Heiko Hickstein

A new procedure for the removal of protein bound drugs and toxins

To extend the applicability of dialysis to the removal of albumin bound toxins, a new dialysis procedure was developed. A double sided albumin impregnated high-flux polysulfon dialyzer was used together with a closed loop dialysate compartment with an albumin containing dialysate solution, that was purified on line in a three step process with a charcoal and resin adsorbent, and another dialyzer for a normal dialysis or filtration of the albumin containing dialysate that was then recycled to the albumin impregnated dialyzer. The system effectively removed strongly albumin bound toxins like unconjugated bilirubin or free fatty acids from plasma and blood in vitro and in vivo and therefore could be considered a possible therapeutic means for the treatment of acute liver failure or acute and chronic intoxications with albumin bound toxins, e.g., in drug overdose or chronic renal failure.

Pharmacokinetics of Piperacillin-Tazobactam in Anuric Intensive Care Patients during Continuous Venovenous Hemodialysis

ABSTRACT The pharmacokinetics of piperacillin-tazobactam were investigated in eight anuric intensive care patients treated by continuous venovenous hemodialysis (CVVHD). The elimination half-life of piperacillin was 4.3 ± 1.2 h, and that of tazobactam was 5.6 ± 1.3 h. The contribution of CVVHD to the overall elimination was relevant (>25%) for both drugs.

Albumin dialysis MARS: knowledge from 10 years of clinical investigation.

A decade ago, albumin dialysis was introduced as a new extracorporeal detoxification method for patients with liver failure. Today, the molecular adsorbent recirculating system is the most frequently used type of albumin dialysis and most studied liver-support technique. Numerous preclinical and clinical studies demonstrated the importance of albumin as a scavenger for molecules with pathophysiological relevance in liver failure. Albumin dialysis enables the selective regeneration of albumin. The resulting increase of albumin binding capacity is paralleled by improvement of central and local hemodynamics and liver, brain, and kidney functions. The treatment can contribute to liver regeneration and prolongation of patient survival in the context of acute liver failure, decompensated chronic liver disease, and bridging of patients to liver transplantation. Proper patient selection is critical for clinical success. Aggressive treatment of infections and sepsis seems to be a decisive prerequisite for its safe and efficient use. Cautious anticoagulation with heparin is the common standard. Citrate use is recommended for patients prone to bleeding. Taken together, albumin dialysis represents a valuable therapeutic tool for the treatment of various types of liver failure. Ongoing and future studies will help define the optimal patient selection and technical process parameters such as session length and frequency of treatment.

Treatment of Thyrotoxic Crisis With Plasmapheresis and Single Pass Albumin Dialysis: A Case Report

Thyrotoxic crisis (thyroid storm) is a life-threatening condition. Standard therapy is based on thiamazole, prednisolone, and nonselective beta-blockers. Extracorporeal plasmapheresis is an additional tool for removing circulating thyroxine in patients who do not respond quickly to conventional standard therapy. As thyroxine can be bound by albumin, the aims of the present therapy report were to investigate the potential of extracorporeal single-pass albumin dialysis (SPAD) to remove thyroid hormones and to compare it with plasmapheresis. A 68-year-old female with thyrotoxic crisis refractory to conventional therapy underwent two sessions of plasmapheresis without clinical response. For the treatment dose to be increased, the patient was then treated with a modified continuous veno-venous hemodialysis with a dialysate containing 4% of human serum albumin (SPAD) intended to bind and remove thyroxines continuously. In total, the patient received three sessions of plasmapheresis and four SPAD treatments. Thyroxine levels were detected in the patient and in exchanged plasma or albumin dialysate, respectively, to calculate the amount removed. The main finding was that SPAD treatments were tolerated well by the patient. Due to continuous approach, SPAD sessions removed more thyroid hormone than plasmapheresis did, resulting in the improvement of the clinical status of the patient (reduction of heart rate and catecholamine dosage), which enabled bridging the patient to thyroidectomy as the ultimate surgical treatment. This is the first clinical report of the use of albumin dialysis in thyroid storm. SPAD represents a safe and efficient alternative to plasmapheresis as it can be performed continuously in this critical condition.

Autoimmune-associated Congenital Heart Block: Treatment of the Mother With Immunoadsorption

Abstract:  Autoimmune‐associated congenital heart block (CHB) is a rare complication of pregnancy in mothers with Anti‐Ro/SSA antibodies (SSA‐abs), resulting in fetal myocarditis, atrioventricular block, hydrops fetalis and/or intrauterine fetal death. As these antibodies are supposed to be directly involved in the pathogenesis of CHB, their removal should be associated with an improved clinical course. Extracorporeal immunoadsorption (IA) is the most efficient method to remove IgG‐immunoglobulins like SSA‐abs selectively. Two women with high titers of those auto‐antibodies [mothers serum 615 and 612, respectively (normal range <3.0 IU/mL)] were treated with IA two to three times per gestation week in the outpatient department of the University of Rostock. In both patients, the mean removal of IgG (65 ± 6%) to a target near 2.0 g/L after IA was successful. The SSA‐abs were reduced from mean 328 ± 138 and 247 ± 105 pre IA to 88 ± 124 and 98 ± 42 post IA, respectively. One child received a pacemaker due to the persisting atrioventricular block grade III after birth. The second was unaffected. The removal of highly elevated SSA‐antibodies by immunoadsorption is a possible treatment option in pregnant woman with high titers of those antibodies and/or a positive history of clinical complications. Further clinical studies are necessary.

Extracorporeal cell therapy of septic shock patients with donor granulocytes: a pilot study

IntroductionNeutrophil granulocytes are the first defense line in bacterial infections. However, granulocytes are also responsible for severe local tissue impairment. In order to use donor granulocytes, but at the same time to avoid local side effects, we developed an extracorporeal immune support system. This first-in-man study investigated whether an extracorporeal plasma treatment with a granulocyte bioreactor is tolerable in patients with septic shock. A further intention was to find suitable efficacy end-points for subsequent controlled trials.MethodsThe trial was conducted as a prospective uncontrolled clinical phase I/II study with 28-day follow-up at three university hospital intensive care units. Ten consecutive patients (five men, five women, mean age 60.3 ± 13.9 standard deviation (SD) years) with septic shock with mean ICU entrance scores of Acute Physiology and Chronic Health Evaluation (APACHE) II of 29.9 ± 7.2 and of Simplified Acute Physiology Score (SAPS) II of 66.2 ± 19.5 were treated twice within 72 hours for a mean of 342 ± 64 minutes/treatment with an extracorporeal bioreactor containing 1.41 ± 0.43 × 10E10 granulocytes from healthy donors. On average, 9.8 ± 2.3 liters separated plasma were treated by the therapeutic donor cells. Patients were followed up for 28 days.ResultsTolerance and technical safety during treatment, single organ functions pre/post treatment, and hospital survival were monitored. The extracorporeal treatments were well tolerated. During the treatments, the bacterial endotoxin concentration showed significant reduction. Furthermore, noradrenaline dosage could be significantly reduced while mean arterial pressure was stable. Also, C-reactive protein, procalcitonin, and human leukocyte antigen DR (HLA-DR) showed significant improvement. Four patients died in the hospital on days 6, 9, 18 and 40. Six patients could be discharged.ConclusionsThe extracorporeal treatment with donor granulocytes appeared to be well tolerated and showed promising efficacy results, encouraging further studies.Trial registrationClinicalTrials.gov Identifier: NCT00818597

Response to Therapeutic Plasma Exchange as a Rescue Treatment in Clinically Isolated Syndromes and Acute Worsening of Multiple Sclerosis: A Retrospective Analysis of 90 Patients

Objectives Experience with therapeutic plasma exchange (TPE) for acute relapses in clinically isolated syndrome (CIS) or multiple sclerosis (MS) patients has been derived from small and inhomogeneous patient populations so far. In the present study, we retrospectively evaluated features associated with TPE response in a larger cohort of CIS and MS patients with acute worsening of disease. Participants Ninety CIS and MS patients with acute relapses or acute worsening of symptoms were firstly treated with TPE. The population consisted of 62 women and 28 men with a median age of 38 years (range 18–69 years). Outcome Measures Primary endpoint was the clinical response to TPE, focused on the functional improvement of the target neurologic deficit. Secondary endpoint was an improvement in expanded disability status scale (EDSS) scoring. Results A clinical response to TPE was observed in 65 out of 90 patients (72.2%), with marked improvement in 18 (20.0%) and moderate improvement in 47 out of 90 patients (52.2%). The median EDSS was reduced from 3.75 before to 3.0 after TPE (p = 0.001). Response to TPE was significantly more frequent in patients with relapsing courses of disease (CIS, RR-MS, p = 0.001), no disease modifying drugs (p = 0.017), gadolinium-positive (Gd+) MRI lesions (p = 0.001) and EDSS ≤ 5.0 before TPE (p = 0.014). In the multiple logistic regression analysis only the detection of Gd+ MRI lesions was significantly altered (p = 0.004). Conclusion Clinical response to TPE was achieved in the majority of our patients. We identified clinical and diagnostic features in CIS and MS relapses that might be helpful to identify patients responding to TPE. Gd+ MRI lesions before treatment were the best predictor of the response to TPE in our cohort.

Therapeutic Plasma Exchange in Glucocorticosteroid-Unresponsive Patients With Clinically Isolated Syndrome

Clinically Isolated Syndromes (CIS) summarize clinical features of possible multiple sclerosis (MS) as a first clinical event of the disease. Escalation therapy in CIS episodes comprises high dose glucocorticosteroid (GCS) treatment followed by therapeutic plasma exchange (TPE) in patients unresponsive to GCS. The aim of our study was to analyze TPE effects in CIS patients. Eleven GCS‐unresponsive patients exhibiting CIS were treated with TPE. A median of 5.0 (range 3–8) treatments were performed with a median exchange volume of 3.0 L (range 2.2–3.5 L). Standard diagnostic results in CIS patients were collected. In 10 out of 11 patients clinical improvement was observed. In Expanded Disability Status Scale (EDSS) Scoring, a commonly used score to assess disability in MS and CIS patients, significant improvement was shown as well. One patient was a non‐responder to TPE. Apheresis treatments were well tolerated in all patients. In the medical control of GCS‐unresponsive CIS episodes, TPE appears to be an effective and well‐tolerated treatment option. TPE response in CIS patients is comparable to TPE results in GCS‐unresponsive MS relapses. Further prospective studies are indicated.

Increase of Octanoate Concentrations During Extracorporeal Albumin Dialysis Treatments

Extracorporeal liver support procedures based on albumin dialysis require the use of pharmaceutical‐grade human serum albumin (HSA). Those preparations contain octanoate, which is added as stabilizer during the production process. For octanoate, a direct involvement in the pathogenesis of liver failure complications as well as an indirect influence by competitive displacement effects at the albumin molecule have been described. During five Single Pass Albumin Dialysis (SPAD) and three Molecular Adsorbent Recirculating System (MARS) treatments the changes of octanoate concentrations in blood and dialysate were investigated. An octanoate increase in patient blood was observed during passage of the filter for both SPAD (585 µmol/L [338–1022 µmol/L]) (median [range]) and MARS (182 µmol/L [71–437 µmol/L]) during the first three hours of treatment. The molar ratio of octanoate/albumin at the blood outflow was significantly higher during SPAD treatments (1.73 [0.86–2.64] vs. 0.54 [0.31–1.1]; P = 0.001) during MARS. Changes of octanoate blood levels during SPAD were significantly higher than during MARS (P < 0.001). The shift of octanoate from the dialysate to the patient was persistent during SPAD (median 67.6 µmol/min), whereas during MARS a decrease over time was observed (from 25.5 to 7.5 µmol/min). During albumin dialysis procedures a transfer of octanoate into patient blood occurs. The time‐course and extent are different between both albumin dialysis procedures. Given the positive clinical effects reported mainly for MARS, the clinical impact of albumin dialysis‐associated transfer of octanoate during extracorporeal liver support needs to be evaluated further.

Protein A immunoadsorption in a pregnant women with habitual abortion

The role of antibodies in the occurrence of recurrent spontaneous miscarriage is well known. However there are many controversial issues in the management of habitual abortion. This paper describes the effect of Protein A immunoadsorption on serum levels of these antibodies and its impact on a case of a successfully treated woman in a outpatient department without need for a central venous catheter. Given the favourable clinical results described in our paper we think it may be relevant for some worse cases in clinical practice and will interest your readers.