ICU and Recovery – Our Trials

Our Trials

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Microvascular monitoring during liver resection surgery (Micro Hep Flow)
Is microvascular perfusion impaired following macrohaemodynamic tabilization after liver resection surgery, compared to microvascular perfusion measured pre-operatively?
Study design – Prospective observational cohort study. No
intervention, pilot study

PECC will be a three-centre, observational cohort study using ultrasound to determine the incidence and natural history of pleural effusions in critically ill patients on the intensive care unit. All patients admitted to the ICU who are on mechanical ventilation will undergo an ultrasound on admission which is in keeping with standard clinical practice on each unit.

Any patient who then remains ventilated for more than 48 will have a repeat scan performed every two days for the duration of their stay. Data will be recorded by participating ICUs until hospital discharge or until day 28. The first scan will be performed within 24 hours of admission in keeping with the clinical practice at each unit. Further scans will only be performed within the context of the study once patient consent or relative assent has been obtained.

Primary Objective
To define the incidence of pleural effusions in mechanically ventilated patients

Secondary Objectives
To determine:
 The natural history of pleural effusions in this cohort.
 The relationship between fluid balance and pleural effusion
incidence/size
 Correlate the ventilatory mechanics with pleural effusion size
 The relationship with time on ventilator
 The relationship with ICU length of stay.

The ADRENAL Study;
ADjunctive coRticosteriod trEatment iN criticAlly ilL patients with septic shock.

• An international multicentre, randomised, blinded, placebo controlled trial comparing intravenous hydrocortisone with placebo in critically ill patients with septic shock.
• 3,800 patients will be enrolled in this study at approx. 50-60 sites. Eligible patients will be randomised to receive either a continuous intravenous infusion of hydrocortisone 200mg or placebo per day for 7 days.
• For all patients, data will be collected at baseline and then daily whilst the patient is in the ICU. Patients will be followed up to day 14, regardless of where the patient resides in the hospital, to monitor the development of bacteraemia. Additional follow up will occur at 90 days and at a 6 months post randomisation.
The primary endpoint for this trial will be death from all causes at 90 days.

Sepsis is a serious condition that occurs when the body reacts severely to an infection. It can result in failure of many of the body’s organs, including the kidney. Sepsisassociated acute kidney injury (SA-AKI) is a serious condition resulting in a death rate of up to 70%, patients who survive are at risk of developing chronic kidney disease (CKD). Currently there is no specific treatment of SA-AKI, and renal replacement therapy (requiring a dialysis
-type machine) is the only supportive option available until the kidney rec
overs.
Alkaline Phosphatase (AP) is an enzyme present in many human cells and organs and helps the body to fight infection and to reduce body-cell damage. A recombinant (combined genetic material) human AP (recAP) was developed by AM Pharma which is administered in higher than natural levels to patients via intravenous (IV) infusion.

The purpose of this study is to determine if recAP is safe and effective inimproving kidney function in patients with SA-AKI, and to determine the effective and safe dose of recAP. The study is in 2 parts. Participants in Part 1 will randomly receive either placebo or 1 of 3 different doses of recAP. In Part 2, participants will receive either placebo or the most effective dose of recap, from part 1.

Participants will be in the study for up to 90 days. There will be a total of 12 visits, daily from Days 1-7, weekly on Days 14, 21 and 28 and follow-up assessments will be on Days 60 and 90. Procedures include: physical examinations, vital signs, electrocardiograms, urine and blood samples for laboratory tests and questionnaires to monitor the disease or side effects of the drug.

Prevention of Respiratory Insufficiency after Surgical Management

A pragmatic randomised controlled trial of continuous positive airway pressure (CPAP) to prevent respiratory complications and improve survival following major abdominal surgery

Methodology International, multi-centre randomised controlled trial with open study group allocation.
Duration 48 months (until October 2019)
Objectives To determine whether early postoperative continuous positive airway pressure (CPAP) reduces the incidence of subsequent respiratory complications and improves one- year survival following major intra-peritoneal surgery.
Benefit If CPAP is associated with an improvement in patient outcomes then it may be introduced as a standard of care for these patients improving overall morbidity and mortality rates, reducing hospital length of stay, freeing resources for use in other areas.
Number of patients 4800 patients
End points The primary outcome measure is a composite of pneumonia, re-intubation, or death within 30 days of randomisation.

Secondary outcomes

Postoperative infection, mechanical ventilation at 30 days

All cause mortality, Quality adjusted life years at 1 year

The burden of the effects of acute muscle wasting is inexorably rising. This is due to an aging population and a growing number of elderly patients undergoing major surgery and requiring critical care . The association between critical illness and the development of muscle loss and consequence weakness is known as intensive care unit-acquired weakness (ICU-AW) and affects up to 25% of ICU patients who require mechanical ventilation for at least 7 days. The mechanisms are highly complex and incompletely understood. However, the implications for recovery and thereafter resumption of prior work and lifestyle are well recognised.

What is only recently gaining recognition is that acute muscle loss (myopenia) can occur after uncomplicated elective surgery: both cardiac and non-cardiac surgery. Shared pathophysiological mechanisms between post-operative myopenia and ICU-AW seem likely – including systemic inflammation and decreased muscular activity. Although the implications of post-operative myopenia are undetermined they are likely to be deleterious. The risk of delayed recovery from surgery due to muscle weakness is recognised in ‘Enhanced Recovery’ programmes that promote early mobilisation.

Vitamin D has an important role in the regulation of bone metabolism and various infectious, cardiovascular and respiratory diseases.  The majority of vitamin D is provided through the direct action of sunlight in the skin and some stems from dietary sources.  Vitamin D has to undergo an activation process within the kidneys to be active in the body.

 

It has been shown that vitamin D deficiency is relatively common in patients who are critically ill and associated with worse outcomes.  It is also well know that patients with chronic end stage renal failure develop vitamin D deficiency and should routinely receive vitamin di supplements to prevent fractures and cardiovascular problems (NICE recommendation).  To date, it is not known whether this also applies to patients with acute kidney failure, also known as acute kidney injury (AKI).

 

Our hypothesis is that critically ill patients with AKI have significantly lower vitamin D levels than critically ill patients without AKI.

 

We plan to measure vitamin D levels and related hormones in 63 patients with AKI and 63 ill patients without AKI over a period of 5 days.  In addition, we plan to do an additional measurement on day of discharge from ICU.  To understand better how vitamin D is regulate in AKI, we plan to measure different types of vitamin d (D2 and D3) parathyroid hormone (PTH0, fibroblast growth factor 23 and vitamin D binding protein and perform a gene expression analysis of vitamin D.

 

All blood samples will be frozen until batch analysis in 2 different laboratories at the sponsor’s lab.  The sponsor will also collect the demographic data, routine laboratory results, severity of illness scores and outcome data.

 

There will be no change in clinical management.

The Cheetah Medical Starling SV device (‘the device’) is being tested as a novel treatment for patients with sepsis and refractory hypotension. This study will determine if assessing fluid responsiveness with the device can lead to less IV fluid being given and improve the outcome of patients with sepsis, compared with the usual standard of care. The ability to measure the heart function before giving IV fluid has proved to have good patient benefit, this study will support this practice.

Participants will be randomised in a 2:1 treatment to control group to receive either treatment using the Cheetah Medical Starling SV device (‘the device’) or the standard of care treatment.

Participants must be aged 18 and over, have a diagnosis of sepsis and refractory hypotension and be anticipating an ICU admission. Participants will be ineligible if they have been in hospital for more than 24 hours after arrival and if they suffer from any other significant medical history or require immediate surgery.

Participants may experience a rash at the site of the device sensors. Participants may also experience slight bruising around the skin where the needle is inserted into the vein for blood sampling.

Participants will be recruited in the Accident and Emergency department of the Royal Surrey County Hospital after their diagnosis. Participants should not expect any benefit from participating in the study. Participation in this study is voluntary, and the volunteer may choose to the leave the study at any time without any specific reason. Before the initiation of the study volunteers will be informed (verbally and in writing) of potential risks. Detailed information about all study procedures and the inconveniences these might pose on the volunteers will be explained. Informed consent will be obtained from all participants or their representative if they are unable to give consent themselves.

Sepsis is the term used to describe serious infections. It is caused by microbes, such as bacteria, and one of the most important things in treating patients with sepsis is to give them effective antibiotics as soon as possible to treat the underlying infection.

Many different microbes can cause sepsis. Currently, the usual way to find out for sure which one to target in any particular patient is to wait for it to grow in a laboratory from a sample of their blood, or other samples. As it takes at least 24-48 hours to grow in the laboratory, doctors choose ‘best guess’ antibiotics that can treat a lot of different

microbes before they know which one would be the most effective. These are not always the best antibiotics for that particular individual, and sometimes patients only get the most effective treatment after a result from the laboratory becomes available.

Randox Ltd has recently developed a new bedside device based on technology that is able to identify bacteria in patients’ blood within just one hour. Looking only for characteristic fragments of over 40 different microbes means that doctors’ decisions about which treatment to give patients will not need to wait for over a day for the microbe to grow in

a laboratory. This will allow treatments to be better targeted from a much earlier stage.

We will evaluate the new test in at least 15 intensive care units (ICUs) across the UK and on 4501 blood samples from patients. Whenever a blood sample is taken for culture as part of routine care, a sample will also be taken for analysis with the new test. Results will be compared to the laboratory culture each time to permit an assessment of how accurate the new test is.

The emergence of multiply resistant pathogens and the need for improved antimicrobial stewardship are major healthcare issues. Empirical use of broad-spectrum antibiotics contributes significantly to resistance in both the individual and in the population’s ecology. Measures to reduce the use of broad-spectrum antibiotics wherever possible are therefore advocated worldwide. The rapid, point of care, test when used in patients with suspected sepsis has the potential to guide antibiotic treatment at an early stage; therefore, this has the potential to benefit both individual patients and wider society.

 

In order to have confidence in the diagnostic accuracy of the new test, allowing its widespread implementation in practice, it needs to undergo validation across a range of hospital sites and a broad case mix of patients. This need will be met in the present study.

Confidentiality guidelines will be strictly adhered to. To maintain confidentiality, all study reports and communication will be anonymised and will not be identifiable to the patient. Research blood samples will be taken, stored and transferred to Queen’s University Belfast. Consent will specifically be sought for these samples to be stored and for

their future use in ethically approved research. All research samples will be anonymised.

There are no known conflicts of interest within the Trial Management Group. All members of the Trial Steering Committee will be confirmed by the Sponsor prior to appointment.

The research proposal, trial protocol and associated documentation has been reviewed by members of the Trial Management Group and Sponsor. The three main ethical issues that have been identified are:

 

1. Enrolment of participants from a vulnerable group.

Patients in ICU are incapacitated by physical illness such that they are typically unable to  influence the care that patients receive. Furthermore, the new instrument will not come into direct contact with patients.give informed consent for trial participation themselves. Where ever possible, consent will be taken directly from the patient, however, our consent

procedure addresses the issue of capacity. For patients who are unable to give informed consent for themselves, consent or personal/nominated consultee opinion will therefore be obtained in line with the legal requirements for obtaining consent in patients without capacity. This approach has been detailed in subsequent sections herein and also in the protocol.

 

2. Use of a deferred consent approach for obtaining blood samples.

At all sites other than those in Scotland, a deferred consent process will be applied. Samples will be taken as outlined in section 9 of the protocol and will be held at site pending consent being obtained for inclusion in the study. No sample will be tested or further stored without consent having first been obtained and it is expected that participants’

consent (or their personal/nominated consultee opinion) will be confirmed within 72 hours of samples being taken.

The reason for this approach is:

(i) the importance of obtaining blood samples for evaluating the new test before antibiotic treatment has been started, or as soon as possible thereafter. This is because the sensitivity of tests for micro-organisms is reduced by prior antibiotic treatment – which would therefore reduce the reliability of this research.

(ii) this enables the research sample to be taken during the same blood draw as the standard care tests that participants will be receiving irrespective of this research (i.e. blood cultures). This is beneficial for minimising bias in the study by strictly pairing the new test with the reference standard. Furthermore, it reduces the need for additional

sampling, by venepuncture, minimising potential discomfort for participants.

 

3. Use of a non-CE-marked instrument for testing samples.

This raises the possibility of the new test producing inaccurate results. However this poses no risks to participants’

health as the results we obtain from the new test will not be returned to the clinical team and hence cannot be used to

DREAMY is a multi-centre, observational study to investigate the incidence of accidental awareness under general anaesthesia (AAGA) using a direct questioning methodology in women having childbirth-related surgery. A recent national audit conducted by the Royal College of Anaesthetists (NAP5 [1]) highlighted obstetric patients as being a

disproportionately high risk for AAGA. Unfortunately, the true incidence of AAGA and its downstream psychological consequences remain unclear for obstetric patients. Approximately 2% of women need to receive a general anaesthetic (GA) in order to safely deliver their babies by caesarean section or for other surgical procedures related to

childbirth. In this study we will screen women post-operatively for recall of events during the GA using a set of standardised questions, known as the Brice questionnaire [2]. Women will be asked questions within 24 hours of surgery and again on the following day whilst still in hospital. They will be contacted by telephone on day 30 following the index GA to complete the questionnaire again. Any women reporting awareness will be fed into a pathway of supportive care and receive screening for evidence of psychological harm at 1, 3, 6, 9 and 12 months after surgery.

Individual cases will be reviewed by an expert panel to categorise the AAGA event and identify where lessons can be learnt to improve future care for obstetric surgical patients.

1. 5th National Audit Project. RCoA and AAGBI. 2014. http://nap5.org.uk/NAP5report 2. Brice DD, Hetherington RR, Utting JE. A simple study of awareness and dreaming during anaesthesia. British

Journal of Anaesthesia 1970; 42: 535-42.

 

The primary ethical issue in any obstetric study is to ensure the welfare of the mother and the baby take priority over any research aims. The psychosocial and physical vulnerability of mothers should always be considered.   This study does not involve any physical intervention that could cause harm or distress. In principle the DREAMY study is

concerned with monitoring satisfactory performance of general anaesthesia and detecting a risk of general anaesthesia in obstetric patients. It is already standard practice to routinely follow up any woman who receives anesthesia in childbirth (either epidural or general anaesthesia) [1]. The primary measurement tool (i.e. the Brice

questionnaire [2], which has been amended for current use [3]) is short and has been designed with the intention to not present any significant risk or burden to the patient. It has a record of extensive use in previous research into

accidental awareness under general anaesthesia (AAGA) [4], allowing comparison to be made with other patient groups. Timing of routine clinical follow up of post-surgical obstetric patients means that potential participants can be screened and introduced to the study whilst inpatients by local investigators without requiring multiple additional

encounters. Participation is voluntary, explicit consent will be taken and the patient is under no obligation to enroll and complete the questionnaires if they do not wish to.

 

The primary ethical issues relate to timing of the study around childbirth and that by encouraging a patient to recall if they dreamed or not during the operation then adverse memories may be triggered at this sensitive time. However, since this questionnaire has been used previously with no report of ill effects, we are confident that the risk of stress induced by the questions is low. Furthermore, as an investigation into GA satisfaction it is worth considering that: (a) satisfaction questionnaires are routine; (b) Brice questioning is routine and in indeed recommended practice; (c)

satisfaction with GA is primarily concerned with the absence of recall. In fact, it could be considered advantageous to investigate the presence of awareness early, whilst a patient is still under the care of the hospital team, rather than to allow symptoms of illness, discomfort or adverse memories to go unexplored and unexplained or to emerge at a later

time.

 

The DREAMY study is expected to identify cases of AAGA that might otherwise have been missed; some of these cases may be identified at the 30 day follow telephone questionnaire. With patient consent, the local care team will be notified by the research investigators that one of their patients has subsequently reported AAGA. Through sharing of

this information and promotion of structured follow up pathways, participants who experience AAGA will benefit from support services provided by local clinical care teams.

 

Women who receive general anaesthesia for caesarean section are more likely to have received this in the context of an emergency situation (severe maternal or fetal compromise necessitating delivery). Recruiting women and seeking consent will require tactful and sympathetic handling. Prior to approaching a woman the local investigator will seek

multidisciplinary input from the midwifery and obstetric teams to judge a woman’s suitability to participate. All investigators will be sensitive to the views of multidisciplinary team who will be informed of the project if a woman agrees to participate.

The only intrusion for participating women is phone calls, however these are not medical interventions. For this study the Brice questionnaire will be administered on three occasions within 30 days of the index general anaesthetic.

 

Single early Brice questionnaire application is insufficient to reliably detect AAGA, hence the “thrice Brice” methodology

with timing arranged to capture early recall of experiences in hospital and at 30 days post-operatively (in keeping with

other comparable studies using the Brice questionnaire [3]). Although most women will be at home with babies at the

30 day follow up point, neonatal outcomes and social situations may not always be so straightforward. The ethical

justification and practicalities of gathering and sharing information related to maternal or infant health have been

careful considered. All data governance for the study is in strict accordance with Caldicott principles, particularly

around sharing of identifiable personal information with non-direct care team investigators. Telephone follow up

procedures are structured so as to be minimally burdensome, sensitively worded and cost neutral to participants.

Feedback of clinical relevant information (but not of relevance to the direct research questions) that might arise during

30 day follow up telephone conversation and the responsibility for acting upon this will be passed onto the local care

teams accordingly. Since post-natal women will already be under routine midwifery and/or GP follow up during this

time period, very few issues are expected to occur.

From a management perspective the primary issue is achieving consistent and professional delivery of Brice

questionnaires and associated data collection at the appropriate time after surgery throughout the planned 12 month

study duration. Fortunately, the combination of support from the Obstetric Anaesthetists Association (OAA) [5] and Pan

London Perioperative Research Network (PLAN) [6] means that an established system is in place to conduct and

support high quality management of the study at a local and regional level. The decision to conduct 30 day telephone

follow up by a non-local investigator team is to ensure consistent and reliable follow up consultations and to allow

local teams to focus on clinical care responsibilities. Although this does necessitate sharing of personal information

outside the direct care team, we feel that our proposed usage meets the required ethical framework.

Ethically it would be preferable to have no exclusion criteria for participation in the study, to allow the experience of all

women receiving general anaesthesia during childbirth to be investigated. However, for pragmatic and operational

reasons the application and use of translators to allow non-English language speaking participant involvement is not

possible.

Explicit written consent will be taking for participation in the study; with a clear explanation that this will involve sharing

of personal information with research investigators that are outside the direct care team. The vast majority of potential

participants are anticipated to be young adults with intact capacity. Variance in capacity is not expected to be a

particular problem in this study, but will be assessed on a per case basis. All local investigators will be GCP training and working as medical doctors, with inherent experience and responsibilities for patient assessment and information governance.

There is also a significant logistical challenge in investigating a rare event (AAGA) in a population of patients that is also uncommon (women needing a general anaesthetic for childbirth-related surgery; approximately 2% of all childbirths). For this reasons the DREAMY study is designed as multi-centre observational research requiring data

collection of many months. Justification has been provided for expected recruitment to the study and that the numbers anticipated will provide meaningful results. It is however possible that expansion of the recruitment duration or numbers of centres may be required, if actual recruitment does not meet expected levels. Despite these challenges

we believe that the DREAMY study represents a pragmatic and achievable proposition, with potential to generate  important patient-facing results relevant to improving standards of obstetric anaesthesia care.

This is an observational study.

We will seek patient consent for participation. A Participant Information Sheet will be provided which will explain the reasons for data collection and give an overview of the data which will be collected and stored. Data will be stored in the PQIP Database which has already received a favourable REC/CAG opinion.

We anticipate a large number of hospitals participating, at least 70 in the first year, and we hope that this number will rise in years to come. This may pose some organisational challenges but both the Chief Investigator, and the organisation supporting this study (the National Institute for Academic Anaesthesia’s Health Services Research Centre based at the Royal College of Anaesthetists) have experience in running major multi-centre studies involving up to 200 Trusts, therefore we are confident that we have the administrative and organizational capacity to manage the study.

3There is currently no national or comprehensive database which records postoperative complications on patients in the UK outside a few specific surgical complications (e.g. return to operating room) or procedures (e.g. nephrectomy).

 

This is an important omission as significant postoperative complications are up to 10 times more common than short-term mortality after surgery, and have been independently associated with reduced postoperative survival and quality of life. We currently have no way of measuring and therefore improving upon these important outcomes. We also know from the US, that there is wide variation in “failure to rescue” between different healthcare institutions – i.e. if a patient develops a postoperative complication, whether they die or not after this complication varies up to 15-fold between different healthcare providers. We do not have access to this type of information in the UK presently, and this study will provide these data.

 

PQIP will measure both objective outcomes (morbidity and mortality) and also outcome from the patient perspective after major surgery. The web-based data entry system will include the features which have been suggested by stakeholders to be important for facilitating the use of data for improvement, such as near-real time feedback, feedback provided in easily understandable and graphical formats, and explanations for statistical analyses and risk adjustment techniques.

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