Short-acting P2Y12 blockade to reduce platelet dysfunction and coagulopathy during experimental extracorporeal circulation and hypothermia.

BACKGROUND: Extracorporeal circulation (ECC) and hypothermia are routinely used in cardiac surgery to maintain stable circulatory parameters and to increase the ischaemic tolerance of the patient. However, ECC and hypothermia cause platelet activation and dysfunction possibly followed by a devastating coagulopathy. Stimulation of the adenosinediphosphate (ADP) receptor P(2)Y(12) plays a pivotal role in platelet activation. This experimental study tested P(2)Y(12) receptor blockade as an approach to protect platelets during ECC. METHODS: Human blood was treated with the short-acting P(2)Y(12) blocker cangrelor (1 µM, t(1/2)<5 min) or the P(2)Y(12) inhibitor 2-MeSAMP (100 µM) and circulated in an ex vivo ECC model at normothermia (37°C) and hypothermia (28°C). Before and after circulation, markers of platelet activation and of coagulation (thrombin-antithrombin complex generation) were analysed. During hypothermic ECC in pigs, the effect of reversible P(2)Y(12) blockade on platelet function was evaluated by cangrelor infusion (0.075 µg kg(-1) min(-1)). RESULTS: During ex vivo hypothermic ECC, P(2)Y(12) blockade inhibited platelet granule release (P<0.01), platelet-granulocyte binding (P<0.05), and platelet loss (P<0.001), whereas no effects on platelet-ECC binding, platelet CD42bα expression, glycoprotein IIb/IIIa activation, or thrombin-antithrombin complex generation were observed. During hypothermic ECC in pigs, cangrelor inhibited platelet-fibrinogen binding (P<0.05) and ADP-induced platelet aggregation (P<0.001). Platelet function was rapidly restored after termination of cangrelor infusion. CONCLUSIONS: P(2)Y(12) blockade by cangrelor prevents platelet activation during ECC and hypothermia. Owing to its short half-life, platelet inhibition can be well controlled, thus potentially reducing bleeding complications. This novel pharmacological strategy has the potential to reduce complications associated with ECC and hypothermia.

[Volume replacement in intensive care medicine]. / Volumentherapie in der Intensivmedizin.

Volume substitution represents an essential component of intensive care medicine. The amount of fluid administered, the composition and the timing of volume replacement seem to affect the morbidity and mortality of critically ill patients. Although restrictive volume strategies bear the risk of tissue hypoperfusion and tissue hypoxia in hemodynamically unstable patients liberal strategies favour the development of avoidable hypervolemia with edema and resultant organ dysfunction. However, neither strategy has shown a consistent benefit. In order to account for the heavily varying oxygen demand of critically ill patients, a goal-directed, demand-adapted volume strategy is proposed. Using this strategy, volume replacement should be aligned to the need to restore tissue perfusion and the evidence of volume responsiveness. As the efficiency of volume resuscitation for correction of tissue hypoxia is time-dependent, preload optimization should be completed in the very first hours. Whether colloids or crystalloids are more suitable for this purpose is still controversially discussed. Nevertheless, a temporally limited use of colloids during the initial stage of tissue hypoperfusion appears to represent a strategy which uses the greater volume effect during hypovolemia while minimizing the risks for adverse reactions.

[Management of complex thrombocytopenia with thrombelastometry : a case of simultaneous posttransfusion purpura and heparin-induced thrombocytopenia]. / Management einer komplexen Thrombozytopenie mithilfe der Thrombelastometrie : Koinzidenz von posttransfusioneller Purpura und Heparin-induzierter Thrombozytopenie.

The case presented describes the combined onset of heparin-induced thrombocytopenia II (HIT) and post-transfusion purpura (PTP) 5-10 days following exposure to heparin and blood transfusion during aortic dissection repair. On day 4 the platelet count decreased by 40% and D-dimers started to increase again. Despite a low clinical probability for HIT-II at this time (4T score of 3) serological testing was done the next day and yielded a negative test result. Following a transient rise after platelet transfusion another 40% decrease in platelet count occurred on day 8. To increase precision of the 4T score, screening ultrasonography was performed and identified a clinically unapparent jugular vein thrombosis. As this increased the 4T score to 6 points, serological testing was repeated and now showed the presence of HIT-II antibodies. Despite switching from heparin to argatroban the platelet count continued to decrease to <5×10(3)/µl. Conventional clotting tests showed a prolonged prothrombin time and severe hypofibrinogenemia. Because of the female sex, age >50 years, history of pregnancy and transfusion 8 days before, PTP was suspected. The alteration of the plasmatic coagulation, however, could not be explained by PTP. Therefore, disseminated intravascular coagulation (DIC) and interference of argatroban with conventional clotting tests were considered as alternative diagnoses. In order to differentiate between the two alternatives rotational thrombelastometry (ROTEM®) was performed and revealed an increased functional fibrinogen level without signs of hyperfibrinolysis. This argued for an interference of argatroban with the Clauss method of fibrinogen measurement and rendered DIC unlikely. Under suspicion of PTP, treatment with immunoglobulin was initiated and blood transfusions were avoided. Detection of PTP antibodies 1 day later confirmed the combined presence of PTP and HIT-II. As hyperfibrinogenemia compensated for the effects of thrombocytopenia on clot firmness in ROTEM®, anticoagulation with lepirudin was started at 9×10(3) platelets/µl only. The next day the platelet count increased to 32×10(3)/µl and clot firmness returned to normal. No thromboembolic complications and no relevant bleeding were observed. In summary, this case shows for the first time that HIT-II and PTP can occur in parallel in patients with simultaneous exposure to heparin and blood transfusions. Confounding effects of argatroban on conventional clotting tests may mimic DIC under these circumstances and make diagnosis difficult. Careful evaluation of the time-related magnitude in platelet decrease, patient history, course of D-dimers, screening ultrasonography and ROTEM® seem to be helpful to initiate early appropriate therapy before serological test results become available. In contrast to the Clauss method of fibrinogen measurement, assessment of clot firmness in ROTEM® is not influenced by argatroban. Moreover, ROTEM® reveals the compensatory effects of increased functional fibrinogen on clot firmness during severe thrombocytopenia as an important variable for anticoagulation therapy during thrombocytopenia with increased thromboembolic risk.

Thrombelastometry-guided thrombolytic therapy in massive pulmonary artery embolism.

We report a case of a patient who suffered a massive pulmonary embolism with cardiac arrest on post-operative day 4 after a Whipple operation. Despite thrombolytic therapy with the recommended maximal bolus of 50 mg recombinant tissue type plasminogen activator (rt-PA), thrombelastometry showed no signs of fibrinolysis and cardiogenic shock persisted, after only a transient hemodynamic improvement. Not until a repeat bolus of 25 mg rt-PA and an infusion of 50 mg/h did thrombelastometry demonstrate complete fibrinolysis. Although only residual emboli were seen on computed tomography, the patient died secondary to refractory right heart failure. This demonstrates that the standard dosing of thrombolytics may fail in a subgroup of patients, and suggests that thrombelastometry may be useful for early dose adjustment when standard dosing regimens fail.

Audit of motor weakness and premature catheter dislodgement after epidural analgesia in major abdominal surgery.

In a quality improvement audit on epidural analgesia in 300 patients after major abdominal surgery, we identified postoperative lower leg weakness and premature catheter dislodgement as the most frequent causes of premature discontinuation of postoperative epidural infusion. Lower limb motor weakness occurred in more than half of the patients with lumbar epidural analgesia. In a second period monitoring 177 patients, lumbar catheter insertion was abandoned in favour of exclusive thoracic placement for epidural catheters. Additionally, to prevent outward movement, the catheters were inserted deeper into the epidural space (mean (SD) 5.2 (1.5) cm in Period Two vs 4.6 (1.3) cm in Period One). Lower leg motor weakness declined from 14.7% to 5.1% (odds ratio 0.35; 95% confidence interval 0.16-0.74) between the two periods. Similarly, the frequency of premature catheter dislodgement was reduced from 14.5% to 5.7% (odds ratio 0.35; 95% confidence interval 0.17-0.72). With a stepwise logistic regression model we demonstrated that the odds of premature catheter dislodgement was reduced by 43% for each centimetre of additional catheter advancement in Period Two. We conclude that careful audit of specific complications can usefully guide changes in practice that improve success of epidural analgesia regimens.

[Intraoperative echocardiography: impact on surgical decision-making]. / Intraoperative Echokardiographie : Einfluss auf das chirurgische Management.

Since the introduction of intraoperative echocardiography into clinical practice in the 1970's its use and utility in the perioperative period has become increasingly more evident. Especially in patients undergoing cardiac surgical procedures intraoperative echocardiography has gained great diagnostic importance. Intraoperative transesophageal echocardiography (TEE) and epiaortic ultrasound are two important and complementing diagnostic modalities in this patient population. The clinical information obtained with intraoperative TEE in certain cases might have a direct impact on surgical decision-making and therefore may positively influence patient outcome. In patients undergoing non-cardiac surgical procedures, TEE can be a valuable tool in high-risk patients, in patients experiencing hemodynamic instability or in those suffering intraoperative cardiac arrest. Intraoperative TEE might allow a primary diagnosis of the underlying etiology and facilitate the institution of further therapeutic interventions. In addition TEE can be performed during ongoing cardiopulmonary resuscitation and does not interfere with patient management. This review introduces the clinician to the current evidence of the impact of intraoperative echocardiography on intraoperative surgical decisions during surgical procedures. It helps the clinician to identify indications and realize the potential applications of intraoperative echocardiography.

[Mastocytosis. A challenge in anaesthesiology]. / Mastozytose. Herausforderung in der Anästhesie.

Mastocytosis is a general term for a heterogeneous group of rare disorders. Many agents used in anaesthesia can trigger mast cell degranulation with release of histamine, prostaglandin, tryptase and heparin. Therefore, patients with mastocytosis are high-risk patients when undergoing anaesthesia. The management of these patients in anaesthesia will be discussed on the basis of the literature and illustrated with the discussion of three case reports. A premedication with antihistamines and a glucocorticoid is recommended. For induction of general anaesthesia propofol, etomidate, ketamine, a fentanyl-type opioid, cis-atracurium or pancuronium are recommended. Anaesthesia can be maintained either by a total intravenous technique or with a volatile anaesthetic such as sevoflurane.

[The GABA(A) receptor family: possibilities for the development of better anesthetics]. / Die GABA(A)-Rezeptor-Familie: Möglichkeiten für die Entwicklung besserer Anästhetika.

Clinically used anesthetics show amnestic, sedative, hypnotic and immobilizing properties. On a molecular level these drugs affect several receptors in the cell membrane of neurons. By using genetically engineered mice a linkage can now be made between actions on certain receptors and clinically desired and undesired effects. Experiments show that a certain GABA(A) receptor subtype mediates hypnosis and immobility, whereas another subtype is involved in side-effects like sedation and hypothermia. These findings form the basis for the development of new drugs, acting highly specific and with fewer side-effects.

[Perioperative echocardiography: basic principles]. / Perioperative Echokardiographie: Technische Grundlagen für den Kliniker.

Over the past decades, echocardiography has undergone a continuous evolution in technology that has promoted its clinical application and acceptance throughout perioperative medicine. These technological advances include improvements in transducer development that permit superior imaging quality and a wider selection of probes for epicardial, epiaortic, and surface echocardiography which can also be used in conjunction with multiplane transesophageal echocardiography. Moreover, the addition of Doppler technology and digital acquisition has secured the role of echocardiography as a valuable and relatively noninvasive diagnostic tool for the assessment of cardiovascular disease and hemodynamic monitoring throughout the perioperative period. Therefore, it has become increasingly important for perioperative physicians to understand the basic principles and underlying fundamental concepts pertaining to the technology and physics of echocardiography, as well as its inherent limitations. The current review outlines the modes and applications of different echocardiographic techniques used in perioperative echocardiography including M-mode, two-dimensional echocardiography, and Doppler assessment of blood flow. In addition, the limitations of these techniques and typical artifacts associated with the perioperative use of echocardiography are described.

[Memantine and Complex Regional Pain Syndrome (CRPS): effects of treatment and cortical reorganisation]. / Memantine und komplexes regionales Schmerzsyndrom (CRPS): Behandlungseffekte und kortikale Reorganisation.

BACKGROUND: In recent studies a central nervous system involvement in the pathogenesis of Complex Regional Pain Syndrome (CRPS) was suggested, stimulating the introduction of central acting drugs. Animal studies have demonstrated an increased expression of the N-methyl-D-aspartate (NMDA) receptors in experimental neuropathic pain. PURPOSE: The aim of this study was to investigate the relationship between NMDA receptor blockers and CRPS. METHOD: Three patients suffering from CRPS of one upper extremity where treated with oral NMDA antagonist Memantine for eight weeks. Patients expressed their pain levels with a visual analog scale ranging from zero to ten at rest and after fist clenching. Furthermore, the range of movement of the fingers and the wrist were documented. To assess force, a pinchmeter and a dynamometer were used. Cortical reorganisation was studied with functional Magnetic Resonance Imaging (fMRI) and Magnetoencephalography (MEG). RESULTS: Six months after treatment with Memantine no rest pain was present in any of the patients. Furthermore, an increase in finger movement was observed after six-month follow-up with no deficits and free movement ranges. Additionally, wrist movement was improved and an increase of force was measured after six months with the dynamometer and the pinchmeter. Moreover the functional impairment, cortical reorganisation was observed in all patients before treatment. These changes returned to a normal pattern after eight weeks of treatment with Memantine. CONCLUSION: These first results demonstrate central nervous system involvement in the development and maintenance of CRPS. The results (functional, pain, fMRI, MEG) after treatment with Memantine indicate the importance of the NMDA receptor system in neuropathic pain syndromes and provide a promising approach for the treatment of CRPS.

Physician response to implementation of genotype-tailored antiplatelet therapy.

Physician responses to genomic information are vital to the success of precision medicine initiatives. We prospectively studied a pharmacogenomics implementation program for the propensity of clinicians to select antiplatelet therapy based on CYP2C19 loss-of-function variants in stented patients. Among 2,676 patients, 514 (19.2%) were found to have a CYP2C19 variant affecting clopidogrel metabolism. For the majority (93.6%) of the cohort, cardiologists received active and direct notification of CYP2C19 status. Over 12 months, 57.6% of poor metabolizers and 33.2% of intermediate metabolizers received alternatives to clopidogrel. CYP2C19 variant status was the most influential factor impacting the prescribing decision (hazard ratio [HR] in poor metabolizers 8.1, 95% confidence interval [CI] [5.4, 12.2] and HR 5.0, 95% CI [4.0, 6.3] in intermediate metabolizers), followed by patient age and type of stent implanted. We conclude that cardiologists tailored antiplatelet therapy for a minority of patients with a CYP2C19 variant and considered both genomic and nongenomic risks in their clinical decision-making.

Implementation of an interactive computer-assisted infection monitoring program at the bedside.

A new computer-assisted infection monitoring (CAI) software program has been developed for use in an intensive-care unit (ICU). By means of an interactive dialogue with physicians at the bedside, infection diagnoses and therapeutic decisions were recorded prospectively during a 3-month test period. By linking epidemiological data with information about therapeutic decisions, CAI could assess the quality of the therapeutic decisions. Antibiotics chosen empirically before the availability of any culture results, matched the antibiotic susceptibility patterns of the subsequently identified pathogens in 74% of the cases. Therapy chosen in collaboration with the computer after the pathogen was known, but before sensitivity results were available, corresponded with the eventual antibiograms of the microorganisms in 90% of the cases. Data analysis by CAI allowed us to assess critically the diagnostic and therapeutic habits in our ICU. Using the query-by-example method, CAI automatically calculated device-associated infection rates.

Systemic antibiotic treatment of nosocomial pneumonia.

Nosocomial pneumonia continues to represent a significant cause of morbidity and mortality in hospitalized patients. Bacteria are responsible for greater than 90% of the pneumonias, the most common isolates being aerobic Gram-negative bacilli and S. aureus. Cornerstones of treatment are intravenous antibiotics and supportive care. In the individual case the true etiology is usually unknown; therefore empiric broad spectrum treatment is commonly used based on the prevalence of local pathogens, their antibiotic sensitivity pattern and on host factors. Combination antibiotic regimens, including beta-lactams and aminoglycosides, are considered as standard therapy and are associated with clinical success rates of greater than 80%. Monotherapy with broad spectrum antibiotics, such as third generation cephalosporins, imipenem and fluoroquinolones, can be considered as equally effective in non-neutropenic patients and in the absence of P. aeruginosa infection. More active and less toxic antibiotics are still needed for problematic pathogens such as methicillin-resistant S. aureus strains, multiresistant Enterobacteriaceae and Pseudomonas species. Because further improvement in morbidity and mortality may be limited with antibiotics alone, new emphasis should be placed on prevention of infection and the use of immunotherapy.

Certain batches of albumin solutions influence the expression of endothelial cell adhesion molecules.

OBJECTIVE: Increased levels of soluble adhesion molecules, a decreased PO2/FIO2 ratio and a tendency to worsened outcome have been reported following the use of human albumin in critical illness. The reasons are not yet understood. Since albumin solutions have previously been shown to contain proinflammatory mediators, a direct upregulation of adhesion molecules by contaminated batches may explain these findings. To examine this, we studied the effects of different albumin preparations on endothelial cell adhesion molecules in vitro. DESIGN: Experimental study. SETTING: Laboratory for cell biology. METHODS: Human umbilical venous endothelial cell cultures (n = 4) were incubated for 6 h at 5 mg/ml with four different human albumin solutions (HA1-4) from different manufacturers. Medium served as the control. Using flow cytometry, the effects on E-selectin, ICAM-1 and VCAM-1 expression were determined on unstimulated cells and on cells stimulated with tumour necrosis factor alpha at 0.5 ng/ml for 4 h. MEASUREMENTS AND RESULTS: On unstimulated cells, HA1 and HA4, two different batches from the same manufacturer, increased ICAM-1 by 22% and 15%, respectively. After stimulation, both solutions resulted in a 19% increased expression of E-Selectin. In addition, HA4 decreased VCAM-1 on stimulated cells (p < or = 0.05). Two albumin preparations from other manufacturers did not produce significant effects. CONCLUSIONS: Some albumin solutions directly modulate adhesion molecule expression on endothelial cells. This may, at least in part, explain the previous finding of increased soluble adhesion molecules and a decreased PO2/FIO2 ratio in critically ill patients undergoing volume replacement with human albumin.

Prevention of colonization and respiratory infections in long-term ventilated patients by local antimicrobial prophylaxis.

In a randomized clinical trial the prophylactic effects of locally administered antimicrobials on quantitative colonization and respiratory infections were studied in intubated patients with an expected period of mechanical ventilation of greater than 6 days. Nineteen patients received 50 mg of polymyxin B and 80 mg of gentamicin distributed among nose, oropharynx and stomach at 6-h intervals, as well as 300 mg of amphotericin B in the oropharynx. Twenty untreated patients served as controls. In the control group colonization by respiratory pathogens was more common (oropharynx 19 vs 6 patients (p less than 0.001); trachea 19 vs 11 (p less than 0.01)), and the number as well as the count of the colonizing species was usually higher. Fourteen patients of the control group developed respiratory infections, including nine cases of pneumonia, as compared to four patients with prophylaxis, including one case of pneumonia (p less than 0.01). Pneumonia-associated deaths were prevented with prophylaxis; however, the overall mortality remained unchanged. Respiratory infections in the prophylaxis group were associated with organisms resistant to the agents used, but the overall occurrence of resistance was not increased, as compared to the control group. We conclude that unrestrained upper airway colonization by respiratory pathogens and respiratory tract infection were causally related. Local antimicrobial prophylaxis proved to be a highly effective strategy for the prevention of potentially life-threatening pneumonias in critically ill patients, but in the present study the host setting appeared to be the major determinant of outcome.

The syndrome of inappropriate secretion of antidiuretic hormone (SIADH)--treatment with lithium.

Two patients with SIADH after brain trauma are described. Features of SIADH are "inappropriate" antidiuresis and excessive natriuresis with negative sodium balance resulting in hyponatremia and plasma hypoosmolality which may lead to cerebral dysfunction. Oral lithium carbonate was beneficial in both patients. With plasma levels of lithium around 1 mmol/l a temporary impairment of renal concentrating ability and antinatriuresis with normalization of plasma sodium and plasma osmolality was observed. The SIADH subsided about 4 months after the original trauma, long after gross neurological symptoms had resolved.

Effect of comprehensive validation of the template isolation procedure on the reliability of bacteraemia detection by a 16S rRNA gene PCR.

The influence of the DNA extraction method on the sensitivity and specificity of bacteraemia detection by a 16S rRNA gene PCR assay was investigated. The detection limit of the assay was 5 fg with purified DNA from Escherichia coli or Staphylococcus aureus, corresponding to one bacterial cell. However, with spiked blood samples, the detection limits were 10(4) and 10(6) CFU/mL, respectively. The sensitivity of the S. aureus assay was improved to the level of the E. coli test with the addition of proteinase K to the commercial DNA extraction kit protocol. Ten (16.6%) of 60 amplification reactions were positive with templates isolated from sterile blood, while PCR reagent controls were negative, thereby indicating contamination during the DNA extraction process. Blood samples were spiked with serial dilutions of E. coli and S. aureus cells, and six PCR results were obtained from three extractions for each blood sample. A classification threshold system was devised, based on the number of positive reactions for each sample. Samples were deemed positive if at least four positive reactions were recorded, making it possible to avoid false-positive results caused by contamination. These results indicate that a comprehensive validation procedure covering all aspects of the assay, including DNA extraction, can improve considerably the validity of PCR assays for bacteraemia, and is a prerequisite for the meaningful detection of bacteraemia by PCR in the clinical setting.

Phantom limb pain: a report of two cases.

The efficacy of pre-emptive analgesia for phantom limb pain is still unclear. It is generally accepted that pre hyphen;amputation pain increases the incidence of phantom and stump pain, even if pre-emptive analgesia is performed before and during surgery and in the postoperative period. Two cases of traumatic upper limb amputations are described here with no pre-existing pain. Both received similar antinociceptive treatment by continuous block of the brachial plexus through infusion of ropivacaine 0.375% at 5 ml/h for 10 days. Treatment of case 1 was initiated immediately after surgery; however, this amputee developed intensive phantom limb pain which persisted at 6 months. Early use of the prosthesis after surgery was not possible for this patient. The intensity of phantom limb pain in case 2 decreased significantly after 6 months, even though brachial plexus blockade was not started until 5 weeks post-trauma. This patient used a functional prosthesis intensively beginning early after amputation. Serial magnetoencephalographic recordings were performed in both patients. Only case 2 showed significant changes of cortical reorganization. In case 1 markedly less cortical plasticity was found. A combination of relevant risk factors such as a painful neuroma, behavioural and cognitive coping strategies and the early functional use of prostheses are discussed as important mechanisms contributing to the development of phantom pain and cortical reorganization.

Elimination of linezolid by an in vitro extracorporeal circuit model.

Linezolid is an oxazolidinone antibiotic with activity against important grampositive aerobic bacteria, including nosocomial pathogens. It is not known whether dosage adjustments are necessary in patients treated with continuous renal replacement therapies. This in vitro study was conducted to investigate the elimination of linezolid in an in vitro continuous hemo(dia)filtration model using different filter materials (polysulfone, polyacrylonitrile, polyamide), surface areas, and different modes of renal replacement therapies. Linezolid was measured using HPLC with UV-detection. No adsorption of linezolid to any of the tested membranes was detected. Recovery of linezolid in the ultrafiltrate was 98.2 +/- 10.5% in the filtration mode. During dialysis, recovery was significantly less (87.6 +/- 16.1%; p = 0.02). Linezolid elimination was not altered by filter size, when polysulfone filters with surface areas of 0.7 m2 and 1.3 m2 were tested. In conclusion, the dosage recommendations for linezolid are independent of the filter materials. However, the elimination is significantly higher during hemofiltration compared to dialysis.

Elimination of meropenem by continuous hemo(dia) filtration: an in vitro one-compartment model.

Meropenem is a carbapenem antibiotic with a wide spectrum of activity against most gram positive and gram negative bacteria including anaerobes. Dose adjustments are necessary during continuous renal replacement therapies of acute renal failure. This in vitro study was conducted to investigate the influence of different filter materials, surface areas (AN-69 0.6 m2 and 0.9 m2, polysulfone 0.75 m2, polyamide 0.6 m2), and increasing flow rates (from 3.3 - 26.7 ml/min) on the elimination of meropenem in an in vitro continuous hemo(dia)filtration model. Meropenem was measured using HPLC with UV-detection. While the clearance increased proportionally to increasing dialysate flow rates in filters with a surface area of 0.9 m2, a peak clearance was reached in the small filters at flow rates of 10.0 ml/min (polyamide 0.6 m2) and 18.3 ml/min (AN-69 0.6 m2), when tested under the same conditions. This indicated incomplete dialysate saturation due to the diminished time available for meropenem to equilibrate with the dialysate solution. No adsorption to either of the tested membranes was detected. Dosage recommendations derived from clinical studies might be appropriate when different filter materials, but similar operational settings of the continuous replacement therapy, are applied. Reduction of the recommended dose might be necessary, when renal replacement therapies with lower flow rates and/or filters with smaller surface areas are carried out.