Nishkantha Arulkumaran

University College London | UCL · Centre for Intensive Care Medicine

COVID-19 is associated with higher inflammatory markers, illness severity and mortality in males compared to females. Differences in immune responses to COVID-19 may underpin sex- specific outcome differences. We hypothesised that anti-IL-6 receptor monoclonal antibodies are associated with heterogenous treatment effects between male and female pat...

Introduction: Guidelines recommend respiratory fluoroquinolone monotherapy or β-lactam plus macrolide combination therapy as first-line options for hospitalized adults with mild to moderate community-acquired pneumonia (CAP). Efficacy of these regimens has not been adequately evaluated. Methods: We performed a systematic review and meta-analysis...

Acute kidney injury (AKI) is a common clinical syndrome, with an incidence of 20% among patients admitted to hospital. It is frequently associated with other co-morbidities and advancing age. AKI is an independent risk factor for morbidity and mortality. Despite this, AKI is often missed, undertreated, or inadequately followed up, with potential mi...

Building synthetic protocells and prototissues hinges on the formation of biomimetic skeletal frameworks. Recreating the complexity of cytoskeletal and exoskeletal fibers, with their widely varying dimensions, cellular locations and functions, represents a major material hurdle and intellectual challenge which is compounded by the additional demand...

Unlabelled: To ascertain the association between cholesterol and triglyceride levels on ICU admission and mortality in patients with sepsis. Data sources: Systematic review and meta-analysis of published studies on PubMed and Embase. Study selection: All observational studies reporting ICU admission cholesterol and triglyceride levels in criti...

Mitochondrial dysfunction and immune cell dysfunction are commonplace in sepsis and are associated with increased mortality risk. The short chain fatty acid, butyrate, is known to have anti-inflammatory effects and promote mitochondrial biogenesis. We therefore explored the immunometabolic effects of butyrate in an animal model of sepsis. Isolated...

Background Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality. Corticosteroids may be a beneficial adjunct in the treatment of bacterial pneumonia. Research question Is there any benefit of corticosteroid therapy in the management of bacterial CAP among patients requiring hospitalization? Study Design and Methods Pub...

Background: Doxycycline has been recommended as a treatment option for non-severe community-acquired pneumonia (CAP) in adults. We sought to review the evidence for the efficacy of doxycycline in adult patients with mild-to-moderate CAP. Methods: We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) of doxycyc...

Introduction Macrolide antibiotics have immunomodulatory properties which may be beneficial in viral infections. However, the precise effects of macrolides on T cell responses to COVID, differences between different macrolides, and synergistic effects with other antibiotics have not been explored. Methods We investigated the effect of antibiotics...

Background: The COVID-19 pandemic increased the use of broad-spectrum antibiotics due to diagnostic uncertainty, particularly in critical care. Multiprofessional communication became more difficult, weakening stewardship activities. Aim: To determine changes in bacterial co-/secondary infections and antibiotics used in COVID-19 patients in criti...

Background Bactericidal antibiotics are generally assumed to be superior to bacteriostatic antibiotics as first-line treatment for pneumonia. Objectives We performed a systematic review, meta-analysis, and trial sequential analysis (TSA) of randomized controlled trials of bactericidal versus bacteriostatic antibiotics to ascertain clinical outcome...

Background: SARS-CoV-2-specific antibodies, particularly those preventing interaction between the viral spike receptor-binding domain and the host angiotensin-converting enzyme 2 receptor, may prevent viral entry into host cells and disease progression. / Objective: We performed a systematic review, meta-analysis, trials sequential analysis (TSA) a...

PurposeThe integration of palliative care into intensive care units (ICUs) is advocated to mitigate physical and psychological burdens for patients and their families, and to improve end-of-life care. The most efficacious palliative care interventions, the optimal model of their delivery and the most appropriate outcome measures in ICU are not clea...

BACKGROUND: Excess mitochondrial reactive oxygen species (mROS) in sepsis is associated with organ failure, in part by generating inflammation through the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. We determined the impact of a mitochondrial-targeted antioxidant (MitoTEMPO) on mitochondrial dysfunction in renal proximal...

Objectives Recent studies have demonstrated mortality benefits from corticosteroid use in COVID-19 patients requiring respiratory support. However, clinical practice may warrant the use of corticosteroids outside the context of a clinical trial. Such data are rarely, if ever, reported. We explored the use of corticosteroids for adult respiratory di...

Objectives: Multiple mechanisms have been proposed to explain disease severity in coronavirus disease 2019. Therapeutic approaches need to be underpinned by sound biological rationale. We evaluated whether serum levels of a range of proposed coronavirus disease 2019 therapeutic targets discriminated between patients with mild or severe disease. D...

Background: Our objective was to the describe indications, management, complications and outcomes of renal replacement therapy (RRT) in COVID-19 critically ill patients. To contextualise these findings, comparisons were made against 36 non-COVID-19 consecutive patients requiring RRT on ICU. Methods: We conducted a retrospective single centre obs...

Background SARS-CoV-2-specific antibodies, particularly those preventing interaction between the viral spike receptor-binding domain and the host angiotensin-converting enzyme 2 receptor, may prevent viral entry into host cells and disease progression. Objective We performed a systematic review, meta-analysis, trials sequential analysis (TSA) and...

Background Excess mitochondrial reactive oxygen species (mROS) in sepsis is associated with organ failure, in part by generating inflammation through the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. We determined the impact of a mitochondrial-targeted antioxidant (MitoTEMPO) on mitochondrial dysfunction in renal proximal t...

Purpose: Interleukin-6 (IL-6) levels discriminate between patients with mild and severe COVID-19, making IL-6 inhibition an attractive therapeutic strategy. We conducted a systematic review, meta-analysis, trial sequential analysis (TSA), and meta-regression of randomized-controlled trials to ascertain the benefit of IL-6 blockade with tocilizumab...

Patients with COVID-19 ARDS have distinct physiological and immunological phenotypes compared to patients with non-COVID ARDS. Patients with COVID-19 ARDS (n = 32) had a significant improvement in PaO2: FiO2 ratio (p = 0.046) following low-dose steroid treatment, unlike patients with non-COVID ARDS (n = 16) (p = 0.529). Patients with COVID-19 ARDS...

Background Emergence of variants with specific mutations in key epitopes in the spike protein of SARS-CoV-2 raises concerns pertinent to mass vaccination campaigns and use of monoclonal antibodies. We aimed to describe the emergence of the B.1.1.7 variant of concern (VOC), including virological characteristics and clinical severity in contemporaneo...

Metabolically active gasotransmitters (nitric oxide, carbon monoxide and hydrogen sulfide) are important signalling molecules that show therapeutic utility in oxidative pathologies. The reduced form of selenium, hydrogen selenide (HSe-/H2Se), shares some characteristics with these molecules. The simple selenide salt, sodium hydroselenide (NaHSe) sh...

Introduction: Acute respiratory distress syndrome (ARDS) is associated with significant morbidity and mortality. We undertook a meta-analysis of randomized controlled trials (RCTs) to determine the mortality benefit of non-specialist therapeutic interventions for ARDS available to general critical care units. Evidence acquisition: A systematic s...

An amendment to this paper has been published and can be accessed via the original article.

DNA nanotechnology produces precision nanostructures of defined chemistry. Expanding their use in biomedicine requires designed biomolecular interaction and function. Of topical interest are DNA nanostructures that function as vaccines with potential advantages over nonstructured nucleic acids in terms of serum stability and selective interaction w...

It remains unclear if intubation and ventilation earlier in the disease course confers a survival advantage in acute respiratory distress syndrome. Our objective was to determine whether patients with COVID-19 who died following mechanical ventilation were more advanced in their disease compared to survivors. Forty-seven patients admitted directly...

Severe COVID‐19 disease is a hyperinflammatory, pro‐thrombotic state. We undertook plasma exchange (PEX) to determine its effects on organ function and thrombo‐inflammatory markers. Seven critically ill adults with severe COVID‐19 respiratory failure (PaO2:FiO2 ratio < 200 mm Hg) requiring invasive or noninvasive ventilatory support and elevated th...

Introduction Severe COVID-19 disease is associated with a hyperinflammatory, pro-thrombotic state and a high mortality. A thrombotic phenotype rather than a coagulopathy is suggested and we undertook plasma exchange to determine its effects on organ function and thrombo-inflammatory markers. Methods Plasma exchange was carried out in seven critical...

Objective: The objective of this study was to conduct a meta-analysis and trial sequential analysis (TSA) of published randomized controlled trials (RCTs) to determine whether mortality benefit exists for extracorporeal blood purification techniques in sepsis. Data sources: A systematic search on MEDLINE, Embase, and the Cochrane Central Registe...

Background: To compare differences in indications, management, complications and outcomes of renal replacement therapy (RRT) in COVID-19 patients compared to non-COVID critically ill patients. Methods: We conducted a retrospective observational single centre cohort study in UK. Patients with COVID-19 requiring RRT, compared to consecutive, non-COVI...

Objective: This study aimed to determine the relationship between early postoperative nonsteroidal anti-inflammatory drug (NSAID) administration and postoperative acute kidney injury (AKI) and anastomotic leak. Summary background data: NSAIDs have analgesic, opioid-sparing, and anti-inflammatory effects. However, their postoperative use is limited...

Objective: To investigate methods of antibiotic duration minimization and their effect on mortality and infectious complications in critically ill patients. Data sources: A systematic search of PubMed, Embase (via Ovid), clinicaltrials.gov, and the Cochrane Central Register of Controlled Trials (via Wiley) (CENTRAL, Issue 2, 2015). Study select...

The belief that, for the individual patient, the benefit of prompt and continued use of antimicrobials outweighs any potential harm is a significant barrier to improved stewardship of these vital agents. Antimicrobial stewardship may be perceived as utilitarian rationing, seeking to preserve the availability of effective antimicrobials by limiting...

Abstract Background Trainee research collaboratives (TRCs) have pioneered high quality, prospective ‘snap-shot’ surgical cohort studies in the UK. Outcomes After Kidney injury in Surgery (OAKS) was the first TRC cohort study to attempt to collect one-year follow-up data. The aims of this study were to evaluate one-year follow-up and data completion...

Conducting clinical trials in critical care is integral to improving patient care. Unique practical and ethical considerations exist in this patient population that make patient recruitment challenging, including narrow recruitment timeframes and obtaining patient consent often in time-critical situations. Units currently vary significantly in thei...

We were surprised to read the letter by Berti and colleagues ¹ , commenting on our recent article on the incidence of arterial and venous thrombosis in antineutrophil cytoplasmic antibody–associated vasculitis (AAV) ² . They make the unjustified comment that “the incidence estimates for [arterial (ATE) and venous thrombosis events (VTE)] may be inf...

Background: Even though data suggest that palliative care (PC) improves patient quality of life, caregiver burden, cost, and intensive care unit (ICU) length of stay, integration of PC in the ICU is far from being universally accepted. Poor understanding of what PC provides is one of the barriers to the widespread implementation of their services...

We thank Dr. Rothschild for his interest ¹ in our article ² on the incidence of arterial and venous thrombosis in antineutrophil cytoplasmic antibody–associated vasculitis (AAV). He raises the interesting issue of susceptibility to both arterial and venous thrombotic events, which is also characteristic of antiphospholipid syndrome.

Background: Patients who require acute initiation of dialysis have higher mortality rates when compared with patients with planned starts. Our primary objective was to explore the reasons and risk factors for acute initiation of renal replacement therapy (RRT) among patients with end-stage kidney disease (ESKD). Our secondary objective was to dete...

Objective: To determine the incidence of arterial thrombotic events (ATE) and venous thromboembolism (VTE) in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Methods: This is a retrospective cohort study presenting the incidence of ATE (coronary events or ischemic stroke) and VTE [pulmonary embolism (PE) or deep venous thrombosi...

The peri‐operative use of angiotensin‐converting enzyme inhibitors or angiotensin‐2 receptor blockers is thought to be associated with an increased risk of postoperative acute kidney injury. To reduce this risk, these agents are commonly withheld during the peri‐operative period. This study aimed to investigate if withholding angiotensin‐converting...

Objective: To summarize the results of randomized controlled trials on the use of vasopressin as a vasopressor agent in cardiac surgery. Design: Meta-analysis. Participants: Six-hundred-twenty-five adult patients undergoing elective or emergency cardiac surgery. Interventions: Arginine vasopressin infusion (n = 313) or control/standard thera...

Sepsis is a major clinical problem associated with significant organ dysfunction and high mortality. The ATP-sensitive P2X7 receptor activates the NLRP3 inflammasome and is a key component of the innate immune system. We used a fluid-resuscitated rat model of fecal peritonitis and acute kidney injury (AKI) to investigate the contribution of this pu...

Data S1. Supplementary data.

Videolaryngoscopy (VL) may improve the success of orotracheal intubation compared with direct laryngoscopy (DL). We performed a systematic search of PubMed, Embase, and CENTRAL databases for studies comparing VL and DL for emergency orotracheal intubations outside the operating room. The primary outcome was rate of first-pass intubation, with subgr...

Introduction: We evaluated intensive care medicine trainees' practice of emergency intubations in the United Kingdom. Methods: Retrospective analysis of 881 in-hospital emergency intubations over a three-year period using an online trainee logbook. Results: Emergency intubations out-of-hours were less frequent than in-hours, both on weekdays a...

Objective: To explain the paradigm of significant renal functional impairment despite preserved hemodynamics and histology in sepsis-induced acute kidney injury. Design: Prospective observational animal study. Setting: University research laboratory. Subjects: Male Wistar rats. Intervention: Using a fluid-resuscitated sublethal rat model o...

Importance A number of common clinical conditions are associated with severe inflammation, including sepsis and major surgery. The excessive inflammatory response results in shock states and ‘multiorgan dysfunction syndrome’ (MODS), which is often the final common pathway before death. Objective To understand the mechanisms that underlie MODS and...

Background The fluid challenge is considered the gold standard for diagnosis of fluid responsiveness. The objective of this study was to describe the fluid challenge techniques reported in fluid responsiveness studies and to assess the difference in the proportion of ‘responders,’ (PR) depending on the type of fluid, volume, duration of infusion an...

Objectives: Organizational factors are associated with outcome of critically ill patients and may vary by time of day and day of week. We aimed to identify the association between out-of-hours admission to critical care and mortality. Data sources: MEDLINE (via Ovid) and EMBASE (via Ovid). Study selection: We performed a systematic search of t...

Co-presentation with both ANCA and anti-GBM antibodies is thought to be relatively rare. Current studies of such ‘double-positive’ cases report small numbers and variable outcomes. To study this further we retrospectively analyzed clinical features and long-term outcomes of a large cohort of 568 contemporary patients with ANCA-associated vasculitis...

Objectives: To characterize the temporal pattern of a panel of blood and urinary biomarkers in an animal model of fecal peritonitis and recovery. Design: Prospective observational animal study. Setting: University research laboratory. Subjects: Male Wistar rats. Interventions: A fluid-resuscitated, long-term (3 d) rat model of sepsis (feca...

Background: We aimed to identify any association between day and time of admission to critical care and acute hospital outcome. Methods: We conducted a cohort study using prospectively collected data from the national clinical audit of adult critical care. We included 195 428 unplanned admissions from 212 adult general critical care units in Eng...

Acute kidney injury (AKI) is a common clinical problem within the intensive care unit. Sepsis is implicated in half the cases of AKI; in those patients requiring acute renal replacement therapy there is an associated mortality of 50%. However, other than maintenance of an adequate circulation, no specific therapy exists for septic AKI. This is in l...

Background: Clinical trials in critical care are often resource-intense, with many unique challenges. Barriers to effective recruitment and implementation of study intervention have not been explored in a UK context. Aim: To identify facilitating factors and barriers to enrolling patients into critical care clinical trials within the UK from cli...

Mitochondria are an essential part of the cellular infrastructure, being the primary site for high-energy adenosine triphosphate production through oxidative phosphorylation. Clearly, in severe systemic inflammatory states, like sepsis, cellular metabolism is usually altered, and end organ dysfunction is not only common, but also predictive of long...