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Background: Coagulopathy is part of the pathological host response to infection in sepsis. Higher plasma concentrations of both tissue factor (TF) and tissue factor pathway inhibitor (TFPI) are associated with occurrence of disseminated intravascular coagulation (DIC), multi-organ dysfunction and increased mortality in patients with sepsis. Currently no treatment approaches specifically targeting this axis are available. We hypothesize that therapeutic plasma exchange (TPE) might limit this coagulopathy by restoring the balance of plasma proteins. Methods: This was a pooled post-hoc biobank analysis including 51 patients with early (shock onset < 24 h) and severe (norepinephrine dose > 0.4 μg/kg/min) septic shock, who were either receiving standard of care treatment (SOC, n = 14) or SOC + one single TPE (n = 37). Plasma concentrations of TF and TFPI were measured both at- and 6 h after study inclusion. The effect of TPE on concentrations of TF and TFPI was investigated and compared to SOC patients. Further, baseline TF and TFPI concentrations were used to modulate and predict clinical response to adjunctive TPE, indicated by longitudinal reduction of lactate concentrations over the first 24 h following study inclusion. Results: TPE led to a significant reduction in circulating concentrations of both TF and TFPI while no difference was observed in the SOC group. Relative change of TF within 6 h was + 14 (-0.8 to + 30.4) % (p = 0.089) in the SOC and −18.3 (−32.6 to −2.2) % (p < 0.001) in the TPE group (between group p < 0.001). Similarly, relative change of TFPI was + 14.4 (−2.3 to + 30.9) % (p = 0.076) in the SOC and −20 (−32.8 to −7.9) % (p < 0.001) in the TPE group (between group p = 0.022). The ratio of TF to TFPI remained unchanged in both SOC and TPE groups. SOC patients exhibited an increase in lactate over the initial 24 h when TF and TFPI concentrations were higher at baseline. In contrast, patients undergoing TPE experienced a sustained longitudinal reduction of lactate concentrations across all levels of baseline TF and TFPI elevations. In a multivariate mixed−effects model, higher baseline TF (p = 0.003) and TFPI (p = 0.053) levels led to greater longitudinal lactate concentration reduction effects in the TPE group. Conclusions: Adjunctive TPE in septic shock is associated with a significant removal of both TF and TFPI, which may contribute to the early hemodynamic improvement observed in septic shock patients receiving TPE. Higher baseline TF (and TFPI) plasma concentrations were identified as a putative predictor of treatment response that could be useful for predictive enrichment strategies in future clinical trials. [ABSTRACT FROM AUTHOR]

Introduction: The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup suggests hemodialysis in severe lithium poisoning if specific criteria are met. One criterion is if the expected time to obtain a lithium concentration <1.0 mEq/L with optimal management is >36 h. There are a lack of data regarding which patient characteristics are associated with the rate at which patients achieve a lithium concentration <1.0 mEq/L. Methods: We conducted a retrospective chart review analyzing hospital electronic medical records. Inclusion criteria consisted of a lithium concentration >1.2 mEq/L during hospitalization. We excluded patients who received extracorporeal treatment before 36 h elapsed from time of initial lithium concentration >1.2 mEq/L. The primary analysis consisted of a Cox regression and a secondary analysis evaluated the nomogram method described by Buckley and colleagues for predicting prolonged supratherapeutic lithium concentration. Results: One hundred and one patients were included in the study. The median time to reach a lithium concentration <1.0 mEq/L was 42.5 h (IQR: 33.8–51.1). Older patients, patients taking a thiazide, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, patients with a higher initial lithium concentration, and patients with higher sodium concentrations achieved a lithium concentration <1 mEq/L at a slower rate. For the nomogram analysis, sensitivity (61.5%) and specificity (54.5%) were moderate, the positive predictive value (16.7%) was poor, and the negative predictive value (90.6%) was excellent. Discussion: The results from our primary analysis suggest that identifying higher serum sodium concentration and use of certain antihypertensives that decrease glomerular filtration rate as predictors of an increased time to reach a therapeutic lithium concentration may help identify patients who meet the Extracorporeal Treatments in Poisoning criteria for hemodialysis. The nomogram method performed similarly to prior validation studies. Conclusions: In this retrospective chart review of patients with supratherapeutic lithium concentrations, we identified several risk factors for prolonged supratherapeutic lithium concentrations. [ABSTRACT FROM AUTHOR]

Barbiturates are a class of sedative and hypnotic drugs. These are commonly used as antiepileptics and anesthetic agents now. Current usage of sedatives in India is about 1.08%, and the abuse is about 0.11%. Barbiturate overdose or poisonings can lead to severe central nervous system depression, potentially life-threatening respiratory depression, and may lead to respiratory arrest. Treatment in the majority of cases of barbiturate poisoning is artificial ventilation and other supportive therapies. Extracorporeal treatments (ECTRs) are required in only 0.1% of cases of poisoning. There is a lack of prospective intervention studies for obvious ethical reasons; however, the ECTR in poisoning (EXTRIP) workgroup recommends the use of ECTRs in severe barbiturate overdose/poisoning. [ABSTRACT FROM AUTHOR]

Metformin-associated lactic acidosis is a well-described and commonly encountered condition associated with significant morbidity and mortality. Patients with metformin-associated lactic acidosis are frequently managed in the intensive care unit with supportive care, including volume resuscitation and consideration of an extracorporeal treatment to correct metabolic acidemia and remove metformin and lactate. The Extracorporeal Treatments in Poisoning Workgroup published evidence-based consensus recommendations in 2015 regarding the use of extracorporeal treatment in metformin toxicity. These recommendations list both clinical and biochemical indications, and they outline the rationale and evidence supporting each recommendation. Subsequent publications have provided new information regarding metformin-associated lactic acidosis and its treatment. A retrospective study showed that patients who did not meet the Extracorporeal Treatments in Poisoning Workgroup criteria for initiation of an extracorporeal treatment had a 100% survival. In patients who met the criteria, survival was approximately 75%; only 66% of these patients received an extracorporeal treatment, and this treatment did not appear to impact survival. Two other retrospective studies in patients diagnosed with metformin-associated lactic acidosis noted that extracorporeal treatments did not improve survival. However, those who received an extracorporeal treatment were more severely ill, potentially supporting a benefit from this intervention. A systematic review of patients receiving continuous kidney replacement therapy identified an overall survival that was higher than the overall survival in patients included in the Workgroup publication. This led the authors to suggest that intermittent hemodialysis may not be the preferred treatment for metformin toxicity. However, a closer look at the Workgroup data identified improved survival with each decade since the initial reports in the 1970s. Furthermore, there are multiple reports of persistent metformin-associated lactic acidosis that did not improve with standard continuous kidney replacement therapy, prompting an increase in the dosage of the extracorporeal treatment. The data supporting these observations are largely derived from retrospective studies, which have inherent biases, so prospective studies are required. Case-based decision-making is always necessary, but in general, we continue to follow the Extracorporeal Treatments in Poisoning Workgroup criteria because a convincing reason for changing these has not yet been presented. This includes the use of intermittent hemodialysis where possible, particularly in cases of severe poisoning. For patients with less severe poisoning or when intermittent hemodialysis is not readily available, it is reasonable to trial continuous modalities with careful observation for deterioration. [ABSTRACT FROM AUTHOR]

In this paper, we report on the utilization of micro-technology based tools to fight viral infections. Inspired by various hemoperfusion and immune-affinity capture systems, a blood virus depletion device has been developed that offers highly efficient capture and removal of the targeted virus from the circulation, thus decreasing virus load. Single-domain antibodies against the Wuhan (VHH-72) virus strain produced by recombinant DNA technology were immobilized on the surface of glass micro-beads, which were then utilized as stationary phase. For feasibility testing, the virus suspension was flown through the prototype immune-affinity device that captured the viruses and the filtered media left the column. The feasibility test of the proposed technology was performed in a Biosafety Level 4 classified laboratory using the Wuhan SARS-CoV-2 strain. The laboratory scale device actually captured 120,000 virus particles from the culture media circulation proving the feasibility of the suggested technology. This performance has an estimated capture ability of 15 million virus particles by using the therapeutic size column design, representing three times over-engineering with the assumption of 5 million genomic virus copies in an average viremic patient. Our results suggested that this new therapeutic virus capture device could significantly lower virus load thus preventing the development of more severe COVID-19 cases and consequently reducing mortality rate. [ABSTRACT FROM AUTHOR]

Summary: A number of clinical treatment modalities involve contact between blood and biomaterials: these include extracorporeal circuits such as hemodialysis, cardiopulmonary bypass, plasmapheresis, and intravascular treatments. Common side effects arising from these treatments are caused by activation of the cascade systems of the blood. Many of these side effects are mediated via the complement system, including thromboinflammatory reactions and rejection of implants. Depending on the composition of the materials, complement activation is triggered via all the activation pathways but is by far mostly driven by the alternative pathway amplification loop. On biomaterial surfaces the alternative pathway amplification is totally unregulated and leads under optimal conditions to deposition of complement fragments, mostly C3b, on the surface leading to a total masking of the underlying surface. In this review, we discuss the mechanism of the complement activation, clinical consequences of the activation, and potential strategies for therapeutic regulation of the activation, using hemodialysis as demonstrator. [ABSTRACT FROM AUTHOR]

Continuous renal replacement therapy is an extracorporeal blood purification therapy that aims to support kidney and other organ functions over an extended period. The high-quality continuous renal replacement therapy requires understanding basic mechanisms of clearance, factors influencing these processes, and the appropriate selection of treatment candidates. This article reviews the different aspects of continuous renal replacement therapy in critically ill pediatric patients. [ABSTRACT FROM AUTHOR]

Introduction: Valproic acid (VPA) toxicity commonly results in a self-limited state of CNS depression that is managed with supportive care and levocarnitine. In massive overdose, patients can develop toxic encephalopathy, shock, multisystem organ failure, and death. We present a case with relevant toxicokinetics of a patient presenting with a profoundly elevated VPA concentration resulting in survival, treated with supportive care including high-dose continuous venovenous hemodiafiltration (CVVHDF). Case Report: A 17-year-old female presented to an emergency department after being found unresponsive at home with concern for massive VPA ingestion. She arrived obtunded and hypotensive with initial VPA concentration of 2226 mg/L, estimated 9 h post-ingestion. Her early hospital course was marked by hypotension requiring multiple vasopressors, and her workup was notable for multiple severe metabolic derangements. High-dose CVVHDF was initiated upon transfer to a tertiary children's hospital with the aim to enhance VPA removal and normalize metabolic derangements. At that time, her VPA concentration was 1071 mg/L. Apparent half-life of VPA improved modestly with extracorporeal treatment, but her metabolic derangements and hemodynamic instability corrected rapidly. Her clinical course was complicated by necrotizing pancreatitis, pancytopenia requiring transfusions of multiple cell lines, coma, and seizures. She ultimately recovered with normal neurological function. [ABSTRACT FROM AUTHOR]

Ethylene glycol is metabolized to toxic metabolites that cause acute kidney injury, metabolic acidemia, and death. The treatment of patients with ethylene glycol poisoning includes competitively inhibiting alcohol dehydrogenase with ethanol or fomepizole to prevent the formation of toxic metabolites, and extracorporeal treatments such as hemodialysis to remove ethylene glycol and its metabolites. In the absence of significant metabolic acidemia or kidney injury, it is hypothesized that extracorporeal treatments may be obviated without adverse outcomes to the patient if alcohol dehydrogenase inhibitors are used. The objectives of this study are to: (1) identify indicators predicting ADH inhibitor failure in patients with ethylene glycol poisoning treated with either ethanol or fomepizole for whom extracorporeal treatment was not performed (aside from rescue therapy, see below) (prognostic study), and (2) validate if the anion gap, shown in a previous study to be the best surrogate for the glycolate concentration, is associated with acute kidney injury and mortality (anion gap study). We conducted a systematic review to identify all reported patients with ethylene glycol poisoning treated without extracorporeal treatments but with either fomepizole (fomepizole monotherapy) or ethanol (ethanol monotherapy). Analyses were performed using both one case per patient and all cases (if multiple events were reported for a single patient). Data were compiled regarding poisoning, biochemistry, and outcomes. Treatment failure was defined as mortality, worsening of acid-base status, extracorporeal treatments used as rescue, or a worsening of kidney or neurological function after alcohol dehydrogenase inhibition was initiated. Also, we performed an analysis of previously described anion gap thresholds to determine if they were associated with outcomes such as acute kidney injury and mortality. Of 115 publications identified, 96 contained case-level data. A total of 180 cases were identified with ethanol monotherapy, and 231 with fomepizole monotherapy. Therapy failure was noted mostly when marked acidemia and/or acute kidney injury were present prior to therapy, although there were cases of failed ethanol monotherapy with minimal acidemia (suggesting that ethanol dosing and/or monitoring may not have been optimal). Ethylene glycol dose and ethylene glycol concentration were predictive of monotherapy failure for ethanol, but not for fomepizole. In the anion gap study (207 cases), death and progression of acute kidney injury were almost nonexistent when the anion gap was less than 24 mmol/L and mostly observed when the anion gap was greater than 28 mmol/L. This review suggests that in patients with minimal metabolic acidemia (anion gap <28 mmol/L), fomepizole monotherapy without extracorporeal treatments is safe and effective regardless of the ethylene glycol concentration. Treatment failures were observed with ethanol monotherapy which may relate to transient subtherapeutic ethanol concentrations or very high ethylene glycol concentrations. The results are limited by the retrospective nature of the case reports and series reviewed in this study and require prospective validation. [ABSTRACT FROM AUTHOR]

Background The Seraph® 100 Microbind® Affinity Blood Filter is a haemoperfusion device that is licensed for the reduction of pathogens, including several viruses, in the blood. It received Emergency Use Authorization for the treatment of severe coronavirus disease 2019 (COVID-19) by the Food and Drug Administration (FDA). Several studies have shown that the blood viral load of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) correlates with adverse outcomes and removal of the nucleocapsid of the SARS-CoV-2 virus by the Seraph® 100 has been recently demonstrated. The aim of this registry was to evaluate the safety and efficacy of Seraph® 100 treatment for COVID-19 patients. Methods Twelve hospitals from six countries representing two continents documented patient and treatment characteristics as well as outcome parameters without reimbursement. Additionally, mortality and safety results of the device were reported. A total of 102 treatment sessions in 82 patients were documented in the registry. Four patients were excluded from mortality analysis due to incomplete outcome data, which were available in the other 78 patients. Results Overall, a 30-day mortality rate of 46.2% in the 78 patients with complete follow-up was reported. The median treatment time was 5.00 h (4.00–13.42) and 43.1% of the treatments were performed as haemoperfusion only. Adverse events of the Seraph® 100 treatment were reported in 8.8% of the 102 treatments and represented the premature end of treatment due to circuit failure. Patients who died were treated later in their intensive care unit (ICU) stay and onset of COVID symptoms. They also had higher ferritin levels. Multivariate Cox regression revealed that delayed Seraph® 100 treatment after ICU admission (>60 h), as well as bacterial superinfection, were associated with mortality. While average predicted mortality rate according to Sequential Organ Failure Assessment (SOFA) score in ICU patients was 56.7%, the observed mortality was 50.7%. In non-ICU patients, Coronavirus Clinical Characterisation Consortium (4C) score average predicted a mortality rate of 38.0%, while the observed mortality rate was 11.1%. Conclusions The treatment of COVID-19 patients with Seraph® 100 is well tolerated and the circuit failure rate was lower than previously reported for kidney replacement therapy (KRT) in COVID-19 patients. Mortality correlated with late initiation of Seraph treatment after ICU admission and bacterial superinfection. Compared with predicted mortality according to 4C and SOFA scores, mortality of Seraph® 100-treated patients reported in the registry was lower. [ABSTRACT FROM AUTHOR]

Background: Deficiency of immunoglobulins of the classes IgG, IgG1, IgA and IgM is associated with severity of disease and mortality in sepsis and septic shock. Therapeutic plasma exchange (TPE) with fresh frozen plasma (FFP) has recently gained attention as an adjunctive therapeutic option in early septic shock. We hypothesized that TPE might modulate immunoglobulin deficiencies besides sole elimination of circulating injurious molecules. Methods: We conducted a prospective single center study with TPE in 33 patients with early septic shock (onset < 12 h) requiring high doses of norepinephrine (NE > 0.4mg/kg/min). Clinical and biochemical data, including measurement of immunoglobulin subgroups IgG, IgG1, IgM and IgA were obtained before and after TPE. The following immunoglobulin cut-off values were used to analyze subgroups with low immunoglobulin concentrations at baseline (IgG ≤ 6.5, IgG1 ≤ 3, IgM ≤ 1.5 and IgA ≤ 0.35 g/L). Results: At inclusion, median (IQR) SOFA score was 18 (15-20) and NE dose was 0.8 (0.6-1.2) mg/kg/min. The majority of patients demonstrated profound reductions in immunoglobulins levels of all classes. Globally, immunoglobulin levels were not significantly changed after a single TPE session. However, in patients with low baseline immunoglobulin levels a significant increase in all classes was observed (IgG 1.92 (0.96-3) g/L (þ41%), IgG1 2.1 (1.46-2.32) g/L (þ96%), IgA 0.44 (0.12-0.62) g/L (59%) and IgM 0.18 (0.14-0.34) g/L (þ55%), p < 0.001 for comparison to patients above cut-off). Conclusions: The majority of early and severe septic shock patients had reduced immunoglobulin levels and a single TPE could attenuate immunoglobulin deficiencies of all classes. The clinical relevance of this observation has to be investigated in a proper designed trial. [ABSTRACT FROM AUTHOR]

Background: Disruption of the endothelial glycocalyx (eGC) is observed in septic patients and its injury is associated with multiple-organ failure and inferior outcomes. Besides this biomarker function, increased blood concentrations of shedded eGC constituents might play a mechanistic role in septic organ failure. We hypothesized that therapeutic plasma exchange (TPE) using fresh frozen plasma might influence eGC-related pathology by removing injurious mediators of eGC breakdown while at the time replacing eGC protective factors. Methods: We enrolled 20 norepinephrine-dependent (NE > 0.4 μg/kg/min) patients with early septic shock (onset < 12 h). Sublingual assessment of the eGC via sublingual sidestream darkfield (SDF) imaging was performed. Plasma eGC degradation products, such as heparan sulfate (HS) and the eGC-regulating enzymes, heparanase (Hpa)-1 and Hpa-2, were obtained before and after TPE. A 3D microfluidic flow assay was performed to examine the effect of TPE on eGC ex vivo. Results were compared to healthy controls. Results: SDF demonstrated a decrease in eGC thickness in septic patients compared to healthy individuals (p = 0.001). Circulating HS levels were increased more than sixfold compared to controls and decreased significantly following TPE [controls: 16.9 (8–18.6) vs. septic patients before TPE: 105.8 (30.8–143.4) μg/ml, p < 0.001; vs. after TPE: 70.7 (36.9–109.5) μg/ml, p < 0.001]. The Hpa-2 /Hpa-1 ratio was reduced in septic patients before TPE but normalized after TPE [controls: 13.6 (6.2–21.2) vs. septic patients at inclusion: 2.9 (2.1–5.7), p = 0.001; vs. septic patients after TPE: 13.2 (11.2–31.8), p < 0.001]. Ex vivo stimulation of endothelial cells with serum from a septic patient induced eGC damage that could be attenuated with serum from the same patient following TPE. Conclusions: Septic shock results in profound degradation of the eGC and an acquired deficiency of the protective regulator Hpa-2. TPE removed potentially injurious eGC degradation products and partially attenuated Hpa-2 deficiency. Trial registration clinicaltrials.gov NCT04231994, retrospectively registered 18 January 2020 [ABSTRACT FROM AUTHOR]

Aims: Two guidelines for haemodialysis in lithium poisoning, one from the Extracorporeal TReatments in Poisoning (EXTRIP) workgroup and a single centre retrospective one (Paris) differ. We compared outcomes in lithium poisoning based on these criteria with a primary outcome of worsening neurological symptoms in patients for whom EXTRIP and Paris criteria were discordant. Methods: Poison centre data were queried for lithium poisoned patients for whom haemodialysis was either recommended or performed. Patients were categorized according to EXTRIP and Paris criteria and excluded if the peak lithium concentration was <1.2 mmol/L or if neurological follow‐up was unavailable. Comparative analyses were only performed when both criteria could be assessed. Results: In total, 219 patients were analysed. Paris criteria were met in 70 and EXTRIP criteria in 178. Forty two patients were excluded because Paris criteria could not be evaluated. When Paris and EXTRIP both supported haemodialysis, 50/57 (88%) of patients who received haemodialysis improved, as did all 3 who did not receive haemodialysis. When Paris and EXTRIP did not support haemodialysis, all nondialysed patients did well. Among the 86 patients for whom EXTRIP supported haemodialysis but Paris did not, 4/19 (21%) patients not dialysed deteriorated (P =.02; odds ratio = 8.7, 95% confidence interval = 1.5–51.8), 1 of whom died. All 8 patients for whom Paris criteria supported haemodialysis but EXTRIP did not were dialysed and improved. Conclusions: When the EXTRIP and Paris criteria are discordant, EXTRIP criteria outperforms the Paris criteria at identifying potentially ill patients who might benefit from haemodialysis. [ABSTRACT FROM AUTHOR]

Isoniazid toxicity from self‐poisoning or dosing errors remains common in regions of the world where tuberculosis is prevalent. Although the treatment of isoniazid poisoning is centered on supportive care and pyridoxine administration, extracorporeal treatments (ECTRs), such as hemodialysis, have been advocated to enhance elimination of isoniazid. No systematic reviews or evidence‐based recommendations currently exist on the benefit of ECTRs for isoniazid poisoning. The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup systematically collected and rated the available evidence on the effect of and indications for ECTRs in cases of isoniazid poisoning. We conducted a systematic review of the literature, screened studies, extracted data on study characteristics, outcomes, and measurement characteristics, summarized findings, and formulated recommendations following published EXTRIP methods. Forty‐three studies (two animal studies, 34 patient reports or patient series, and seven pharmacokinetic studies) met inclusion criteria. Toxicokinetic or pharmacokinetic analysis was available for 60 patients, most treated with hemodialysis (n = 38). The workgroup assessed isoniazid as "Moderately Dialyzable" by hemodialysis for patients with normal kidney function (quality of evidence = C) and "Dialyzable" by hemodialysis for patients with impaired kidney function (quality of evidence = A). Clinical data for ECTR in isoniazid poisoning were available for 40 patients. Mortality of the cohort was 12.5%. Historical controls who received modern standard care including appropriately dosed pyridoxine generally had excellent outcomes. No benefit could be extrapolated from ECTR, although there was evidence of added costs and harms related to the double lumen catheter insertion, the extracorporeal procedure itself, and the extracorporeal removal of pyridoxine. The EXTRIP workgroup suggests against performing ECTR in addition to standard care (weak recommendation, very low quality of evidence) in patients with isoniazid poisoning. If standard dose pyridoxine cannot be administered, we suggest performing ECTR only in patients with seizures refractory to GABAA receptor agonists (weak recommendation, very low quality of evidence). [ABSTRACT FROM AUTHOR]

Purpose: To assess whether extracorporeal treatment (ECTR) improves outcome of patients with metformin-associated lactic acidosis (MALA) and to evaluate the clinical applicability of the Extracorporeal Treatments in Poisoning Workgroup (EXTRIP) criteria for starting ECTR in metformin poisoning. Methods: Patients with metformin serum concentrations above 2 mg/l who were admitted in the Deventer Teaching Hospital between January 2000 and July 2019 and complied with the definition of MALA (pH < 7.35 and lactate concentration > 5 mmol/l) were included. Mortality and clinical parameters of patients treated with ECTR or not were compared. In addition, treatment of MALA in clinical practice was verified against the criteria of EXTRIP. Results: Forty-two patients were included. Lactate (13.8 versus 10.5 mmol/l, p = 0.01), creatinine (575 versus 254 umol/l, p < 0.01)), metformin (29.4 versus 8.6 mg/l, p < 0.01) concentrations, and vasopressor requirement (72% versus 23%, p < 0.01) were significantly higher in the ECTR-group. Blood pH (7.05 versus 7.19, p = 0.03) and bicarbonate (6 versus 11 mmol/l, p < 0.01) were significantly lower. Mortality, length of hospital stay, and mechanical ventilation requirement were not statistically different. In 83% of patients, treatment of MALA was in accordance with the EXTRIP criteria. Conclusions: Although there was no statistical benefit in mortality shown from ECTR, ECTR might be lifesaving in MALA, considering the ECTR-group was significantly sicker than the non-ECTR-group. The majority of patients were treated in line with the EXTRIP criteria. Severity of lactic acidosis and renal impairment were the main indications for initiating ECTR. [ABSTRACT FROM AUTHOR]

Background: A dysbalanced coagulation system is part of the pathological host response to infection in sepsis. Activation of pro-coagulant pathways and attenuation of anti-coagulant activity ultimately lead to microvascular stasis and consequent organ failure. No treatment approaches specifically targeting this axis are available. We explored the effects of therapeutic plasma exchange (TPE) on microvascular coagulation dysbalance in septic shock.Methods: We conducted a prospective single-center study enrolling 31 patients with early septic shock (onset < 12 h) requiring high doses of norepinephrine (NE > 0.4 μg/kg/min). Clinical and biochemical data, including measurement of protein C; a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 (ADAMTS13); and von Willebrand factor antigen (vWF:Ag), were obtained before and after TPE against fresh frozen plasma.Results: Antithrombotic acting proteins such as antithrombin-III (ATIII) and protein C were markedly reduced in septic patients, but their activity increased after TPE (ATIII, 51% (41-61) vs. 63% (48-70), p = 0.029; protein C, 47% (38-60) vs. 62% (54-69), p = 0.029). Median ADAMTS13 activity was increased by TPE from 27 (21-42) % before to 47 (38-62) % after TPE (p < 0.001). In contrast, vWF:Ag was elevated and could be reduced by TPE (353 (206-492) IU/dL vs. 170 (117-232) IU/dL, p < 0.001). Regression analysis yielded a correlation between ADAMTS13 activity and platelet count (p = 0.001, R2 = 0.316).Conclusions: Septic shock was associated with activation of pro-coagulant pathways and simultaneous depletion of anti-coagulant factors. TPE partially attenuated this dysbalance by removing pro- and by replacing anti-coagulant factors.Trial Registration: ClinicalTrials.gov, NCT03065751. Retrospectively registered on 28 February 2017. [ABSTRACT FROM AUTHOR]

Establishment of real‐time monitoring technique for blood viscosity during extracorporeal treatment is strongly desired. We have demonstrated that the red blood cell aggregation degree, which highly correlates with the blood viscosity, can be estimated by the microscopic observation of the red blood cell over a transparent blood circuit tube and the two‐dimensional correlation process executed between time different images. In this paper, for estimation precision improvement, a maximum likelihood design of correlation region based on calculation of local flow vector has been attempted. [ABSTRACT FROM AUTHOR]

Extracorporeal treatment (ECTR) represents a treatment modality promoting removal of endogenous or exogenous poisons and supporting or temporarily replacing a vital organ. This article aims to provide a brief overview of the technical aspects and the potential indications and limitations of the different ECTRs, highlighting the important characteristics of poison amenable to ECTR and the most appropriate prescriptions used in the setting of acute poisoning. The various principles that govern poison elimination by ECTR (diffusion, convection, adsorption, and centrifugation) and how components of the ECTR can be adjusted to maximize clearance have also being discussed. [ABSTRACT FROM AUTHOR]

Lithium is a commonly prescribed treatment for bipolar affective disorder. However, treatment is complicated by lithium’s narrow therapeutic index and the influence of kidney function, both of which increase the risk of toxicity. Therefore, careful attention to dosing, monitoring, and titration is required. The cause of lithium poisoning influences treatment and 3 patterns are described: acute, acute-on-chronic, and chronic. Chronic poisoning is the most common etiology, is usually unintentional, and results from lithium intake exceeding elimination. This is most commonly due to impaired kidney function caused by volume depletion from lithium-induced nephrogenic diabetes insipidus or intercurrent illnesses and is also drug-induced. Lithium poisoning can affect multiple organs; however, the primary site of toxicity is the central nervous system and clinical manifestations vary from asymptomatic supratherapeutic drug concentrations to clinical toxicity such as confusion, ataxia, or seizures. Lithium poisoning has a low mortality rate; however, chronic lithium poisoning can require a prolonged hospital length of stay from impaired mobility and cognition and associated nosocomial complications. Persistent neurological deficits, in particular cerebellar, are described and the incidence and risk factors for its development are poorly understood, but it appears to be uncommon in uncomplicated acute poisoning. Lithium is readily dialyzable, and rationale support extracorporeal treatments to reduce the risk or the duration of toxicity in high-risk exposures. There is disagreement in the literature regarding factors that define patients most likely to benefit from treatments that enhance lithium elimination, including specific plasma lithium concentration thresholds. In the case of extracorporeal treatments, there are observational data in its favor, without evidence from randomized controlled trials (none have been performed), which may lead to conservative practices and potentially unnecessary interventions in some circumstances. More data are required to define the risk–benefit of extracorporeal treatments and their use (modality, duration) in the management of lithium poisoning. [ABSTRACT FROM AUTHOR]

The outcome of acute drug poisoning is good. In only a few occasions specific treatments are needed. Toxicological screenings are recommended when acute drug poisoning is suspected. In this retrospective observational study the impact of routine screening on treatment decisions was analyzed. All patients with acute drug poisoning admitted to the emergency department of our university hospital during one year (2013) were retrospectively analyzed. The patients were categorized into two groups: those who received specific therapies due to the poisoning and those who received only symptomatic treatment. Results: There were a total of 318 cases with acute drug poisoning of which 120 led to intensive care treatment. Toxicological screening was performed in 225 cases (70.8%). The screening tests were more often taken from patients who were unconscious (89%) or had altered consciousness (79%) than from patients with normal consciousness (63%, P<0.001). The rate of specific treatment was higher among screened patients compared with patients without screening (18.7 vs 1.1%, P<0.001). However, unexpected screening results were found in 37 of the 225 screened patients out of whom only 6 cases received specific treatment. Most patients with acute drug poisoning were toxicologically screened, but every sixth had an unexpected finding. The rate of patients with unexpected screening result receiving specific treatment was low. [ABSTRACT FROM AUTHOR]

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Background: The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup was formed to provide recommendations on the use of extracorporeal treatments (ECTR) in poisoning. Here, we present our results for digoxin.Methods: After a systematic literature search, clinical and toxicokinetic data were extracted and summarized following a predetermined format. The entire workgroup voted through a two-round modified Delphi method to reach a consensus on voting statements. A RAND/UCLA Appropriateness Method was used to quantify disagreement, and anonymous votes were compiled and discussed in person. A second vote was conducted to determine the final workgroup recommendations.Results: Out of 435 articles screened, 77 met inclusion criteria. Onlyin-vitro, animal studies, case reports and case series were identified yielding a very low quality of evidence for all recommendations. Based on data from 84 patients, including six fatalities, it was concluded that digoxin is slightly dialyzable (level of evidence = B), and that ECTR is unlikely to improve the outcome of digoxin-toxic patients whether or not digoxin immune Fab (Fab) is administered. Despite the lack of robust clinical evidence, the workgroup recommended against the use of ECTR in cases of severe digoxin poisoning when Fab was available (1D) and also suggested against the use of ECTR when Fab was unavailable (2D).Conclusion: ECTR, in any form, is not indicated for either suspected or proven digoxin toxicity, regardless of the clinical context, and is not indicated for removal of digoxin-Fab complex. [ABSTRACT FROM AUTHOR]

Background: Therapeutic plasma exchange (TPE) is either performed using a highly permeable filter with standard multifunctional renal replacement equipment (mTPE) or a centrifugation device (cTPE). Although both techniques are well established in clinical practice, performance of these two modes of TPE was never compared in a prospective randomized fashion. Thus we aimed to compare two commercially available therapeutic apheresis systems: mTPE (Octonova with Plasmaflo filter) and cTPE (Spectra Optia apheresis system). Methods: Twenty-one patients (age 51.6 ± 13.5 years; 10 F/11 M; BMI 25.1 ± 5.0 kg/m) were enrolled in this randomized, prospective, paired, crossover study performed in the Hannover Medical School, Germany. First treatment (either mTPE or cTPE) was chosen by an online randomization list. The primary endpoints were plasma removal efficiency with 1.2× of the total plasma volume exchanged. Secondary endpoints were total amount of plasma substances removed, such as IgG and fibrinogen. Further, the treatment effect on platelet count and complications were evaluated. Results: Despite a comparable volume of the processed plasma, mTPE treatment time was 10.5 % longer than cTPE treatment time ( p < 0.05), resulting in a 10 % lower plasma removal rate of the mTPE treatment. Both treatments were comparable in terms of decrease in median (IQR) IgG [pre-mTPE 5.34 (3.48-8.37), post-mTPE 1.96 (1.43-2.84) g/L; pre-cTPE 5.88 (3.42-8.84), post-cTPE 1.89 (1.21-3.52) g/L]. Also the median (IQR) amount of IgG removed in mTPE [13.14 (7.42-16.10) g] was not different from the cTPE treatment [9.30 (6.26-15.69) g]. This was also true for IgM removal. Platelet loss during mTPE was nearly twice as much as with cTPE (15 ± 9 versus 7 ± 9 %, p < 0.05). Conclusion: Although the centrifugal procedures were conducted using flow rates that could easily be obtained using peripheral access, plasma removal efficiency was significantly higher and treatment time was significantly lower in cTPE as compared to mTPE. Despite this lower treatment time, the decline in markers of procedure efficacy was comparable. Especially in centers performing many procedures per year, cTPE in contrast to mTPE can reduce treatment time without compromising treatment efficacy. [ABSTRACT FROM AUTHOR]

Copyright of Journal of the Turkish Society of Intensive Care / Türk Yogun Bakim Dernegi Dergisi is the property of Galenos Yayinevi Tic. LTD. STI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Introduction. Valproic acid (VPA) is an antiepileptic drug that is now used for a variety of neurological and psychiatric indications. Clinical manifestations of severe VPA poisoning include central nervous system depression, hypotension, electrolyte and acid–base disturbances, and hyperammonemia. Although extracorporeal methods have been used to enhance VPA elimination, the indications for and effectiveness of these methods have not been fully characterized. Methods. A systematic literature search was performed, which identified 31 reports of the use of extracorporeal elimination in VPA poisoning. Results. VPA has a low molecular weight of 144 Da and a low volume of distribution, but at therapeutic concentrations, it is highly protein bound (85–95%). Protein-binding studies during hemodialysis demonstrate that at high VPA concentrations protein binding is saturated, allowing substantial clearance of the free VPA fraction. Case reports consistently show that during hemodialysis the elimination half-life of VPA can be reduced to around 2 h and the enhanced VPA clearance is often associated with improvement clinically. Hemoperfusion also enhances VPA elimination, but its effectiveness may be limited by column saturation. “In-series” hemodialysis and hemoperfusion have been used, but the combination offers little benefit over hemodialysis alone. Continuous renal replacement techniques are increasingly being used although continuous venovenous hemofiltration and continuous venovenous hemodiafiltration do not appear to be as effective as hemodialysis. No controlled trials are available comparing clinical outcomes with or without extracorporeal elimination in VPA poisoning. Novel techniques such as slow low-efficiency dialysis with filtration and supplementation of the dialysate with albumin are being evaluated. Indications. Extracorporeal methods of elimination should be considered in patients with features of severe VPA poisoning (coma or hemodynamic compromise) and plasma VPA concentration >850 mg/L (coma is more likely to be present at concentrations >850 mg/L), particularly if severe hyperammonemia and electrolyte and acid–base disturbances are present. Conclusions. Based on limited anecdotal evidence, hemodialysis appears to be the extracorporeal method of choice to enhance VPA elimination in acute poisoning. Controlled, randomized trials are required to better characterize the effect of extracorporeal treatment on clinical outcome. [ABSTRACT FROM AUTHOR]

The pathogenesis of sepsis begins with the proliferation of micro-organisms at a site of infection, followed by invasion of the bloodstream and other organs. Gram-negative bacteria account for a large part of sepsis cases. The structural component of Gram-negative bacteria, endotoxin or lipopolysaccharide (LPS), induces the synthesis and release of endogenous mediators of sepsis. A growing number of investigations of the molecular mechanisms occurring in sepsis, point to endotoxin as a central mediator leading to multi-organ failure and death. In numerous clinical trials, attempts to target molecules downstream of endotoxin have been made, but have not been associated with improved survival. We describe an affinity-based system for the selective removal of endotoxin from plasma. The small-scale device, a 1.5 ml cartridge, contains beads that bind endotoxin with high specificity and efficiency. In addition, evidence is presented that this device does not affect plasma hemostasis, nor does it activate the complement system. Taken together, these results represent a proof of principle for endotoxin removal from plasma, which may be of clinical value to treat sepsis by extracorporeal circulation of the blood through a scaled-up version of this endotoxin-removing device. [ABSTRACT FROM PUBLISHER]

The pathogenesis of sepsis begins with the proliferation of micro-organisms at a site of infection, followed by invasion of the bloodstream and other organs. Gram-negative bacteria account for a large part of sepsis cases. The structural component of Gram-negative bacteria, endotoxin or lipopolysaccharide (LPS), induces the synthesis and release of endogenous mediators of sepsis. A growing number of investigations of the molecular mechanisms occurring in sepsis, point to endotoxin as a central mediator leading to multi-organ failure and death. In numerous clinical trials, attempts to target molecules downstream of endotoxin have been made, but have not been associated with improved survival. We describe an affinity-based system for the selective removal of endotoxin from plasma. The small-scale device, a 1.5 ml cartridge, contains beads that bind endotoxin with high specificity and efficiency. In addition, evidence is presented that this device does not affect plasma hemostasis, nor does it activate the complement system. Taken together, these results represent a proof of principle for endotoxin removal from plasma, which may be of clinical value to treat sepsis by extracorporeal circulation of the blood through a scaled-up version of this endotoxin-removing device. [ABSTRACT FROM AUTHOR]

In the course of the last four years our group has had experience with the development of an exciting new concept for the treatment of the exfoliative erythrodermic form of cutaneous T cell lymphoma (CTCL), leukemic form, as well as other T cell mediated diseases: extracorporeal photopheresis (EP). In our first experience with this new therapeutic approach, clinical response was observed in 6 of the 7 patients studied. Skin pathology improved significantly so that 5 of 7 patients were able to resume their normal daily activities. Laboratory response was significant in all 7 as measured by a decrease in abnormal T lymphocytes. In spite of an individually adjusted maintenance therapy no significant side effects have been observed. Our initial observations with this new and apparently safe approach for treatment of CTCL and other T cell mediated diseases (e. g. pemphigus vulgaris) suggest that further more extensive clinical trials as well as research into the basic underlying mechanisms involved are warranted. [ABSTRACT FROM AUTHOR]

Background: Toxic alcohols have been implicated in accidental ingestions and intentional exposures. Recognition of toxic alcohol poisoning is challenging. The main treatment modalities include antidotes with alcohol dehydrogenase inhibitors and dialysis. Current guidelines exist for both methanol and ethylene glycol intoxication. However, treatment consensus related to other toxic alcohols is limited. Furthermore, uncertainties regarding thresholds for when to initiate antidotes and dialysis persist. As a consequence, variations exist in the interventions utilized for management of all toxic alcohol poisonings. To our knowledge, no prior systematic review of clinical outcomes of toxic alcohols exists. The objective of this study is to summarize existing evidence on short- and long-term outcomes of patients following toxic alcohol poisonings, including methanol, ethylene glycol, isopropanol, propylene glycol, and diethylene glycol. Methods: A literature search in PubMed, MEDLINE, and EMBASE will be performed based on pre-determined criteria. There will be no restrictions on publication dates or languages. The search will be supplemented by manual scan of bibliographies of eligible studies and gray literature assessment. Observational studies and clinical trials will be included in this review. Once eligible studies have been selected based on pre-specified criteria, two investigators will extract relevant data independently and perform quality assessment per validated tools. A pooled analysis of mortality and short- and long-term secondary outcomes will be performed. Pre-specified subgroup analyses will be performed according to the type of toxic alcohol intoxication, mode of renal replacement therapy, and medical interventions received. A meta-analysis will be performed if three or more studies with similar populations, type of toxic alcohol poisoning, and outcome measures, as well as adequate quality, are identified. This review will be reported according to the recommendations of the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) Statement. Discussion: This systematic review aims to synthesize current evidence in the short- and long-term outcomes of post-toxic alcohol poisoning. The results will enhance the understanding of patient morbidity and mortality after toxic alcohol poisoning, help inform uniform concrete management guideline development, identify gaps in the current state of knowledge, and provide evidence to help implement post-treatment follow-up. Systematic review registration: PROSPERO CRD42018101955 [ABSTRACT FROM AUTHOR]

Background: Given the pathophysiological key role of the host response to an infection rather than the infection per se, an ideal therapeutic strategy would also target this response. This study was designed to demonstrate safety and feasibility of early therapeutic plasma exchange (TPE) in severely ill individuals with septic shock.Methods: This was a prospective single center, open-label, nonrandomized pilot study enrolling 20 patients with early septic shock (onset < 12 h) requiring high doses of norepinephrine (NE; > 0.4 μg/kg/min) out of 231 screened septic patients. Clinical and biochemical data were obtained before and after TPE. Plasma samples were taken for ex-vivo stimulation of human umbilical vein endothelial cells (HUVECs) to analyze barrier function (immunocytochemistry and transendothelial electrical resistance (TER)). Cytokines were measured by cytometric bead array (CBA) and enzyme-linked immunosorbent assays (ELISAs). An immediate response was defined as > 20% NE reduction from baseline to the end of TPE.Results: TPE was well tolerated without the occurrence of any adverse events and was associated with a rapid reduction in NE (0.82 (0.61-1.17) vs. 0.56 (0.41-0.78) μg/kg/min, p = 0.002) to maintain mean arterial pressure (MAP) above 65 mmHg. The observed 28-day mortality was 65%. Key proinflammatory cytokines and permeability factors (e.g., interleukin (IL)-6, IL-1b, and angiopoietin-2) were significantly reduced after TPE, while the protective antipermeability factor angiopoietin-1 was not changed. Ex-vivo stimulation of HUVECs with plasma obtained before TPE induced substantial cellular hyperpermeability, which was completely abolished with plasma obtained after TPE.Conclusions: Inclusion of early septic shock patients with high doses of vasopressors was feasible and TPE was safe. Rapid hemodynamic improvement and favorable changes in the cytokine profile in patients with septic shock were observed. It has yet to be determined whether early TPE also improves outcomes in this patient cohort. An appropriately powered multicenter randomized controlled trial is desirable.Trial Registration: Clinicaltrials.gov, NCT03065751 . Retrospectively registered on 28 February 2017. [ABSTRACT FROM AUTHOR]