2 Research recommendations
The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of research recommendations is detailed in the full guideline.
What are the symptoms and signs of bacterial meningitis and meningococcal disease in children and young people aged under 16 years that differentiate between these conditions and minor self-limiting infections (including those characterised by fever)?
Research is needed from primary and secondary care settings on the diagnostic accuracy of symptoms and signs suggestive of bacterial meningitis and meningococcal disease in children and young people. The research should focus on identifying individual symptoms and signs, or groups of symptoms and signs that are effective as predictors of bacterial meningitis and meningococcal disease. These symptoms and signs should also differentiate effectively between these conditions and minor self-limiting infections. The research should include consideration of the effectiveness of symptoms and signs of acute feverish illness as predictors of meningococcal disease. Consideration should also be given to the age of the child or young person (in terms of the relevance of particular symptoms and signs) and the clinical setting at presentation. Suitable study designs would include diagnostic accuracy studies as well as observational studies (such as case–control studies), and the research could include a systematic review of studies that have already been published.
What are the normal ranges for blood and CSF parameters in children and young people in the UK?
Bacterial meningitis is a rare disease that is not easily distinguishable clinically from aseptic meningitis. It is, however, important to recognise those children who are most likely to have bacterial meningitis to direct appropriate management of the condition and to avoid inappropriate treatment of aseptic meningitis. Since the introduction of vaccines to protect against Hib, meningococcus serogroup C and pneumococcus, no high‑quality studies involving previously healthy children and young people have been conducted in the UK to determine normal ranges for blood test results or CSF findings in bacterial and aseptic meningitis. Such studies are needed to provide reference values to help interpret blood test results and CSF findings in children (especially neonates) and young people with suspected bacterial meningitis.
How effective is albumin 4.5% solution compared with crystalloid saline 0.9% solution for fluid resuscitation in children and young people with septic shock?
There are theoretical reasons why albumin solution may be more effective than crystalloid solution in children and young people with septic shock. However, no clinical studies have evaluated the effectiveness of albumin solution in children and young people with meningococcal disease. Concerns about the safety of colloids such as albumin solution led to a widespread change in clinical practice in the 1990s to using crystalloid solutions, despite a lack of evidence of equivalent effectiveness. Although albumin solution is considerably more expensive than crystalloid solution, a small additional benefit of albumin over crystalloid (one death prevented in more than 14,000 treated cases) would make the use of albumin solution cost effective. Randomised controlled trials are therefore needed to compare the effectiveness of albumin and crystalloid solutions in children and young people with septic shock.
What is the effectiveness of corticosteroids as an adjunct to antibiotic treatment in neonates with suspected or confirmed bacterial meningitis?
Neonatal bacterial meningitis is associated with high morbidity, despite the availability of antibiotics that are highly effective against the leading causes of bacterial meningitis in this age group. New approaches to management are needed because there are currently no vaccines to protect against infection from the causative organisms. Corticosteroids are effective as an adjunct to antibiotic treatment in older children with meningitis caused by Hib, and in adults with bacterial meningitis. However, there is insufficient evidence to support a recommendation for adjunctive corticosteroid treatment in neonates. Extrapolation from older age groups would be inappropriate because the spectrum of organisms causing infection in neonates is different, and the impact on the developing brain of the causative organisms during inflammation may not be the same. A large-scale randomised controlled trial is therefore needed to compare the effectiveness of antibiotic treatment plus corticosteroids with antibiotic treatment alone in neonates with suspected or confirmed bacterial meningitis.
How effective is steroid replacement treatment in children and young people with vasopressor-unresponsive shock caused by septicaemia, including meningococcal septicaemia?
Well-conducted but relatively small randomised controlled trials involving adults only suggest that low-dose corticosteroid replacement treatment may ameliorate haemodynamic failure and inflammatory dysregulation associated with severe sepsis. Such treatment may also improve outcomes following septic shock. Severe sepsis in children and young people differs from that in adults, in that multiple-organ dysfunction is less common in children and young people, and mortality is lower. A randomised controlled trial involving children and young people is needed to evaluate the effectiveness of corticosteroid replacement treatment. Studies involving adults suggest that those with normal adrenal function have worse outcomes if they receive steroids than those with adrenal dysfunction, and so the proposed trial should consider whether testing for adrenal dysfunction before starting steroid replacement treatment improves outcomes.