Tony Whitehouse

ABSTRACTBackgroundHydroxychloroquine and chloroquine have been proposed as treatments for coronavirus disease 2019 (COVID-19) on the basis of in vitro activity, uncontrolled data, and small randomized studies.MethodsThe Randomised Evaluation of COVID-19 therapy (RECOVERY) trial is a randomized, controlled, open-label, platform trial comparing a range of possible treatments with usual care in patients hospitalized with COVID-19. We report the preliminary results for the comparison of hydroxychloroquine vs. usual care alone. The primary outcome was 28-day mortality.Results1561 patients randomly allocated to receive hydroxychloroquine were compared with 3155 patients concurrently allocated to usual care. Overall, 418 (26.8%) patients allocated hydroxychloroquine and 788 (25.0%) patients allocated usual care died within 28 days (rate ratio 1.09; 95% confidence interval [CI] 0.96 to 1.23; P=0.18). Consistent results were seen in all pre-specified subgroups of patients. Patients allocated...

To assess the stability of retinal structure and blood flow measures over time and in different clinical settings using portable optical coherence tomography angiography (OCTA) as a potential biomarker of central perfusion in critical illness, 18 oesophagectomy patients completed retinal structure and blood flow measurements by portable OCT and OCTA in the eye clinic and intensive therapy unit (ITU) across three timepoints: (1) pre-operation in a clinic setting; (2) 24–48 h post-operation during ITU admission; and (3) seven days post-operation, if the patient was still admitted. Blood flow and macular structural measures were stable between the examination settings, with no consistent variation between pre- and post-operation scans, while retinal nerve fibre layer thickness increased in the post-operative scans (+2.31 µm, p = 0.001). Foveal avascular zone (FAZ) measurements were the most stable, with an intraclass correlation coefficient of up to 0.92 for right eye FAZ area. Blood f...

Systematic reviews of early rehabilitation within intensive care units have highlighted the need for robust multi-centre randomised controlled trials with longer term follow up. This trial aims to explore the feasibility of earlier and enhanced rehabilitation for patients mechanically ventilated for ≥5days and to assess the impact on possible long term outcome measures for use in a definitive trial. Patients admitted to a large UK based intensive care unit and invasively ventilated for ≥5days were randomised to the rehabilitation intervention or standard care on a 1:1 basis, stratified by age and SOFA score. The rehabilitation intervention involved a structured programme, with progression along a functionally based mobility protocol according to set safety criteria. 103 out of 128 eligible patients were recruited into the trial, achieving an initial recruitment rate of 80%. Patients in the intervention arm mobilized significantly earlier (8days vs 10 days, p=0.035), at a more acute ...

ObjectivesTo safely expand and adapt the normal workings of a large critical care unit in response to the COVID-19 pandemic.MethodsIn April 2020, UK health systems were challenged to expand critical care capacity rapidly during the first wave of the COVID-19 pandemic so that they could accommodate patients with respiratory and multiple organ failure. Here, we describe the preparation and adaptive responses of a large critical care unit to the oncoming burden of disease. Our changes were similar to the revolution in manufacturing brought about by ‘Long Shops’ of 1853 when Richard Garrett and Sons of Leiston started mass manufacture of traction engines. This innovation broke the whole process into smaller parts and increased productivity. When applied to COVID-19 preparations, an assembly line approach had the advantage that our ICU became easily scalable to manage an influx of additional staff as well as the increase in admissions. Healthcare professionals could be replaced in case o...

BackgroundFor long-stay patients on the adult intensive care unit, the gut microbiota plays a key role in determining the balance between health and disease. However, it remains unclear which ICU patients might benefit from interventions targeting the gut microbiota or the pathogens therein.MethodsWe undertook a prospective observational study of twenty-four ICU patients, in which serial faecal samples were subjected to shotgun metagenomic sequencing, phylogenetic profiling and microbial genome analyses.ResultsTwo-thirds of patients experienced a marked drop in gut microbial diversity (to an inverse Simpson’s index of <4) at some stage during their stay in ICU, often accompanied by absence or loss of beneficial commensal bacteria. Intravenous administration of the broad-spectrum antimicrobial agent meropenem was significantly associated with loss of gut microbial diversity, but administration of other antibiotics, including piperacillin-tazobactam, failed to trigger statistically...

Landiolol is an injectable ultrashort acting beta-blocker with high beta1 selectivity indicated for heart rate control of atrial fibrillation in the emergency and critical care setting. Accordingly, landiolol is associated with a significantly reduced risk of arterial hypotension and negative inotropic effects. Based on this particular profile along with the clinical experience in Japan for more than a decade landiolol represents a promising agent for the management of elevated heart rate and atrial fibrillation in intensive care patients even with catecholamine requirements. This article provides a review and perspective of landiolol for heart rate control in intensive care patients based on the current literature.

In various medical and surgical conditions, research has found that centers with higher patient volumes have better outcomes. This relationship has not previously been explored for status epilepticus. This study sought to examine whether centers that see higher volumes of patients with status epilepticus have lower in-hospital mortality than low-volume centers. Cohort study, using 2010-2015 data from the nationwide Case Mix Programme database of the U.K.'s Intensive Care National Audit and Research Centre. Greater than 90% of ICUs in United Kingdom, Wales, and Northern Ireland. Twenty-thousand nine-hundred twenty-two adult critical care admissions with a primary or secondary diagnosis of status epilepticus or prolonged seizure. Annual hospital status epilepticus admission volume. We used multiple logistic regression to evaluate the association between hospital annual status epilepticus admission volume and in-hospital mortality. Hospital volume was modeled as a nonlinear variabl...

Mortality from critical illness is improving, but survivors suffer from prolonged weakness and psychological and cognitive impairments. Maximising the recovery after critical illness has been highlighted as a research priority, especially in relation to an ageing population who present with higher rates of pre-morbid disability. Small studies have shown that starting rehabilitation early within the intensive care unit (ICU) improves short-term outcomes. Systematic reviews have highlighted the need for robust multicentre randomised controlled trials with longer term follow-up. The study design is a randomised controlled study to explore the feasibility of providing earlier and enhanced rehabilitation to mechanically ventilated patients at high risk of ICU-acquired weakness within the ICU. The rehabilitation intervention involves a structured programme, with progression along a functionally based mobility protocol according to set safety criteria. The overall aim of the intervention i...

Sepsis is a common cause of morbidity and mortality and is associated with significant costs to the healthcare organizations. We performed a systematic review and meta-analysis to assess whether high or low-dose statin therapy improved mortality in patients with sepsis. The trials analyzed in this study were multicenter or single center randomized control studies using statins for sepsis in a hospital setting. The patients included were adults with suspected or confirmed infection. This study found eight randomized controlled trials where participants were given either a statin or placebo daily for 14-28 days, the duration of their illness, or until their death or discharge, which ever occurred first. This meta-analysis measured the effect of statin therapy on in hospital and 28 days mortality. In unselected patients, there was no demonstrable difference in the 28 days mortality (relative risk [RR] 0.88 95% confidence interval [CI], 0.70-1.12 and P = 0.16). There was also no signifi...

Previous studies of intrarenal perfusion and tissue oxygenation have produced a wide range of results and have not matched tissue oxygen tension (tPo2) with concurrent changes in flow in three distinct regions. We thus used an anesthetized rat model of hemorrhage-reperfusion to address this question. Combined tpo2/laser-Doppler fiber-optic probes were simultaneously sited in cortical, corticomedullary (CMJ), and medullary regions of the left kidney. Total renal blood flow was measured in separate experiments. Recordings were made during exsanguination of 10 and 20% of estimated blood volume at 10-min intervals, followed by shed-blood resuscitation after a further 10 min. The decay in tpo2 was then recorded following total cessation of blood flow, allowing estimation of local oxygen consumption. During exsanguination, tPo2 was maintained in all intrarenal regions, despite significant falls in blood pressure and total renal blood flow. However, intrarenal flow was redistributed with r...

We hypothesized that intensivists unfamiliar with an ICU team and the context of that ICU would affect patient outcomes. We examined differences in mortality when ICU patients were admitted under intensivists routinely working in that ICU and compared with those admitted by intensivists familiar with an ICU elsewhere in the same hospital. A 5-year natural experimental crossover study involving patients admitted to four ICUs in a large U.K. teaching hospital. During a period of service reconfiguration, intensivists routinely rostered to work in one ICU worked in another of the hospital's four ICUs. "Home" intensivists were those who continued to work in their usual ICU; "visitor" intensivists were those who delivered care in an unfamiliar ICU. Patient data were obtained from electronic patient records to provide analysis on sex, age, admission Sequential Organ Failure Assessment score, date and time of admission, and admission type (elective, transfer, or unpl...

We hypothesized that intensivists unfamiliar with an ICU team and the context of that ICU would affect patient outcomes. We examined differences in mortality when ICU patients were admitted under intensivists routinely working in that ICU and compared with those admitted by intensivists familiar with an ICU elsewhere in the same hospital. A 5-year natural experimental crossover study involving patients admitted to four ICUs in a large U.K. teaching hospital. During a period of service reconfiguration, intensivists routinely rostered to work in one ICU worked in another of the hospital's four ICUs. "Home" intensivists were those who continued to work in their usual ICU; "visitor" intensivists were those who delivered care in an unfamiliar ICU. Patient data were obtained from electronic patient records to provide analysis on sex, age, admission Sequential Organ Failure Assessment score, date and time of admission, and admission type (elective, transfer, or unpl...

To estimate the economic impact of a Tegaderm(TM) chlorhexidine gluconate (CHG) gel dressing compared with a standard intravenous (i.v.) dressing (defined as non-antimicrobial transparent film dressing), used for insertion site care of short-term central venous and arterial catheters (intravascular catheters) in adult critical care patients using a cost-consequence model populated with data from published sources. A decision analytical cost-consequence model was developed which assigned each patient with an indwelling intravascular catheter and a standard dressing, a baseline risk of associated dermatitis, local infection at the catheter insertion site and catheter-related bloodstream infections (CRBSI), estimated from published secondary sources. The risks of these events for patients with a Tegaderm CHG were estimated by applying the effectiveness parameters from the clinical review to the baseline risks. Costs were accrued through costs of intervention (i.e. Tegaderm CHG or standard intravenous dressing) and hospital treatment costs depended on whether the patients had local dermatitis, local infection or CRBSI. Total costs were estimated as mean values of 10,000 probabilistic sensitivity analysis (PSA) runs. Tegaderm CHG resulted in an average cost-saving of £77 per patient in an intensive care unit. Tegaderm CHG also has a 98.5% probability of being cost-saving compared to standard i.v. dressings. The analyses suggest that Tegaderm CHG is a cost-saving strategy to reduce CRBSI and the results were robust to sensitivity analyses.

To develop a liver function-related risk prediction tool to identify acute-on-chronic liver failure patients at greatest risk of in-hospital mortality. The LiFe (liver, injury, failure, evaluation) score, was constructed based on the opinions of 157 intensivists within the European Society for Intensive Care Medicine. Experts were surveyed and instructed to weigh the diagnostic importance of each feature of a proposed prediction model. We performed a retrospective cohort study of 1916 patients with chronic liver disease admitted to a medical or surgical ICU between 1997, and 2011 in three large hospitals in Boston, USA, and London, UK, with arterial lactate, total bilirubin and INR drawn at ICU admission. The derivation cohort consisted of ICU patients from Brigham and Women's Hospital and Massachusetts General Hospital in Boston (n = 945), and the validation cohort comprised patients from Kings College Hospital, London, admitted to the Liver Intensive Therapy Unit (n = 971). A clinical prediction model was derived and validated based on a logistic regression model describing the risk of in-hospital mortality as a function of the predictors (arterial lactate 0-1.9, ≥2.0-3.9, ≥4.0-5.9, ≥6.0 mg/dL; total bilirubin 0-1.9, ≥2.0-3.9, ≥4.0-5.9, ≥6.0 mg/dL; INR 0-1.9, ≥2.0-3.9, ≥4.0-5.9, ≥6.0) at ICU admission. Performance analysis of the LiFe score against SOFA, CLIF-SOFA, APACHE II and SAPS II was completed in the validation cohort of critically ill cirrhotic patients. The derivation cohort (n = 941) was 53 % male with a mean age of 65 years and an in-hospital mortality rate of 30 %. The validation cohort (n = 971) was 63 % male with mean age of 51 years and an in-hospital mortality rate of 52 %. The C statistic for the prediction model was 0.74 (95 % CI 0.70-0.77) in the derivation cohort and 0.77 (95 % CI 0.74-0.80) in the validation cohort. In the validation cohort, in-hospital mortality was 17 % in the low-risk group (0 risk score points), 28 % in the intermediate-risk group (1-3 points), 47 % in the high-risk group (4-8 points), and 77 % in the very high-risk group (>8 points). In the validation cohort, the C statistics for SOFA, CLIF-SOFA, APACHE II, and SAPS II were 0.80, 0.81, 0.77, and 0.78, respectively. Further, a significant positive correlation exists between LiFe score and acute-on-chronic liver failure grade, (r = 0.478, P < 0.001). Our LiFe score calculated from arterial lactate, total bilirubin and INR at ICU admission is a simple, quick and easily understandable score that may increase clinical utility for risk prediction in ICU patients with acute-on-chronic liver failure. The LiFe score can be used in place of physiological based scores for early risk prediction in patients with chronic liver disease but is not intended to replace CLIF-SOFA as a benchmark for prognostication.

Introduction The UK population is ageing with increasing number of elderly patients suffering traumatic brain injury (TBI). The purpose of this study was to identify national TBI admission demographics, analyse the temporal evolution of TBI mortality in a single centre and conduct a systematic review of the literature to identify whether there is an age bias amongst researchers studying TBI. Methods National demographics for TBI were obtained from Health Episode Statistics. TBI patients admitted from 2000 to 2011 to Cambridge University Hospitals Neurocritical Care Unit (NCCU) were divided into age groups (<60, 60-74, ≥75 years). Temporal evolution of mortality was analysed using a logistic regression method. A systematic literature review was conducted to identify primary TBI research studies. Patient's ages were extracted and an average mean age was calculated and compared over time. Results From 1998, national TBI admissions have increased with the greatest rise in >60-year age group (p < 0.0001). In a tertiary referral critical care unit (n = 1145), the 60-74 year age group (compared to <60) had a significantly lower improvement in mortality over time (OR: 1.15, 95% CI: 1.02-1.31). A literature review revealed a mean age of 32.73 years (SD ± 12.85) for patients recruited to primary TBI studies. Conclusion Despite increased admissions of elderly patients following TBI and static mortality (single centre, 60-74 year age group) there is little or no evidence of a corresponding increase in the age of patients recruited for TBI studies. In addition to the difficulties this presents in forming evidence-based decisions for the patient with TBI, it may also represent a wider problem for ICU research in an ever-ageing critical care population. More research needs to be conducted to establish the treatment end points for an ageing population.

Beta blockers are some of the most studied drugs in the pharmacopoeia. They are already widely used in medicine for treating hypertension, chronic heart failure, tachyarrhythmias, and tremor. Whilst their use in the immediate perioperative patient has been questioned, the use of esmolol in the patients with established septic shock has been recently reported to have favourable outcomes. In this paper, we review the role of the adrenergic system in sepsis and the evidence for the use of beta stimulation and beta blockers from animal models to critically ill patients.

A major source of microbial colonization of short-term central venous catheters (CVC) is the patients' endogenous skin microorganisms located at the CVC insertion site. The aim of this study was to determine if a transparent film dressing incorporating a 2% (weight/weight) chlorhexidine gluconate (CHG) gel decreases CVC and insertion site microbial colonization compared with a nonantimicrobial dressing in adult patients in critical care. On CVC removal, samples for microbiological investigation were taken from both the skin surrounding the CVC insertion site and also from sutures securing the CVC. The sutures and intradermal and tip sections of the CVC were also collected for microbiological investigation. Microorganisms recovered from the samples were subsequently tested for susceptibility to CHG. There was a significant reduction in the number of microorganisms recovered from the CVC insertion site, suture site, sutures, and catheter surface in the CHG dressing group (n = 136)...

Vancomycin is a glycopeptide antibiotic widely used in the management of meticillin-resistant Staphylococcus aureus (MRSA). Guidelines currently recommend vancomycin be administered by intermittent infusion, despite recent research suggesting that continuous infusion (CI) may be associated with lower rates of vancomycin-associated nephrotoxicity. In 2012, Cataldo et al. presented a meta-analysis supporting the use of CI. Here we present an updated meta-analysis, inclusive of a recently published large-scale retrospective study. PubMed, EMBASE and Cochrane Reviews databases were searched using the keywords 'vancomycin' and 'continuous' or 'intermittent' or 'infusion' or 'discontinuous' or 'administration'. Seven studies were included in the final analysis. Using a random-effects model, a non-significant trend of reduced nephrotoxicity in those who received vancomycin by CI (risk ratio=0.799, 95% confidence interval 0.523-1.220; P=0.299) was identified. A large, randomised controlled trial is necessary to confirm these results.

The Acute Respiratory Distress Syndrome Network (ARDSnet) group compared low tidal volume ventilation with standard ventilatory strategies [1]; early goal directed therapy (EGDT) advocated administering fluids, blood products, and dobutamine to achieve oxygen delivery goals to septic patients on arrival in the emergency department [2]; and intensive insulin therapy was used to maintain tight glucose parameters in surgical patients [3]. These are landmark but disparate trials that have demonstrated major improvements in outcome and feature in the Surviving Sepsis Campaign Guidelines for managing sepsis [4]. In this chapter, we discuss the role mitochondrial dysfunction plays in critical illness and its manifestation as a disruption of cellular energetics. We suggest that the positive outcomes from the above-mentioned trials relate to a reduction of impaired mitochondrial function and a reduction in the subsequent generation of inflammatory signals.

To evaluate the influence of vancomycin dose, serum trough concentration, and dosing strategy on the evolution of acute kidney injury in critically ill patients. Retrospective, single-center, observational study. University Hospital ICU, Birmingham, UK. All critically ill patients receiving vancomycin from December 1, 2004, to August 31, 2009. None. The prevalence of new onset nephrotoxicity was reported using Risk, Injury, Failure, Loss, End-stage renal disease criteria, and independent factors predictive of nephrotoxicity were identified using logistic regression analysis. Complete data were available for 1,430 patients. Concomitant vasoactive therapy (odds ratio = 1.633; p < 0.001), median serum vancomycin (odds ratio = 1.112; p < 0.001), and duration of therapy (odds ratio = 1.041; p ≤ 0.001) were significant positive predictors of nephrotoxicity. Intermittent infusion was associated with a significantly greater risk of nephrotoxicity than continuous infusion (odds ratio = 8.204; p ≤ 0.001). In a large dataset, higher serum vancomycin concentrations and greater duration of therapy are independently associated with increased odds of nephrotoxicity. Furthermore, continuous infusion is associated with a decreased likelihood of nephrotoxicity compared with intermittent infusion. This large dataset supports the use of continuous infusion of vancomycin in critically ill patients.

To assess the degree of environmental contamination with methicillin-resistant Staphylococcus aureus (MRSA) in critical care and the likelihood of subsequent new patient acquisition if carriers were or were not moved to single rooms. Randomized sequential sampling of bed areas. Intensive care units of two teaching hospitals. Medical and surgical patients requiring critical care. Six environmental sites around randomly selected patients plus two communal sites were sampled using contact plates during periods when patients with MRSA were physically isolated or not. Admission, weekly, and discharge screening patient swabs were taken to identify patients admitted with, or newly acquiring, MRSA. A total of 2,436 samples were taken from environments around 114 patients, plus a further 349 samples from doctors' hands and telephones. Of the 47 bed areas where MRSA strains were identified that were not found initially on patients, only one patient subsequently acquired the same strain. Five other patients became colonized with new MRSA strains, but these were not found in their environment beforehand. Of 52 patients colonized with MRSA, 34 had a similar strain found subsequently in their environment. Whereas the MRSA-colonized patient frequently contaminates his or her local environment, transmission of MRSA from the environment to the patient was not commonly identified. Studies elucidating possible routes of MRSA transmission are urgently needed to inform infection control policies.