Management of invasive meningococcal disease in children and young people: summary of SIGN guidelines
BMJ 2008; 336 doi: https://doi.org/10.1136/bmj.a129 (Published 12 June 2008) Cite this as: BMJ 2008;336:1367
- U Theilen, consultant in paediatric intensive care1,
- L Wilson, specialist registrar in public health2,
- G Wilson, consultant paediatric anaesthetist3,
- J O Beattie, consultant paediatrician 4,
- S Qureshi, programme director, SIGN5,
- D Simpson, consultant in paediatric anaesthesia and intensive care 1
- on behalf of the Guideline Development Group
- 1Department of Anaesthesia and Paediatric Critical Care, Royal Hospital for Sick Children, Edinburgh EH9 1LF
- 2Department of Public Health and Health Policy, University of Glasgow, Glasgow
- 3High Dependency Unit, Royal Aberdeen Children’s Hospital, Aberdeen
- 4Department of Emergency Medicine, Royal Hospital for Sick Children, Glasgow
- 5Scottish Intercollegiate Guideline Network, Edinburgh
- Correspondence to: D Simpson dave.simpson{at}luht.scot.nhs.uk
Why read this summary?
Despite the successful introduction of immunisation with meningococcal group C conjugate vaccine in 1999,1 invasive meningococcal disease continues to cause substantial morbidity and mortality.2 Most deaths occur in the first 24 hours, often before specialist care starts. The challenge therefore is to identify those patients who will progress rapidly from non-specific early presentation to life threatening disease.3
Major changes to the organisation of health care in the United Kingdom, particularly in the provision of resuscitation and paediatric intensive care, have been associated with dramatically improved outcomes over recent decades.4 5 However, lack of high quality evidence to inform changes in clinical practice has been a particular challenge in developing this evidence based guideline. This article summarises the most recent guidance from the Scottish Intercollegiate Guidelines Network (SIGN) on the management of invasive meningococcal disease in children and young people.6
Recommendations
SIGN recommendations are based on systematic reviews of best available evidence. The strength of the evidence is graded as A, B, C, or D (fig 1⇓), but the grading does not reflect the clinical importance of the recommendations. Recommended best practice (“good practice points”), based on the clinical experience of the guideline development group, is also indicated (as GPP).
Fig 1 Explanation of SIGN grades of recommendations
Signs and symptoms
Invasive meningococcal disease has an early, non-specific stage with signs such as fever, lethargy, irritability, nausea, and poor feeding. These signs are commonly found in children with self limiting viral illnesses, so a confident differential diagnosis at an early stage is very difficult. Observational studies have associated leg pain, cold extremities, and abnormal skin colour with developing invasive meningococcal disease.7 This non-specific early stage commonly lasts for several hours before invasive meningococcal disease progresses rapidly to three general disease patterns8:
Clinical meningitis—This is characterised by fever, lethargy, vomiting, headache, photophobia, neck stiffness, and positive Kernig’s sign (pain after the patient’s hip is flexed 90° and the knee extended)and Brudzinski’s sign (flexing the patient’s neck causes flexion of the patient’s hips and knees). Petechiae or purpura may also be present. Some infants and young children with meningitis display less specific features, such as poor feeding, irritability, a high pitched cry, and a full fontanelle.
Meningococcal septicaemia—Occurring in about 20% of cases, this is characterised by fever, petechiae, purpura, and shock. This presentation is associated with poorer outcome.
A mixed picture of septicaemia and meningitis.
Early assessment and treatment
Figure 2⇓ and the list below outline the assessment and diagnosis of meningococcal disease in children and young people. The following points are important.
Do not automatically exclude meningococcal disease as a potential diagnosis if young children present with non-specific symptoms such as fever, lethargy, poor feeding, nausea, vomiting, or irritability in the first four to six hours of illness (D).
Reassess children with non-specific symptoms at initial presentation, in whom meningococcal disease cannot be excluded, within four to six hours (GPP).
Advise carers to seek further clinical advice if the child’s condition deteriorates (for example, a rash develops) before planned reassessment. Take account of local arrangements for health care.
Consider diagnosis of invasive meningococcal disease in an ill child with the following features: fever; extremity pain; cold hands and feet; skin mottling; headache; neck stiffness; altered mental state; petechial rash (D).
In children with symptoms or signs that are highly suggestive of meningococcal disease, do not delay treatment by interval assessment or pending investigations (D). Administer parenteral antibiotics (out of hospital, intramuscular benzylpenicillin is widely used)9 and arrange urgent hospital assessment (D).
A generalised petechial rash, beyond the distribution of the superior vena cava, or a purpuric rash in any location, in an ill child is strongly suggestive of meningococcal septicaemia—urgently treat and refer to hospital (D).
Fig 2 Assessment and diagnosis of invasive meningococcal disease in children and young people
Hospital care
The absence of senior specialist input from paediatrics, anaesthesia, and intensive care—including the absence of consultant supervision during the first 24 hours in hospital—has been associated with increased mortality.10
After arrival at hospital, children with suspected invasive meningococcal disease should be reviewed and treated promptly by a senior and experienced clinician (D).
Discuss management of children with progressive invasive meningococcal disease with staff in the paediatric intensive care unit at an early stage (D).
Confirming the diagnosis
To confirm the diagnosis in all children with suspected invasive meningococcal disease, take blood for culture (D) and polymerase chain reaction (C) as soon as possible after admission to hospital; however, this should not delay treatment.9
In patients with suspected invasive meningococcal disease and features of septicaemia, lumbar puncture is not recommended in the initial assessment. It may be considered later if there is diagnostic uncertainty and unsatisfactory clinical progress and if there are no contraindications such as coagulopathy, low platelets, cardiovascular instability, or neurological concerns (GPP).
In patients with clinical meningitis without features of septicaemia (purpura), do lumbar puncture if there are no contraindications (D).
Treatment
Intravenous fluids—Consensus exists for the use of early, aggressive intravenous fluid therapy in adults and children diagnosed with invasive meningococcal disease in whom there are signs of shock.
If signs of shock are present, administer a rapid infusion of intravenous fluids as isotonic crystalloid or colloid solution up to 60 ml/kg, given as three boluses of 20 ml/kg, with reassessment after each bolus (B).
Fluid resuscitation in excess of 60 ml/kg (B), plus inotropic support (D), is often required.
Evidence of circulatory failure and the need for repeated intravenous fluid boluses should prompt early consultation with intensive care as inotropic and ventilatory support may be required (GPP).
Antibiotics—Administer as follows:
Administer intravenous cefotaxime as initial treatment for previously well children aged over 3 months and diagnosed with invasive meningococcal disease (B).
Once daily ceftriaxone monotherapy may be substituted if parenteral agents containing calcium (such as intravenous calcium, parenteral nutrition, or Hartmann’s solution) have not been used in the preceding 48 hours (GPP). This is a precaution following reports of fatal interactions in neonates.
When parenteral antibiotics are indicated for infants aged less than 3 months, administer cefotaxime plus an antibiotic active against listeria (such as ampicillin or amoxicillin; GPP).
In children with invasive meningococcal disease, antibiotic treatment should last seven days, assuming satisfactory clinical progress (GPP).
Corticosteroids—Administer as follows:
Steroids are not recommended for treating children with meningococcal septicaemia (B) except in the case of inotrope-resistant shock.
In children starting empirical treatment for bacterial meningitis of unknown aetiology (A) or in children with confirmed meningococcal meningitis (B), administer parenteral dexamethasone (0.15 mg/kg every six hours) with, or within 24 hours of, the first antibiotic dose, and continue for four days.
Intensive care—Take the following action:
For patients who continue to deteriorate despite appropriate supportive treatment, arrange transfer to paediatric intensive care (D).
For children with fluid-resistant shock, consider early ventilatory support after inotropes are started (GPP).
Before and during intubation, consider volume loading. Use anaesthetic agents that maintain cardiovascular stability (D).
In children with refractory hypotension (inotrope-resistant shock) intravenous vasopressin and steroid dose titration are appropriate rescue strategies (GPP).
For children with inotrope-dependent septic shock, severe metabolic acidosis, acute or impending renal failure, and complex or problematic fluid balance, consider continuous venovenous haemofiltration (GPP).
Prevention of secondary transmission
Liaise with the local public health department to ensure appropriate public health actions.
Chemoprophylaxis with some antibiotics (ciprofloxacin, rifampicin, minocycline, ampicillin) has been found to be effective. Offer prophylaxis to those who have had prolonged close contact in a household setting with a child with meningococcal disease during the seven days before onset of illness (C). Close contacts are defined as those living or sleeping in the same household (including extended household); pupils in the same dormitory; boyfriends and girlfriends; and university students sharing a kitchen in a hall of residence.9
In isolated cases of meningococcal disease, prophylaxis is not indicated for pupils in the same nursery, school, or class as a child diagnosed with meningococcal disease, unless they are a close contact (D).
Before discharge from hospital, offer meningococcal C vaccine (D).
Follow-up care
Consider the following potential morbidities (C), depending on the individual case severity, and manage accordingly.
Hearing loss.
Neurological complications.
Psychiatric, psychosocial and behavioural problems.
Bone and joint complications (such as discrepancy in leg length), with awareness that these may not be apparent for many years after illness.
Post-necrotic scarring with possible requirements for amputations and skin grafting.
Renal impairment, particularly in those who required acute renal replacement therapy.
Potential for post-traumatic stress disorder in both the children and their families.
Overcoming barriers
In primary care, the challenge is to discriminate the few children with early meningococcal disease from the many with self limiting viral illnesses. The recent guideline from the National Institute for Health and Clinical Excellence (NICE) may help in the preschool age group.11 Postgraduate training programmes for primary care practitioners should include specific education in the recognition and early management of seriously ill children. In secondary care, such children should be reviewed by a senior paediatrician shortly after arrival in hospital. Patients needing intensive or high dependency care should receive support from a multidisciplinary team with input from anaesthetics and intensive care staff, ideally coordinated by a lead consultant in acute paediatrics. For critically ill children, there should be early dialogue with the regional paediatric intensive care unit, with a remit to advise on early management and provide a dedicated transfer team when necessary.
The interface between primary, secondary, and paediatric intensive care requires clearly defined lines of communication at senior level and would benefit from regular feedback and teaching (such as critical care outreach study days). Further improvements in outcome will depend on the quality of care at all three levels and, importantly, on the interface between them.
Further information on the guidance
We are not aware of published evidence investigating inconsistent practice in the management of invasive meningococcal disease in children and young people, although substantial variations clearly occur in clinical practice.12 13 Evidence exists that, by introducing consistent practice—in the form of centralised care for paediatric intensive care patients in general14 and management of invasive meningococcal disease in particular10—outcomes have been improved. Swift recognition of disease and prompt involvement of specialist teams have been described as critical factors in this process.10
What’s new?
Evidence based guideline
Clinical practice guidelines for the recognition and early management of meningococcal disease in children have been in use for some time.15 16 We believe this is the first time an established formal process systematically scrutinising the existing literature has been used to produce an evidence based guideline for this disease.
Flow chart for early management in primary care
In primary care, the challenge is to discriminate the few children with early meningococcal disease from the many with self limiting viral illnesses. Recent cohort studies associated factors such as leg pain, cold extremities, and abnormal skin colour with developing invasive meningococcal disease.7 These signs from early non-specific disease are present several hours before specific signs of meningitis and septicaemia. The guideline development group suggests a flow chart (fig 2⇑) to facilitate early management, taking into account the carer’s involvement in the management and local arrangements for health care, particularly out of hours provision.
Selection of initial antibiotics in hospital care
A recent alert from the US Food and Drug Administration on reports of fatal interaction in neonates between ceftriaxone and solutions containing calcium led to a change of recommended antibiotic treatment.17 We are not aware of reports on such interactions in children, but we believed it would be prudent not to use ceftriaxone as a first line antibiotic at an early stage of the disease, when use of solutions containing calcium (such as intravenous calcium, Hartmann’s solution, or parenteral nutrition) is likely. This is in keeping with recent recommendations from regulatory bodies in the UK.18 We recommend intravenous cefotaxime as initial treatment for invasive meningococcal disease in previously well children aged over 3 months, which should be supported by antibiotics active against listeria (such as ampicillin or amoxicillin) in infants aged under 3 months. Once no parenteral solutions containing calcium have been used for at least 48 hours, cefotaxime may be replaced by ceftriaxone, which simplifies care delivery (once daily use) and has a proved track record of carrier elimination.
Use of corticosteroids
The use of corticosteroids in septicaemia and meningitis has changed following recent publications, so the initial management of children with septicaemia and those with meningitis has to be clearly distinguished.
Corticosteroids in septicaemia—In adult septic shock, a recent very large randomised controlled trial did not confirm improved outcome reported in earlier trials, and an increased number of adverse effects were seen in the treatment group.19 No randomised controlled trials exist on the use of corticosteroid therapy in children with septic shock. Corticosteroids are therefore not recommended for the treatment of children with meningococcal septicaemia, with the notable exception of steroid dose titration as rescue treatment in case of suspected absolute adrenal insufficiency with inotrope resistant septic shock.
Corticosteroids in bacterial meningitis—In bacterial meningitis in children, large systematic reviews showed the effectiveness of corticosteroids in significantly reducing the number of children with severe hearing loss and a trend towards reduction of other neurological sequelae.20 Reduced numbers of neurological sequelae were also reported in children and adults with meningococcal meningitis, but this trend did not reach statistical significance.20 21 Given that neurological complications are rarer in meningococcal meningitis than in other forms of bacterial meningitis, this lack of statistical significance has been interpreted to be “due to limited power [of these studies] from low event rates rather than no benefit; certainly there is no evidence of a detrimental effect.”22 As the body of evidence is consistently in the direction of benefit, we felt confident in recommending the use of corticosteroids for children starting empirical antibiotic treatment for bacterial meningitis of unknown aetiology and for children with (confirmed) meningococcal meningitis. Although smaller studies have suggested that a two day course of steroids may be as effective as a four day course, the original recommendation in the systematic review explicitly stated that the results of the meta-analysis were only applicable to a four day regimen and specifically recommended such a duration of treatment. This was based on studies with a total of 1478 children.20 Insufficient data on a two day course have been published to justify a deviation from the original recommendation of a four day course of dexamethasone.
Activated protein C
Activated protein C improves outcome in the management of severe sepsis in adults. In children, an open-label phase II trial and a phase III randomised controlled trial of activated protein C have shown a higher incidence of serious adverse events compared with adult studies. In particular, a higher incidence of serious haemorrhagic events was found.23 24 The recommendation, therefore, is not to use activated protein C in children with invasive meningococcal disease.
Follow-up
The guidelines also include a chapter on follow-up after discharge from hospital care. This section gives an overview of the evidence of long term problems observed in some of the patients surviving intensive care and in their families and carers, including problems with post-traumatic stress.
Organisational aspects of care
The outcome from septic shock in children has improved dramatically over recent decades, with mortality falling from 60% in the early 1980s to 9% in 1999.4 Some of these improvements will be attributable to changes in clinical practice informed by the published evidence. This factor alone, however, seems to be insufficient to explain such an improvement in outcome. In particular, many papers were physiological experiments, case series, and cohort studies, thereby not providing high levels of evidence. Changes to organisational aspects of health care—in particular changes to the provision of resuscitation and paediatric intensive care—have been associated with these improved outcomes.5 Furthermore, effective communication between primary, secondary, and paediatric intensive care is vital to ensure rapid escalation of treatment in the early phase of invasive meningococcal disease. The guideline development group believes that the importance of these organisational aspects can hardly be overestimated.
Methodology
The development of the guideline followed established SIGN methodology based on a systematic review of the evidence. SIGN is a collaborative network of clinicians, other healthcare professionals, and patient organisations and is part of NHS Quality Improvement Scotland. Further details about SIGN and the guideline development methodology are contained in SIGN 50: A Guideline Developer’s Handbook (see www.sign.ac.uk).
Updates and reviews of new evidence
The guideline will be considered for review after three years. Any updates to the guideline in the interim period will be noted on the SIGN website (www.sign.ac.uk).
Other useful information
The guideline also has a section dealing with questions frequently asked by patients, parents, and carers and provides an extensive list of resources on the possible physical and psychological implication of invasive meningococcal disease.
Future research and remaining uncertainties
The guideline development group identified the following areas for further research.
Evaluation of the effectiveness of health education campaigns aimed at increasing awareness and recognition of meningococcal disease
Prospective validation of the predictive value of early symptoms in diagnosing meningococcal disease in a population of children presenting in the community with undifferentiated illness
Which signs and symptoms are definitive markers for referring a child to secondary care
Research to determine whether there are any prehospital interventions which are efficacious in reducing mortality and morbidity in children and young people with suspected invasive meningococcal disease
Procalcitonin assay as an indicator of severity and a predictor of outcome
Research to identify the normal compartment pressures in children
Uncertainty about capability of cefotaxime to eliminate carrier status
Outcome of current pilot study on outcome of physiological doses of steroids in paediatric septic shock
Extension of the role of vasopressin in management of meningococcal septic shock
Research into the role and importance of organisational changes to—and the interface between—primary, secondary, and intensive care
The members of the guideline development group are David Simpson (chair), consultant in paediatric anaesthesia and intensive care, Royal Hospital for Sick Children, Edinburgh; Lynsey Andrews, medical information officer, Meningitis Research Foundation, Edinburgh; Roland Armes, consultant in emergency and paediatric emergency medicine, Aberdeen Royal Infirmary and Royal Aberdeen Children’s Hospital; Jack Beattie, consultant paediatrician, Royal Hospital for Sick Children, Glasgow; Tom Beattie, consultant in paediatric emergency medicine, Royal Hospital for Sick Children, Edinburgh; Emma Breene, general practitioner, Garthdee Medical Practice, Aberdeen; Elizabeth Chalmers, consultant haematologist, Royal Hospital for Sick Children, Glasgow; Joyce Coppola, health protection nurse specialist, Fife NHS Board; Anne Currie, assistant Scotland manager, Meningitis Trust, Glasgow; Margaret Dolan, pharmaceutical adviser, NHS National Services Scotland, Edinburgh; Rosie Hague, consultant in paediatric infectious diseases and immunology, Royal Hospital for Sick Children, Glasgow; Pota Kalima, consultant clinical microbiologist, Western General Hospital, Edinburgh; Una MacFadyen, consultant paediatrician, Stirling Royal Infirmary; Graham MacKenzie, locum consultant in public health medicine, Fife NHS Board; Ailsa McLellan, consultant paediatric neurologist, Royal Hospital for Sick Children, Edinburgh; Jim McMenamin, consultant epidemiologist, Health Protection Scotland, Glasgow; Daren Mochrie, head of accident and emergency services, Scottish Ambulance Service, Ayr; John J M O’Dowd, general practitioner and specialist registrar in public health medicine, Lanarkshire NHS Board; Margaret Pelosi, lay representative, Glasgow; Jane Richardson, senior nurse, Royal Hospital for Sick Children, Edinburgh; Jennifer Scarth, consultant in paediatric intensive care, Royal Hospital for Sick Children, Glasgow; Ailsa Stein, programme manager, SIGN; Ken Stewart, consultant plastic surgeon, Royal Hospital for Sick Children, Edinburgh; Ulf Theilen, consultant in paediatric intensive care, Royal Hospital for Sick Children, Edinburgh; Adam Watts, specialist registrar in orthopaedics, Royal Hospital for Sick Children, Edinburgh; Joanna Welsh, information officer, SIGN; Graham Wilson, consultant anaesthetist, Royal Aberdeen Children’s Hospital; Louise Wilson, specialist registrar in public health, University of Glasgow.
Footnotes
This is one of a series of BMJ summaries of new guidelines, which are based on the best available evidence; they highlight important recommendations for clinical practice, especially where uncertainty or controversy exists.
Contributors: All authors have contributed towards the writing of the summary. UT and DS are the guarantors.
Funding: No funding was received for writing this summary .
Competing interests: None declared.
Provenance and peer review: Commissioned; not externally peer reviewed.