Peter Abel

Treatment of severe neurological deficits with IgG depletion through immunoadsorption in patients with Escherichia coli O104:H4-associated haemolytic uraemic syndrome: a prospective trial

BACKGROUND In May 2011, an outbreak of Shiga toxin-producing enterohaemorrhagic E coli O104:H4 in northern Germany led to a high proportion of patients developing post-enteritis haemolytic uraemic syndrome and thrombotic microangiopathy that were unresponsive to therapeutic plasma exchange or complement-blocking antibody (eculizumab). Some patients needed ventilatory support due to severe neurological complications, which arose 1 week after onset of enteritis, suggesting an antibody-mediated mechanism. Therefore, we aimed to assess immunoadsorption as rescue therapy. METHODS In our prospective non-controlled trial, we enrolled patients with severe neurological symptoms and confirmed recent E coli O104:H4 infection without other acute bacterial infection or raised procalcitonin concentrations. We did IgG immunoadsorption processing of 12 L plasma volumes on 2 consecutive days, followed by IgG replacement (0·5 g/kg intravenous IgG). We calculated a composite neurological symptom score (lowest score was best) every day and assessed changes before and after immunoadsorption. FINDINGS We enrolled 12 patients who initially presented with enteritis and subsequent renal failure; 10 (83%) of 12 patients needed renal replacement therapy by a median of 8·0 days (range 5-12). Neurological complications (delirium, stimulus sensitive myoclonus, aphasia, and epileptic seizures in 50% of patients) occurred at a median of 8·0 days (range 5-15) and mandated mechanical ventilation in nine patients. Composite neurological symptom scores increased in the 3 days before immunoadsorption to 3·0 (SD 1·1, p=0·038), and improved to 1·0 (1·2, p=0·0006) 3 days after immunoadsorption. In non-intubated patients, improvement was apparent during immunoadsorption (eg, disappearance of aphasia). Five patients who were intubated were weaned within 48 h, two within 4 days, and two patients needed continued ventilation for respiratory problems. All 12 patients survived and ten had complete neurological and renal function recovery. INTERPRETATION Antibodies are probably involved in the pathogenesis of severe neurological symptoms in patients with E coli O104:H4-induced haemolytic uraemic syndrome. Immunoadsorption can safely be used to rapidly ameliorate these severe neurological complications. FUNDING Greifswald University and Hannover Medical School.

Biosensors for in vivo glucose measurement: can we cross the experimental stage

The development of in vivo working glucose sensors needs two decades, so far. The availability of long term functional implantable biosensors for continuous glucose measurings is a basic prerequisite for the individualized optimum insulin treatment of diabetics. Enzymatic electrochemical sensors are described which realize a functional stability over more than 2 years in vitro, however their function in vivo is limited due to certain bioincompatibility expressed by inflammation of the surrounding tissue, exudates, and immun reactions. The paper reflects an overview concerning different sensor covering materials used as more or less suitable diffusion membranes. From experimental studies in animals and human volunteers conclusions are drawn for further developmental steps of biosensors for in vivo use and for the applicability of glucose sensors for transient diagnostic purposes and as a basis for glucose controlled therapeutic measures. The results demonstrate that further progress aimed at long term biostability of implanted biosensors needs to solve technological problems and the serial production of sensors with really comparable qualities as a prerequisite for clinical trials.

Outcome of severe lactic acidosis associated with metformin accumulation

IntroductionMetformin associated lactic acidosis (MALA) may complicate metformin therapy, particularly if metformin accumulates due to renal dysfunction. Profound lactic acidosis (LA) generally predicts poor outcome. We aimed to determine if MALA differs in outcome from LA of other origin (LAOO).MethodsWe conducted a retrospective analysis of all patients admitted with LA to our medical ICU of a tertiary referral center during a 5-year period. MALA patients and LAOO patients were compared with respect to parameters of acid-base balance, serum creatinine, hospital outcome, Simplified Acute Physiology Score II (SAPS II) and Sequential Organ Failure Assessment (SOFA) score, using Pearsons Chi-square or the Mann-Whitney U-test.ResultsOf 197 patients admitted with LA, 10 had been diagnosed with MALA. With MALA, median arterial blood pH was significantly lower (6.78 [range 6.5 to 6.94]) and serum lactate significantly higher (18.7 ± 5.3 mmol/L) than with LAOO (pH 7.20 [range 6.46 to 7.35], mean serum lactate 11.2 ± 6.1 mmol/L). Overall mortality, however, was comparable (MALA 50%, LAOO 74%). Furthermore, survival of patients with arterial blood pH < 7.00 (N = 41) was significantly better (50% vs. 0%) if MALA (N = 10) was the underlying condition compared to LAOO (N = 31).ConclusionsCompared to similarly severe lactic acidosis of other origin, the prognosis of MALA is significantly better. MALA should be considered in metformin-treated patients presenting with lactic acidosis.

Comparison of pulmonary artery and aortic transpulmonary thermodilution for monitoring of cardiac output in patients with severe heart failure: validation of a novel method.

Objective:Hemodynamic monitoring with the pulmonary artery catheter is frequently used in the management of severe heart failure. For measurement of cardiac output (CO), transpulmonary thermodilution (TPTD) has recently been adopted into clinical practice as an alternative to pulmonary artery thermodilution. However, no data have been published on the comparability of the two methods for patients with severely reduced left ventricular function. Our objective was to evaluate the correlation between these two methods of CO determination in patients with severe left ventricular dysfunction. Design:Prospective observational clinical study. Setting:Cardiological intermediate care unit and medical intensive care unit of a university hospital. Patients:Twenty-nine patients with left ventricular ejection fraction <35% and symptoms of heart failure (New York Heart Association class III–IV). Intervention:None. Measurements and Main Results:The two methods of intermittent CO measurement were compared by simultaneously recording the results of pulmonary artery thermodilution and TPTD after injection of a cold saline bolus. Measurements were performed when clinically necessary. A total of 325 data pairs were analyzed. Mean CO of both methods was 4.4 L/min with a bias of 0.45 L/min (2 sd 1.20 L/min), resulting in a percentage error of 27.3%. Conclusion:In patients with severely impaired left ventricular function, measurement of CO by TPTD provides valid results.

Influence of polymerization parameters and entrapment in poly(hydroxyethyl methacrylate) on activity and stability of GOD

Abstract The functional stability of biosensors used in vivo seems, most probably, to be limited by enzyme instability. Therefore, investigations have been carried out on enzyme stabilization by immobilization using poly(hydroxyethyl methacrylate) (pHEMA). On one hand, there are several factors connected to polymerization of the monomer hydroxyethyl methacrylate (HEMA) able to influence the activity of enzymes during their entrapment in the polymer. The factors we investigated are: the concentration of the monomer, different temperatures (50–65°C), ultraviolet radiation, and the concentration of radicals generated by different initiator concentrations. Glucose oxidase (GOD) was used as a model enzyme. It was found that the most important GOD inactivating factors are the monomer itself and temperatures higher than 50°C. On the other hand, despite of these influences a long term stable immobilization of GOD by entrapment in pHEMA could be realized.

Stability of immobilized enzymes as biosensors for continuous application in vitro and in vivo

Abstract The surplus of enzyme activity is a main prerequisite for the proper long-term function of enzymatic biosensors based on a diffusion-controlled process at any time. Long-term functional stability in vitro could be reached with sensor preparations using human serum albumin (HSA, Rhodalbumin) and glutaraldehyde (GDA, 25%,) as a mixture with glucose oxidase (GOD, EC 1.1.3.4., Aspergillus niger , 300 IU/mg) covered by polyurethane (PUR, Tecoflex EG 80 A) as a membrane with well-defined diffusion qualities. A very rapidly decreasing sensitivity has been observed after sensor implantation. As a reason for this, a reversible enzyme inhibition has been hypothesized, underlined by a slow restoration of the sensitivity up to the original one over a period of 5 days after sensor explantation. The same immobilization procedure on the surface of electrochemical sensors has been used very successful in the case of lactate oxidase (LOD, Pedicoccus species, 35 IU/mg). Dependent on the covering membrane lactate measurements in the range of 0.05 up to 50 mM lactate, concentration in milk and products of that can be realized. Further research has been pointed at the development of such immobilization methods which guarantee sufficient enzyme stability at in vivo conditions, too.

Subpicosecond-pulse laser microstructuring for enhanced reproducibility of biosensors

Abstract Curved substrates can be micro-structured by laser ablation, which is not possible with standard lithographic methods. The novel femtosecond-pulse laser technique allows the production of defined and reproducible micro-perforations of originally analyte-impermeable membranes. The trans-membrane analyte flux can be controlled both by the variation of the laser focus diameter resulting in different areas of single perforations, and the number of perforations in arrays on small membrane areas. This leads to a higher degree of variability as well as reproducibility of the diffusion qualities of sensor membranes, and marks the main innovation with this technique compared to the hand-made mechanical perforation by specially grinded needles used up to now. Touchless micro-perforation of small membrane areas with negligible heat damage of the structures adjacent to the perforation allows the application of ‘analyte door’ membranes directly onto curved surfaces of miniaturized needle-sensors assigned for in vivo glucose monitoring, for the first time.

Improvement of enteral nutrition in intensive care unit patients by a nurse-driven feeding protocol

AIMS AND OBJECTIVES To examine whether early enteral nutrition (EN) of critically ill patients could be improved by a nurse-driven implementation of an existing feeding protocol. DESIGN Before and after design. METHODS Responsibility for starting and timely escalating EN - subject to physicians ordering before - was assigned to the intensive care unit (ICU) nursing staff. A short written instruction was extracted from the comprehensive standard operating procedure (SOP) for nutrition. The nursing team was trained to use this instruction; after completing the training they managed early EN autonomously. Time to start of enteral feeding and applied quantity in the first 5 ICU days were recorded prospectively for the patients treated during the following 6 months. The data were compared to a retrospectively analysed cohort from 6 months before, which was fed according to the SOP-based prescription of the physician on duty. RESULTS A total of 101 and 97 patients were included, respectively, before and after the intervention. Following intervention, enteral feeding started significantly earlier (28 ± 20 h versus 47 ± 34 h, p<0.001), within 24 h in 64% versus 25% (p<0.0001); and for each of the first 5 days, the proportion of patients meeting their nutritional goal was significantly higher. CONCLUSIONS Assigning the responsibility for implementation of an existing SOP to the nursing team led to earlier start of enteral feeding and more frequent achievement of caloric targets in ICU patients. RELEVANCE TO CLINICAL PRACTICE Adherence to guidelines regarding early start and timely escalation of EN can be improved if ICU nursing staff is responsible for translating it into action with the help of a written algorithm.

Biosensor-controlled perfusion culture to estimate the viability of cells.

A perfusion cell culture is characterised by the continuous addition of fresh nutrient medium and the withdrawal of an equal volume of used medium, allowing the realisation of cell cultivation conditions that are approximated as closely as possible to the in vivo situation. The combination of a perfusion cell culture with an enzyme glucose biosensor allows the glucose consumption of the cell culture to be monitored continuously. The resulting biosensor-controlled perfusion cell culture is a complex biomonitoring system that is useful for checking the metabolic state of a perfusion cell culture continuously and non-invasively over several days. With this experimental setup, it has been possible to test detrimental external effects on living systems at early stages, in vitro, but under in vivo-like conditions.

CytoSorb, a novel therapeutic approach for patients with septic shock: a case report

Introduction Hemoadsorption using CytoSorb has gained attention as a potential immunotherapy to control systemic inflammation and sepsis. We report on a patient with septic shock, successfully treated with CytoSorb therapy. Methods A 72-year-old male with periodically recurring infectious episodes was admitted with the suspicion of urosepsis. In the following hours his hemodynamic situation deteriorated markedly, exhibiting respiratory-metabolic acidosis, elevated inflammatory marker plasma levels, a severely disturbed coagulation, increased retention parameters, liver dysfunction, and confirmation of bacteria and leucocytes in urine. After admission to the ICU in a state of septic shock the patient received renal support with additional hemoadsorption using CytoSorb. Three CytoSorb sessions were run during the following days. Results The first and consecutive second session resulted in a reduction of procalcitonin, C-reactive protein and bilirubin and a markedly reduced need for vasopressors while hemodynamics improved significantly (i.e., cardiac index, extravascular lung water). Due to a recurring inflammatory “second hit” episode, another session with CytoSorb was run, resulting in a marked decrease in leukocytosis and liver (dys)function parameters. Conclusions The rapid hemodynamic stabilization with reduction of vasopressor needs within hours and reduction of the capillary leakage as well as a quick reduction in infection markers were the main conclusions drawn from the use of CytoSorb in this patient. Additionally, treatment appeared to be safe and was well tolerated. Despite the promising results of CytoSorb application in this patient, further studies are necessary to elucidate to what extent these favorable consequences are attributable to the adsorber itself.