Respiratory and metabolic acidosis correction with the ADVanced Organ Support system.

BACKGROUND: The lung, the kidney, and the liver are major regulators of acid-base balance. Acidosis due to the dysfunction of one or more organs can increase mortality, especially in critically ill patients. Supporting compensation by increasing ventilation or infusing bicarbonate is often ineffective. Therefore, direct removal of acid may represent a novel therapeutic approach. This can be achieved with the ADVanced Organ Support (ADVOS) system, an enhanced renal support therapy based on albumin dialysis. Here, we demonstrate proof of concept for this technology. METHODS: An ex vivo model of either hypercapnic (i.e., continuous CO2 supply) or lactic acidosis (i.e., lactic acid infusion) using porcine blood was subjected to hemodialysis with ADVOS. A variety of operational parameters including blood and dialysate flows, different dialysate pH settings, and acid and base concentrate compositions were tested. Comparisons with standard continuous veno-venous hemofiltration (CVVH) using high bicarbonate substitution fluid and continuous veno-venous hemodialysis (CVVHD) were also performed. RESULTS: Sixty-one milliliters per minute (2.7 mmol/min) of CO2 was removed using a blood flow of 400 ml/min and a dialysate pH of 10 without altering blood pCO2 and HCO3- (36 mmHg and 20 mmol/l, respectively). Up to 142 ml/min (6.3 mmol/min) of CO2 was eliminated if elevated pCO2 (117 mmHg) and HCO3- (63 mmol/l) were allowed. During continuous lactic acid infusion, an acid load of up to 3 mmol/min was compensated. When acidosis was triggered, ADVOS multi normalized pH and bicarbonate levels within 1 h, while neither CVVH nor CVVHD could. The major determinants to correct blood pH were blood flow, dialysate composition, and initial acid-base status. CONCLUSIONS: In conclusion, ADVOS was able to remove more than 50% of the amount of CO2 typically produced by an adult human. Blood pH was maintained stable within the physiological range through compensation of a metabolic acid load by albumin dialysate. These in vitro results will require confirmation in patients.

Evaluation of an ADVanced Organ Support (ADVOS) system in a two-hit porcine model of liver failure plus endotoxemia.

BACKGROUND: Novel extracorporeal procedures are constantly being developed and evaluated for use in patients with sepsis. Preclinical evaluation of such procedures usually requires testing in large animal models. In the present work, the safety and efficacy of a recently developed ADVanced Organ Support (ADVOS) system in a newly developed large animal two-hit model of liver failure combined with endotoxemia were tested. METHODS: After establishing the model in more than 50 animals, a randomized study was performed. An inflammatory cholestatic liver injury was initially provoked in pigs. Three days after surgery, endotoxin was gradually administered during 7½ h. Animals were randomized to receive standard medical treatment either with (ADVOS group, n = 5) or without ADVOS (control group, n = 5). The ADVOS treatment was started 2½ h after endotoxemia and continued for 7 h. Survival, cardiovascular, respiratory, renal, liver, coagulation, and cerebral parameters were analyzed. RESULTS: Three days after surgery, cholestatic injury resulted in hyperbilirubinemia [5.0 mg/dl (IQR 4.3-5.9 mg/dl)], hyperammonemia [292 µg/dl (IQR 291-296 µg/dl)], leukocytosis [20.2 103/µl (IQR 17.7-21.8 103/µl)], and hyperfibrinogenemia [713 mg/dl (IQR 654-803 mg/dl)]. After endotoxemia, the ADVOS procedure stabilized cardiovascular, respiratory, and renal parameters and eliminated surrogate markers as bilirubin [2.3 (IQR 2.3-3.0) vs. 5.5 (IQR 4.6-5.6) mg/dl, p = 0.001] and creatinine [1.4 (IQR 1.1-1.7) vs. 2.3 (IQR 2.1-3.1) mg/dl, p = 0.01]. Mortality: All animals in the ADVOS group survived, while all animals in the control group expired during the 10-h observation period (p = 0.002). No adverse events related to the procedure were observed. CONCLUSIONS: The ADVOS procedure showed a promising safety and efficacy profile and improved survival in a sepsis-like animal model with dysfunction of multiple organs. An amelioration of major organ functions (heart and lung) combined with removal of markers for kidney and liver function was observed.

Multi-modal treatment of calciphylaxis with sodium-thiosulfate, cinacalcet and sevelamer including long-term data.

BACKGROUND: Calciphylaxis is a rare, yet life-threatening disease mainly occurring in dialysis patients. Traditional options of treatment remain unsatisfactory. METHODS: Here we present a novel, combined approach, treating calciphylaxis with IV sodium thiosulfate, cinacalcet and sevelamer. In a case series five hemodialysis patients, have been successfully treated with this regimen. Treatment and survival data were analyzed using descriptive statistics. RESULTS: In all patients, a rapid decrease in pain, improvement of general condition and wound healing within six months occurred. Side effects were low. Drug dosages: IV sodium thiosulfate initial dose 119.4 +/- 84.9 g/m(2)/week, maintenance dose 40.6 +/- 9 g/m(2)/week; cinacalcet: maintenance dose 36 +/- 32.9 mg/d and sevelamer maintenance dose 3320 +/-1671 mg/d. One and two year survivals were 100 % and 80 %, respectively. We also report on long-term application of IV sodium thiosulfate of up to 52 months. Patient survival after diagnosis was 52, 84, 21, 36 and 30 months, respectively. Survival since initiation of hemodialysis was 76, 136, 89, 36 and 35 months, respectively. CONCLUSION: This novel combined approach, a multi-modal treatment of calciphylaxis with persistent hyperparathyroidism, using IV sodium thiosulfate, cinacalcet and sevelamer seems to improve the outcome of this devastating disease.

Evaluation of the Hepa Wash® treatment in pigs with acute liver failure.

BACKGROUND: Mortality of patients with acute liver failure (ALF) is still unacceptably high. Available liver support systems are still of limited success at improving survival. A new type of albumin dialysis, the Hepa Wash® system, was newly introduced. We evaluated the new liver support system as well as the Molecular Adsorbent Recycling System (MARS) in an ischemic porcine model of ALF. METHODS: In the first study animals were randomly allocated to control (n=5) and Hepa Wash (n=6) groups. In a further pilot study, two animals were treated with the MARS-system. All animals received the same medical and surgical procedures. An intraparenchymal intracranial pressure was inserted. Hemodynamic monitoring and goal-directed fluid therapy using the PiCCO system was done. Animals underwent functional end-to-side portacaval shunt and ligation of hepatic arteries. Treatment with albumin dialysis was started after fall of cerebral perfusion pressure to 45 mmHg and continued for 8 h. RESULTS: All animals in the Hepa Wash group survived the 13-hour observation period, except for one that died after stopping treatment. Four of the control animals died within this period (p=0.03). Hepa Wash significantly reduced impairment of cerebral perfusion pressure (23±2 vs. 10±3 mmHg, p=0.006) and mean arterial pressure (37±1 vs. 24±2 mmHg, p=0.006) but had no effect on intracranial pressure (14±1 vs. 15±1 mmHg, p=0.72). Hepa Wash also enhanced cardiac index (4.94±0.32 vs. 3.36±0.25 l/min/m2, p=0.006) and renal function (urine production, 1850 ± 570 vs. 420 ± 180 ml, p=0.045) and eliminated water soluble (creatinine, 1.3±0.2 vs. 3.2±0.3 mg/dl, p=0.01; ammonia 562±124 vs. 1382±92 µg/dl, p=0.006) and protein-bound toxins (nitrate/nitrite 5.54±1.57 vs. 49.82±13.27 µmol/l, p=0.01). No adverse events that could be attributed to the Hepa Wash treatment were observed. CONCLUSIONS: Hepa Wash was a safe procedure and improved multiorgan system failure in pigs with ALF. The survival benefit could be the result of ameliorating different organ functions in association with the detoxification capacity of water soluble and protein-bound toxins.

Citrate pharmacokinetics and calcium levels during high-flux dialysis with regional citrate anticoagulation.

BACKGROUND: Regional citrate anticoagulation is a very effective anticoagulation method for haemodialysis. However, it is not widely used, primarily due to the risk of hypocalcaemia. We studied citrate and calcium kinetics to better understand safety aspects of this anticoagulation method. METHODS: During 15 haemodialysis treatments with a calcium-free dialysis solution, citrate was infused pre-dialyser and calcium was substituted post-dialyser. Systemic and extracorporeal citrate and calcium concentrations were repeatedly measured to calculate citrate and calcium pharmacokinetics. RESULTS: Removal by dialysis constituted the major elimination pathway of citrate (83 +/- 5%). Systemic citrate load and concentrations were low (17 +/- 7 mmol/4 h, 0.3 +/- 0.15 mmol/l). Combined use of calcium-free dialysate and citrate infusion increased diffusible calcium to 80% of total calcium and induced substantial dialytic loss of calcium (43 +/- 4 mmol/4 h). Since calcium was substituted, systemic calcium balances were positive (approximately +5 mmol) and concentrations stable. Calcium supplementation correlated with calcium dialytic losses, which in turn were dependent on total calcium and haematocrit. CONCLUSIONS: When using calcium-free dialysate during citrate anticoagulation, hypocalcaemia is very likely unless calcium is re-infused, because large amounts of calcium are lost in the dialysate. However, an accumulation of citrate in the patient's systemic circulation is an unlikely cause of hypocalcaemia since most of the citrate is removed by dialysis. Calcium substitution and monitoring are the most important safety measures. We propose a rational approach based on haematocrit and total calcium for the choice of the starting calcium supplementation rate.

Treatment of septic patients with an arginine-based endotoxin adsorber column improves hemodynamics and reduces oxidative stress: results of a feasibility study.

BACKGROUND: Mortality of severe sepsis and septic shock is unacceptably high. Adsorptive removal of endotoxin may interrupt the inflammatory cascade triggered by lipopolysaccharide. METHODS: Prospective feasibility study with plasma separation and adsorption (PSA) treatment using a novel arginine-coated adsorber column was performed in a tertiary care gastroenterological intensive care unit. RESULTS: 10 patients with severe sepsis/septic shock (median APACHE II score: 27, hospital mortality 40%) were treated with PSA on 5 consecutive days. There were no serious adverse events. No patient died during the treatment period. During treatment sessions, mean arterial pressure and cardiac power index increased while vasopressors could be reduced. Advanced oxidation protein products and in vitro pro- apoptotic activity of plasma decreased. We could not demonstrate any changes in endotoxin levels. CONCLUSIONS: PSA resulted in a reduction of indicators of oxidative stress and pro-apoptotic activity of the plasma and an improvement in hemodynamic parameters, suggesting increased myocardial contractility and reduced septic vasodilation.

Haemodialysis for the prevention of contrast-induced nephropathy: outcome of 31 patients with severely impaired renal function, comparison with patients at similar risk and review.

RATIONALE AND OBJECTIVES: To investigate whether haemodialysis prevents contrast-induced nephropathy (definition: increase of serum-creatinine of >or= 0.5 mg/dL within 7 days). MATERIALS AND METHODS: Thirty-one patients (mean serum-creatinine 4.01 +/- 1.83 mg/dL) were dialyzed for 4.36 +/- 1.0 hours within one hour after 278.4 +/- 160.5 mL of contrast medium. RESULTS: Dialysis resulted in a significant reduction of serum-creatinine (2.25 +/- 1.46 mg/dL; P< 0.0001) and stable mean serum-creatinine levels 2, 3, 4, and 7 days after contrast medium and at discharge compared with baseline values. However, 19 patients (61%) developed contrast-induced nephropathy within 7 days. Four patients had to be repeatedly dialyzed. A comparison of our patients' 48 hours-incidence of contrast-induced nephropathy (9/31; 29%) versus patients at comparable risk included in seven previous studies demonstrated a prophylactic effect of dialysis only versus a subgroup in one study. CONCLUSIONS: Data provide no hint that haemodialysis prevents contrast-induced nephropathy. Therefore, postprocedural dialysis should be restricted to patients participating in clinical studies.