NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Soares MO, Welton NJ, Harrison DA, et al. An Evaluation of the Feasibility, Cost and Value of Information of a Multicentre Randomised Controlled Trial of Intravenous Immunoglobulin for Sepsis (Severe Sepsis and Septic Shock): Incorporating a Systematic Review, Meta-Analysis and Value of Information Analysis. Southampton (UK): NIHR Journals Library; 2012 Feb. (Health Technology Assessment, No. 16.7.)

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An Evaluation of the Feasibility, Cost and Value of Information of a Multicentre Randomised Controlled Trial of Intravenous Immunoglobulin for Sepsis (Severe Sepsis and Septic Shock): Incorporating a Systematic Review, Meta-Analysis and Value of Information Analysis.

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Appendix 11Study protocol

An evaluation of the feasibility, cost and value of information of a multicentre randomised controlled trial of intravenous immunoglobulin for sepsis (severe sepsis and septic shock)

Study Protocol

Version 1.0

29 July 2008

Protocol Number: ICNARC/02/02/09

1. Project title

08/70: An evaluation of the feasibility, cost and value of information of a multicentre randomised controlled trial of intravenous immunoglobulin for sepsis (severe sepsis and septic shock)

2. How the project has changed since the outline proposal was submitted

No outline stage was required.

3. Planned investigation

Research objectives

The aim of this project is to evaluate the feasibility, cost and value of information of conducting a multicentre randomised controlled trial (RCT) to assess the clinical and cost-effectiveness of intravenous immunoglobulin (IVIg) for adult patients severely ill with sepsis in the UK.

This aim will be achieved by addressing the following research questions:

  • What is the existing evidence for the benefit of IVIg for adult patients with sepsis?
  • What are the key sources of heterogeneity within this evidence and are existing results subject to potential publication bias or any other sources of bias?
  • What is existing practice within the NHS with regard to management and treatment of adult patients with sepsis, and how does this relate to current best practice according to research evidence and international guidelines?
  • What is the current usage of, and demand for, IVIg for sepsis?
  • What is the expected value of perfect information for the decision problem of treating adult patients with sepsis using IVIg both versus existing practice and versus best practice without IVIg?
  • What would be the anticipated research costs, treatment costs and NHS support costs for conducting an RCT of IVIg for adult patients with sepsis?
  • What is the feasibility of being able to conduct an RCT of IVIg for adult patients with sepsis within the NHS, with regard to the availability of IVIg and availability of eligible patients?
  • What would be the optimal design for a new RCT of IVIg for adult patients with sepsis?
  • What is the expected value of sample information from this RCT?

Existing research

Sepsis is a major public health problem

Sepsis is a syndrome characterised by a systemic inflammatory response to infection that leads to rapid acute organ failure and potentially rapid decline to death.1 In 2006, we reported an increasing incidence of severe sepsis (sepsis resulting in organ dysfunction) in UK adult critical care units, rising from 50 to 70 cases per 100,000 population per year over the last decade.2 This now represents approximately 31,000 patient episodes per year. Similarly high incidence rates have been reported elsewhere.3 We found 29% of all admissions to adult, general critical care units were associated with severe sepsis in the first 24 hours following admission and had an in-hospital mortality of 45% (approximately 15,000 deaths per year).2

International guidelines for management of sepsis (severe sepsis and septic shock)

Most clinicians look to the international guidelines for guidance on the management and treatment of patients with sepsis.

In early 2008, the current, third edition of clinical practice guidelines, building on two previous editions in 2001 and 2004 were published.4 The 2001 publication incorporated literature from the preceding ten years, the 2004 publication incorporated the evidence available to the end of 2003 and the current guidelines were based on an updated search into early 2007.

The 2008 guidelines process included a modified Delphi method, a consensus conference, several subsequent meetings/teleconferences/electronic discussions among subgroups and members of the entire committee and two follow-up nominal group meetings in 2007. Differences of opinion among committee members about interpretation of evidence, wording of proposals, or strength of recommendations were resolved using a specifically developed set of rules.

The scope of the guidelines was wide and subgroups were formed, each charged with updating recommendations in specific areas. Initial resuscitation and infection issues covered: initial resuscitation; diagnosis; antibiotic therapy; and source identification and control. Haemodynamic support and adjunctive therapy covered: fluid therapy; vasopressors; inotropic therapy; steroids; and recombinant human activated protein C. Other supportive therapy covered: blood product administration; mechanical ventilation; sedation, analgesia and neuromuscular blockade; glucose control; renal replacement; bicarbonate therapy; deep-vein thrombosis prophylaxis; stress ulcer prophylaxis; selective digestive tract decontamination; and consideration for limitation of support. IVIg, however, was neither considered nor was the evidence reviewed (personal communication: G Ramsay).

For the 2008 guidelines, quality of evidence was judged by pre-defined Grades of Recommendation, Assessment, Development and Evaluation (GRADE) criteria – a structured system for rating quality of evidence and grading strength of recommendation in clinical practice.5 The GRADE system is based on a sequential assessment of the quality of evidence – as high (Grade A), moderate (Grade B), low (Grade C), or very low (Grade D) – and the strength of the recommendation – as strong (Grade 1) or weak (Grade 2). The rating of quality of evidence and strength of recommendation is explicitly separate and constitutes a crucial and defining feature of the GRADE approach. The grade of recommendation, strong or weak, is considered of greater clinical importance than a difference in level of quality of evidence. For example, RCTs begin as high quality evidence, but may be downgraded due to limitations in implementation, inconsistency or imprecision of the results, indirectness of the evidence, and possible reporting bias.

Of 62 recommendations, only 23 (37%) were strong (Grade 1) recommendations based on high/ moderate (Grade A/B) evidence and only eight (13%) were strong recommendations on high-quality evidence (1A), listed below:

  • Do not use low-dose dopamine for renal protection.
Recombinant human activated protein C (rhAPC)
  • Adult patients with severe sepsis and low risk of death (e. g.: APACHE II < 20 or one organ failure) should not receive rhAPC.
Mechanical ventilation of sepsis-induced acute lung injury (ALI)/ARDS
  • Use a weaning protocol and a spontaneous breathing trial (SBT) regularly to evaluate the potential for discontinuing mechanical ventilation.

    SBT options include a low level of pressure support with continuous positive airway pressure 5 cm H2O or a T-piece.

    Before the SBT, patients should:

    be arousable

    be haemodynamically stable without vasopressors

    have no new potentially serious conditions

    have low ventilatory and end-expiratory pressure requirement

    require FiO2 levels that can be safely delivered with a face mask or nasal cannula.

  • Do not use a pulmonary artery catheter for the routine monitoring of patients with ALI/ ARDS.
Deep-vein thrombosis (DVT) prophylaxis
  • Use either low-dose unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH), unless contraindicated.
  • Use a mechanical prophylactic device, such as compression stockings or an intermittent compression device, when heparin is contraindicated.
Stress ulcer prophylaxis
  • Provide stress ulcer prophylaxis using H2 blocker. Benefits of prevention of upper GI bleed must be weighed against the potential for development of ventilator-associated pneumonia.

Surviving Sepsis Campaign

Most clinicians look to the Surviving Sepsis Campaign (SSC) for guidance on the translation and implementation of the international guidelines into practice. The SSC, an initiative of the European Society of Intensive Care Medicine, the International Sepsis Forum, and the Society of Critical Care Medicine, was developed to improve the management, diagnosis, and treatment of sepsis.

The SSC partnered with the Institute for Healthcare Improvement (IHI) to incorporate its ‘bundle concept’. A bundle was defined by the SSC/IHI as a group of interventions related to a disease process that, when implemented together, result in better outcomes than when implemented individually. The SSC claim that ‘the science behind the elements of the bundle is so well-established that their implementation should be considered a generally accepted practice’. They also indicate that bundle components can be easily measured as completed or not completed and, as such, the overall bundle—all of the elements taken together—can also be measured as completed or not completed.

Two bundles were developed: the resuscitation bundle that must be completed within six hours and the management bundle that must be completed within 24 hours. The SSC describe the bundles as a distillation of the concepts and recommendations found in the second set of international clinical guidelines published in 2004.

Resuscitation bundle
  • Measure serum lactate.
  • Obtain blood cultures prior to antibiotic administration.
  • Administer broad-spectrum antibiotic within three (emergency department)/one (nonemergency department) hours of admission.
  • In the event of hypotension and/or serum lactate > 4 mmol/L:

    deliver initial minimum of 20 ml/kg of crystalloid or equivalent

    apply vasopressors for hypotension not responding to initial fluid resuscitation to maintain mean arterial pressure (MAP) > 65 mmHg.

  • In the event of persistent hypotension despite fluid resuscitation (septic shock) and/or lactate > 4 mmol/L:

    achieve a central venous pressure (CVP) of ≥ 8 mmHg

    achieve a central venous oxygen saturation (ScvO2) ≥ 70% or mixed venous oxygen saturation (SvO2) ≥ 65%.

Management bundle
  • Administer low-dose steroids for septic shock in accordance with a standardized ICU policy. If not administered, document why the patient did not qualify for low-dose steroids based upon the standardized protocol;
  • Administer recombinant human activated protein C (rhAPC) in accordance with a standardized ICU policy. If not administered, document why the patient did not qualify for rhAPC;
  • Maintain glucose control ≥ 70, but ≤ 150 mg/dL;
  • Maintain a median inspiratory plateau pressure (IPP) < 30 cm H2O for mechanically ventilated patients.

UK practice in the management and treatment of sepsis

Little information on current practice in the management and treatment of sepsis in the UK exists; and especially prior to the inception of the SSC.

The SSC was formally launched in the UK in June 2005 with a Steering Group formed in September 2005 to aid the introduction of the SSC bundles into hospitals. The Steering Group was composed of representatives from critical care organisations including: the European Society of Intensive Care Medicine; the Intensive Care Society; the British Association of Critical Care Nurses; the Royal College of Nurses; the College of Emergency Medicine; and clinical and managerial staff from Critical Care Networks across the UK. However, despite the claim from the SSC, the fact that many of the bundle elements lacked a rigorous evidence base and that there was no prospective evaluation of bundles per se resulted in low adoption and poor compliance, in large part due to substantial clinical equipoise.

To address low adoption/poor compliance with the bundles, Survive SEPSIS (, an education programme developed in the UK and approved by the SSC, was launched in September 2007.6 The launch was designed to bring about the creation of a national network of centres with the aim of raising compliance with the resuscitation bundle (which was 11%) and the management bundle (which was 36%). Compliance targets of 25% for the resuscitation bundle and 50% for the management bundle have been set for April 2009.

In the UK as elsewhere, major challenges lie in placing central venous catheters, starting vasoactive infusions, and measuring central venous oxygen saturation outside the critical care environment. This contributes to further non-compliance with the resuscitation bundle and, in view of the timing (there is an extra 18 hours available in which to complete the management bundle), to around three times as many patients receiving the management bundle as the resuscitation bundle, despite compliance with both being low.7

This led to the creation of a UK concept of the Sepsis Six – six tasks to be completed by non-specialist staff within the first hour (give 100% oxygen, take blood cultures, give IV antibiotics, start IV fluid resuscitation, check haemoglobin and lactate, place and monitor urinary catheter) – and the need for close and early liaison with critical care to complete the elements for early goal-directed therapy (the last two elements of the resuscitation bundle).

Data from a web-based survey of UK emergency physicians, acute care physicians and intensivists in 2007 (personal communication: Dr Michael Reade) indicated that more than 90% of respondents were aware of the concept of early goal-directed therapy, the basis of the resuscitation bundle, and yet very few delivered this in routine practice.

Data from an audit of rhAPC (one of the elements in the management bundle), conducted by ICNARC between 2002 and 2006, indicate that only one in sixteen (approximately 6%) of admissions with severe sepsis receive this.8

Intravenous immunoglobulin

IVIg is a blood product derived from human donor blood. The serum from around 1000 to 15,000 donors is required for each batch.9 The mechanism of action of IVIg is complex, but is increasingly being understood.10 IVIg is predominantly used in neurology, haematology, immunology and dermatology, but also in nephrology, rheumatology, ophthalmology and other specialties.9 New uses are emerging and off-label use increasing.11

IVIg has been proposed as an adjuvant therapy for sepsis since the 1980s, and a number of (predominantly small) RCTs have been performed. Numerous systematic reviews and meta-analyses of IVIg in sepsis have been performed. These have predominantly included the same trials, but have reached differing conclusions.12

A Cochrane systematic review in 2002 concluded that polyclonal IVIg had a stronger effect than monoclonal IVIg,13 and subsequent systematic reviews have focussed on polyclonal preparations only,1418 with one review restricted to Immunoglobulin M-enriched IVIg only.15 Pooled treatment effects in these reviews varied from an odds ratio of 0.35 to a relative risk of 0.79 for all-cause mortality, and all primary analyses were statistically significant. Four of the meta-analyses, when repeated in subsets of high-quality trials (varying from selection of three to eight trials), produced results that were more variable and, in three of the four, were not statistically significant.

Differences between the meta-analyses conducted to date include: the age groups studied – some studies pooled adult, paediatric and neonatal results together, whereas others analysed different age groups separately or restricted to studies in adults only; different inclusion criteria for the severity of infection/sepsis; different definitions of ‘high quality’; and different choices of effect estimate (odds ratio or relative risk) and model (fixed or random effects).

Evaluation of subgroup effects in the different systematic reviews suggested treatment effects may vary by type of IVIg preparation (IgM-enriched versus standard), dose, and duration, as well as by methodological quality, although again these effects were not consistent across the different meta-analyses. In addition, the meta-analysis of Laupland et al. examined funnel plots and found evidence of significant publication bias.17

As a result of the heterogeneity across studies and inconsistencies in results, the majority of authors concluded that there was insufficient evidence to recommend IVIg as an adjuvant therapy for sepsis and that more evidence, in the form of a large, well-conducted RCT, was required.

Issues and debate on the use of IVIg for sepsis

IVIg is a scarce resource worldwide. Costs have escalated, associated with a reduced demand for plasma-derived factor VIII and albumin. In addition, there are supply issues unique to the UK, that further limit the availability of IVIg. Where IVIg was previously produced in the UK using plasma sourced from within the UK as a by-product of blood donations, plasma must now be imported due to the risk of variant Creuzfeldt Jakob disease (vCJD). In addition, the closure of one UK manufacturer (the Scottish National Blood Transfusion Service) and withdrawal of batches of IVIg due to safety concerns have led to both local and national, transient and longer-term, shortages.

In response to this, the Department of Health implemented a Demand Management Programme for IVIg. The Programme consists of three components: the Demand Management Plan for Immunoglobulin Use;19 Clinical Guidelines for Immunoglobulin Use;20 and the National Immunoglobulin Database. Revised editions of both the Demand Management Plan and Clinical Guidelines were launched in May 2008. Indications for IVIg use are colour-coded in the following way:19

  • red: a disease for which treatment is considered the highest priority because of a risk to life without treatment
  • blue: a disease for which there is a reasonable evidence base but where other treatment options are available
  • grey: a disease for which the evidence base is weak, in many cases because the disease is rare; treatment should be considered on a case-by-case basis, prioritised against other competing demands
  • black: a disease for which there is evidence to suggest that IVIg is not an appropriate treatment and treatment is not recommended.

‘Sepsis in the intensive care unit not related to specific toxins or Clostridium difficile’ is currently a black indication, and consequently IVIg should not be used under any circumstances.20 The Clinical Guidelines do, however, make a research recommendation that, ‘there is a need for adequately powered high quality RCTs to assess the impact of IVIg in severe sepsis in the general ICU’.20

In view of the heterogeneity of results of existing RCTs, and the unique supply and demand issues for IVIg, there is an urgent need to establish whether such a trial is necessary and feasible, and whether the costs of carrying out the trial are outweighed by the potential benefit of the resulting information.

Research methods

The study will be conducted in four related phases of work:

Flow diagram.

Flow diagram

Phase I

Objective: To define the appropriate decision problem and to develop a provisional decision-analytic model structure consistent with this and relevant to an NHS setting. To define the requirements for the subsequent phases of work.

Phase I will be based on a review of previous systematic reviews, recent national and international guidelines for the management of sepsis, high quality epidemiological studies and existing cost-effectiveness studies (including any previous decision-analytic models). Initial high-level searches for systematic reviews and guidelines will be conducted by searching major databases including MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Pascal, Science Citation Index (SCI), BIOSIS, Latin American and Caribbean Health Sciences (LILACS), Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment Database (HTA). These will be combined with more focused searches in relation to epidemiological and cost-effectiveness studies. For the cost-effectiveness review, additional searches of NHS EED and HEED will also be carried out, along with a search of the Economics Working Papers archive (IDEAS). These reviews will be supplemented by discussion with key individuals involved in service provision and policy.

A key element of this phase will be to identify relevant population subgroups, alternative treatment strategies and outcomes to be considered in the decision-analytic model. Our preliminary review of the literature suggests that there are a number of potentially relevant subgroups who are readily identifiable and differ in their underlying mortality risk. Subgroups may be based on: age; ethnicity; underlying condition; pre-existing organ insufficiency; immunocompromised state; acute severity of illness; infectious organism; site of infection; presence of septic shock; and the number and type of organs failing.2,21 These subgroups will be revised during this phase of the work Relevant strategies will comprise both different types of IVIg preparations (including different doses and duration) as well as alternative comparators to IVIg, including current NHS practice as well as alternative strategies proposed for improving the current management and treatment of sepsis (e.g. the resuscitation and management bundles proposed by the SSC). Relevant outcomes will include morbidity, short- and long-term mortality, health-related quality of life, and time course of return to premorbid function.22

The aim of this phase will be to define the appropriate decision problem relating to the relevant patient populations, alternative interventions (including IVIg) and outcomes to be considered. These will be used to develop a provisional decision-analytic model structure consistent with these issues. This will also serve to identify relevant data sources to be considered in more detail in subsequent phases and to identify the key questions that need to be addressed therein.

At the end of this phase, the results will be presented to the Expert Group in order to obtain feedback on the relevance of the decision problem and the provisional model structure and to ensure that key issues have been appropriately identified at an early stage.

Phase II

Objective: To obtain appropriate inputs for the decision model parameters based on evidence synthesis approaches employing meta-analysis, primary data analysis and other published evidence. To establish current NHS practice based on a national survey and re-analysis of existing audit data, and also to reflect potential anticipated changes to current practice.

Phase I will be used to identify both the range of parameters required to populate the decision model as well as key uncertainties in model parameters themselves. Through this process, we will determine which parameters require more detailed consideration of the primary literature or analysis of locally applicable primary or secondary data, and those which can be populated from existing reviews based on update searches. Phase II will thus comprise a more in-depth review and synthesis of the different inputs required to populate the proposed model.

Although the detailed specification of this phase will be determined by the results of Phase I, our initial expectations are that this work will entail a number of distinct elements including: (i) establishing the clinical effectiveness of IVIg; (ii) defining the current standard of care in the NHS by establishing current practice and associated outcomes, as well as anticipating potential changes to current practice and/or potential barriers to change; (iii) establishing the relative effectiveness of alternative comparators; (iv) estimating resource use and quality of life considerations (attributed to both morbidity and also premature mortality). It will also be essential to consider how these elements relate to the relevant and important population subgroups identified during Phase I.

i. The clinical effectiveness of IVIg

The application of appropriate methods of evidence synthesis to the existing RCTs of IVIg represents a major element of the proposed work and represents an important extension to the ‘critical appraisal of existing systematic reviews’ outlined in the commissioning brief. As previously stated, our initial review of the various systematic reviews and accompanying meta-analyses have identified a number of important differences between studies. These differences arise in terms of the studies included, the application of separate inclusion/exclusion criteria as well as differences in the subsequent methodologies and analytical approaches employed therein. Consequently, despite the comparatively high-number of previous systematic reviews in this area, the subsequent interpretation and conclusions drawn have often been quite different. These differences also reflect the different approaches employed with respect to evaluation of subgroups and approaches to dealing with heterogeneity more generally across the existing studies. In addition, despite evidence of significant publication bias, there appear to have been few formal attempts to attempt to account for this within existing studies.

These issues are likely to be important factors that need to be adequately understood and reflected in the inputs into the decision model, in order to ensure that subsequent research recommendations are not compromised by potential confounders. Appropriate methods of synthesis are thus required to deal with the heterogeneity both within and between individual RCTs, as well as accounting for potential publication bias. These methods will need to consider the different subgroups, outcomes, comparators and follow-up times reported across the various studies.

It should be emphasised that, in considering the need for and design of a future randomised trial, it is essential that the main causes of heterogeneity in the existing evidence base are understood as far as is possible. Otherwise, there is a danger that a new trial will be just as difficult to interpret as the existing RCT evidence. Apart from the factors mentioned above, we anticipate that much of the heterogeneity arises from differences between trials in the extent to which patients can benefit from IVIg treatment, and thus from differences in patient populations. The evidence synthesis will, therefore, combine the available trial evidence with data on background mortality rates in the underlying conditions.

The review of existing meta-analyses will be used as the main source for identifying relevant RCTs of IVIg. However, additional update searches will also be conducted by searching the major databases considered in Phase I to ensure that any more recent studies are also included.

ii. Defining the current standard of care in the NHS

The second major element of work will be used to define the current standard of care in the NHS, establishing current practice and associated outcomes, as well as anticipating changes to current practice and/or potential barriers to change. This element will provide the contextual basis for informing the potential improvements that may be achieved through the use of IVIg as well as potentially providing a source of baseline data for the decision model itself.

We anticipate that this element will be principally informed by: (a) a national survey of current UK practice; (b) re-analysis of existing national audit data; and (c) analysis of available data on current usage of, and demand for, IVIg for severe sepsis.

(a) A survey of Clinical Directors for all adult, general critical care units in the UK will be conducted. To maximise response rate, both electronic and paper questionnaires will be used and followed up by direct telephone contact with non-responders at 2–4 weeks. Other evidence based strategies for increasing response rates will also be employed.23 ICNARC has an established network of contacts in critical care units in the UK and in a recently-conducted (December 2007) survey on ventilator bundle compliance achieved an 84% response rate.

The survey instrument will encompass aspects of the management and treatment of sepsis, both related to the SSC bundles (individual elements within the resuscitation and management bundles) and to other interventions for which a strong evidence base exists (e.g. selective decontamination of the digestive tract). Barriers to bundle elements/important interventions will be explored, estimated future uptake and compliance determined, and views of the potential role for IVIg elicited.

(b) Analyses will be conducted using data from the Case Mix Programme, the voluntary, national comparative audit of patient outcome from adult, general critical care units in England, Wales and Northern Ireland ongoing in 207 units (over 80% coverage). In units participating in the Case Mix Programme, prospective, raw, clinical data are abstracted retrospectively, to precise rules and definitions, by trained, local data collectors and undergo extensive validation, locally and centrally.24 The Case Mix Programme Database has been independently assessed to be of high quality (

Using the Case Mix Programme Database (over 720,000 admissions) and once relevant population subgroups have been established (Phase I), baseline event rates, outcomes, resource utilisation etc associated with usual sepsis care will be estimated, both overall and the variation compared across subgroups.

(a) and (b) Current practice data from the survey will be linked to outcome data (crude and risk-adjusted) from the Case Mix Programme Database to further inform the model.

(c) Any off-licence use of IVIg for sepsis, and declined requests for use, will be identified from the National Immunoglobulin Database. The National Immunoglobulin Database records data on all uses of IVIg and declined requests to use IVIg in the NHS. The process for obtaining permissions to access these data has been commenced.

iii. The relative effectiveness of alternative comparators

Based on the material examined in Phase I and on advice from the Expert Group, we will have identified what constitute best current practice and alternative comparators that should be considered alongside IVIg. Existing audit and other published data from existing meta-analyses and guidelines will be used to identify baseline outcomes and event rates. These sources will also be relied on to provide data on the relative effectiveness of any alternative comparators that require consideration.

iv. Resource utilisation, costs and quality of life

Additional data on resource utilisation, costs and quality of life will also be required in order to determine the potential cost-effectiveness of IVIg. Data on resource utilisation will be derived from national audit data and other relevant evidence identified during Phase I. These estimates will provide the basis for estimating the overall costs of managing sepsis, together with the potential impact of the alternative interventions. Resource utilisation will reflect the inputs associated with the interventions themselves as well as the resources associated with sepsis related events (e.g. length of ICU stay, overall length of hospital stay, etc.). These data will be combined with national sources of cost data (e.g. NHS Reference Costs, British National Formulary, etc.) in order to estimate the total costs associated with each strategy considered.

In order to estimate Quality-Adjusted Life Years (QALYs) required for the cost-effectiveness analysis, it will be necessary to systematically search for appropriate published utility or preference scores related to different patient groups and the impact of sepsis. Additional evidence will also need to be considered to quantify potential life-years lost due to premature mortality.

Resource utilisation, costs and quality of life data related to potential complications and side-effects of IVIg will also be considered (e.g. infection by contaminated blood, pulmonary oedema, allergic/anaphylactic reactions, etc.). Safety aspects of IVIg need careful consideration, as it is generally considered poor practice to give IVIg to patients that have a co-existing infection.

At the end of this phase, the Expert Group will meet to provide interpretation to the sources of information identified above and inform the final inputs to the decision model.

Phase III

Objective: To determine the cost-effectiveness of IVIg and to estimate the value of additional primary research.

Phase III comprises two related aspects:

i. Cost-effectiveness analysis

The decision model will be populated using the most appropriate data identified during Phase II. The mean cost-effectiveness of IVIg compared with current NHS practice and other relevant comparators will be determined based on an assessment of NHS and Personal Social Service costs and QALYs. Consistent with available evidence, the model will also report the cost-effectiveness of alternative treatments for specific subgroups of patients. This may include cost-effectiveness by patients' underlying risk of particular clinical events.

The model will be probabilistic in order to appropriately characterise the uncertainty in the data used to populate the model and to present the uncertainty in these results to decision makers.25 Each parameter input in the model will thus be entered as an uncertain, rather than a fixed, parameter by assigning probability distributions to reflect the precision of their estimation. Using Monte Carlo simulation, this parameter uncertainty, is translated into uncertainty in the overall results. This ultimately helps decision makers understand the probability that, in choosing to fund an intervention, they are making the wrong decision – that is, decision uncertainty. This is presented using cost-effectiveness acceptability curves which show the probability that each intervention is cost-effective conditional on a range of possible threshold values which NHS decision makers attach to an additional QALY.26

The expected cost and QALYs for each of the strategies will be estimated. Strategies will be compared by estimating incremental cost-effectiveness ratios (ICERs), where appropriate. Conventional decision rules will be used to identify strategies which are either dominated or subject to extended dominance.27 The remaining, non-dominated, strategies will be compared in terms of their ICERs (representing the incremental cost per additional QALY gained). The ICERs will be compared against thresholds representing the incremental cost per QALY used by the National Institute for Health and Clinical Excellence (NICE) to establish value for money in the NHS (in the region of £20,000-£30,000). These thresholds will be used to identify the optimal strategy in terms of cost-effectiveness considerations.

Variability in cost-effectiveness will be investigated by clinical subgroups. For each subgroup, separate ICERs and cost-effectiveness acceptability curves will be presented, and an optimal strategy will be identified using the threshold cost per QALY estimates.

ii. Value of information analysis

To evaluate future research priorities and to establish whether investment in a large scale randomised trial is likely to be cost-effective, we will use formal methods based on value of information approaches. These approaches will assess the need for major investment in future research and also prioritise the potential research questions.28

The expected value of perfect information (EVPI) will be estimated for the overall decision problem and for key parameters.29 EVPI represents the expected costs of decision uncertainty since perfect information would eliminate the possibility of making the wrong decision. Hence, EVPI for the overall decision problem represents the value of eliminating all uncertainty and EVPI for key parameters (termed partial EVPI) represents the value of eliminating uncertainties in particular subsets of parameters. Separate analyses will be undertaken to reflect the variability considered in the decision model itself. Per patient EVPI estimates will be scaled up to reflect the relevant UK population size and will adopt an appropriate time horizon.

EVPI also represents the maximum amount that a decision-maker should be willing to pay for additional evidence to inform this decision in the future. EVPI provides an upper bound on the value of additional research. This valuation provides an initial hurdle, acting as a necessary requirement for determining the potential efficiency of further primary research. Applying this decision rule, additional research should only be considered if the EVPI exceeds the expected cost of the research. In addition to providing a global estimate of the total cost of uncertainty related to all inputs in the model, EVPI can also be estimated for individual parameters (and groups of parameters) contained in the model. The objective of this analysis (termed partial EVPI) is to identify the model parameters where it would be most worthwhile obtaining more precise estimates.

At the end of this phase, the results will be presented to the Expert Group to obtain their feedback and to identify key issues related to the potential design, feasibility and costs of a subsequent trial. If this phase establishes that it could be cost-effective and feasible to carry out further research, separate value of information approaches will be used to identify the optimal design and sample size as part of Phase IV

Phase IV

Objective: To develop a draft protocol outlining the optimal design, sample size, potential costs and value of commissioning a substantive trial using expected value of sample information (EVSI) approaches.

Phase IV will use EVSI calculations in order to determine the appropriate design, optimal sample size and allocation rate for a future trial.30 Information from the evidence synthesis on possible differences in treatment effectiveness in different patient groups will be used to generate EVSI per group. EVSI calculations will be set against the potential costs of obtaining such a sample. The difference between the value of the sample (EVSI) and the costs of obtaining the sample are the expected net benefit of sampling and reflect the societal return to the proposed research. The costs themselves comprise both the direct resource costs (representing the fixed costs of further research and the marginal reporting/treatment costs) and opportunity costs including those attributed to different sample sizes and/or longer follow-up periods.

The results from the EVSI approaches will provide the basis for a draft proposal for the trial itself. The draft proposal will be discussed with the Expert Group to discuss feasibility and obtain final feedback and input into the proposal and overall report.

Results of the project will be disseminated to the critical care community through the Intensive Care Society and the Annual Meeting of the Case Mix Programme (attended by representatives of around 200 UK critical care units), and to the wider research community and service users via the ICNARC website.

Ethical arrangements

This study combines evidence synthesis from existing literature, a survey of organisational practice and analysis of existing audit data. The study does not require approval from an NHS Research Ethics Committee.

Analyses of existing data will make use of data collected for the Case Mix Programme. Support for the collection and use of patient identifiable data has been approved for the Case Mix Programme by the Patient Information Advisory Group (PIAG) under Section 251 of the NHS Act 2006 (originally enacted under Section 60 of the Health and Social Care Act 2001) – Approval Number: PIAG 2-10(f)/2005. Section 251 support is reviewed annually by PIAG and covers all aspects of data management including data security. ICNARC is also registered under the Data Protection Act.

Research Governance

The project will be managed according to the Medical Research Council's Guidelines for Good Research Practice ( and Procedure for Inquiring into Allegations of Scientific Misconduct ( ICNARC has developed its own policies and procedures based on these MRC guidelines, which are adhered to for all research activities at ICNARC. In addition, ICNARC has contractual confidentiality agreements with all members of staff. Policies regarding alleged scientific misconduct and breach of confidentiality are reinforced by disciplinary procedures.

Day-to-day running of the project will be overseen by a Project Management Group (KMR, DAH, SJP, AEA, NJW, Research Fellow), which will meet face-to-face at the start and end of each phase of the project and will maintain contact throughout the phases by telephone and electronic conferencing. An Expert Group, consisting of the other co-applicants plus the service user representative (see below), will meet at pre-defined, regular intervals throughout the study.

Project timetable and milestones

See Appendix 1 for project timetable.





  • Month 1 (Apr 2009): Project Management Group meet.
  • Month 2 (May 2009): Provisional model structure presented to Expert Group.
  • Month 6 (Sep 2009): Literature searches/evidence synthesis complete; Survey complete; Analysis of Case Mix Programme Database and National Immunoglobulin Database complete.
  • Month 7 (Oct 2009): Expert Group meet to interpret above results.
  • Month 10 (Jan 2010): Cost-effectiveness analysis and value of information analysis results presented to Expert Group.
  • Month 12 (Mar 2010): Draft protocol and costs for multicentre RCT presented to Expert Group for final input; Final report to HTA.


ICNARC, and KMR and DAH as senior researchers within ICNARC, have a track record in the conduct and dissemination of results of large, multicentre research studies and methodological studies in both adult and paediatric intensive care (e.g. PAC-Man – 1014 patients in 65 units – the first, academic, multicentre RCT in UK adult critical care funded by NIHR HTA). KMR has extensive experience as Principal Investigator for both methodological and evaluative research studies in critical care. DAH has considerable experience of designing, conducting and analysing multicentre studies, and has particular expertise in risk adjustment and analysis of observational data. Further details of ICNARC's research can be seen at

SJP is a senior researcher at the Centre for Health Economics and currently leads the Technology Appraisal Programme of work for NICE within the centre. He is also a lead member and manager of the NICE Decision Support Unit. SJP has extensive experience related to the methodology and application of decision-analytic modelling, evidence synthesis and value of information approaches, including previous pilot work for the HTA Programme using value of information to inform commissioning decisions. Further details of the work of the Centre for Health Economics can be seen at

AEA is the PI of an MRC-funded research programme ‘Multi-parameter evidence synthesis in epidemiology and decision making’, formerly within the Health Services Research Collaboration and now transferred to University of Bristol. NJW is a Senior Research Fellow within the programme. They are internationally recognised for their extensive expertise in advanced evidence synthesis methods, and particular experience with synthesis for disease natural history and with comparisons of multiple treatment alternatives, in a cost-effectiveness setting. NJW and AEA have also contributed landmark publications on EVI analysis, several in collaboration with the Centre for Health Economics in York. Further details of their work can be seen at

GR, RB and MS are internationally renowned opinion leaders in the field of severe sepsis and sepsis trials. GR is a member of the SSC Executive Committee, and both GR and RB are members of the SSC Guidelines Committee and were authors on the recently updated international guidelines for the management of severe sepsis and septic shock MS is an expert in the basic science relating to severe sepsis and was the Intensive Care Society representative to the Department of Health IVIg Guideline Development Group. WACS is a leading expert in the mechanism of action of IVIg and is a member of the Department of Health IVIg Expert Working Group, involved with the development of the Demand Management Plan and Clinical Guidelines.

Service Users

ICNARC has a history of involving and listening to users' views and experiences and has access to a wide range of users (patients and their families and close friends) from its recent funding of two DIPEx modules ( and

All involvement of service users in this study will follow the guidelines and recommendations for good practice from INVOLVE ( Maureen Dalziel will join the Expert Group as a service user representative. Maureen is a public health physician by training, and a member of ICNARC's Board of Trustees, and has held senior board appointments within the NHS and the Department of Health. However, of specific relevance to this project, Maureen also has personal experience of critical care, having previously been admitted to a critical care unit with severe sepsis.

Justification of support required

KMR (5%, 12 months) will oversee the running of the project and chair the Expert Group. DAH (10%, 12 months) will undertake analyses of the Case Mix Programme Database to inform the decision model. SJP (10%, 12 months) and AEA (5%, 12 months) will oversee the evidence synthesis and decision analysis work, which will primarily be carried out by NJW (50%, 12 months) and a Research Fellow (50%, 12 months) based in the Centre for Health Economics, York (to be recruited). An Administrative Assistant at ICNARC (25%, 12 months) will co-ordinate the administrative aspects of the project, including arranging the Project Management Group and Expert Group meetings, and will administer and follow up the survey of current practice. No costs have been included for clinical co-applicants on the basis of time commitment to the project, but all members of the Expert Group will receive an honorarium for meetings attended.

Project infrastructure costs (Project Management Group and Expert Group meetings) will ensure proper governance of the project. To maximise dissemination of the project results, costs have been included for one researcher to attend an international conference to present the results. Consumables required to administer and follow-up the survey of current practice have been based on actual figures from previous national surveys administered by ICNARC. Costs for literature searching and document retrieval were provided by the Centre for Reviews and Dissemination, York Indirect costs for staff based at ICNARC have been included as 46% of Direct Staff Costs as agreed with HTA Finance Manager, Kim Wherry, 24 July 2008.


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© 2012, Crown Copyright.

Included under terms of UK Non-commercial Government License.

Bookshelf ID: NBK97434


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