee. Department of Anesthesiology and Intensive Care, Hospital Niguarda, Milan, Italy, and Anesthesiology Clinic, University of Düsseldorf, Germany. [email protected] Abstract BACKGROUND: Current practices for renal replacement therapy (RRT) in ICU remain poorly defined. The observational DOse REsponse Multicentre International collaborative initiative (DO-RE-MI) survey addresses the issue of how the different modes of RRT are currently chosen and performed. The primary endpoint of DO-RE-MI will be the delivered dose versus in ICU, 28-day, and hospital mortality, and the secondary endpoint, the hemodynamic response to RRT. Here, we report the first preliminary descriptive analysis after 1-year recruitment. METHODS: Data from 431 patients in need of RRT with or without acute renal failure (mean age 61.2+15.9) from 25 centers in 5 countries (Spain, Italy, Germany, Portugal, France) were entered in electronic case report forms (CRFs) available via the website acutevision.net. RESULTS: On admission, 51% patients came from surgery, 36% from the emergency department, and 16% from internal medicine. On admission, mean SOFA and SAPS II were 13 and 50, respectively. The first criteria to initiate RRT was the RIFLE in 38% (failure: 70%, injury: 25%, risk: 22%), the second the high urea/creatinine, and the third immunomodulation. A total of 3,010 cumulative CRF were reported: continuous venovenous hemodiafiltration (CVVHDF) 60%, continuous venovenous hemofiltration (CVVH) 15%, intermittent hemodialysis (IHD) 15%, high-volume hemofiltration (HVHF) 7%, continuous venovenous hemodialysis (CVVHD) 1%, and coupled plasma filtration adsorption/CVVD 2%. In 15% of cases, the patient was shifted to another modality. Mean blood flow rates (ml/min) in the different modalities were: 145 (CVVHDF), 200 (CVVH), 215 (IHD), 283 (HVHF), and 150 (CVVHD). Downtime ranged from 8 to 28% of the total treatment time. Clotting of the circuit accounted for 74% of treatment interruptions. CONCLUSIONS: Despite a large variability in the criteria of choice of RRT, CVVHDF remains the most used (49%). Clotting and clinical reasons were the most common causes for RRT downtime. In continuous RRT, a large variability in the delivered dose is observed in the majority of patients and often in the same patient from one day to another. Preliminary analysis suggests that in a large number of cases the delivered dose is far from the 'adequate' 35 ml/h/kg