Publications by authors named "Anita Reddy"

67 Publications

Glucose metabolism and pyruvate carboxylase enhance glutathione synthesis and restrict oxidative stress in pancreatic islets.

Cell Rep 2021 Nov;37(8):110037

Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston 02115, MA, USA; Department of Medicine, Harvard Medical School, 240 Longwood Ave., Boston, MA 02115, USA. Electronic address:

Glucose metabolism modulates the islet β cell responses to diabetogenic stress, including inflammation. Here, we probed the metabolic mechanisms that underlie the protective effect of glucose in inflammation by interrogating the metabolite profiles of primary islets from human donors and identified de novo glutathione synthesis as a prominent glucose-driven pro-survival pathway. We find that pyruvate carboxylase is required for glutathione synthesis in islets and promotes their antioxidant capacity to counter inflammation and nitrosative stress. Loss- and gain-of-function studies indicate that pyruvate carboxylase is necessary and sufficient to mediate the metabolic input from glucose into glutathione synthesis and the oxidative stress response. Altered redox metabolism and cellular capacity to replenish glutathione pools are relevant in multiple pathologies beyond obesity and diabetes. Our findings reveal a direct interplay between glucose metabolism and glutathione biosynthesis via pyruvate carboxylase. This metabolic axis may also have implications in other settings where sustaining glutathione is essential.
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http://dx.doi.org/10.1016/j.celrep.2021.110037DOI Listing
November 2021

Association of Catecholamine Dose, Lactate, and Shock Duration at Vasopressin Initiation With Mortality in Patients With Septic Shock.

Crit Care Med 2021 Sep 24. Epub 2021 Sep 24.

Department of Pharmacy, Cleveland Clinic, Cleveland, OH. Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH. Respiratory Institute, Cleveland Clinic, Cleveland, OH.

Objectives: To determine the association of catecholamine dose, lactate concentration, and timing from shock onset at vasopressin initiation with in-hospital mortality.

Design: Retrospective, observational study using segmented and multivariable logistic regression to evaluate the associations of catecholamine dose, lactate concentration, and timing from shock onset at vasopressin initiation with in-hospital mortality.

Setting: Multiple hospitals within the Cleveland Clinic Health System.

Patients: Adult patients who met criteria for septic shock based on the U.S. Centers for Disease Control and Prevention Adult Sepsis Event definition.

Interventions: All patients received continuous infusion vasopressin as an adjunct to catecholamine vasopressors.

Measurements And Main Results: In total, 1,610 patients were included with a mean Acute Physiology and Chronic Health Evaluation III 109.0 ± 35.1 and Sequential Organ Failure Assessment 14.0 ± 3.5; 41% of patients survived the hospital admission. At the time of vasopressin initiation, patients had median (interquartile range) lactate concentration 3.9 mmol/L (2.3-7.2 mmol/L), norepinephrine-equivalent dose 25 µg/min (18-40 µg/min), and 5.3 hours (2.1-12.2 hr) elapsed since shock onset. The odds of in-hospital mortality increased 20.7% for every 10 µg/min increase in norepinephrine-equivalent dose up to 60 µg/min at the time of vasopressin initiation (adjusted odds ratio, 1.21 [95% CI, 1.09-1.34]), but no association was detected when the norepinephrine-equivalent dose exceeded 60 µg/min (adjusted odds ratio, 0.96 [95% CI, 0.84-1.10]). There was a significant interaction between timing of vasopressin initiation and lactate concentration (p = 0.02) for the association with in-hospital mortality. A linear association between increasing in-hospital mortality was detected for increasing lactate concentration at the time of vasopressin initiation, but no association was detected for time elapsed from shock onset.

Conclusions: Higher norepinephrine-equivalent dose at vasopressin initiation and higher lactate concentration at vasopressin initiation were each associated higher in-hospital mortality in patients with septic shock who received vasopressin.
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http://dx.doi.org/10.1097/CCM.0000000000005317DOI Listing
September 2021

UCP1 governs liver extracellular succinate and inflammatory pathogenesis.

Nat Metab 2021 05 17;3(5):604-617. Epub 2021 May 17.

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.

Non-alcoholic fatty liver disease (NAFLD), the most prevalent liver pathology worldwide, is intimately linked with obesity and type 2 diabetes. Liver inflammation is a hallmark of NAFLD and is thought to contribute to tissue fibrosis and disease pathogenesis. Uncoupling protein 1 (UCP1) is exclusively expressed in brown and beige adipocytes, and has been extensively studied for its capacity to elevate thermogenesis and reverse obesity. Here we identify an endocrine pathway regulated by UCP1 that antagonizes liver inflammation and pathology, independent of effects on obesity. We show that, without UCP1, brown and beige fat exhibit a diminished capacity to clear succinate from the circulation. Moreover, UCP1KO mice exhibit elevated extracellular succinate in liver tissue that drives inflammation through ligation of its cognate receptor succinate receptor 1 (SUCNR1) in liver-resident stellate cell and macrophage populations. Conversely, increasing brown and beige adipocyte content in mice antagonizes SUCNR1-dependent inflammatory signalling in the liver. We show that this UCP1-succinate-SUCNR1 axis is necessary to regulate liver immune cell infiltration and pathology, and systemic glucose intolerance in an obesogenic environment. As such, the therapeutic use of brown and beige adipocytes and UCP1 extends beyond thermogenesis and may be leveraged to antagonize NAFLD and SUCNR1-dependent liver inflammation.
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http://dx.doi.org/10.1038/s42255-021-00389-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207988PMC
May 2021

Reinfection Rates Among Patients Who Previously Tested Positive for Coronavirus Disease 2019: A Retrospective Cohort Study.

Clin Infect Dis 2021 11;73(10):1882-1886

Center for Value-Based Care Research, Cleveland Clinic, Cleveland, Ohio, USA.

Background: Protection afforded from prior disease among patients with coronavirus disease 2019 (COVID-19) infection is unknown. If infection provides substantial long-lasting immunity, it may be appropriate to reconsider vaccination distribution.

Methods: This retrospective cohort study of 1 health system included 150 325 patients tested for COVID-19 infection via polymerase chain reaction from 12 March 2020 to 30 August 2020. Testing performed up to 24 February 2021 in these patients was included. The main outcome was reinfection, defined as infection ≥90 days after initial testing. Secondary outcomes were symptomatic infection and protection of prior infection against reinfection.

Results: Of 150 325 patients, 8845 (5.9%) tested positive and 141 480 (94.1%) tested negative before 30 August. A total of 1278 (14.4%) positive patients were retested after 90 days, and 62 had possible reinfection. Of those, 31 (50%) were symptomatic. Of those with initial negative testing, 5449 (3.9%) were subsequently positive and 3191 of those (58.5%) were symptomatic. Protection offered from prior infection was 81.8% (95% confidence interval [CI], 76.6-85.8) and against symptomatic infection was 84.5% (95% CI, 77.9-89.1). This protection increased over time.

Conclusions: Prior infection in patients with COVID-19 was highly protective against reinfection and symptomatic disease. This protection increased over time, suggesting that viral shedding or ongoing immune response may persist beyond 90 days and may not represent true reinfection. As vaccine supply is limited, patients with known history of COVID-19 could delay early vaccination to allow for the most vulnerable to access the vaccine and slow transmission.
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http://dx.doi.org/10.1093/cid/ciab234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989568PMC
November 2021

Home testing for COVID-19: Benefits and limitations.

Cleve Clin J Med 2021 Mar 1. Epub 2021 Mar 1.

Department of Critical Care and Medical Operations, Respiratory Institute, Cleveland Clinic, Cleveland, OH.

The home test kits for detecting SARS-CoV-2 infection with Food and Drug Administration emergency use authorization primarily use either isothermal nucleic acid amplification or antigen detection, and each test has advantages and limitations in terms of sensitivity and specificity, cost, results reporting, and results turnaround time. In clinical studies, these tests provide accurate positive results in symptomatic individuals, although negative results are less accurate. There are also accuracy concerns for positive results in asymptomatic individuals. These factors have implications for their clinical interpretation and use.
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http://dx.doi.org/10.3949/ccjm.88a.ccc071DOI Listing
March 2021

Response.

Chest 2021 02;159(2):878-879

Department of Critical Care Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, OH. Electronic address:

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http://dx.doi.org/10.1016/j.chest.2020.09.078DOI Listing
February 2021

Choosing Wisely For Critical Care: The Next Five.

Crit Care Med 2021 03;49(3):472-481

Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Objectives: To formulate new "Choosing Wisely" for Critical Care recommendations that identify best practices to avoid waste and promote value while providing critical care.

Data Sources: Semistructured narrative literature review and quantitative survey assessments.

Study Selection: English language publications that examined critical care practices in relation to reducing cost or waste.

Data Extraction: Practices assessed to add no value to critical care were grouped by category. Taskforce assessment, modified Delphi consensus building, and quantitative survey analysis identified eight novel recommendations to avoid wasteful critical care practices. These were submitted to the Society of Critical Care Medicine membership for evaluation and ranking.

Data Synthesis: Results from the quantitative Society of Critical Care Medicine membership survey identified the top scoring five of eight recommendations. These five highest ranked recommendations established Society of Critical Care Medicine's Next Five "Choosing" Wisely for Critical Care practices.

Conclusions: Five new recommendations to reduce waste and enhance value in the practice of critical care address invasive devices, proactive liberation from mechanical ventilation, antibiotic stewardship, early mobilization, and providing goal-concordant care. These recommendations supplement the initial critical care recommendations from the "Choosing Wisely" campaign.
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http://dx.doi.org/10.1097/CCM.0000000000004876DOI Listing
March 2021

Effect of Phenylephrine Push Before Continuous Infusion Norepinephrine in Patients With Septic Shock.

Chest 2021 05 13;159(5):1875-1883. Epub 2020 Dec 13.

Department of Pharmacy, Cleveland Clinic, Cleveland, OH. Electronic address:

Background: IV pushes of phenylephrine may be used for patients with septic shock with the intent of rapidly achieving mean arterial pressure (MAP) goals. However, the clinical effectiveness and safety of this approach are unclear.

Research Question: In patients with septic shock, is administration of a phenylephrine push before norepinephrine initiation associated with a higher incidence of hemodynamic stability?

Methods: This retrospective, multicenter cohort study included adult patients with septic shock initiated on norepinephrine. Propensity scores for initial phenylephrine push receipt were generated, and patients receiving an initial phenylephrine push were propensity score-matched 1:2 to those not receiving an initial phenylephrine push. The primary outcome was achievement of hemodynamic stability (defined as maintaining MAP of ≥ 65 mm Hg for at least 6 h without an increase in continuous infusion vasoactive agent dosage) within 3 and 12 h of norepinephrine initiation.

Results: Of 1,317 included patients, 181 received an initial phenylephrine push; 141 phenylephrine push patients were matched to 282 patients not receiving a phenylephrine push. More patients who received a phenylephrine push achieved hemodynamic stability at hour 3 than those who did not receive a phenylephrine push (28.4% vs 18.8%; risk difference, 10%; 95% CI, 0.9%-18%). Phenylephrine push receipt was associated independently with hemodynamic stability within 3 h (adjusted OR, 1.8; 95% CI, 1.09-2.97), but not at 12 h (adjusted OR, 1.42; 95% CI, 0.93-2.16). Phenylephrine push receipt was associated independently with higher ICU mortality (adjusted OR, 1.88; 95% CI, 1.1-3.21).

Interpretation: Phenylephrine pushes were associated with a higher incidence of early, but not sustained, hemodynamic stability and were associated independently with higher ICU mortality. Caution is warranted when clinicians are considering the use of phenylephrine pushes in patients with septic shock.
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http://dx.doi.org/10.1016/j.chest.2020.11.051DOI Listing
May 2021

Safety of bedside placement of tunneled dialysis catheter in COVID-19 patients.

J Vasc Access 2020 Dec 3:1129729820976269. Epub 2020 Dec 3.

Department of Nephrology and Hypertension, Glickman Urological & Kidney Institute, Cleveland Clinic and Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA.

COVID-19 patients admitted to the ICU have high incidence of AKI requiring prolonged renal replacement therapy and often necessitate the placement of a tunneled dialysis catheter (TDC). We describe our experience with two cases of COVID-19 patients who underwent successful bedside placement of TDC under ultrasound guidance using anatomical landmarks without fluoroscopy guidance. Tunneled dialysis catheter placement under direct fluoroscopy remains the standard of care; but in well selected patients, placement of tunneled dialysis catheter at the bedside using anatomic landmarks without fluoroscopy can be safely and successfully performed without compromising the quality of care and avoid transfer of COVID-19 infected patients outside the ICU.
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http://dx.doi.org/10.1177/1129729820976269DOI Listing
December 2020

Hemodynamic Response to Vasopressin Dosage of 0.03 Units/Min vs. 0.04 Units/Min in Patients With Septic Shock.

J Intensive Care Med 2022 Jan 28;37(1):92-99. Epub 2020 Nov 28.

Department of Critical Care Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, OH, USA.

Background: Arginine vasopressin (AVP) is suggested as an adjunct to norepinephrine in patients with septic shock. Guidelines recommend an AVP dosage up to 0.03 units/min, but 0.04 units/min is commonly used in practice based on initial studies. This study was designed to compare the incidence of hemodynamic response between initial fixed-dosage AVP 0.03 units/min and AVP 0.04 units/min.

Methods: This retrospective, multi-hospital health system, cohort study included adult patients with septic shock receiving AVP as an adjunct to catecholamine vasopressors. Patients were excluded if they received an initial dosage other than 0.03 units/min or 0.04 units/min, or AVP was titrated within the first 6 hours of therapy. The primary outcome was hemodynamic response, defined as a mean arterial pressure ≥65 mm Hg and a decrease in catecholamine dosage at 6 hours after AVP initiation. Inverse probability of treatment weighting (IPTW) based on the propensity score for initial AVP dosage receipt was utilized to estimate adjusted exposure effects.

Results: Of the 1536 patients included in the observed data, there was a nearly even split between initial AVP dosage of 0.03 units/min (n = 842 [54.8%]) and 0.04 units/min (n = 694 [45.2%]). Observed patients receiving AVP 0.03 units/min were more frequently treated at the main campus academic medical center (96.3% vs. 52.2%, p < 0.01) and in a medical intensive care unit (87.4% vs. 39.8%, p < 0.01). The IPTW analysis included 1379 patients with achievement of baseline covariate balance. There was no evidence for a difference between groups in the incidence of hemodynamic response (0.03 units/min 50.0% vs. 0.04 units/min 53.1%, adjusted relative risk 1.06 [95% CI 0.94, 1.20]).

Conclusions: Initial AVP dosing varied by hospital and unit type. Although commonly used, an initial AVP dosage of 0.04 units/min was not associated with a higher incidence of early hemodynamic response to AVP in patients with septic shock.
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http://dx.doi.org/10.1177/0885066620977181DOI Listing
January 2022

Effectiveness and Safety of Twice Daily Versus Thrice Daily Subcutaneous Unfractionated Heparin for Venous Thromboembolism Prophylaxis at a Tertiary Medical Center.

J Pharm Pract 2020 Oct 5:897190020961210. Epub 2020 Oct 5.

Department of Pharmacy, Cleveland Clinic, Cleveland, OH, USA.

Background: The direct comparison of twice daily (BID) and thrice daily (TID) dosing of subcutaneous low dose unfractionated heparin (LDUH) for venous thromboembolism (VTE) prophylaxis in a mixed inpatient population is not well-studied.

Objective: This study evaluated the effectiveness and safety of BID compared to TID dosing of LDUH for prevention of VTE.

Methods: Retrospective, single-center analysis of patients who received LDUH for VTE prophylaxis between July and September 2015. Outcomes were identified by ICD-9 codes. A matched cohort was created using propensity scores and multivariate analysis was conducted to identify independent risk factors for VTE. The primary outcome was incidence of symptomatic VTE.

Results: In the full cohort, VTE occurred in 0.71% of patients who received LDUH BID compared to 0.77% of patients who received LDUH TID ( = 0.85). There was no difference in major ( = 0.85) and minor ( = 0.52) bleeding between the BID and TID groups. For the matched cohort, VTE occurred in 1.4% of BID patients and 2.1% of TID patients ( = 0.32). Major bleed occurred in 0.36% of BID patients and 0.52% of TID patients ( = 0.7), while a minor bleed was seen in 3.4% of BID patients and 2.1% of TID patients ( = 0.13). Personal history of VTE ( = 0.002) and weight ( = 0.035) were independently associated with increased risk of VTE.

Conclusion: This study did not demonstrate a difference in effectiveness or safety between BID and TID dosing of LDUH for VTE prevention.
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http://dx.doi.org/10.1177/0897190020961210DOI Listing
October 2020

pH-Gated Succinate Secretion Regulates Muscle Remodeling in Response to Exercise.

Cell 2020 10 17;183(1):62-75.e17. Epub 2020 Sep 17.

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA. Electronic address:

In response to skeletal muscle contraction during exercise, paracrine factors coordinate tissue remodeling, which underlies this healthy adaptation. Here we describe a pH-sensing metabolite signal that initiates muscle remodeling upon exercise. In mice and humans, exercising skeletal muscle releases the mitochondrial metabolite succinate into the local interstitium and circulation. Selective secretion of succinate is facilitated by its transient protonation, which occurs upon muscle cell acidification. In the protonated monocarboxylic form, succinate is rendered a transport substrate for monocarboxylate transporter 1, which facilitates pH-gated release. Upon secretion, succinate signals via its cognate receptor SUCNR1 in non-myofibrillar cells in muscle tissue to control muscle-remodeling transcriptional programs. This succinate-SUCNR1 signaling is required for paracrine regulation of muscle innervation, muscle matrix remodeling, and muscle strength in response to exercise training. In sum, we define a bioenergetic sensor in muscle that utilizes intracellular pH and succinate to coordinate tissue adaptation to exercise.
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http://dx.doi.org/10.1016/j.cell.2020.08.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778787PMC
October 2020

Abrupt Discontinuation Versus Down-Titration of Vasopressin in Patients Recovering from Septic Shock.

Shock 2021 02;55(2):210-214

Department of Pharmacy, Cleveland Clinic, Cleveland, Ohio.

Purpose: To compare patient outcomes based on management of arginine vasopressin (AVP) during the recovery phase of septic shock (abrupt vs. tapering discontinuation).

Patients And Methods: Multicenter, retrospective cohort study of patients receiving AVP with concomitant norepinephrine for septic shock. Primary outcome measure was time to intensive care unit (ICU) discharge (from decision to titrate or stop AVP). Secondary outcomes included ICU and hospital mortality, and incidence of hypotension.

Results: A total of 958 (73%) abrupt discontinuation and 360 (27%) down-titration patients were included. Patient characteristics and septic shock treatment courses were similar between groups. Median time to ICU discharge was similar between abrupt discontinuation (7.9 days, 95% CI 7.2-8.7 days) and tapered patients (7.3 days, 95% CI 6.3-9.3 days, P = 0.60). After controlling for baseline discrepancies, down-titration was not an independent predictor of time to ICU discharge (HR = 0.99, 95% CI: 0.85-1.15, P = 0.91). There was no difference in ICU mortality (21.8% vs. 18.0%, P = 0.13) or hospital mortality (28.9% vs. 31.1%, P = 0.44). Although incidence of hypotension was similar (39.7% vs. 41.7%, P = 0.53), patients in the down-titration group more frequently required an escalation of AVP dose (5.7% vs. 11.1%, P < 0.001). Median AVP duration was shorter in the abrupt discontinuation group (1.4 days [IQR: 0.6-2.6 days] vs. 1.8 days [IQR: 1.1-3.2 days], P < 0.001).

Conclusions: A difference in time to ICU discharge was not detected between abrupt AVP discontinuation and down-titration in patients recovering from septic shock. In patients recovering from septic shock, abrupt discontinuation of AVP appears to be safe and may lead to shortened AVP duration.
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http://dx.doi.org/10.1097/SHK.0000000000001609DOI Listing
February 2021

Design, creation and in vitro testing of a reduced immunogenicity humanized anti-CD25 monoclonal antibody that retains functional activity.

Protein Eng Des Sel 2019 12;32(12):543-554

Formerly of AbbVie, Redwood City, CA, USA.

Humanized and fully human sequence-derived therapeutic antibodies retain the capacity to induce anti-drug antibodies. Daclizumab (humanized version of the murine anti-Tac antibody; E.HAT) was selected for a proof of concept application of engineering approaches to reduce potential immunogenicity due to its demonstrated immunogenicity in the clinic. Reduced immunogenicity variants of E.HAT were created by identifying and modifying a CD4+ T cell epitope region in the VH region. Variant epitope region peptides were selected for their reduced capacity to induce CD4+ T cell proliferative responses in vitro. Variant antibody molecules were created, and CD25 affinity and potency were similar to the unmodified parent antibody. Fab fragments from the variant antibodies induced a lower frequency and magnitude of responses in human peripheral blood mononuclear cells proliferation tests. By the empirical selection of two amino acid mutations, fully functional humanized E.HAT antibodies with reduced potential to induce immune responses in vitro were created.
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http://dx.doi.org/10.1093/protein/gzaa017DOI Listing
December 2019

Interhospital transport of patients with COVID-19: Cleveland Clinic approach.

Cleve Clin J Med 2020 Jun 9. Epub 2020 Jun 9.

Department of Critical Care Medicine, Respiratory Institute, Cleveland Clinic.

Hospital-to-hospital transportation of patients in the COVID-19 era presents unique challenges to ensuring the safety of both patients and health care providers. Crucial factors to address include having adequate supplies of protective equipment and ensuring their appropriate use, defining patient care procedures during transport, and decontamination post-transport. Transport vehicles need to have adequate physical space, an isolated driver compartment, NS HEPA filtration of air. Having a standardized intake process can help identify patients who would benefit from transport to another facility.
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http://dx.doi.org/10.3949/ccjm.87a.ccc045DOI Listing
June 2020

Operationalizing COVID-19 testing: Who, what, when, where, why, and how.

Cleve Clin J Med 2021 Mar 5. Epub 2021 Mar 5.

Pathology and Laboratory Medicine Institute, Cleveland Clinic.

The authors review the rationale behind and approaches to testing for COVID-19, the quality of currently available tests, the role of data analytics in strategizing testing, and using the electronic medical record and other programs designed to steward COVID-19 testing and follow-up of patients.
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http://dx.doi.org/10.3949/ccjm.87a.ccc048DOI Listing
March 2021

Association Between Compliance With the Sepsis Quality Measure (SEP-1) and Hospital Readmission.

Chest 2020 08 10;158(2):608-611. Epub 2020 Mar 10.

Department of Critical Care Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, Ohio. Electronic address:

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http://dx.doi.org/10.1016/j.chest.2020.02.042DOI Listing
August 2020

A Quantitative Tissue-Specific Landscape of Protein Redox Regulation during Aging.

Cell 2020 03 27;180(5):968-983.e24. Epub 2020 Feb 27.

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA. Electronic address:

Mammalian tissues engage in specialized physiology that is regulated through reversible modification of protein cysteine residues by reactive oxygen species (ROS). ROS regulate a myriad of biological processes, but the protein targets of ROS modification that drive tissue-specific physiology in vivo are largely unknown. Here, we develop Oximouse, a comprehensive and quantitative mapping of the mouse cysteine redox proteome in vivo. We use Oximouse to establish several paradigms of physiological redox signaling. We define and validate cysteine redox networks within each tissue that are tissue selective and underlie tissue-specific biology. We describe a common mechanism for encoding cysteine redox sensitivity by electrostatic gating. Moreover, we comprehensively identify redox-modified disease networks that remodel in aged mice, establishing a systemic molecular basis for the long-standing proposed links between redox dysregulation and tissue aging. We provide the Oximouse compendium as a framework for understanding mechanisms of redox regulation in physiology and aging.
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http://dx.doi.org/10.1016/j.cell.2020.02.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164166PMC
March 2020

First-in-Human Phase I Study of ABBV-838, an Antibody-Drug Conjugate Targeting SLAMF7/CS1 in Patients with Relapsed and Refractory Multiple Myeloma.

Clin Cancer Res 2020 05 22;26(10):2308-2317. Epub 2020 Jan 22.

CHU de Nantes, Hôtel Dieu - HME, Nantes Cedex 1, France.

Purpose: ABBV-838 is an antibody-drug conjugate targeting a unique epitope of CD2 subset 1, a cell-surface glycoprotein expressed on multiple myeloma cells. This phase I/Ib first-in-human, dose-escalation study (trial registration ID: NCT02462525) evaluated the safety, pharmacokinetics, and preliminary activity of ABBV-838 in patients with relapsed and refractory multiple myeloma (RRMM).

Patients And Methods: Eligible patients (≥18 years) received ABBV-838 (3+3 design) intravenously starting from 0.6 mg/kg up to 6.0 mg/kg for 3-week dosing intervals (Q3W). Patients could continue ABBV-838 for up to 24 months. Assessment of alternate dosing intervals (Q1W and Q2W) was conducted in parallel.

Results: As of March 2017, 75 patients received at least one dose of ABBV-838. The most common any-grade treatment-emergent adverse events (TEAE) were neutropenia and anemia (28.0% each), fatigue (26.7%), and nausea (25.3%). Grade 3/4/5 TEAEs were reported in 73.3% of patients across all treatment groups; most common were neutropenia (20.0%), anemia (18.7%), and leukopenia (13.3%). Grade 3/4/5 ABBV-838-related TEAEs were reported by 40.0% of patients across all treatment groups. Overall, 4.0% of patients experienced TEAEs leading to death, none ABBV-838 related. The MTD was not reached; the selected recommended dose for the expansion cohort was 5.0 mg/kg Q3W. Pharmacokinetic analysis showed that exposure was approximately dose proportional. The overall response rate was 10.7%; very good partial responses and partial responses were achieved by 2 (2.7%) and 6 (8.0%) patients, respectively.

Conclusions: These results demonstrate that ABBV-838 is safe and well-tolerated in patients with RRMM with a very limited efficacy.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1431DOI Listing
May 2020

Mortality, Morbidity, and Costs After Implementation of a Vasopressin Guideline in Medical Intensive Care Patients With Septic Shock: An Interrupted Time Series Analysis.

Ann Pharmacother 2020 04 3;54(4):314-321. Epub 2019 Nov 3.

Cleveland Clinic, Cleveland, OH, USA.

Vasopressin decreases vasopressor requirements in patients with septic shock. However, the optimal norepinephrine dose for initiation or cessation of vasopressin is unclear. Analyze monthly intensive care unit (ICU) mortality rates 1 year preimplementation and postimplementation of a guideline suggesting a norepinephrine dose of 50 µg/min or more for initiation of vasopressin and early cessation of vasopressin. This retrospective quasi-experimental study included adult patients with septic shock admitted to the medical ICU of a tertiary care medical center over 2 years. Time periods were evaluated with interrupted time series analysis. A total of 1148 patients were included: 573 patients preguideline and 575 patients postguideline. Group characteristics were well balanced at baseline, except patients postguideline had higher sequential organ failure assessment scores. Postguideline, fewer patients were initiated on vasopressin (305 [53.2%] vs 217 [37.7%], absolute difference -15.5% [95% CI -21.2% to -9.8%]), and the norepinephrine dose at vasopressin initiation was higher (median 25 [interquartile range 18, 40] µg/min vs 40 [22, 52] µg/min; median difference 15 [95% CI 11 to 19] µg/min; < 0.01). After guideline implementation, there was no evidence for a difference in ICU mortality rate slope (slope change 0.07% [95% CI -0.8% to 1.0%] per month; 0.87), but the vasoactive cost level decreased by US$183 (95% CI -US$327 to -US$39) per patient immediately after implementation. Implementation of a guideline suggesting a high norepinephrine dose threshold for vasopressin initiation and early vasopressin cessation in patients with septic shock appears to be safe and may decrease vasoactive costs.
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http://dx.doi.org/10.1177/1060028019886306DOI Listing
April 2020

Association Between Volume of Fluid Resuscitation and Intubation in High-Risk Patients With Sepsis, Heart Failure, End-Stage Renal Disease, and Cirrhosis.

Chest 2020 02 14;157(2):286-292. Epub 2019 Oct 14.

Respiratory Institute, Cleveland Clinic, Cleveland, OH.

Background: Initial fluid resuscitation volume for sepsis is controversial, particularly in patients at high baseline risk for complications. This study was designed to assess the association between 30 mL/kg crystalloids and intubation in patients with sepsis or septic shock and heart failure, end-stage renal disease, or cirrhosis.

Methods: This propensity score-matched retrospective cohort study included patients with sepsis or septic shock admitted to a large medical ICU. Primary exposure was IV fluid volume in the first 6 h following sepsis diagnosis, divided into two cohorts: ≥ 30 mL/kg (standard group) and < 30 mL/kg (restricted group). The primary outcome was need for mechanical ventilation within 72 h following initiation of fluid resuscitation. Secondary outcomes were length of stay, ventilator days, and time to intubation.

Results: A total of 208 patients were included, with 104 (50%) in the restricted group (< 30 mL/kg) and 104 in the standard group (≥ 30 mL/kg). No difference in intubation incidence was detected between the two groups, with 36 patients (35%) in the restricted group and 33 (32%) in the standard group (adjusted OR, 0.75; 95% CI, 0.41-1.36; P = .34) intubated. There was no difference between standard and restricted groups in alive ICU-free days (17 ± 11 days vs 17 ± 10 days; P = .64), duration of mechanical ventilation (10 ± 12 days vs 11 ± 16 days; P = .96), or hours to intubation (16 ± 19 h vs 14 ± 15; P = .55).

Conclusions: No differences were detected in the incidence of intubation in patients with sepsis and cirrhosis, end-stage renal disease, or heart failure who received guideline-recommended fluid resuscitation with 30 mL/kg compared with patients initially resuscitated with a lower fluid volume.
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http://dx.doi.org/10.1016/j.chest.2019.09.029DOI Listing
February 2020

Bispectral Index for Titrating Sedation in ARDS Patients During Neuromuscular Blockade.

Am J Crit Care 2019 09;28(5):377-384

Stephanie Bass, Seth R. Bauer, Heather Torbic, and Sarah Welch are intensive care unit clinical pharmacists, Cleveland Clinic, Cleveland, Ohio; Seth Bauer is also the critical care clinical coordinator for the Department of Pharmacy, Cleveland Clinic. Mark L. Vance is a decentralized clinical staff pharmacist at Vidant Medical Center, Greenville, North Carolina. Anita Reddy is a staff physician in the Department of Critical Care Medicine and quality officer for the medical intensive care unit, Cleveland Clinic. Erin Roach is an intensive care unit clinical pharmacist at Atrium Healthcare System, Charlotte, North Carolina. Abhijit Duggal is a staff physician in the Department of Critical Care Medicine, Cleveland Clinic.

Background: Despite a lack of data from intensive care patients, bispectral index monitors are often used to measure the depth of sedation for critically ill patients with acute respiratory distress syndrome (ARDS) who require continuous neuromuscular blocking agents.

Objective: To evaluate differences in the effectiveness and safety of monitoring sedation by using bispectral index or traditional methods in patients with ARDS who are receiving continuous neuromuscular blocking agents.

Methods: This noninterventional, single-center, retrospective cohort study included adult patients with ARDS who are receiving a neuromuscular blocking agent. Daily sedation and analgesia while a neuromuscular blocking agent was being administered were compared between patients with and patients without orders for titration based on bispectral index values. Clinical outcomes also were evaluated.

Results: Overall, sedation and analgesia did not differ between patients with and patients without titration based on bispectral index. Compared with patients without such titration, patients with bispectral index-based titration experienced more dose adjustments for the sedation agent (median [interquartile range], 7 [4-11] vs 1 [0-5], respectively, < .001) and the analgesic (1 [0-2] vs 0 [0-1], respectively; = .003) during the first 24 hours of neuromuscular blockade, but this was not associated with any difference in clinical outcomes.

Conclusions: Titration based on bispectral index did not result in a significant difference in sedation or analgesia exposure, or clinical outcomes, from that achieved with traditional sedation monitoring in patients with ARDS who were receiving a neuromuscular blocking agent, despite more dose adjustments during the first 24 hours of receiving the neuromuscular blocking agent.
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http://dx.doi.org/10.4037/ajcc2019917DOI Listing
September 2019

Effect of Detailed Titration Instructions on Time to Hemodynamic Stability in ICU Patients Requiring Norepinephrine.

Jt Comm J Qual Patient Saf 2019 09 15;45(9):606-612. Epub 2019 Jul 15.

Background: This study was conducted to assess the effect of titration instructions on patients receiving norepinephrine.

Methods: In a single-center, retrospective cohort of patients who received at least 24 hours of norepinephrine as their first vasopressor (n = 1,303), patients were classified by whether they received norepinephrine before (n = 616) or after (n = 687) titration instructions were added.

Results: Patients in the two groups had significant differences at baseline. On univariate analysis, time to hemodynamic stability was significantly longer in the post group (32 minutes [interquartile range (IQR): 12-65] vs. 10 minutes [IQR: 0-26]; p < 0.01). On multivariate analysis, addition of titration instructions was associated with an increase of 24 minutes in time to hemodynamic stability after accounting for differences in baseline systolic blood pressure, fluid boluses before norepinephrine, baseline arrhythmia, and number of other vasopressors or titratable infusions (p = 0.02).

Conclusion: In this evaluation, time to hemodynamic stability was significantly longer after addition of norepinephrine titration instructions even when accounting for differences in baseline characteristics.
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http://dx.doi.org/10.1016/j.jcjq.2019.05.003DOI Listing
September 2019

Optimal norepinephrine-equivalent dose to initiate epinephrine in patients with septic shock.

J Crit Care 2019 10 3;53:69-74. Epub 2019 Jun 3.

Department of Pharmacy, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH, USA.

Purpose: The specific norepinephrine dose at which epinephrine should be added in septic shock is unclear. This study sought to determine the norepinephrine-equivalent dose at epinephrine initiation that correlated with hemodynamic stability.

Methods: Septic shock patients receiving both norepinephrine and epinephrine were included in this study. Classification and regression tree analysis was conducted to determine breakpoints in norepinephrine-equivalent dose predicting hemodynamic stability, with two cohorts identified. The primary outcome was hemodynamic stability, and secondary outcomes were shock-free survival, time to achieve hemodynamic stability, and change in SOFA score.

Results: Optimal dose group was identified as initiating epinephrine when norepinephrine-equivalent dose was between 37 and 133 μg/min. A total of 138 and 61 patients were classified in optimal and non-optimal dose groups, respectively. Baseline characteristics were similar between groups except vasopressin use was more frequent in the optimal dose group. More patients in optimal dose group versus non-optimal dose group achieved hemodynamic stability (40 [29%] vs. 9 [14.8%]), absolute risk difference 14.2% [95% CI 2.5-25.9%]; p = .03). On multivariable analysis, initiating epinephrine within the optimal norepinephrine-equivalent dose range was independently associated with higher odds of hemodynamic response (OR 3.06 [95% CI 1.2-7.6]; p = .02). No differences were observed in other secondary outcomes.

Conclusions: Initiation of epinephrine when patients were receiving norepinephrine-equivalent doses of 37-133 μg/min was associated with a higher rate of hemodynamic stability.
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http://dx.doi.org/10.1016/j.jcrc.2019.05.024DOI Listing
October 2019

Operational Aspects of a Clinical Decision Support Program.

Clin Lab Med 2019 06;39(2):215-229

Respiratory Institute, Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, 9500 Euclid Avenue/ G6-156, Cleveland, OH 44195, USA.

Clinical decision support tools that involve improving test utilization should be jointly overseen by a laboratory stewardship committee and the hospital informatics team. The roles of these groups vary by institution and may overlap. This is a team effort and collaboration is a must. The effectiveness of these efforts in an institution depends on the receptiveness of leadership and providers, as well as the effectiveness of the associated committees. Examples of the challenges and successes of laboratory stewardship interventions that have been operationalized at the Cleveland Clinic that use clinical decision support tools, as well as associated literature, are reviewed.
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http://dx.doi.org/10.1016/j.cll.2019.01.002DOI Listing
June 2019

TSP1 and TSP2 deficiencies affect LOX protein distribution in the femoral diaphysis and pro-peptide removal in marrow-derived mesenchymal stem cells in vitro.

Connect Tissue Res 2019 09 2;60(5):495-506. Epub 2019 Apr 2.

a Department of Orthopaedic Surgery , University of Michigan , Ann Arbor , MI , USA.

Thrombospondin-1 and 2 have each been implicated in collagen fibrillogenesis. We addressed the possibility that deficits in lysyl oxidase (LOX) contribute to the extracellular matrix (ECM) phenotype of TSP-deficient bone. We examined detergent insoluble (mature cross-linked) and soluble (newly secreted) ECM fractions prepared from diaphyseal cortical bone. Detergent-insoluble hydroxyproline content, an indicator of cross-linked collagen content and LOX function, was reduced in female TSP-deficient bones. In male diaphyses, only TSP2 deficiency affected insoluble hydroxyproline content. Western blot suggested that removal of the LOX-pro-peptide (LOPP), an indication of LOX activation, was not affected by TSP status. Instead, the distribution of pro-LOX and mature LOX between immature and mature ECM was altered by TSP-status. LOX was also examined in primary marrow-derived mesenchymal stem cells (MSC) treated with ascorbate. Relative LOPP levels were elevated compared to WT in MSC conditioned medium from female TSP-deficient mice. When cells were serum starved to limit LOX pro-peptide removal, pro-LOX levels were elevated in TSP2-/- cells compared to wild-type. This phenotype was associated with a transient increase in BMP1 levels in TSP2-/- conditioned medium. TSP2 was detected in bone tissue and osteoblast cell culture. TSP1 was only detected in insoluble ECM prepared from WT diaphyseal bone samples. Our data suggest that the trimeric thrombospondins contribute to bone matrix quality by regulating the distribution of pro and mature LOX between newly secreted, immature ECM and mature, cross-linked ECM.
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http://dx.doi.org/10.1080/03008207.2019.1593391DOI Listing
September 2019

Sulforaphane enriched transcriptome of lung mitochondrial energy metabolism and provided pulmonary injury protection via Nrf2 in mice.

Toxicol Appl Pharmacol 2019 02 5;364:29-44. Epub 2018 Dec 5.

Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.

Nrf2 is essential to antioxidant response element (ARE)-mediated host defense. Sulforaphane (SFN) is a phytochemical antioxidant known to affect multiple cellular targets including Nrf2-ARE pathway in chemoprevention. However, the role of SFN in non-malignant airway disorders remain unclear. To test if pre-activation of Nrf2-ARE signaling protects lungs from oxidant-induced acute injury, wild-type (Nrf2) and Nrf2-deficient (Nrf2) mice were given SFN orally or as standardized broccoli sprout extract diet (SBE) before hyperoxia or air exposure. Hyperoxia-induced pulmonary injury and oxidation indices were significantly reduced by SFN or SBE in Nrf2 mice but not in Nrf2 mice. SFN upregulated a large cluster of basal lung genes that are involved in mitochondrial oxidative phosphorylation, energy metabolism, and cardiovascular protection only in Nrf2 mice. Bioinformatic analysis elucidated ARE-like motifs on these genes. Transcript abundance of the mitochondrial machinery genes remained significantly higher after hyperoxia exposure in SFN-treated Nrf2 mice than in SFN-treated Nrf2 mice. Nuclear factor-κB was suggested to be a central molecule in transcriptome networks affected by SFN. Minor improvement of hyperoxia-caused lung histopathology and neutrophilia by SFN in Nrf2 mice implies Nrf2-independent or alternate effector mechanisms. In conclusion, SFN is suggested to be as a preventive intervention in a preclinical model of acute lung injury by linking mitochondria and Nrf2. Administration of SFN alleviated acute lung injury-like pathogenesis in a Nrf2-dependent manner. Potential AREs in the SFN-inducible transcriptome for mitochondria bioenergetics provided a new insight into the downstream mechanisms of Nrf2-mediated pulmonary protection.
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http://dx.doi.org/10.1016/j.taap.2018.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658087PMC
February 2019

Inter-rater Agreement for Abstraction of the Early Management Bundle, Severe Sepsis/Septic Shock (SEP-1) Quality Measure in a Multi-Hospital Health System.

Jt Comm J Qual Patient Saf 2019 02 30;45(2):108-111. Epub 2018 Nov 30.

is Staff Physician and Quality Officer, Medical ICU, Respiratory Institute, Cleveland Clinic.

Background: The Early Management Bundle, Severe Sepsis/Septic Shock (SEP-1) quality measure is complex to abstract, which may lead to discrepancies between abstractors. This study was designed to evaluate inter-rater agreement between abstractors at individual hospitals in a health system and a lead abstractor on abstraction elements and measure compliance for SEP-1.

Methods: Patient cases qualifying for abstraction for SEP-1 over a four-month period in 2016 were initially abstracted at a local hospital and then centrally by a lead abstractor. Abstraction results were retrospectively compared to determine inter-rater agreement.

Results: A total of 580 SEP-1 cases were abstracted locally and centrally. Each site contributed a median (interquartile range) of 63 (49, 86) cases. There was complete concordance of measure-related elements in 391 cases (67%) (inter-rater agreement: κ = 0.40, p < 0.01). The most common discrepancy (60 cases) was severe sepsis presentation time. There was a weak correlation between SEP-1 compliance adjudicated locally and centrally (r = 0.41, p < 0.01). The average change in monthly SEP-1 measure compliance at each site after central adjudication was a 1% increase but ranged from a 49% decrease to a 40% increase.

Conclusions: Concordance on SEP-1 abstraction elements between local and expert adjudicators was fair, and SEP-1 performance varied considerably from initial site-reported performance. The detailed nature of SEP-1 can lead to unreliable abstraction, which may lead to inaccurate reporting of compliance with the measure and affect comparability of performance between hospitals. Abstraction by a dedicated team for SEP-1 can reduce variability and improve efficiency.
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http://dx.doi.org/10.1016/j.jcjq.2018.10.002DOI Listing
February 2019

Initiation of venovenous extracorporeal membrane oxygenation in a patient receiving induction chemotherapy for acute myelogenous leukemia.

J Oncol Pharm Pract 2019 Sep 24;25(6):1491-1496. Epub 2018 Jul 24.

1 Respiratory Institute, Cleveland Clinic, Cleveland, OH, USA.

Background: Acute respiratory failure is a leading cause of intensive care unit admission in patients with hematological malignancies; it carries a mortality rate exceeding 50%. Venovenous extracorporeal membrane oxygenation use in patients with acute hematologic malignancies concurrently receiving induction chemotherapy is not well studied.

Case Presentation: A 44-year-old male developed acute respiratory distress syndrome in the setting of newly diagnosed acute myelogenous leukemia. He underwent successful induction chemotherapy while on venovenous extracorporeal membrane oxygenation. His course was complicated by a devastating subarachnoid hemorrhage. Life support modalities were discontinued in accordance to the wishes of the family.

Conclusion: There is a lack of data to guide use of induction chemotherapy in patients with acute hematologic malignancies requiring venovenous extracorporeal membrane oxygenation, particularly with regard to dosing, safety, and efficacy of chemotherapeutic agents. This case highlights a potential role of venovenous extracorporeal membrane oxygenation in select young acute myelogenous leukemia patients who might benefit from this intervention and warrants further research.
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http://dx.doi.org/10.1177/1078155218788735DOI Listing
September 2019

Hypotension Risk Based on Vasoactive Agent Discontinuation Order in Patients in the Recovery Phase of Septic Shock.

Pharmacotherapy 2018 03 8;38(3):319-326. Epub 2018 Feb 8.

Department of Pharmacy, Cleveland Clinic, Cleveland, Ohio.

Study Objectives: Patients with septic shock often require vasoactive agents for hemodynamic support; however, the optimal approach to discontinuing these agents once patients reach the recovery phase is currently unknown. The objective of this evaluation was to compare the incidence of hypotension within 24 hours based on the discontinuation order of norepinephrine (NE) and vasopressin (AVP) in patients in the recovery phase of septic shock.

Design: Retrospective cohort study.

Setting: The medical, surgical, and neurosciences intensive care units (ICUs) at a large tertiary care academic medical center.

Patients: A total of 585 adults in the recovery phase of septic shock who received fixed-dose AVP for at least 6 hours as an adjunct to NE between September 2011 and August 2015 were included. Of these patients, 155 had AVP discontinued first, and 430 had NE discontinued first.

Measurements And Main Results: Hypotension was evaluated during the 24-hour period after discontinuation of the first vasoactive agent and was defined as mean arterial pressure less than 60 mm Hg with one or more of the following interventions: increased remaining vasoactive agent dose by 25%, reinstitution of the discontinued agent, or administration of at least 1 L of fluid bolus. Time to hypotension was evaluated with survival analysis, and risk of hypotension was evaluated with multivariable Cox proportional hazards regression. No significant difference between groups was noted in the incidence of hypotension within 24 hours (55% in the AVP discontinued first group vs 50% in the NE discontinued first group, p=0.28) or ICU mortality (45.2% vs 40.0%, p=0.26). After adjustment for baseline factors with multivariable Cox proportional hazards regression, having AVP discontinued first was independently associated with an increased risk of hypotension with a time-varying effect that decreased over time (HR(t) = e , p<0.001).

Conclusion: In patients recovering from septic shock treated with concomitant AVP and NE, no significant difference was noted in the incidence of hypotension based on discontinuation order of these agents.
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http://dx.doi.org/10.1002/phar.2082DOI Listing
March 2018
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