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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.)

7Conclusions

Implications for health care

Our meta-analysis, the first to simultaneously allow for type of IVIG (IVIG or IVIGAM), choice of control (no treatment or albumin), study quality/publication bias and other potential covariates, indicated that the treatment effect of IVIG on mortality for patients with severe sepsis is borderline significant with a large degree of heterogeneity in treatment effect between individual studies. Based on the results of combining the available evidence, and until further evidence becomes available, the immediate implications for health care are as per current policy and practice for off-label use of IVIG in severe sepsis (i.e. colour-coded black as treatment not recommended).

Recommendations for research

Although the EVI analyses suggested substantial expected net benefit from a large multicentre RCT evaluating the clinical effectiveness of IVIG, the remaining uncertainties around the design of such a study mean that we are unable to recommend it at this time. Our recommendations for research focus on filling the knowledge gaps to inform a future multicentre RCT prior to recommending its immediate design and conduct.

Modelling indicated that there were issues with bias associated with trial methodology, publication and small-study effects with the current evidence. The large degree of heterogeneity in treatment effects between studies, however, could be explained (best-fitting model) by a measure of study quality (i.e. use of albumin as control – as an indicator of proper blinding to treatment as a proxy for study quality – associated with decreased effect) and duration of IVIG therapy (longer duration associated with increased effect). In-depth discussion within the Expert Group on duration of IVIG therapy, with daily dose and total dose also clearly inter-related, indicated no clear clinical rationale for this association and exposed a lack of evidence on the understanding of the mechanism of action of IVIG in severe sepsis (evidence also being weak on how IVIG works in toxic states, such as toxic syndrome).

Intravenous immunoglobulin as an adjunctive treatment can be a physiological replacement and/or a pharmacological treatment (immunomodulation) and, with marked differences in the immunological profile during severe sepsis, the Expert Group identified research to better understand the mechanism(s) of action of IVIG preparations (10 products are licensed for use in the UK with few evaluated in previous RCTs) in the severe sepsis population, and dose-ranging/ finding studies to inform the dose, duration and timing of intervention(s) for a future multicentre RCT, as the highest priority. Note that IVIGAM (Pentaglobin) has been evaluated most in the severe sepsis population, but is not licensed for use in the UK. The response in children may be very different from that in adults. Modern IVIG preparations are more concentrated. Though an adjunctive treatment, evidence in severe sepsis suggests that early treatment is beneficial. Sufficient supplies of IVIG for a future RCT would require consideration.

Recommendation 1

Research on the mechanism(s) of action of IVIG preparation(s) in the severe sepsis population commencing with a thorough review of existing research prior to embarking on any new research.

Recommendation 2

Informed by recommendation 1, dose-ranging/finding studies to identify dose, timing of dose and safety data (tolerability/side-effects) to inform the intervention(s) for a future multicentre RCT.

There was a dearth of long-term outcome and cost/resource data on severe sepsis survivors to inform the cost-effectiveness analyses. Either by exploiting existing databases, through record linkage, or by initiating a prospective cohort study, long-term survival, including quality of survival and costs of survival for several years after the initial severe sepsis episode, should be explored.

Recommendation 3

Research to inform the long-term survival, including quality and costs of survival for the severe sepsis population.

Recommendation 4

Results of recommendations 13 should be re-evaluated for their impact on our EVI analyses.

The primary target population is adult patients with severe sepsis. There is increasing awareness that the syndrome described as severe sepsis represents a large and extremely heterogeneous group of patients. The heterogeneity of the severe sepsis population has plagued large, multicentre RCTs and there is a realisation that the focus should be on more homogeneous, specific, severe sepsis subpopulations. Heterogeneity appears to exist at the genetic, biochemical and clinical level, all of which may be associated. The current focus of research on severe sepsis has been in the identification of relevant genetic, biochemical and clinical markers with the aim better describing more homogeneous severe sepsis subpopulations, providing more rapid bedside markers for the early identification of sepsis and establishing which patients are most likely to benefit from therapy. Such advancements should inform the final design of a multicentre RCT of IVIG.

Recommendation 5

Recommendations 13 require knowledge of, and design of the definitive RCT for IVIG in severe sepsis requires a comprehensive review of, the emerging evidence surrounding the heterogeneity of the severe sepsis population at the genetic, biochemical and clinical level.

In summary, although the results highlight the value for money obtained in conducting further primary research in this area, the biggest limitation for such research regards the uncertainties over the heterogeneous nature of severe sepsis and the mechanism of action of IVIG. Resolving these would allow for better definition of the plausibility of the effectiveness scenarios presented and, consequently, a better understanding of the cost-effectiveness of this treatment. This information would also inform the design of future, primary evaluative research.

© 2012, Crown Copyright.

Included under terms of UK Non-commercial Government License.

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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