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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.)

1Introduction

Background

Definitions of severe sepsis and septic shock

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. Sepsis, severe sepsis and septic shock are generic terms and do not represent a single homogeneous disease; rather they are terms for a common syndrome.

In an attempt to formalise a definition for the sepsis syndrome, in 1991, a consensus conference was convened by the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM).1 This conference defined the concept of the systemic inflammatory response syndrome (SIRS) – a systemic activation of the innate immune response, regardless of cause. SIRS could be triggered by multiple insults, including infection, trauma, burns and pancreatitis. SIRS was considered to be present if two or more of the following four specific conditions were satisfied:

Sepsis was defined as SIRS (above) in response to infection, severe sepsis as sepsis associated with organ dysfunction, hypoperfusion or hypotension and septic shock as sepsis with hypotension despite adequate fluid resuscitation (Figure 1). These definitions have formed the basis of entry criteria to the majority of recent studies investigating sepsis.

FIGURE 1. Definitions of sepsis, severe sepsis and septic shock.

FIGURE 1

Definitions of sepsis, severe sepsis and septic shock.

In 2001, another consensus conference was convened, sponsored by the SCCM, the European Society of Intensive Care Medicine (ESICM), ACCP, the American Thoracic Society and the Surgical Infection Society.2 This consensus conference agreed the concept of SIRS, but considered the 1991 definition too non-specific to be useful. The basic definition of sepsis as ‘the clinical syndrome defined by the presence of both infection and a systemic inflammatory response’ remained unchanged but, in place of the SIRS criteria, the 2001 consensus definitions recommend a wider list of ‘possible signs of systemic inflammation in response to infection’. The definitions of severe sepsis as sepsis associated with organ dysfunction, and septic shock as sepsis associated with hypotension despite adequate fluid resuscitation, remained unchanged.

Epidemiology of severe sepsis in the UK NHS

Estimates of severe sepsis in the UK NHS derive from adult critical-care units in the Intensive Care National Audit & Research Centre (ICNARC) Case Mix Programme (CMP) Database. These indicate an increasing treated incidence of severe sepsis in critical care, rising from 50 to 70 cases per 100,000 population per year over the last decade.3 This now represents approximately 31,000 critical-care unit patient episodes per year. Similarly high incidence rates have been reported elsewhere.4 Overall, 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%, corresponding to approximately 15,000 deaths per year. These estimates may underestimate the overall burden of severe sepsis within critical-care units in the UK, because of the limitation of the available data restricting analysis to severe sepsis present during the first 24 hours following admission to the critical-care unit.

Severity of severe sepsis has often been summarised by the number of organ dysfunctions (i.e. the number of distinct organ systems with dysfunction). However, although the number of organ dysfunctions is strongly associated with mortality (rising from 22% for single organ dysfunction to 86% for five organ dysfunctions), the particular combination of organ dysfunctions is also important, with the combination of both cardiovascular and renal organ dysfunction associated with particularly high mortality.5

Intravenous immunoglobulin

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.6 The mechanisms of action of IVIG are complex, but are increasingly being understood.7 IVIG is predominantly used in neurology, haematology, immunology and dermatology, but also in nephrology, rheumatology, ophthalmology and other specialties. However, new uses are emerging and off-label use is increasing.8

Intravenous immunoglobulin has been proposed as an adjuvant therapy for severe sepsis/septic shock since the 1980s and a number of (predominantly small) randomised controlled trials (RCTs) have been conducted. The Cochrane systematic review of the use of IVIG in severe sepsis/septic shock describes the clinical rationale for this as follows: ‘The cascade of harmful effects from sepsis and septic shock has been postulated to be largely due to the lipid A component of the endotoxin molecule in Gram-negative bacteria. Thus the use of antibodies against different components of the endotoxin molecule has been the target of various investigations’.9 Numerous systematic reviews and meta-analyses of IVIG in severe sepsis/septic shock have been performed.915 As a result of the heterogeneity across studies and inconsistencies in results, the majority of authors have concluded that there is insufficient evidence to recommend IVIG as an adjuvant therapy for severe sepsis/septic shock and that more evidence, in the form of a large, well-conducted RCT, is required.

Current policy and practice with intravenous immunoglobulin for severe sepsis and septic shock in the UK

Intravenous immunoglobulin 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 owing to the risk of variant Creutzfeldt Jakob disease. In addition, the closure of one UK manufacturer (the Scottish National Blood Transfusion Service) and withdrawal of batches of IVIG because of 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,16 Clinical Guidelines for Immunoglobulin Use17 and the National Immunoglobulin Database. Indications for IVIG use are colour-coded in the following way:

  • 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, and
  • 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. The Clinical Guidelines for Immunoglobulin Use 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 (intensive care unit).17

In view of the heterogeneity of results from existing RCTs and the unique supply and demand issues for IVIG (especially in the UK), a research priority was identified to establish if such a trial was necessary and feasible and if the costs of carrying out the trial were outweighed by the potential benefit of the resulting information.

Aims and objectives

The aim of this study was to evaluate the feasibility, cost and value of information of conducting a large, high-quality, multicentre RCT to assess the clinical effectiveness and cost-effectiveness of IVIG for adult patients severely ill with sepsis (severe sepsis or septic shock) in the UK.

The specific objectives were:

  • to describe current practice in the management of adult patients severely ill with sepsis (severe sepsis or septic shock) in the UK
  • to assess the clinical effectiveness of IVIG for severe sepsis and septic shock, and to obtain the appropriate inputs for the relative efficacy parameters and the key uncertainties associated with these parameters, required to populate the decision model
  • to develop a decision-analytic model structure and identify key parameter inputs consistent with the decision problem and relevant to an NHS setting
  • to populate the decision model and determine the cost-effectiveness of IVIG and to estimate the value of additional primary research.
© 2012, Crown Copyright.

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Cover of 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
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.
Health Technology Assessment, No. 16.7.
Soares MO, Welton NJ, Harrison DA, et al.
Southampton (UK): NIHR Journals Library; 2012 Feb.

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