Publications by authors named "Lui G Forni"

104 Publications

RAND appropriateness panel to determine the applicability of UK guidelines on the management of acute respiratory distress syndrome (ARDS) and other strategies in the context of the COVID-19 pandemic.

Thorax 2021 May 27. Epub 2021 May 27.

Guy's and St Thomas' NHS Foundation Trust, London, UK.

Background: COVID-19 has become the most common cause of acute respiratory distress syndrome (ARDS) worldwide. Features of the pathophysiology and clinical presentation partially distinguish it from 'classical' ARDS. A Research and Development (RAND) analysis gauged the opinion of an expert panel about the management of ARDS with and without COVID-19 as the precipitating cause, using recent UK guidelines as a template.

Methods: An 11-person panel comprising intensive care practitioners rated the appropriateness of ARDS management options at different times during hospital admission, in the presence or absence of, or varying severity of SARS-CoV-2 infection on a scale of 1-9 (where 1-3 is inappropriate, 4-6 is uncertain and 7-9 is appropriate). A summary of the anonymised results was discussed at an online meeting moderated by an expert in RAND methodology. The modified online survey comprising 76 questions, subdivided into investigations (16), non-invasive respiratory support (18), basic intensive care unit management of ARDS (20), management of refractory hypoxaemia (8), pharmacotherapy (7) and anticoagulation (7), was completed again.

Results: Disagreement between experts was significant only when addressing the appropriateness of diagnostic bronchoscopy in patients with confirmed or suspected COVID-19. Adherence to existing published guidelines for the management of ARDS for relevant evidence-based interventions was recommended. Responses of the experts to the final survey suggested that the supportive management of ARDS should be the same, regardless of a COVID-19 diagnosis. For patients with ARDS with COVID-19, the panel recommended routine treatment with corticosteroids and a lower threshold for full anticoagulation based on a high index of suspicion for venous thromboembolic disease.

Conclusion: The expert panel found no reason to deviate from the evidence-based supportive strategies for managing ARDS outlined in recent guidelines.
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http://dx.doi.org/10.1136/thoraxjnl-2021-216904DOI Listing
May 2021

Postoperative acute kidney injury in adult non-cardiac surgery: joint consensus report of the Acute Disease Quality Initiative and PeriOperative Quality Initiative.

Nat Rev Nephrol 2021 May 11. Epub 2021 May 11.

Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA.

Postoperative acute kidney injury (PO-AKI) is a common complication of major surgery that is strongly associated with short-term surgical complications and long-term adverse outcomes, including increased risk of chronic kidney disease, cardiovascular events and death. Risk factors for PO-AKI include older age and comorbid diseases such as chronic kidney disease and diabetes mellitus. PO-AKI is best defined as AKI occurring within 7 days of an operative intervention using the Kidney Disease Improving Global Outcomes (KDIGO) definition of AKI; however, additional prognostic information may be gained from detailed clinical assessment and other diagnostic investigations in the form of a focused kidney health assessment (KHA). Prevention of PO-AKI is largely based on identification of high baseline risk, monitoring and reduction of nephrotoxic insults, whereas treatment involves the application of a bundle of interventions to avoid secondary kidney injury and mitigate the severity of AKI. As PO-AKI is strongly associated with long-term adverse outcomes, some form of follow-up KHA is essential; however, the form and location of this will be dictated by the nature and severity of the AKI. In this Consensus Statement, we provide graded recommendations for AKI after non-cardiac surgery and highlight priorities for future research.
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http://dx.doi.org/10.1038/s41581-021-00418-2DOI Listing
May 2021

Comparison of C-C motif chemokine ligand 14 with other biomarkers for adverse kidney events after cardiac surgery.

J Thorac Cardiovasc Surg 2021 Mar 10. Epub 2021 Mar 10.

Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Muenster, Muenster, Germany. Electronic address:

Objective: Outcomes after acute kidney injury are affected by both the severity and the duration of the insult. Patients with persistent acute kidney injury have higher major adverse kidney events, including 90-day mortality, renal replacement therapy, and persistent kidney dysfunction. Methods to identify these patients are urgently needed to improve outcomes. The purpose of this study was to evaluate whether biomarkers, including C-C motif chemokine ligand 14, were able to predict persistent acute kidney injury and major adverse kidney events after cardiac surgery.

Methods: This study was a single-center, prospective, observational study. Patients who developed moderate or severe acute kidney injury (Kidney Disease Improving Global Outcomes 2 or 3) within 72 hours after cardiac surgery were enrolled with a primary end point of persistent severe acute kidney injury (Kidney Disease Improving Global Outcomes 3) lasting 72 hours or more.

Results: A total of 100 patients were available for the primary analysis, and 37 met the primary end point. C-C motif chemokine ligand 14 was the most predictive biomarker for the primary end point with an area under the curve of 0.930 (95% confidence interval, 0.881-0.979). The area under the curve of C-C motif chemokine ligand 14 was significantly higher than the area under the curve for the other biomarkers analyzed. C-C motif chemokine ligand 14 was significantly higher in end point positive patients at enrollment (4.47 ng/mL [2.35-11.5] vs 0.67 ng/mL [0.38-1.07]; P = .001). Sensitivity and specificity were 78% and 95% at a cutoff value of 2.21 ng/mL, respectively. C-C motif chemokine ligand 14 was also highly accurate for predicting renal replacement therapy within 7 days (area under the curve, 0.915; 95% confidence interval, 0.858-0.972; P < .001).

Conclusions: Elevated C-C motif chemokine ligand 14 levels predict persistent acute kidney injury in cardiac surgery patients with moderate or severe acute kidney injury. This new biomarker may help stratify patients destined to receive renal replacement therapy and identify patients who may benefit from novel therapeutic approaches to acute kidney injury.
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http://dx.doi.org/10.1016/j.jtcvs.2021.03.016DOI Listing
March 2021

Perioperative acute kidney injury following major abdominal surgery.

Br J Hosp Med (Lond) 2021 Mar 31;82(3):1-9. Epub 2021 Mar 31.

Intensive Care Unit, Royal Surrey Hospital Foundation Trust, Guildford, UK.

Major abdominal surgery is associated with significant morbidity, not least the development of acute kidney injury. As a common perioperative complication, acute kidney injury is associated with increased length of stay, increased risk of perioperative infection and the potential development of chronic kidney disease. Moreover, the development of acute kidney injury is independently associated with an increased risk of death. Perioperative acute kidney injury is not a single entity, but describes a clinical syndrome with multiple causes including physical causes related to the surgical procedure, ischaemia-reperfusion injury and the use of potential nephrotoxins. Currently, acute kidney injury is defined by changes in serum creatinine level and urine output criteria, which although robust in heterogenous populations, may not perform as accurately in the perioperative period. This article discusses these issues including the potential role of novel biomarkers for early detection of perioperative acute kidney injury, as well as the use of predictive modelling. Treatment is mainly supportive but evidence suggests that more targeted therapy may lead to improved outcomes.
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http://dx.doi.org/10.12968/hmed.2020.0661DOI Listing
March 2021

Clinical decision-making in older adults following emergency admission to hospital. Derivation and validation of a risk stratification score: OPERA.

PLoS One 2021 18;16(3):e0248477. Epub 2021 Mar 18.

Department of Clinical & Experimental Medicine, Faculty of Health Sciences, University of Surrey, Guildford, United Kingdom.

Objectives Of The Study: Demographic changes alongside medical advances have resulted in older adults accounting for an increasing proportion of emergency hospital admissions. Current measures of illness severity, limited to physiological parameters, have shortcomings in this cohort, partly due to patient complexity. This study aimed to derive and validate a risk score for acutely unwell older adults which may enhance risk stratification and support clinical decision-making.

Methods: Data was collected from emergency admissions in patients ≥65 years from two UK general hospitals (April 2017- April 2018). Variables underwent regression analysis for in-hospital mortality and independent predictors were used to create a risk score. Performance was assessed on external validation. Secondary outcomes included seven-day mortality and extended hospital stay.

Results: Derivation (n = 8,974) and validation (n = 8,391) cohorts were analysed. The model included the National Early Warning Score 2 (NEWS2), clinical frailty scale (CFS), acute kidney injury, age, sex, and Malnutrition Universal Screening Tool. For mortality, area under the curve for the model was 0.79 (95% CI 0.78-0.80), superior to NEWS2 0.65 (0.62-0.67) and CFS 0.76 (0.74-0.77) (P<0.0001). Risk groups predicted prolonged hospital stay: the highest risk group had an odds ratio of 9.7 (5.8-16.1) to stay >30 days.

Conclusions: Our simple validated model (Older Persons' Emergency Risk Assessment [OPERA] score) predicts in-hospital mortality and prolonged length of stay and could be easily integrated into electronic hospital systems, enabling automatic digital generation of risk stratification within hours of admission. Future studies may validate the OPERA score in external populations and consider an impact analysis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248477PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971558PMC
March 2021

Prevention of Cardiac Surgery-Associated Acute Kidney Injury by Implementing the KDIGO Guidelines in High-Risk Patients Identified by Biomarkers: The PrevAKI-Multicenter Randomized Controlled Trial.

Anesth Analg 2021 Aug;133(2):292-302

From the Department of Anesthesiology, Intensive Care Medicine and Pain Medicine, University Hospital Münster, Münster, Germany.

Background: Prospective, single-center trials have shown that the implementation of the Kidney Disease: Improving Global Outcomes (KDIGO) recommendations in high-risk patients significantly reduced the development of acute kidney injury (AKI) after surgery. We sought to evaluate the feasibility of implementing a bundle of supportive measures based on the KDIGO guideline in high-risk patients undergoing cardiac surgery in a multicenter setting in preparation for a large definitive trial.

Methods: In this multicenter, multinational, randomized controlled trial, we examined the adherence to the KDIGO bundle consisting of optimization of volume status and hemodynamics, functional hemodynamic monitoring, avoidance of nephrotoxic drugs, and prevention of hyperglycemia in high-risk patients identified by the urinary biomarkers tissue inhibitor of metalloproteinases-2 [TIMP-2] and insulin growth factor-binding protein 7 [IGFBP7] after cardiac surgery. The primary end point was the adherence to the bundle protocol and was evaluated by the percentage of compliant patients with a 95% confidence interval (CI) according to Clopper-Pearson. Secondary end points included the development and severity of AKI.

Results: In total, 278 patients were included in the final analysis. In the intervention group, 65.4% of patients received the complete bundle as compared to 4.2% in the control group (absolute risk reduction [ARR] 61.2 [95% CI, 52.6-69.9]; P < .001). AKI rates were statistically not different in both groups (46.3% intervention versus 41.5% control group; ARR -4.8% [95% CI, -16.4 to 6.9]; P = .423). However, the occurrence of moderate and severe AKI was significantly lower in the intervention group as compared to the control group (14.0% vs 23.9%; ARR 10.0% [95% CI, 0.9-19.1]; P = .034). There were no significant effects on other specified secondary outcomes.

Conclusions: Implementation of a KDIGO-derived treatment bundle is feasible in a multinational setting. Furthermore, moderate to severe AKI was significantly reduced in the intervention group.
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http://dx.doi.org/10.1213/ANE.0000000000005458DOI Listing
August 2021

COVID-19 infection and the kidney.

Br J Hosp Med (Lond) 2020 Oct 6;81(10):1-8. Epub 2020 Oct 6.

Department of Clinical and Experimental Medicine, Faculty of Health Sciences, University of Surrey, Guildford, UK.

Despite initial reports, renal involvement, including acute kidney injury, has emerged as a serious complication of COVID-19 disease, particularly in critically ill patients. The reported prevalence varies considerably, which may reflect reporting practices, although differences in pre-existing comorbidities and socioeconomic factors, and differences between ethnic groups, almost certainly contribute. Renal involvement may present as an active urinary sediment or as changes in serum creatinine levels and urine output leading to acute kidney injury. In common with acute kidney injury complicating critical illness, the cause is often multifactorial and often presents as part of a multiorgan dysfunction syndrome. Treatment is, in the main, supportive, with kidney replacement therapy required in nearly 25% of reported cases. Few data currently exist as to the long-term burden of COVID-19-associated acute kidney injury but evidence suggests that only approximately one-third of patients are discharged with recovered renal function.
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http://dx.doi.org/10.12968/hmed.2020.0574DOI Listing
October 2020

Quality of Care for Acute Kidney Disease: Current Knowledge Gaps and Future Directions.

Kidney Int Rep 2020 Oct 6;5(10):1634-1642. Epub 2020 Aug 6.

Section of Nephrology, Department of Medicine, University of Chicago, Chicago, Illinois, USA.

Acute kidney injury (AKI) and acute kidney disease (AKD) are common complications in hospitalized patients and are associated with adverse outcomes. Although consensus guidelines have improved the care of patients with AKI and AKD, guidance regarding quality metrics in the care of patients after an episode of AKI or AKD is limited. For example, few patients receive follow-up laboratory testing of kidney function or post-AKI or AKD care through nephrology or other providers. Recently, the Acute Disease Quality Initiative developed a consensus statement regarding quality improvement goals for patients with AKI or AKD specifically highlighting efforts regarding quality and safety of care after hospital discharge after an episode of AKI or AKD. The goal is to use these measures to identify opportunities for improvement that will positively affect outcomes. We recommend that health care systems quantitate the proportion of patients who need and actually receive follow-up care after the index AKI or AKD hospitalization. The intensity and appropriateness of follow-up care should depend on patient characteristics, severity, duration, and course of AKI of AKD, and should evolve as evidence-based guidelines emerge. Quality indicators for discharged patients with dialysis requiring AKI or AKD should be distinct from end-stage renal disease measures. Besides, there should be specific quality indicators for those still requiring dialysis in the outpatient setting after AKI or AKD. Given the limited preexisting data guiding the care of patients after an episode of AKI or AKD, there is ample opportunity to establish quality measures and potentially improve patient care and outcomes. This review will provide specific evidence-based and expert opinion-based guidance for the care of patients with AKI or AKD after hospital discharge.
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http://dx.doi.org/10.1016/j.ekir.2020.07.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569680PMC
October 2020

COVID-19-associated acute kidney injury: consensus report of the 25th Acute Disease Quality Initiative (ADQI) Workgroup.

Nat Rev Nephrol 2020 12 15;16(12):747-764. Epub 2020 Oct 15.

Division of Nephrology, Department of Medicine, University of Alabama, Birmingham, AL, USA.

Kidney involvement in patients with coronavirus disease 2019 (COVID-19) is common, and can range from the presence of proteinuria and haematuria to acute kidney injury (AKI) requiring renal replacement therapy (RRT; also known as kidney replacement therapy). COVID-19-associated AKI (COVID-19 AKI) is associated with high mortality and serves as an independent risk factor for all-cause in-hospital death in patients with COVID-19. The pathophysiology and mechanisms of AKI in patients with COVID-19 have not been fully elucidated and seem to be multifactorial, in keeping with the pathophysiology of AKI in other patients who are critically ill. Little is known about the prevention and management of COVID-19 AKI. The emergence of regional 'surges' in COVID-19 cases can limit hospital resources, including dialysis availability and supplies; thus, careful daily assessment of available resources is needed. In this Consensus Statement, the Acute Disease Quality Initiative provides recommendations for the diagnosis, prevention and management of COVID-19 AKI based on current literature. We also make recommendations for areas of future research, which are aimed at improving understanding of the underlying processes and improving outcomes for patients with COVID-19 AKI.
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http://dx.doi.org/10.1038/s41581-020-00356-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561246PMC
December 2020

Sepsis-associated acute kidney injury: is COVID-19 different?

Kidney Int 2020 12 10;98(6):1370-1372. Epub 2020 Sep 10.

Intensive Care Unit, Royal Surrey Hospital NHS Foundation Trust, Guildford, United Kingdom & Department of Clinical & Experimental Medicine, University of Surrey, Guildford, UK.

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http://dx.doi.org/10.1016/j.kint.2020.08.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481835PMC
December 2020

What every Intensivist should know about COVID-19 associated acute kidney injury.

J Crit Care 2020 12 28;60:91-95. Epub 2020 Jul 28.

Department of Intensive Care, Ghent University, Ghent, Belgium.

Acute kidney injury (AKI) is a serious complication in critically ill patients with COVID-19 with a reported incidence ranging from <5% to >25%. Proposed aetiologies include hypovolemia, hemodynamic disturbance and inflammation but also specific factors like direct viral invasion, microvascular thrombosis, and altered regulation of the renin-angiotensin-aldosterone system. To date, there are no confirmed specific therapies, and prevention and management of AKI should follow established guidelines. Novel therapies specifically targeting COVID-19 related pathologies are under investigation. The incidence of renal replacement therapy (RRT) is variable, ranging from 0-37%. In a pandemic, RRT practice is likely to be determined by the number of patients, availability of machines, consumables and staff, clinical expertise, and acceptable alternatives. Close collaboration between critical care and renal services is essential. In this article, we describe the epidemiology and pathophysiology of COVID-19 associated AKI, outline current management and suggest strategies to provide RRT during a pandemic when resources may be scarce.
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http://dx.doi.org/10.1016/j.jcrc.2020.07.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386261PMC
December 2020

Heparin 2.0: A New Approach to the Infection Crisis.

Blood Purif 2021;50(1):28-34. Epub 2020 Jul 2.

Medical Clinic V, Nephrology | Rheumatology | Blood Purification, Academic Teaching Hospital Braunschweig, Braunschweig, Germany,

In April 2020, the US Food and Drug Administration granted emergency use authorization for certain medical devices to be used in patients with coronavirus disease 2019 (CO-VID-19). This included extracorporeal blood purification devices. This narrative review will give a brief overview regarding some of the extracorporeal devices that could be used to treat COVID-19 patients, including the Seraph® 100 Microbind® Affinity Blood Filter, produced by ExThera Medical (Martinez, CA, USA), first licensed in the European Economic Area in 2019. The Seraph® 100 contains ultrahigh molecular weight polyethylene beads with end point-attached heparin and is approved for the reduction of pathogens from the bloodstream either as a single agent or as an adjunct to conventional anti-infective agents. Bacteria, viruses, fungi, and toxins have been shown to bind to the immobilized heparin in a similar way to the interaction with heparan sulfate on the cell surface. This binding is nonreversible and as such, the pathogens are removed from the bloodstream. In this review, we describe the pathophysiological basis and rationale for using heparin for pathogen removal from the blood as well as exploring the technology behind the adaptation of heparin to deprive it of its systemic anticoagulant activity. In addition, we summarize the in vitro data as well as the available preclinical testing and published clinical reports. Finally, we discuss the enormous potential of this technology in an era of increasing antibiotic resistance and high mortality associated with sepsis and consider the application of this as a possible treatment option for COVID-19.
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http://dx.doi.org/10.1159/000508647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445380PMC
February 2021

Renin and Survival in Patients Given Angiotensin II for Catecholamine-Resistant Vasodilatory Shock. A Clinical Trial.

Am J Respir Crit Care Med 2020 11;202(9):1253-1261

Department of Critical Care, Guy's & St. Thomas' Hospital, King's College London, London, United Kingdom.

Exogenous angiotensin II increases mean arterial pressure in patients with catecholamine-resistant vasodilatory shock (CRVS). We hypothesized that renin concentrations may identify patients most likely to benefit from such therapy. To test the kinetic changes in renin concentrations and their prognostic value in patients with CRVS. We analyzed serum samples from patients enrolled in the ATHOS-3 (Angiotensin II for the Treatment of High-Output Shock) trial for renin, angiotensin I, and angiotensin II concentrations before the start of administration of angiotensin II or placebo and after 3 hours. Baseline serum renin concentration (normal range, 2.13-58.78 pg/ml) was above the upper limits of normal in 194 of 255 (76%) study patients with a median renin concentration of 172.7 pg/ml (interquartile range [IQR], 60.7 to 440.6 pg/ml), approximately threefold higher than the upper limit of normal. Renin concentrations correlated positively with angiotensin I/II ratios ( = 0.39;  < 0.001). At 3 hours after initiation of angiotensin II therapy, there was a 54.3% reduction (IQR, 37.9% to 66.5% reduction) in renin concentration compared with a 14.1% reduction (IQR, 37.6% reduction to 5.1% increase) with placebo ( < 0.0001). In patients with renin concentrations above the study population median, angiotensin II significantly reduced 28-day mortality to 28 of 55 (50.9%) patients compared with 51 of 73 patients (69.9%) treated with placebo (unstratified hazard ratio, 0.56; 95% confidence interval, 0.35 to 0.88;  = 0.012) ( = 0.048 for the interaction). The serum renin concentration is markedly elevated in CRVS and may identify patients for whom treatment with angiotensin II has a beneficial effect on clinical outcomes.Clinical trial registered with www.clinicaltrials.gov (NCT02338843).
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http://dx.doi.org/10.1164/rccm.201911-2172OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605187PMC
November 2020

Covid-19 and acute kidney injury in hospital: summary of NICE guidelines.

BMJ 2020 May 26;369:m1963. Epub 2020 May 26.

Department of Renal Medicine, Royal Derby Hospital, Derby, UK.

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http://dx.doi.org/10.1136/bmj.m1963DOI Listing
May 2020

Fluid Response Evaluation in Sepsis Hypotension and Shock: A Randomized Clinical Trial.

Chest 2020 10 27;158(4):1431-1445. Epub 2020 Apr 27.

Cheetah Medical, Wilmington, DE; Department of Anesthesiology, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA.

Background: Fluid and vasopressor management in septic shock remains controversial. In this randomized controlled trial, we evaluated the efficacy of dynamic measures (stroke volume change during passive leg raise) to guide resuscitation and improve patient outcome.

Research Question: Will resuscitation that is guided by dynamic assessments of fluid responsiveness in patients with septic shock improve patient outcomes?

Study Design And Methods: We conducted a prospective, multicenter, randomized clinical trial at 13 hospitals in the United States and United Kingdom. Patients presented to EDs with sepsis that was associated hypotension and anticipated ICU admission. Intervention arm patients were assessed for fluid responsiveness before clinically driven fluid bolus or increase in vasopressors occurred. The protocol included reassessment and therapy as indicated by the passive leg raise result. The control arm received usual care. The primary clinical outcome was positive fluid balance at 72 hours or ICU discharge, whichever occurred first.

Results: In modified intent-to-treat analysis that included 83 intervention and 41 usual care eligible patients, fluid balance at 72 hours or ICU discharge was significantly lower (-1.37 L favoring the intervention arm; 0.65 ± 2.85 L intervention arm vs 2.02 ± 3.44 L usual care arm; P = .021. Fewer patients required renal replacement therapy (5.1% vs 17.5%; P = .04) or mechanical ventilation (17.7% vs 34.1%; P = .04) in the intervention arm compared with usual care. In the all-randomized intent-to-treat population (102 intervention, 48 usual care), there were no significant differences in safety signals.

Interpretation: Physiologically informed fluid and vasopressor resuscitation with the use of the passive leg raise-induced stroke volume change to guide management of septic shock is safe and demonstrated lower net fluid balance and reductions in the risk of renal and respiratory failure. Dynamic assessments to guide fluid administration may improve outcomes for patients with septic shock compared with usual care.

Clinical Trial Registration: NCT02837731.
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http://dx.doi.org/10.1016/j.chest.2020.04.025DOI Listing
October 2020

Identification and validation of biomarkers of persistent acute kidney injury: the RUBY study.

Intensive Care Med 2020 05 6;46(5):943-953. Epub 2020 Feb 6.

Department of Medicine, Veterans Affairs Medical Center, 3350 La Jolla Village Dr, San Diego, CA, 92161, USA.

Purpose: The aim of the RUBY study was to evaluate novel candidate biomarkers to enable prediction of persistence of renal dysfunction as well as further understand potential mechanisms of kidney tissue damage and repair in acute kidney injury (AKI).

Methods: The RUBY study was a multi-center international prospective observational study to identify biomarkers of the persistence of stage 3 AKI as defined by the KDIGO criteria. Patients in the intensive care unit (ICU) with moderate or severe AKI (KDIGO stage 2 or 3) were enrolled. Patients were to be enrolled within 36 h of meeting KDIGO stage 2 criteria. The primary study endpoint was the development of persistent severe AKI (KDIGO stage 3) lasting for 72 h or more (NCT01868724).

Results: 364 patients were enrolled of whom 331 (91%) were available for the primary analysis. One hundred ten (33%) of the analysis cohort met the primary endpoint of persistent stage 3 AKI. Of the biomarkers tested in this study, urinary C-C motif chemokine ligand 14 (CCL14) was the most predictive of persistent stage 3 AKI with an area under the receiver operating characteristic curve (AUC) (95% CI) of 0.83 (0.78-0.87). This AUC was significantly greater than values for other biomarkers associated with AKI including urinary KIM-1, plasma cystatin C, and urinary NGAL, none of which achieved an AUC > 0.75.

Conclusion: Elevated urinary CCL14 predicts persistent AKI in a large heterogeneous cohort of critically ill patients with severe AKI. The discovery of CCL14 as a predictor of persistent AKI and thus, renal non-recovery, is novel and could help identify new therapeutic approaches to AKI.
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http://dx.doi.org/10.1007/s00134-019-05919-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210248PMC
May 2020

A potential diagnostic problem on the ICU: Euglycaemic diabetic Ketoacidosis associated with SGLT2 inhibition.

J Crit Care 2020 06 10;57:19-22. Epub 2019 Dec 10.

Intensive Care Unit, Royal Surrey County Hospital NHS Foundation Trust, Egerton Road, Guildford, Surrey GU2 7XX, UK; Department of Clinical and Experimental Medicine, Faculty of Health Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK. Electronic address:

Sodium glucose cotransporter 2 (SGLT2) inhibitors are the latest class of oral hypoglycaemic agents approved to treat type II diabetes. Their use is increasing and as such more patients will present to critical care whilst on this treatment. However, there have been several case reports of euglycaemic diabetic ketoacidosis associated with the use of these agents. Under such circumstances the blood glucose is often normal or only moderately elevated and hence the diagnosis may be delayed resulting in inappropriate therapy. In this review we describe a case of SGLT2 mediated ketoacidosis who presented to our intensive care unit, discuss the proposed pathophysiology behind this development of ketoacidosis as well as its potential prevention, management and treatment.
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http://dx.doi.org/10.1016/j.jcrc.2019.12.007DOI Listing
June 2020

Lung-kidney interactions in critically ill patients: consensus report of the Acute Disease Quality Initiative (ADQI) 21 Workgroup.

Intensive Care Med 2020 04 9;46(4):654-672. Epub 2019 Dec 9.

Center for Critical Care Nephrology, University of Pittsburgh, Pittsburgh, PA, USA.

Background: Multi-organ dysfunction in critical illness is common and frequently involves the lungs and kidneys, often requiring organ support such as invasive mechanical ventilation (IMV), renal replacement therapy (RRT) and/or extracorporeal membrane oxygenation (ECMO).

Methods: A consensus conference on the spectrum of lung-kidney interactions in critical illness was held under the auspices of the Acute Disease Quality Initiative (ADQI) in Innsbruck, Austria, in June 2018. Through review and critical appraisal of the available evidence, the current state of research, and both clinical and research recommendations were described on the following topics: epidemiology, pathophysiology and strategies to mitigate pulmonary dysfunction among patients with acute kidney injury and/or kidney dysfunction among patients with acute respiratory failure/acute respiratory distress syndrome. Furthermore, emphasis was put on patients receiving organ support (RRT, IMV and/or ECMO) and its impact on lung and kidney function.

Conclusion: The ADQI 21 conference found significant knowledge gaps about organ crosstalk between lung and kidney and its relevance for critically ill patients. Lung protective ventilation, conservative fluid management and early recognition and treatment of pulmonary infections were the only clinical recommendations with higher quality of evidence. Recommendations for research were formulated, targeting lung-kidney interactions to improve care processes and outcomes in critical illness.
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http://dx.doi.org/10.1007/s00134-019-05869-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103017PMC
April 2020

The Janus faces of bicarbonate therapy in the ICU: not sure!

Intensive Care Med 2020 03 9;46(3):522-524. Epub 2019 Dec 9.

Centre for Kidney Research and Innovation, School of Medicine, University of Nottingham, Nottingham, UK.

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http://dx.doi.org/10.1007/s00134-019-05885-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7223965PMC
March 2020

Serial Urinary Tissue Inhibitor of Metalloproteinase-2 and Insulin-Like Growth Factor-Binding Protein 7 and the Prognosis for Acute Kidney Injury over the Course of Critical Illness.

Cardiorenal Med 2019 16;9(6):358-369. Epub 2019 Oct 16.

Center for Critical Care Nephrology, Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Introduction: Over the course of critical illness, there is a risk of acute kidney injury (AKI), and when it occurs, it is associated with increased length of stay, morbidity, and mortality. The urinary cell-cycle arrest markers tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7) have been utilized to predict the risk of AKI over the next 12 h from the time of sampling. The aim of this analysis was to evaluate the utility of [TIMP-2] × [IGFBP7] measured serially to anticipate the occurrence of AKI over the first 7 days of critical illness.

Methods: This analysis is from a prospective, blinded, observational, international study of patients admitted to intensive care units. We designed the analysis to emulate a clinician-driven serial testing strategy. Urine samples collected every 12 h up to 3 days from 530 patients were considered for analysis. We evaluated [TIMP-2] × [IGFBP7] results for the first 3 measurements (baseline, 12 and 24 h) and continued to evaluate additional results if any of the first 3 were positive >0.3 (ng/mL)2/1,000. Patients were stratified by number of [TIMP-2] × [IGFBP7] results >0.3 (ng/mL)2/1,000 and number of results >2.0 (ng/mL)2/1,000. The primary endpoint was AKI stage 2-3 defined by the Kidney Disease: Improving Global Outcomes (KDIGO) criteria.

Results: The median (interquartile range) age was 64 (53-74) years, 61% were men, and 79% were Caucasian. The median APACHE III score was 71 (51-93), and 82% required mechanical ventilation. Baseline serum creatinine was 0.8 mg/dL and 164/530 (31%) developed the primary endpoint by day 7 with a median time from baseline to stage 2/3 AKI of 26 (8-56) h. In patients with negative values for the first 3 tests (≤0.3 (ng/mL)2/1,000), the cumulative incidence of the primary endpoint at 7 days was 13.0%. Conversely, for those with one, two, or three strongly positive values (>2.0 (ng/mL)2/1,000), the cumulative incidence for the primary endpoint at 7 days was 57.7, 75.0, and 94.4%, respectively, p < 0.001 for trend. There were 3.4% with test results between 0.3 and 2.0 (ng/mL)2/1,000 at all measurements; one third of those patients developed the primary endpoint. We observed a graded increase in the primary endpoint in Kaplan-Meier plots for successively positive test results over time.

Conclusion: Serial urinary [TIMP-2] × [IGFBP7] at baseline, 12 and 24 h, and up through 3 days are prognostic for the occurrence of stage 2/3 AKI over the course of critical illness. Three consecutive negative values (≤0.3 (ng/mL)2/1,000) are associated with very low (13.0%) incidence of stage 2/3 AKI over the course of 7 days. Conversely, emerging or persistent, strongly positive results [>2.0 [ng/mL]2/1,000] predict very high incidence rates (up to 94.4%) of stage 2/3 AKI. There was a low rate of test results between 0.3 and 2.0 (ng/mL)2/1,000, where the primary endpoint was observed in a third of cases.
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http://dx.doi.org/10.1159/000502837DOI Listing
July 2020

Interventions for improving outcomes in acute kidney injury.

Curr Opin Nephrol Hypertens 2019 11;28(6):567-572

Department of Intensive Care Medicine, Royal Surrey County Hospital NHS Foundation Trust, Guildford.

Purpose Of Review: Since the adoption of the classification of acute kidney injury (AKI) through changes in serum creatinine and/or urine output, much data have accumulated as to the associated risks in terms of morbidity and mortality after the development of AKI. However, until recently, a nihilistic approach persisted which implied that little could be done to alter the clinical course of a patient with AKI even where early identification was achieved. This view is reinforced by the opinion that given the broad cause underlying the syndrome of AKI, a 'one size fits all' approach is unlikely to be successful.

Recent Findings: Recent evidence suggests that the management of AKI may be improved somewhat by simple measures, such as the use of care bundles particularly in the intensive care setting. Moreover, there are other interventions using common treatments, which may prove to be of benefit as well as some early evidence that specific therapeutics may be on the horizon.

Summary: Although a syndrome of significantly differing causes, the application of standardized care bundles appears promising and this approach may be improved by the use of specific therapies, including recombinant alkaline phosphatase, the use of intravenous bicarbonate and remote ischaemic preconditioning may also ameliorate the effects of AKI.
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http://dx.doi.org/10.1097/MNH.0000000000000552DOI Listing
November 2019

The Role of Risk Prediction Models in Prevention and Management of AKI.

Semin Nephrol 2019 09;39(5):421-430

Intensive Care Department, The Royal Surrey County Hospital National Health Service Foundation Trust, Guildford, United Kingdom; Department of Clinical and Experimental Medicine, Faculty of Health Sciences, University of Surrey, Guildford, United Kingdom. Electronic address:

Acute kidney injury is a major health care problem. Improving recognition of those at risk and highlighting those who have developed AKI at an earlier stage remains a priority for research and clinical practice. Prediction models to risk-stratify patients and electronic alerts for AKI are two approaches that could address previously highlighted shortcomings in management and facilitate timely intervention. We describe and critique available prediction models and the effects of the use of AKI alerts on patient outcomes are reviewed. Finally, the potential for prediction models to enrich population subsets for other diagnostic approaches and potential research, including biomarkers of AKI, are discussed.
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http://dx.doi.org/10.1016/j.semnephrol.2019.06.002DOI Listing
September 2019

Does the Implementation of a Quality Improvement Care Bundle Reduce the Incidence of Acute Kidney Injury in Patients Undergoing Emergency Laparotomy?

J Clin Med 2019 Aug 20;8(8). Epub 2019 Aug 20.

Department of Intensive Care Medicine and Surrey Peri-Operative Anaesthesia and Critical Care Collaborative Research Group (SPACER), Royal Surrey County Hospital NHS Foundation Trust, Guildford, Surrey GU2 7XX, UK.

Purpose: Previous work has demonstrated a survival improvement following the introduction of an enhanced recovery protocol in patients undergoing emergency laparotomy (the emergency laparotomy pathway quality improvement care (ELPQuiC) bundle). Implementation of this bundle increased the use of intra-operative goal directed fluid therapy and ICU admission, both evidence-based strategies recommended to improve kidney outcomes. The aim of this study was to determine if the observed mortality benefit could be explained by a difference in the incidence of AKI pre- and post-implementation of the protocol.

Method: The primary outcome was the incidence of AKI in the pre- and post-ELPQuiC bundle patient population in four acute trusts in the United Kingdom. Secondary outcomes included the KDIGO stage specific incidence of AKI. Serum creatinine values were obtained retrospectively at baseline, in the post-operative period and the maximum recorded creatinine between day 1 and day 30 were obtained.

Results: A total of 303 patients pre-ELPQuiC bundle and 426 patients post-ELPQuiC bundle implementation were identified across the four centres. The overall AKI incidence was 18.4% in the pre-bundle group versus 19.8% in the post bundle group p = 0.653. No significant differences were observed between the groups.

Conclusions: Despite this multi-centre cohort study demonstrating an overall survival benefit, implementation of the quality improvement care bundle did not affect the incidence of AKI.
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http://dx.doi.org/10.3390/jcm8081265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724004PMC
August 2019

Use of Cell Cycle Arrest Biomarkers in Conjunction With Classical Markers of Acute Kidney Injury.

Crit Care Med 2019 10;47(10):e820-e826

Center for Critical Care Nephrology, Department of Critical Care Medicine, University of, Pittsburgh, Pittsburgh PA.

Objectives: Decreased urine output and/or increased serum creatinine may herald the development of acute kidney injury or reflect normal physiology. In this secondary analysis of the Sapphire study, we examined biomarkers of cell cycle arrest in the settings of oliguria and/or azotemia to improve risk assessment when used with conventional indices in predicting severe acute kidney injury (Kidney Disease: Improving Global Outcomes 3 defined by the need for renal replacement therapy or changes in urine output, serum creatinine or both) or death.

Design: Prospective, international, Sapphire study.

Setting: Academic Medical Center.

Patients: Patients without acute kidney injury Kidney Disease: Improving Global Outcomes stage 2 or 3.

Interventions: None.

Measurements And Main Results: The primary endpoint being development of severe acute kidney injury or death within 1 week. Secondary analysis examined the relationship between tissue inhibitor of metalloproteinases-2 ([TIMP-2]) and insulin growth factor binding protein 7 ([IGFBP7]) and 9-month death or dialysis conditioned on progression to stage 2-3 acute kidney injury within 1 week. Seventy-nine patients reached the primary endpoint and were more likely to be surgical, with higher nonrenal Acute Physiology and Chronic Health Evaluation III scores and more chronic kidney disease. Stage 1 urine output, serum creatinine, and urinary [TIMP-2]•[IGFBP7] greater than 2.0 were all predictive of progression to the primary endpoint independent from nonrenal Acute Physiology and Chronic Health Evaluation III score. Combinations of predictors increased the hazard ratios considerably (from 2.17 to 4.14 to 10.05, respectively). In the presence of acute kidney injury (stage 1), [TIMP-2]•[IGFBP7] greater than 2.0 leads to an increased risk of death or dialysis at 9 months even in the absence of progression of acute kidney injury (stage 2-3) within 7 days.

Conclusions: Cell cycle arrest biomarkers, TIMP-2 and IGFBP7, improve risk stratification for severe outcomes in patients with stage 1 acute kidney injury by urine output, serum creatinine or both, with risk increasing with each acute kidney injury indicator. Longer term outcomes demonstrate that the associated risks of a [TIMP-2]•[IGFBP7] greater than 2.0 is equivalent to acute kidney injury progression even where no progression from stage 1 acute kidney injury is observed.
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http://dx.doi.org/10.1097/CCM.0000000000003907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750148PMC
October 2019

Quality Improvement Goals for Acute Kidney Injury.

Clin J Am Soc Nephrol 2019 06 17;14(6):941-953. Epub 2019 May 17.

Division of Nephrology, Department of Medicine, University of Michigan, Ann Arbor, Michigan; and.

AKI is a global concern with a high incidence among patients across acute care settings. AKI is associated with significant clinical consequences and increased health care costs. Preventive measures, as well as rapid identification of AKI, have been shown to improve outcomes in small studies. Providing high-quality care for patients with AKI or those at risk of AKI occurs across a continuum that starts at the community level and continues in the emergency department, hospital setting, and after discharge from inpatient care. Improving the quality of care provided to these patients, plausibly mitigating the cost of care and improving short- and long-term outcomes, are goals that have not been universally achieved. Therefore, understanding how the management of AKI may be amenable to quality improvement programs is needed. Recognizing this gap in knowledge, the 22nd Acute Disease Quality Initiative meeting was convened to discuss the evidence, provide recommendations, and highlight future directions for AKI-related quality measures and care processes. Using a modified Delphi process, an international group of experts including physicians, a nurse practitioner, and pharmacists provided a framework for current and future quality improvement projects in the area of AKI. Where possible, best practices in the prevention, identification, and care of the patient with AKI were identified and highlighted. This article provides a summary of the key messages and recommendations of the group, with an aim to equip and encourage health care providers to establish quality care delivery for patients with AKI and to measure key quality indicators.
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http://dx.doi.org/10.2215/CJN.01250119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556737PMC
June 2019

Cytokine removal in human septic shock: Where are we and where are we going?

Ann Intensive Care 2019 May 14;9(1):56. Epub 2019 May 14.

Department of Critical Care, Royal Surrey County Hospital, NHS Foundation Trust, Guildford, UK.

Although improving, the mortality from septic shock still remains high despite increased international awareness. As a consequence, much effort has focused on alternative treatment strategies in an effort to improve outcomes. The application of blood purification therapies to improve immune homeostasis has been suggested as one such method, but these approaches, such as high-volume continuous haemofiltration or cytokine and/or endotoxin removal, have enjoyed little success to date. More recently, the use of sorbent technologies has attracted much attention. These adsorbers are highly effective at removing inflammatory mediators, in particular, cytokines, from the bloodstream. This narrative review is the executive summary of meetings held throughout the 6th International Fluid Academy Days in Antwerp, Belgium (Nov 23-25, 2017), focusing on the current understanding regarding the use of such adsorbers in humans with septic shock. We followed a modified Delphi approach involving a combination of evidence appraisal together with expert opinion in order to achieve recommendations for practice and, importantly, future research.
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http://dx.doi.org/10.1186/s13613-019-0530-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517449PMC
May 2019

Understanding Lactatemia in Human Sepsis. Potential Impact for Early Management.

Am J Respir Crit Care Med 2019 09;200(5):582-589

Regions Hospital, St. Paul, Minnesota; and.

Hyperlactatemia in sepsis may derive from a prevalent impairment of oxygen supply/demand and/or oxygen use. Discriminating between these two mechanisms may be relevant for the early fluid resuscitation strategy. To understand the relationship among central venous oxygen saturation (Scv), lactate, and base excess to better determine the origin of lactate. This was a analysis of baseline variables of 1,741 patients with sepsis enrolled in the multicenter trial ALBIOS (Albumin Italian Outcome Sepsis). Variables were analyzed as a function of sextiles of lactate concentration and sextiles of Scv. We defined the "alactic base excess," as the sum of lactate and standard base excess. Organ dysfunction severity scores, physiologic variables of hepatic, metabolic, cardiac, and renal function, and 90-day mortality were measured. Scv was lower than 70% only in 35% of patients. Mortality, organ dysfunction scores, and lactate were highest in the first and sixth sextiles of Scv. Although lactate level related strongly to mortality, it was associated with acidemia only when kidney function was impaired (creatinine >2 mg/dl), as rapidly detected by a negative alactic base excess. In contrast, positive values of alactic base excess were associated with a relative reduction of fluid balance. Hyperlactatemia is powerfully correlated with severity of sepsis and, in established sepsis, is caused more frequently by impaired tissue oxygen use, rather than by impaired oxygen transport. Concomitant acidemia was only observed in the presence of renal dysfunction, as rapidly detected by alactic base excess. The current strategy of fluid resuscitation could be modified according to the origin of excess lactate.
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http://dx.doi.org/10.1164/rccm.201812-2342OCDOI Listing
September 2019

IDEAL timing of renal replacement therapy in critical care.

Nat Rev Nephrol 2019 01;15(1):5-6

Division of Intensive Care and Emergency Medicine, Department of Internal Medicine, Medical University Innsbruck, Innsbruck, Austria.

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http://dx.doi.org/10.1038/s41581-018-0088-1DOI Listing
January 2019

Oliguria in critically ill patients: a narrative review.

J Nephrol 2018 Dec 8;31(6):855-862. Epub 2018 Oct 8.

Division of Intensive Care and Emergency Medicine, Department of Internal Medicine, Medical University Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria.

Oliguria is often observed in critically ill patients. However, different thresholds in urine output (UO) have raised discussion as to the clinical importance of a transiently reduced UO of less than 0.5 ml/kg/h lasting for at least 6 h. While some studies have demonstrated that isolated oliguria without a concomitant increase in serum creatinine is associated with higher mortality rates, different underlying pathophysiological mechanisms suggest varied clinical importance of reduced UO, as some episodes of oliguria may be fully reversible. We aim to explore the clinical relevance of oliguria in critically ill patients and propose a clinical pathway for the diagnostic and therapeutic management of an oliguric, critically ill patient.
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http://dx.doi.org/10.1007/s40620-018-0539-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244549PMC
December 2018
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