High-dose Infusion Research Articles

Old cells die hard - sympatholysis and the ageing erythrocyte.

Old cells die hard - sympatholysis and the ageing erythrocyte.

BRASH Syndrome: Bradycardia, Renal Failure, AV Blockade, Shock, and Hyperkalemia.

BRASH syndrome, or Bradycardia, Renal Failure, AV blockade, Shock, and Hyperkalemia, has recently become recognized as a collection of objective findings in a specific clinical context pertaining to emergency medicine and critical care. However, there is little emergency medicine and critical care literature specifically evaluating this condition. We sought to define and review BRASH syndrome and identify specific management techniques that differ from the syndromes as they present individually. BRASH syndrome is initiated by synergistic bradycardia due to the combination of hyperkalemia and medications that block the atrioventricular (AV) node. The most common precipitant is hypovolemia or medications promoting hyperkalemia or renal injury. Left untreated, this may result in deteriorating renal function, worsening hyperkalemia, and hemodynamic instability. Patients can present with a variety of symptoms ranging from asymptomatic bradycardia to multiorgan failure. BRASH syndrome should be differentiated from isolated hyperkalemia and overdose of AV-nodal blocking medications. Treatment includes fluid resuscitation, hyperkalemia therapies (intravenous calcium, insulin/glucose, beta agonists, diuresis), management of bradycardia (which may necessitate epinephrine infusion), and more advanced therapies if needed (lipid emulsion, glucagon, or high-dose insulin infusion). Understanding and recognizing the pathophysiology of BRASH syndrome as a distinct entity may improve patient outcomes. BRASH syndrome can be a difficult diagnosis and is due to a combination of hyperkalemia and medications that block the AV node. Knowledge of this condition may assist emergency and critical care providers.

Very High-Dose Furosemide Continuous Infusions: A Case Series

BackgroundThere is paucity of data evaluating the efficacy and safety of very high-dose furosemide continuous infusions (≥40 mg/h) for volume removal. This infusion is a novel strategy of loop diuretic administration that may add valuable data to current literature. Methods and ResultsThis was a retrospective chart review. Patients were eligible for inclusion if prescribed a very high-dose furosemide infusion (defined as ≥40 mg/h, up to 240 mg/h) from April 1, 2017, to January 1, 2019, at Thomas Jefferson University Hospital. Data collected included the change in cumulative urine output, net urine output, incidence of acute kidney injury, occurrences of hypotension, electrolyte abnormalities, body weight, and ototoxicity. Twenty-two patients were included in this analysis. The median change in 24-hour urine output from before to after very high-dose continuous furosemide infusion increased from 1193 mL at 24 hours before infusion initiation to 3518 mL at 24 hours after infusion initiation (P < .01). Serum creatinine increased 24 hours after infusion initiation but decreased within 48 hours. There were no electrolyte abnormalities. Out of 22 patients, only 2 had an occurrence of hypotension. No patients were reported to have ototoxicity. ConclusionsVery high-dose furosemide continuous infusions provide a significant increase in diuresis without worsening renal function, disturbing electrolytes, or increasing the risk of ototoxicity. Further studies are necessary to examine the efficacy and safety of this novel strategy.

Vitamin intervention for cytokine storm in the patients with coronavirus disease 2019.

Vitamin intervention for cytokine storm in the patients with coronavirus disease 2019.

Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial

SummaryBackgroundTranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding.MethodsWe did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124.FindingsBetween July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98).InterpretationWe found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial.FundingUK National Institute for Health Research Health Technology Assessment Programme.

Should we reconsider cefazolin for treating staphylococcal meningitis? A retrospective analysis of cefazolin and cloxacillin cerebrospinal fluid levels in patients treated for staphylococcal meningitis

ObjectivesTo assess the meningeal penetration of cefazolin and cloxacillin in individuals treated for methicillin-susceptible staphylococcal meningitis. MethodsWe retrospectively identified individuals treated for Staphylococcus meningitis with measurements of cefazolin or cloxacillin concentrations in cerebrospinal fluid (CSF) using a validated assay of liquid chromatography coupled with mass spectrometry at the Nantes University Hospital between January 2009 and October 2019. Staphylococcus meningitis was defined by a compatible clinical presentation and a microbiological confirmation (positive CSF culture or positive specific PCR). Medical charts were retrospectively reviewed to collect microbiological and clinical data, and to assess therapeutic success. ResultsAmong the 17 included individuals, eight (47%) were treated with cefazolin and nine (53%) with cloxacillin. Median daily dosages of cefazolin and cloxacillin were 8 g (range 6–12 g) and 12 g (range 10–13 g), respectively. Cefazolin and cloxacillin were mainly administered by continuous infusion. Eleven individuals (65%) were men, median (interquartile range (IQR)) age was 54 years (50; 70), 14 (82%) had postoperative meningitis and 3 (18%) had haematogenous meningitis. Median (IQR) antibiotic CSF concentrations were 2.8 mg/L (2.1; 5.2) and 0.66 mg/L (0.5; 0.9) for cefazolin and cloxacillin groups, respectively. Cloxacillin was discontinued in two individuals for therapeutic failure. ConclusionsPatients with staphylococcal meningitis treated with high-dose continuous intravenous infusion of cefazolin achieved therapeutic concentrations in CSF. Cefazolin appears to be a therapeutic candidate that should be properly evaluated in this indication.

Combined Use of CytoSorb and ECMO in Patients with Severe Pneumogenic Sepsis.

High morbidity and mortality are frequently reported in intensive care patients suffering from severe sepsis with systemic inflammation. With the development of severe respiratory failure, extracorporeal membrane oxygenation (ECMO) is often required. In this study, cytokine adsorption therapy in combination with ECMO is applied in patients with acute respiratory distress syndrome (ARDS) due to severe pneumogenic sepsis. The efficacy of this therapy is evaluated compared with a historical cohort without hemoadsorption therapy. Between January and May 2018, combined high-flow venovenous ECMO and CytoSorb therapy (CytoSorb filter connected to ECMO circuit) was applied in patients (n = 13) with pneumogenic sepsis and ARDS. These patients were prospectively included (CytoSorb group). Data from patients (n = 7) with pneumogenic sepsis and ECMO therapy were retrospectively analyzed (control group). All patients survived in the CytoSorb group, where the 30-day mortality rate reached 57% in the control group. After CytoSorb therapy, we instantly observed a significant reduction in procalcitonin (PCT) and C-reactive protein (CRP) levels compared with the control group. Within 48 hours, the initial high doses of catecholamine could be weaned off only in the CytoSorb group. Our results indicate that CytoSorb in combination with ECMO is an effective therapy to prevent escalation of sepsis with rapid weaning off high-dose catecholamine infusions and quick reduction in PCT and CRP levels. Optimal timing of immunomodulatory therapy and impact on ECMO-related inflammation still need to be furtherly investigated.

Aversive Effects of the Kappa Opioid Agonist U‐50488 Alone and in Combination with the Cannabinoid Agonist CP 55,940 in Male Rats

Kappa (κ) opioid receptor agonists can produce prominent analgesic and diuretic effects when administered alone and these effects can be enhanced by the co‐administration of cannabinoids such as CP 55,940. The purpose of the present experiment was to determine if cannabinoids can also enhance the aversive effects of kappa agonists, because these effects substantially reduce their clinical utility as analgesics and aquaretics. To study the aversive effects of kappa agonists and their interaction with cannabinoids, nine male Long‐Evans rats were trained to respond for food under a fixed‐ratio (FR) schedule of food presentation and then implanted with intravenous (i.v.) catheters. Following recovery, the subjects were transitioned to a multiple FR, FR schedule. More specifically, in the presence of a single white stimulus light, food was presented under a fixed‐ratio 30 (FR‐30) schedule (non‐infusion component), whereas presence of both this white stimulus light and a green stimulus light, an i.v. infusion was presented on the first response of each FR and food was presented on the thirtieth FR response (infusion component). When responding was consistent in both components, varying infusion doses of U‐50488 (0.032 – 0.18 mg/kg) replaced the baseline saline infusion until one of three criterion was met: 3 days in which the variability of responding did not vary by ± 20% of the mean, 3 days of responding at less than 0.3 responses per sec, or a maximum of 8 days. After the criterion was met for each dose substitution, the subjects returned to the baseline in which saline served as the infusion and responding was similar between components. To study the interaction of CP 55,940 with the effects of U‐50488, single acute injections of a dose of CP 55,940 (0.056 mg/kg) were administered prior to sessions in which a dose of U‐50488 was available in the infusion component. Each dose‐infusion combination was administered until subjects met the criterion. These effects were then compared to sessions in which one of two doses of naltrexone (1, 3.2 mg/kg) was administered prior the same U‐50488 infusion doses. When infusions of U‐50488 replaced saline, low infusion doses (e.g., 0.056 mg/kg/infusion) selectively suppressed responding in the infusion component, while higher infusion doses (e.g., 0.18 mg/kg/infusion) decreased responding in both components as the total dose of U‐50488 for the session increased. Administration of CP 55,940 did not produce a marked enhancement of the suppressive effects of U‐50488 at the dose tested, and surprisingly, neither dose of naltrexone antagonized its suppressive effects. Together, these data demonstrate the aversive effects of U‐50488 alone, the absence of a marked enhancement by at least one cannabinoid agonist, and the surprising absence of antagonism by the opioid receptor antagonist naltrexone.

Escape or Fight: Inhibitors in Hemophilia A.

Replacement therapy with coagulation factor VIII (FVIII) represents the current clinical treatment for patients affected by hemophilia A (HA). This treatment while effective is, however, hampered by the formation of antibodies which inhibit the activity of infused FVIII in up to 30% of treated patients. Immune tolerance induction (ITI) protocols, which envisage frequent infusions of high doses of FVIII to confront this side effect, dramatically increase the already high costs associated to a patient's therapy and are not always effective in all treated patients. Therefore, there are clear unmet needs that must be addressed in order to improve the outcome of these treatments for HA patients. Taking advantage of preclinical mouse models of hemophilia, several strategies have been proposed in recent years to prevent inhibitor formation and eradicate the pre-existing immunity to FVIII inhibitor positive patients. Herein, we will review some of the most promising strategies developed to avoid and eradicate inhibitors, including the use of immunomodulatory drugs or molecules, oral or transplacental delivery as well as cell and gene therapy approaches. The goal is to improve and potentiate the current ITI protocols and eventually make them obsolete.

Injectable melatonin: an anti-cancer and anti-viral treatment option

Intravenous infusion of high doses of melatonin would represent the most eligible route to treat conveniently patients hospitalized in critical care units or with undergoing oncologic therapies, wherein adequate, accurate and constant dosages and high levels of melatonin would be required. After several attempts, a stable concentrate bulk solution of 10% melatonin (Survivis®) has been successfully achieved. The injectable route is also referred for lifethreatening injuries.

Non-additive effects of adjunct erythropoietin therapy with therapeutic hypothermia after global cerebral ischaemia in near-term fetal sheep.

Recombinant human erythropoietin (rEpo) is neuroprotective in immature animals, but it is unclear whether the combination of high-dose rEpo therapy with therapeutic hypothermia can further improve outcomes. Hypothermia and rEpo independently improved neuronal survival, with greater improvement with hypothermia, and similarly reduced numbers of caspase-3 positive cells and reactive microglia after 7days recovery. Hypothermia, but not rEpo, was associated with markedly improved EEG power, whereas both interventions improved recovery of EEG frequency. There was no significant improvement in any outcome after combined rEpo and hypothermia compared with hypothermia alone, and of concern, the combination was associated with increased numbers of cortical caspase-3-positive cells compared with ischaemia-hypothermia. These data suggest that the mechanisms of neuroprotection with hypothermia and rEpo overlap and, thus, high-dose rEpo infusion does not appear to be an effective adjunct therapy for therapeutic hypothermia. Therapeutic hypothermia for hypoxic-ischaemic encephalopathy (HIE) provides incomplete neuroprotection. Recombinant human erythropoietin (rEpo) is neuroprotective in immature animals, but it is unclear whether adjunct rEpo therapy with therapeutic hypothermia can further improve outcomes. Near-term fetal sheep received sham-ischaemia (n=9) or global cerebral ischaemia for 30min (ischaemia-vehicle, n=8), followed by intravenous infusion of rEpo (ischaemia-Epo, n=8; 5000U/kg loading dose, then 833.3U/kg/h), cerebral hypothermia (ischaemia-hypothermia, n=8), or rEpo plus hypothermia (ischaemia-Epo-hypothermia, n=8), from 3 to 72h post ischaemia. Fetal brains were collected 7days after cerebral ischaemia. Cerebral ischaemia was associated with severe neuronal loss and microglial induction in the parasagittal cortex and subcortical regions. Hypothermia reduced overall neuronal loss, cortical caspase-3 and reactive microglia in the striatum and cortex, with greater recovery of electroencephalographic (EEG) power and spectral edge (SEF) from 48h onwards. rEpo independently improved neuronal survival in the parasagittal cortex, hippocampal CA4 and thalamus, and reduced cortical caspase-3 and activated microglia in striatal and cortical areas, with greater SEF from 120h onwards. However, ischaemia-Epo-hypothermia did not further improve outcomes compared with ischaemia-hypothermia and was associated with increased numbers of cortical caspase-3-positive cells. These findings suggest that although delayed, prolonged treatment with both hypothermia and rEpo are independently neuroprotective, they have overlapping anti-inflammatory and anti-apoptotic mechanisms, such that the delayed, high-dose rEpo infusion for 3days did not materially augment neuroprotection with therapeutic hypothermia.

Successful treatment with continuous high-dose 5-fluorouracil infusion, followed by oral capecitabine in a patient with advanced gastric cancer with bone marrow metastasis and microangiopathic hemolytic anemia

A 61-year-old male with a history of Stage 1A gastric body adenocarcinoma and s/p radical subtotal gastrectomy + B-II reconstruction 5 years previously presented with general malaise and bone pain. A hemogram revealed severe anemia and thrombocytopenia, which were refractory to blood transfusion. A peripheral blood smear showed marked thrombocytopenia with numerous fragmented red blood cells and normoblasts. A bone marrow biopsy showed metastatic adenocarcinoma of gastric origin. Therefore, he was diagnosed with cancer-associated microangiopathic hemolytic anemia (MAHA). In addition to aggressive transfusion support, high-dose continuous 5-fluorouracil infusion was administered, and the MAHA and thrombocytopenia dramatically resolved. Capecitabine was subsequently administered orally at the outpatient clinic, and his disease was well controlled without the recurrence of MAHA or thrombocytopenia for 1 year. Although most chemotherapies may aggravate cytopenia, our case illustrates that effective chemotherapy can not only control cancer-associated MAHA but also restore cytopenia to normal.

Intraoperative High-Dose Tranexamic Acid Infusion in Vertebral Surgeries: Our Clinical Experiences

Intraoperative High-Dose Tranexamic Acid Infusion in Vertebral Surgeries: Our Clinical Experiences

CURRENT CONCEPTS IN THE MANAGEMENT OF TETANUS

The study focuses on the problem of severe tetanus cases, which continue to be reported worldwide. The population of countries with low vaccination rates, including Ukraine, is particularly at risk. Despite the increase in the level of DPT vaccination in our country among adults and children, it remains insufficient, which leads to the registration of new cases of tetanus. The aim of the study was to analyze the main directions in the treatment of tetanus. The authors searched for information in electronic databases such as MEDLINE/Pub Med and Google Scholar for the last 20 years. The search was performed on such terms as tetanus, treatment, benzodiazepines, tetanus immunoglobulin (medical topics). The main components of modern treatment are analyzed in the paper, which include removal of the pathogen by careful surgical treatment of wounds, rational antibiotic therapy. Drugs of choice for the eradication of vegetative forms of the pathogen are benzylpenicillin and metronidazole, but can also be used antibacterial drugs of other groups (macrolides, tetracyclines, cephalosporins). Specific immunotherapy with tetanus immunoglobulin can neutralize the toxin that freely circulates in the blood. Those who do not have vaccination data are also indicated for the introduction of tetanus toxoid. Intrathecal administration of anti-tetanus immunoglobulin remains a debatable issue. In the treatment of convulsions, drugs of the benzodiazepine group are preferred. Infusions of high doses of magnesium, dexmetomedin, baclofen, propofol or their combination can also be used. In the case of severe muscular rigidity, muscle relaxants of nondepolarizing action are used. If the spasms are prolonged, botulinum toxin A may be recommended as an injection into peripheral muscles. B-blockers (esmolol), dexmetomedin, clonidine are used to overcome autonomic dysfunction of the nervous system. Supportive therapy is important. It is aimed at providing the patient with complete nutrition. Adequate ventilation with early tracheostomy helps to avoid complications of prolonged intubation. The above methods can significantly reduce mortality from tetanus from 100% (in the absence of treatment) to 10%–20%. Keywords: tetanus, management, benzodiazepines, magnesium sulfate, tetanus immunoglobin, tracheostomy.

Rapid-onset vasodilator responses to exercise in humans: Effect of increased baseline blood flow.

What is the central question of this study? What is the effect of an elevated baseline blood flow, induced by high-dose intra-arterial infusion of either adenosine or ATP, on the rapid-onset vasodilatory response to a single forearm muscle contraction? What is the main finding and its importance? The peak response to a single contraction is unaffected by augmented baseline blood flow, and thus, is likely to be attributable to a feedforward vasodilatory mechanism. The hyperaemic responses to single muscle contractions are proportional to exercise intensity, which, in turn, is proportional to tissue metabolic demand. Hence, we tested the hypothesis that the rapid-onset vasodilatory response after a single muscle contraction would be unaffected when baseline blood flow was increased via high-dose intra-arterial infusion of either adenosine (ADO) or ATP. Twenty-four healthy young participants (28±1years) performed a single forearm contraction (20% maximal voluntary contraction) 75min after commencement of a continuous infusion of ADO (n=6), ATP (n=8) or saline (control; n=10). Brachial artery diameter and blood velocity were measured using Doppler ultrasound. Resting forearm vascular conductance (FVC; in millilitres per minute per 100mmHg per decilitre of forearm volume) was significantly higher during ADO (33±17) and ATP infusion (33±17) compared with the control infusion (8±3; P<0.05). The peak FVCs post-contraction during ADO and ATP infusions were significantly greater than during the control infusion (P<0.05), but not different from one another. The peak change in FVC from baseline was similar in all three conditions (control, 14±1; ADO, 24±2; and ATP, 23±6; P=0.15). Total FVC (area under the curve) did not differ significantly between ADO and ATP (333±69 and 440±125); however, total FVC during ATP infusion was significantly greater compared with the control value (150±19; P<0.05). We conclude that the peak response to a single contraction is unaffected by augmented baseline blood flow and is therefore likely to be attributable to a feedforward vasodilatory mechanism.

Characteristics of the nonpulmonary vein foci induced after second-generation cryoballoon ablation for paroxysmal atrial fibrillation.

Pulmonary vein isolation (PVI) using cryoballoon is effective for patients with paroxysmal atrial fibrillation (PAF); however, few reports have evaluated the non-pulmonary vein (PV) foci after cryoballoon ablation. We aimed to evaluate the characteristics of non-PV foci and predictors of atrial fibrillation (AF) recurrence after cryoballoon ablation. This was a single-center retrospective study of 647 patients with PAF who underwent initial PVI using a second-generation cryoballoon. After PVI, all patients underwent high-dose isoproterenol infusion to assess the existence of non-PV foci. Non-PV foci were observed in 211 patients (32.6%), which were most frequently observed in the superior vena cava. Higher age (odds ratio [OR] = 1.02; 95% confidence interval [CI] = 1.00-1.04; P = .025), female sex (OR = 1.65; 95% CI = 1.13-2.41; P = .009), and lower body mass index (OR = 0.95; 95% CI = 0.89-1.00; P = .049) were significantly associated with non-PV foci. The existence of non-PV foci was an independent predictor of AF recurrence (Hazard's ratio = 1.70; 95% CI = 1.12-2.60; P = .014). When non-PV foci were mappable and successfully ablated, patients with non-PV foci showed similar outcomes with those without non-PV foci (1-year AF-free survival rates of 88.5% vs 91.5%; P = .338). Conversely, when we failed to detect and eliminate non-PV foci because they had multiple origins and were not consistently inducible (multichanging non-PV foci), the 1-year AF-free survival rate was 56.4% even after substrate modification. Non-PV foci were observed in one-third of patients with PAF after cryoballoon ablation and were associated with AF recurrence. Catheter ablation for non-PV foci was effective when they were mappable; however, multichanging non-PV foci were associated with worse prognosis.

Diuretic Strategies for Loop Diuretic Resistance in Acute Heart Failure: The 3T Trial

ObjectivesThis study compared combination diuretic strategies in acute heart failure (AHF) complicated by diuretic resistance (DR). BackgroundCombination diuretic regimens to overcome loop DR are commonly used but with limited evidence. MethodsThis study was a randomized, double-blinded trial in 60 patients hospitalized with AHF and intravenous (IV) loop DR. Patients were randomized to oral metolazone, IV chlorothiazide, or tolvaptan therapy. All patients received concomitant high-dose IV infusions of furosemide. The primary outcome was 48-h weight loss. ResultsThe cohort exhibited DR prior to enrollment, producing 1,188 ± 476 ml of urine in 12 h during high-dose loop diuretic therapy (IV furosemide: 612 ± 439 mg/day). All 3 interventions significantly improved diuretic efficacy (p < 0.001). Compared to metolazone (4.6 ± 2.7 kg), neither IV chlorothiazide (5.8 ± 2.7 kg; 1.2 kg [95% confidence interval (CI)]: −2.9 to 0.6; p = 0.292) nor tolvaptan (4.1 ± 3.3 kg; 0.5 kg [95% CI: −1.5 to 2.4; p = 0.456) resulted in more weight loss at 48 h. Median (interquartile range [IQR]) cumulative urine output increased significantly and did not differ among those receiving metolazone (7.78 [IQR: 6.59 to 10.10] l) and chlorothiazide (8.77 [IQR: 7.37 to 10.86] l; p = 0.245) or tolvaptan (9.70 [IQR: 6.36 to 13.81] l; p = 0.160). Serum sodium decreased less with tolvaptan than with metolazone (+4 ± 5 vs. −1 ± 3 mEq/l; p = 0.001), but 48-h spot urine sodium was lower with tolvaptan (58 ± 25 mmol/l) than with metolazone (104 ± 16 mmol/l; p = 0.002) and with chlorothiazide (117 ± 14 mmol/l; p < 0.001). ConclusionsIn this moderately sized DR trial, weight loss was excellent with the addition of metolazone, IV chlorothiazide, or tolvaptan to loop diuretics, without a detectable between-group difference. (Comparison of Oral or Intravenous Thiazides vs. tolvaptan in Diuretic Resistant Decompensated Heart Failure [3T]; NCT02606253)

Overcoming CD19 Antigen Loss in B-Cell Malignancies with CAR T Cells Targeting BAFF-R

Background: The current success in treating hematological malignancies with CD19 targeted chimeric antigen receptor (CAR) T cells is diminished by tumor relapse from target antigen loss. The B-cell activating factor-receptor (BAFF-R), a tumor necrosis factor receptor superfamily protein (TNFRSF13C), is a particularly interesting alternative target in CD19 relapsed disease and in B cell malignancies in general. BAFF-R null mice exhibit greatly reduced normal B-cell numbers and mouse strains expressing a mutant BAFF-R exhibited decreased B-cell life spans and a dramatically reduced peripheral B-cell compartment. Thus, BAFF-R signaling is a driver of B-cell survival, which may limit the capacity of clonal B-cell tumors to escape therapy by down-regulation of antigen expression. We have exploited the potential of the BAFF/BAFF-R axis and developed a proprietary BAFF-R targeting CAR T cell using a single-chain variable fragment (scFv) of a humanized anti-human BAFF-R antibody engineered into a second generation CAR construct containing 4-1BB costimulatory and CD3ζ intracellular signaling domains (Qin et al. Sci. Transl. Med., In Press). BAFF-R CAR T cells were cytotoxic against a panel of human leukemia and lymphoma lines. Adoptively transferred BAFF-R-CAR T cells eradicated 10-day pre-established tumor xenografts after a single treatment and retained efficacy against xenografts deficient in CD19 expression, including CD19-negative variants within a background of CD19-positive lymphoma cells. BAFF-R-, but not CD19-CAR T cells, also demonstrated antitumor effects against an additional CD19 antigen loss primary patient-derived xenograft (PDX) in vivo. Methods and Results: A first-in-human clinical trial of this BAFF-R CAR T cell in B-ALL is planned. To this end, we cloned the BAFF-R CAR construct into a previously FDA approved clinical lentiviral vector (Figure, part A), and produced BAFF-R CAR T cells using both the research prototype and clinical vectors for head-to-head analysis. We observed comparable cytotoxic T lymphocyte activity against previously established leukemia and lymphoma models in vitro. In vivo, NSG mice challenged with Nalm-6 human B-ALL tumors were randomized (n=5/group) for treatment with either BAFF-R CAR produced from the research prototype or clinical vectors. The two experimental groups were indistinguishable in their antitumor efficacy (data not shown). Further, to advance IND enabling studies we also compared clinical CAR T cell manufacturing strategies. We used an early stage TN/MEM subset for CAR T cell production, as used in previous CAR T cell trials at our institution, and using TN/MEM isolated from healthy donor PBMCs achieved 36% transduction efficiency, comparable to clinical experience at City of Hope. Finally, we assessed the therapeutic effects of BAFF-R CAR TN/MEM cells in vivo. We challenged NSG mice on day 0 with 1 x 105 Nalm-6-CD19 deficient (Nalm-6-CD19KO) human ALL tumor cells and randomized them (n=5/group) to receive a single infusion of either low dose (1 x 106) or high dose (2 x 106) BAFF-R-CAR TN/MEM cells on day 10. Because transduction efficiency was 36%, 2.8 or 5.6 x 106 total T cells were infused to yield 1 or 2 x106 BAFF-R-CAR TN/MEM, respectively. Non-transduced T cells from the same donor were used as allogeneic controls (non-CAR). Tumors were monitored by bioluminescent imaging on the days indicated. Both the low and the high dose BAFF-R CAR T cell groups demonstrated complete Nalm-6 CD19KO tumor regressions, compared with controls (Figure, part B). Conclusions: Our studies support the clinical development of BAFF-R CAR T cells and a pending clinical trial of BAFF-R CAR T cell therapy in relapsed/refractory B-ALL patients who have failed prior CD19-targeted immunotherapy. Targeting BAFF-R may thereby add to existing alternative strategies to overcome relapse from CD19 antigen loss. While BAFF-R antigen loss by tumor cells is unlikely, because its expression is critically required for normal B-cell survival, this hypothesis can only be established by clinical testing. Disclosures Qin: InnoLifes: Consultancy, Equity Ownership; Pepromene Bio: Consultancy, Equity Ownership. Aldoss:AUTO1: Consultancy; Helocyte: Consultancy, Honoraria, Other: travel/accommodation/expenses; Jazz Pharmaceuticals: Honoraria, Other: travel/accommodation/expenses, Speakers Bureau; Agios: Consultancy, Honoraria. Kwak:Pepromene Bio: Consultancy, Equity Ownership, Research Funding; InnoLifes: Consultancy, Equity Ownership; Xeme BioPharma, Inc: Consultancy, Equity Ownership; Enzychem LifeSciences: Consultancy; Celltrion, Inc.: Consultancy; Celltrion Healthcare: Consultancy.

Granulocyte Transfusions in a Cohort of Neutropenic Patients with Life-Threatening Infections and Hematologic Diseases

Granulocyte transfusions are inconsistently used despite observational evidence of their efficacy (Seidel et al, 2008). The Resolving Infection in Neutropenia with Granulocytes (RING) trial was incomplete due to poor enrollment and thus was underpowered to assess efficacy of granulocytes in adults with neutropenia and severe infection unresponsive to anti-microbials (Price et al, 2015). Post-hoc analysis showed a group of patients had better clinical responses with higher doses of granulocytes. We hypothesized that patients treated at Stanford University with higher doses of granulocytes had better clinical outcomes than those patients who received lower doses of granulocytes. Granulocyte transfusions are available at Stanford University from well repeat platelet donors who have recent negative infectious disease markers for transfusion-transmitted infections. Donors receive stimulation with steroids about 12 hours prior to collection. After IRB approval, a single center retrospective cohort study was done to assess all patients who had received granulocytes at Stanford University from August 2006 to June 2018. We queried the electronic health record and transfusion service information system for patient demographics, diagnosis, weight, dose and frequency of granulocyte infusion(s), time to ANC recovery &amp;gt;500 and the primary outcome of survival to hospital discharge. There were 45 patients identified within the transfusion service information system, but only 27 had available granulocyte dosing and clinical records for review. To evaluate for most important clinical parameters, random forest classification and regression was performed against survival to hospital discharge and time to neutropenia recovery post initiation of granulocyte infusions respectively (randomForest R package). Cox proportional hazard (coxph) models were determined using mean granulocyte dose per infusion (cells/kg/infusion), total granulocyte dose per admission (cells/kg), age, and duration of neutropenia against survival to discharge and resolution of neutropenia (survival and survminer R packages). Kaplan-Meier survival analysis was performed based on high and low mean granulocyte dosing (&amp;lt;0.6e9cells/kg, which is equivalent to 4 x10e10 in a 70kg patient). Twenty-seven patients age 3 to 80 years (median 38 years) with various hematologic disorders were treated with granulocyte transfusions (median 4 infusions, range 1 - 14). Fifteen of 27 (56%) patients survived to hospital discharge. Random forest classification identified mean granulocyte dose per infusion as the most influential feature in predicting survival to hospital discharge by both mean decrease in accuracy and mean decrease in Gini. Additional influential parameters included total granulocyte dose per kg, age, and duration of neutropenia. Random forest regression could not identify a clear feature that was most influential in predicting time to resolution of neutropenia. Coxph models did not identify a significant feature that predicted survival to discharge. Although all 3 patients who received high dose infusions survived compared to 50% surviving in the low dose group (median survival of 33 days), the results did not achieve significance (p = 0.15). Coxph models identified mean granulocyte dose per kg as significantly associated with resolution of neutropenia (HR 26.15, 95% CI 1.65-413.83, p = 0.021) whereas total granulocyte dose per kg over all infusions was associated with prolonged neutropenia (HR 0.69, 95% CI 0.52-0.92, p = 0.012). We present a series of granulocyte transfusions in 27 neutropenic patients with life-threatening infections not responsive to standard therapies. Though there was not a statistically significant difference in survival between those infused with high versus low dose granulocytes, the mean granulocyte dose infused per kg was associated with a resolution of neutropenia. This suggests that if one prescribes granulocytes for these patients, they should be higher dose (at least 0.6e9cells/kg). 1. Seidel MG, Peters C, Wacker A, et al. Study of granulocyte transfusions in neutropenic patients. Bone Marrow Transplant 2008;42:679-86. 2. Price TH, Boeckh M, Harrison RW, et al. Efficacy of transfusion with granulocytes from G-CSF/dexamethasone-treated donors in neutropenic patients with infection. Blood 2015;126:2153-61. Disclosures No relevant conflicts of interest to declare.

Association of Vitamin D Deficiency with Profound Cardiogenic Shock in Patients Resuscitated From Sudden Cardiac Arrest.

Vitamin D deficiency is associated with various cardiovascular diseases, including sudden cardiac arrest (SCA). Profound cardiogenic shock is associated with morbidity and mortality in patients with SCA. This study investigated the association of vitamin D deficiency with profound cardiogenic shock in patients resuscitated from SCA. We enrolled patients who were successfully resuscitated from out-of-hospital cardiac arrests of a presumed cardiac cause. Profound cardiogenic shock was defined as refractory hypotension requiring high-dose vasopressor infusion (norepinephrine >0.5 mcg/kg/min) despite adequate intravascular volume replacement. Vitamin D levels were measured as plasma 25(OH)D concentrations and severe vitamin D deficiency was defined as 25(OH)D <10 ng/mL. A total of 237 subjects (179 men (76%), mean age 56.5 ± 16.5 years) were included in this study. The first monitored rhythm was shockable in 160 subjects (68%). Mean arrest time and CPR times were 25.6 ± 15.7 and 22.8 ± 15.0 min, respectively. Profound cardiogenic shock was observed in 100 subjects (42%). The mean vitamin D level was 12.3 ± 6.7 ng/mL, and vitamin D deficiency was diagnosed in 109 subjects (46%). In profound cardiogenic shock subjects, vitamin D levels were significantly lower (10.7 ± 7.0 vs. 13.4 ± 6.2 ng/mL, P = 0.002) and severe vitamin D deficiency was observed more frequently (63% vs. 34%, P < 0.001). Subjects with profound cardiogenic shock were likely to have longer arrest times (29.5 ± 17.0 vs. 22.7 ± 14.0 min, P = 0.001), left ventricular systolic dysfunction (LVEF < 40%, 73% vs. 38%, P < 0.001), and baseline renal dysfunction (65% vs. 37%, P < 0.001). Multivariate logistic analysis indicated that vitamin D deficiency was significantly associated with profound cardiogenic shock after SCA (OR 2.71, 95% CI 1.42-5.18, P = 0.003) after adjusting for confounding variables. Severe vitamin D deficiency was strongly associated with profound cardiogenic shock and mortality in patients resuscitated from SCA.