Three Part Question
In [a child with meningococcal shock] does [steroid replacement therapy] decrease [mortality]?
A 3 year old boy is admitted to a paediatric intensive care unit with a history of fever, non-blanching petechial rash, decreased conscious level, and grunting; capillary refill is poor. After screening for sepsis, antibiotics are started. He is intubated, receives fluid resuscitation (total of 100 ml/kg), and a central catheter is placed, showing a central venous pressure of 12 mm Hg. Despite dopamine infusion the attending physician is unable to stabilise his blood pressure, and he requires noradrenaline infusion to achieve and maintain his haemodynamic state.
Secondary (Cochrane library, 2004) and primary (Medline, Embase, Scielo) sources were included in the search. MeSH terms were used in Medline and Embase.
Search strategies: "meningococcal" AND "steroid replacement"; "meningococcal" AND "steroids" (limited to "all children" from 1984 to 2004); "shock, septic" AND "steroids" (limited to "randomised controlled trials" from 1992 to 2004).
Search outcome: 68 hits (3; 52; 13; each search respectively), of which 6 (0; 3; 3) studies were directly relevant to the question.
|Author, date and country
||Study type (level of evidence)
|Annane et al,|
|300 adults with dopamine resistant septic shock divided according to the increase in cortisol in response to short corticotropin test (250 µg) as responders (>9 µg/dl) or non-responders (<9 µg/dl)||Randomised controlled trial (hydrocortisone 200 mg/day + fludrocortisone 50 µg/day v placebo, for 7 days)||28 day survival Time to vasopressor withdraw||28 day mortality of (steroids v placebo) 60/114 v 73/115 in the non-responders and 22/36 v 18/34 for responders–adjusted Odds ratios of 0.54 (0.31–0.97) and 0.97(0.32–2.97), respectively Time to withdraw vasopressor was (steroids v placebo) 7 v 10 days in non-responders (HR of 1.91 (1.29–2.84)) and 9 v 7 days in responders (p = 0.49)||Very specific population
Large confidence intervals, upper limit close to 1
Do not report incidence of hyperglycaemia associated with steroids
Number of patients needed to treat to save 1 additional life is 7 (4–49)|
|Yildaz et al,|
|40 adults with sepsis||Randomised controlled trial (prednisolone (7.5 mg/day, for 10 days)||28 day mortality||8/20 steroid and 12/20 placebo (p = 0.34) Higher difference in APACHE II>20 (not calculated)||Only 9 (22%) shocked Small sample
No power calculation
Trend for improve in survival, specially in the more severe group|
|Bollaert et al,|
|41 adults with septic shock requiring catecholamine for more than 48 hours Response to corticotrophin stimulation test (increase >6 µg/dl)||Randomised controlled trial (300 mg/day hydrocortisone v placebo, for >5 days)||7 day reversal of shock 28 day mortality||7 day reversal of shock (15/22 v 4/19, p = 0.007) Mortality (7/22 v 12/19, p = 0.45) Similar improve (7 d, 28 m) in responder and non-responder||Discontinued early because primary end point was achieved
Late inclusion of patients
Large confidence intervals (7 day reversal of shock 17 to 77%)
Other clinical interventions were not described|
|Bone et al,|
|65 children with meningococcal disease
Divided according to the intensive management required:
I = mild, II = moderate, III = extensive||Prospective cohort study||Admission, 8 am and post-low dose Synachthen test (LDST) cortisol levels AI defined as (a) cortisol lower than 140 nmol/l; (b)LDST cortisol lower than 500 nmol/l||AI = 16.9% (11/65) (a = 8, b = 6) 8am cortisol IIII (p = 0.07) LDST cortisol I = II II>III (p<0.05)||Lost 21 (24%) patients on enrolment
13 (35%) did not have LDST
Doesn't specify previous use steroids|
|De Kleijn et al,|
|62 children with meningococcal sepsis Divided as:
I = sepsis (12) II = shocked survivor (38) III = shocked non-survivor (12)||Prospective cohort study||Admission cortisol and adrenocorticotrophic hormone (ACTH) levels AI defined as cortisol <138 nmol/l, partial AI defined as cortisol from 138 to 497 nmol/l||None had AI 7 (11,3%) children had partial AI Cortisol (nmol/l): I(1158)>II (997)>III (654)||Didn't test response to corticotrophin
12 children were non-shocked
Incidence of partial AI was 14%(7) among shocked|
|Riordan et al,|
|96 children with meningococcal disease Divided as:
meningococcal sepsis (MS = 43); meningococcal meningitis + septicaemia (MM+MS = 46); meningococcal meningitis (MM = 7)||Prospective cohort study||Admission cortisol and mortality||Cortisol (nmol/l): MM 970 MM+MS 1268 MS 1183 Survivors > non-survivors||Sepsis definition is not described.
Do not specify previous steroid treatment
Small group hypotensive (29), with 10.3% incidence of partial AI 10 referral had samples later, lower cortisol and higher mortality|
The use of steroids in septic shock has been discussed for decades. The use of high dose steroids (30 mg/kg of methylprednisolone or equivalent) for a short period has been proven not to improve outcome (Bone, 1987). However, the use of low doses (200–300 mg of hydrocortisone in adults; around 2–5 mg/kg/day in children) for longer periods (replacement therapy) has shown very promising results in adults (Annane, Yildiz, Bollaert). These 3 papers help to summarise the main randomised controlled trials testing the use of steroids in low dose for septic shock. Although there is a discrepancy in the populations (and on the criteria for adrenal insufficiency), replacement therapy with steroids showed either significant reduction in the duration of inotrope requirement and 28 day mortality, or a tendency towards improvement. Although no studies have evaluated the use of steroids in paediatric septic shock, expert opinion (for example, the Society of Critical Care Medicine clinical practice parameters, Carcillo ) recommends the use of hydrocortisone in children with septic shock requiring catecholamines for blood pressure support and adrenal insufficiency, as evidenced by total cortisol lower than 18 mg/dl.
Meningococcal septic shock presents with an early, massive inflammatory response. Although absolute adrenal failure due to adrenal haemorrhage is rare, partial adrenal insufficiency has been described in these children even in the absence of adrenal haemorrhage (Bone 2002, De Kleijn, Riordan) These 3 papers help to summarise the main studies that have evaluated adrenal function in children with meningococcal disease. The incidence of adrenal insufficiency varied from 10.3% to 16.9% in children with shock. Of note, children with very severe disease had lower cortisol levels than children with a moderate presentation(Bone 2002, De Kleijn, Riordan). Moreover, after a low dose Synacthen test, cortisol levels did not increase as much in the more severely affected children as they did in children with mild disease (Bone, 2002). These data support the hypothesis that children with meningococcal shock, particularly the more severely affected, can present with reduced adrenal response
In summary, children with meningococcal shock have increased incidence of abnormal adrenal response, and extrapolation of data from adult septic shock and expert opinion supports the use of hydrocortisone replacement therapy in children with meningococcal shock dependent on catecholamines.
Clinical Bottom Line
Adrenal insufficiency is frequent in adults with septic shock, and there is good evidence to support steroid replacement therapy in this group. (Grade A)
There is no direct evidence regarding the use of steroid replacement therapy in children with meningococcal shock.
There is evidence of suppressed adrenal response (adrenal insufficiency) in children with meningococcal shock. (Grade B)
Steroid replacement is a rational therapy that is likely to be of benefit in children with meningococcal shock. (Grade B)
- Bone RC, Fisher CJ Jr, Clemmer TP. et al. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. Engl J Med 1987;317:653–8.
- Annane D , Sebille V, Charpentier C. et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288:862–71.
- Yildiz O , Doganay M, Aygen B. et al. Physiological-dose steroid therapy in sepsis. Crit Care 2002;6:251–9.
- Bollaert PE, Charpentier C, Levy B. et al. Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med 1998;26:645–50.
- Bone M , Diver M, Selby A. et al. Assessment of adrenal function in the initial phase of meningococcal disease. Pediatrics 2002;110:563–9.
- De Kleijn ED, Joosten KF, Van Rijn B. et al. Low serum cortisol in combination with high adrenocorticotrophic hormone concentrations are associated with poor outcome in children with severe meningococcal disease. Pediatr Infect Dis J 2002;21:330–6.
- Riordan FA, Thomson AP. Ratcliffe JM. et al. Admission cortisol and adrenocorticotrophic hormone levels in children with meningococcal disease: evidence of adrenal insufficiency? Crit Care Med 1999;27:2257–61.
- Carcillo JA, Fields AI. American College of Critical Care Medicine Task Force Committee Members. Clinical practice parameters for hemodynamic support of pediatric and neonatal patients in septic shock. Crit Care Med 2002;30:1365–78.