Chapter 16. The use of corticosteroids in the treatment of severepediatric traumatic brain injury

I. RECOMMENDATIONS

1. Standards. There are insufficientdata to support a treatment standard forthis topic.

2. Guidelines. There are insufficientdata to support a treatment guideline forthis topic. The use of steroids signifi-cantly reduces endogenous cortisol pro-duction. The use of steroids may have anassociated increased risk of complicationsof infection in children.

C. Options. The use of steroids is notrecommended for improving outcome orreducing intracranial pressure (ICP) inpediatric patients with severe traumaticbrain injury (TBI). Despite two class IIstudies failing to show efficacy, the smallsample sizes preclude support for a treat-ment guideline for this topic.

D. Indications from Adult Guidelines.The majority of available evidence indi-cates that steroids do not improve out-come or lower ICP in severely head-injured adult patients (1). The routineuse of steroids is not recommended forthese purposes.

II. OVERVIEW

Corticosteroids have been commonlyused in children, for a wide range of neu-rologic diseases, to reduce edema (due totumors, infection, inflammation) and tolessen its neurologic effects. The poten-tial of steroid use in adults following TBIwas first indicated in literature reportingthe benefits of edema reduction and clin-ical improvement in brain tumor pa-tients. As summarized in the “Guidelinesfor the Management of [Adult] SevereTraumatic Brain Injury” (1), there is ev-idence that steroids are useful in reduc-ing cerebral edema, attenuating free rad-ical production, and affording otherbeneficial effects in experimental modelsof TBI, but clinical evidence did not sup-port its use. In the adult literature re-viewed, corticosteroids did not improvefunctional outcome or prove useful in

reducing ICP in patients with severe TBI.The studies cited in the adult guidelinesdid not specifically report on the use ofcorticosteroids in pediatric patients fol-lowing severe TBI, but there was a sug-gestion of potential efficacy in youngerpatients. A specifically pediatric reviewwas necessary to determine whetherthere is adequate evidence to support rec-ommendations for children.

III. PROCESS

We searched Medline and Healthstarfrom 1966 to 2001 by using the searchstrategy for this question (see AppendixA) and supplemented the results with lit-erature recommended by peers or identi-fied from reference lists. Of 45 potentiallyrelevant studies, eight were used as evi-dence for this question (Table 1).

IV. SCIENTIFIC FOUNDATION

In clinical practice, steroids have beenused in an attempt to reduce posttrau-matic swelling and improve outcome inboth adults and children. The role of ste-roids remains uncertain in the treatmentof TBI, particularly as it relates to thepediatric population.

Cooper et al. (2) performed a prospec-tive, randomized, double-blind clinicaltrial with adults and children using dexa-methasone. There were 76 total patients,ten of whom were �10 yrs of age, and 32who were less �20 yrs of age. Only se-verely injured patients were included,and each of the patients was randomizedto one of three groups—placebo, low-dose steroids, and high-dose steroids. Theadults were given standard doses,whereas the children were given weight-related doses. Assignment to the groupswas randomized on entry into treatment,but there was no stratification by age.Glasgow Outcome Scale (GOS) was as-sessed at 6 months. The analysis per-formed was on the relation of treatmentto outcome. The authors reported that in

older patients there was no difference inoutcome with the use of steroids. Be-cause of the small number of childrenincluded, no conclusions could be drawnregarding steroid use in pediatric TBI.

Fanconi et al. (3) performed a ran-domized, prospective clinical trial on 25pediatric patients using dexamethasoneat 1 mg·kg�1·day�1 for 3 days (n � 13)and 12 controls treated with an alternatestandard regimen. Outcome was deter-mined by 6-month GOS and response byendogenous free cortisol levels. In thisstudy, there was no difference in effect onICP or cerebral perfusion pressure and nodifference in 6-month outcome. Therewas a statistically significant suppressionof cortisol levels up to 6 days posttreat-ment. As well, there was a significantlyincreased bacterial infection rate in thosepatients treated with steroids.

Gobiet (4) reported on a case controlseries of 205 children: 139 who did notreceive steroids, and 66 who did. Theintervention was high-dose dexametha-sone, although no specific dose was re-ported. The nonsteroid treatment groupwas a consecutive sample of 139 patientsfrom the years 1972–1974 who weretreated with neither ICP monitoring noraggressive intensive care unit therapy.The later steroid treatment group (re-cruited 1974–1975) received ICP moni-toring, intensive care unit management,and steroid therapy. There was no lengthof follow-up reported, but the measuresof outcome included mortality rate,length of intubation, ICP, seizures, andscholastic performance. The authors re-ported that there was decreased mortalityrate with the use of steroids but no dif-ference with regard to length of intuba-tion, time of unconsciousness, incidenceof seizures, or neurologic outcome. Acomparison between the groups in thisstudy is compromised because significantdifferences in timing and approach mayconfound many subtle variables of treat-ment. However, given the lack of differ-

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Table 1. Evidence table

Reference Description of StudyDataClass Conclusion

Cooper et al.(2), 1979

Prospective, double-blind study of 76 patients with severehead injury (42 of whom were �20 yrs of age, ten ofwhom were �10 yrs of age). The patients were stratifiedfor severity and treated with placebo or weight-relateddoses in the children. Six-month GOS was thendetermined.

III No significant difference in 6-month outcome in the olderchildren and adults. Potentially improved outcome inchildren �10 yrs of age, although numbers were toosmall to determine true differences.

Fanconi et al.(3), 1988

Prospective, randomized clinical trial of 25 patientstreated with placebo or 1 mg�kg�1�day�1 � 3 days.Endogenous free cortisol and 6-month GOS weredetermined.

II Steroid treatment resulted in no difference in ICP, CPP,or outcome. Steroid treatment significantly suppressedendogenous free cortisol and increased infection rate.

Gobiet (4), 1977 Retrospective review of 205 children who received “high-dose” dexamethasone vs. no steroids. The earlynontreated group was from 1972 to 1974; the treatedgroup was the later, more aggressively treatedpopulation with ICP monitors in treatment ofintracranial hypertension.

III No difference in acute variables or outcome, althoughthere was a suggestion of decreased mortality rate inthe treated group.

Group INo ICP Monitoring or Steroids

Group IIICP Monitoring and Steroids

Number 139 66Died 58 10

% mortality 41.7% 15.8% (p �.001)

Reference Description of StudyDataClass Conclusion

Gobiet (5), 1977 Retrospective review of 100 patients using no steroids,normal dose steroids, and “high-dose” steroids indiffering doses. The different treatment regimens werenot specifically delineated, nor was the relationshipbetween the use of other therapies. Only acutemeasures were performed.

III There was no difference in outcome. Steroids reducedbrain edema, but there were no data confirming this.

Hoppe et al.(6), 1981

Case series of 22 patients maximally treated with aconglomeration of regimens.

III Younger patients had a better outcome.

Age, yrs GOS 1–3 GOS 4–5 % Good Outcome

�20 3 19 86�20 9 14 61

Total 12 33

Reference Description of StudyDataClass Conclusion

James et al.(7), 1979

Case control study of nine patients. Group 1 received noor low-dose steroids, and group 2 received high-dosesteroids. Neurologic exam and 6-month GOS weredetermined.

III No improved long-term outcome based on GOS due tolow numbers, although reported improved GCS, meanICP and ICP wave fluctuations, acute neurologic exam,and ICU and hospital course in the acute period.

Group GOS 1–3 GOS 4–5 % Good Outcome

Group 1, no or low-dose steroids (n � 4) 3 1 25Group 2, high-dose steroids (n � 5) 0 5 100

Total 3 6

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ence between the groups on other vari-ables measured, one might fairlyconclude that the addition of an aggres-sive treatment protocol with ICP moni-toring may reduce mortality rate.

Gobiet et al. (5) reported on the studyof 100 patients, including 40 children,but there was no separate report of re-sults in the pediatric group. The authorsreviewed their experience with ICP mon-itoring, hyperosmolar therapy, and treat-ment with or without high-dose steroidsin two consecutive patient groups. Theearlier patients in the series (1973–1974)all had ICP monitoring and a “standard”therapeutic regimen. The later patients(1975) received steroids in addition to theprevious therapies. No conclusion for theuse of dexamethasone in pediatric TBIcan be drawn from this study because thedata for children are confounded withadult measures.

Hoppe et al. (6) reported a case seriesof 22 patients �19 yrs of age who re-ceived intensive therapy in a multiple-treatment regimen including steroids,barbiturates, and hyperventilation. Thesteroid treatment was dexamethasone120 mg, given at admission, 6 and 72 hrsafter injury, combined with 4 mg every 6hrs. They reported outcomes measuredby 3- and 6-month GOS. Their only con-clusion with regard to children was thatyounger patients had better outcomes,but the authors did not report a specificrelation of outcome to the use of dexa-methasone.

James et al. (7) reported a retrospec-tive case series of nine pediatric patientswith severe TBI. Group 1 received no orlow-dose steroids (dexamethasone � 0.25mg·kg�1·day�1), and group 2 receivedhigh-dose steroids (1 mg/kg every 6 hrsfor two doses and then 1 mg·kg�1·day�1).

The children otherwise received standardtreatment for severe TBI. Outcome wasdetermined by their course and length ofstay in the intensive care unit and in thehospital and 6-month GOS. The authorsconcluded that steroids improved Glas-gow Coma Scale (GCS) and neurologicexam by 7-days postinjury, shortened in-tensive care unit and hospital stay, anddecreased mean ICP and ICP wave fluc-tuations. There was no increase in gas-trointestinal hemorrhage or in pulmo-nary infection. There was no significantdifference in GOS outcome at 6 months,although group 2 tended to have betteroutcomes.

Kloti et al. (8) performed a prospec-tive, randomized clinical trial in 24 se-verely head-injured children. Group 1 re-ceived steroids at 1 mg·kg�1·day�1, andgroup 2 received no steroids. The chil-dren were otherwise treated with stan-

Table 1. Continued

Reference Description of StudyDataClass Conclusion

Kloti et al. (8),1987

Prospective, randomized clinical trial of 24 patients. Group1 received dexamethasone (1 mg�kg�1�day�1), and group2 received no steroids. Urinary-free cortisol in the acuteperiod and 6-month GOS were used for outcome.

IIA There was near complete suppression of endogenouscortisol, and no difference in long-term outcome.

Group GOS 1–4 GOS 5% GoodOutcome

Group 1, steroids 1 (n � 12) 3 9 75Group 2, no steroids 2 (n � 12) 4 8 67Total 7 17

Reference Description of StudyDataClass Conclusion

Kretschmer (9),1983

Retrospective review of 107 patients, 51 of whom receiveda loading dose of dexamethasone, 20–25 mg, and thenreceived a dosing based on whether body weight was �or �35 kg (not based on a mg/kg schedule), inconjunction with standard therapy. This series includedpenetrating injuries, mild to moderate head injuries, aswell as differences in severity between treated andnontreated groups.

III There was lowered mortality rate in the steroid group inpatients with intracranial hematomas and severeinjuries (GCS 5–7), although the small numbersprecluded conclusion of efficacy.

IntracranialHematomas

% ofPatients GCS 5–7

% ofPatients

Group 1 (steroids)Favorable 15 88.2 14 63.6Unfavorable 2 11.8 8 36.4Mortality 2 11.8 3 13.6

Group 2 (no steroids)Favorable 11 57.8 9 60Unfavorable 8 42.1 6 40Mortality 7 36.8 5 33

GOS, Glasgow Outcome Scale; ICP, intracranial pressure; CPP, cerebral perfusion pressure; GCS, Glasgow Coma Scale; ICU, intensive care unit.

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dard therapy. In this study, outcomemeasures included urinary-free cortisolto assess cortisol excretion as well asfunctional outcome using the 6-monthGOS. There was no difference betweenthe two groups with regard to mean ICPstay, duration of intubation, or 6-monthGOS. In group 1, there was completeendogenous cortisol suppression. Ingroup 2 patients, free cortisol was in-creased 20-fold from normal basal condi-tions, reaching maximum levels at 1–3days after injury. In addition, 50% of pa-tients in group 1 developed pneumoniacompared with only 15% in group 2.

Kretschmer (9) reported a retrospec-tive review of 107 head-injured pediatricpatients with a pathologic finding oncomputed tomography scan, 51 of whomreceived steroids. Dexamethasone wasgiven as a bolus (20–25 mg) and then asan infusion based on body weight (aboveor below 35 kg). The patients otherwisereceived standard treatment for severeTBI. The two groups differed signifi-cantly: a) the study included 29 patientswith penetrating injuries, 24 of whomwere in the no-steroid group; b) for con-tusive injury, 29 of 42 patients weretreated with steroids; c) mild to moderatehead injuries (GCS 8–15) were includedbut not equally distributed in assign-ment, resulting in different average se-verity in the treated and nontreatedgroups (mean GCS of 7.4 vs. 9, respec-tively). Outcome was measured by theGOS, but length of follow up was not

reported. Although the overall mortalityrate between groups did not differ (24%vs. 23%, treated vs. untreated, respective-ly), the authors concluded that steroidtreatment reduced mortality rate in pa-tients with intracranial hematomas(36.8% vs. 11.8%) and in those with ini-tial GCS 5–7 (33% vs. 14%). Dexameth-asone, however, was not useful in themost severely injured patients (GCS3–4), the mild and moderately injured, orthose with penetrating injuries. Becausethe groups were not evenly balanced onmechanism of injury or severity, conclu-sions on the efficacy of using steroids inpediatric TBI cannot be drawn from thisstudy.

V. SUMMARY

The majority of available evidence in-dicates that steroids did not improvefunctional outcome in pediatric patientswith severe TBI. A few studies reportedbeneficial effect on outcome, but they allhad design problems, so recommenda-tions for steroid use cannot follow fromtheir results. In addition, there were asmany studies that were inconclusive orlacking any evidence of efficacy. A fewstudies did not show evidence of compli-cations from steroid use, but two othersreported significantly increased rates ofinfection (bacterial infections and pneu-monia) and suppression of endogenouscortisol, which further lessens any enthu-siasm for the use of this treatment. Withthe lack of sufficient evidence for benefi-cial effect and the potential for increasedcomplications and suppression of adrenalproduction of cortisol, the routine use ofsteroids is not recommended for childrenfollowing severe TBI.

VI. KEY ISSUES FOR FUTUREINVESTIGATION

Efficacy

Despite the lack of sufficient clinicalevidence of efficacy, there may be sub-groups of children with severe TBI whomight benefit from the use of high-dosesteroids in treatment. Examples of candi-date conditions are certain types of pa-thology (like diffuse swelling or intracra-nial hematomas), different levels ofseverity (moderately severely injured,GCS 5–7), and age at injury (school-agechildren). Further experimental and clin-

ical studies that use high-dose steroidswith stratification of these variablesamong the comparison groups will benecessary before recommendations fortreatment can be made.

Complications

Future trials also will need to addressthe issue of complications, specifically in-fection and gastrointestinal hemorrhage,and whether preventive interventions(e.g., antibiotics and/or H2 blockers) areeffective in reducing or eliminating oc-currences.

Endogenous Cortisol

There is evidence that endogenouscortisol production is suppressed withthe administration of corticosteroids fol-lowing severe TBI. The significance of thesuppression of endogenous cortisol pro-duction and its effect on clinical courseand outcome, as well as the effect of anincreased catabolic response, needs to beanswered.

REFERENCES

1. Bullock R, Chesnut RM, Clifton G, et al:Guidelines for the management of severe trau-matic brain injury. J Neurotrauma 2000; 17:451–553

2. Cooper PR, Moody S, Clark WK, et al: Dexa-methasone and severe head injury. J Neuro-surg 1979; 51:307–316

3. Fanconi S, Kloti J, Meuli M, et al: Dexameth-asone therapy and endogenous cortisol pro-duction in severe pediatric head injury. Inten-sive Care Med 1988; 14:163–166

4. Gobiet W: Advances in management of severehead injuries in childhood. Neurochirurgica1977; 39:201–210

5. Gobiet W: Monitoring of intracranial pressurein patients with severe head injury. Neuro-chirurgica 1977; 20:35–47

6. Hoppe E, Christensen L, Christensen KN: Theclinical outcome of patients with severe headinjuries, treated with high-dose dexametha-sone, hyperventilation and barbiturates. Neu-rochirurgica 1981; 24:17–20

7. James HE, Maudauss WC, Tibbs A, et al: Theeffect of high dose dexamethasone in childrenwith severe closed head injury. Acta Neuro-chir 1979; 45:225–236

8. Kloti J, Fanconi S, Zachmann M, et al: Dexa-methasone therapy and cortisol excretion insevere pediatric head injury. Childs Nerv Syst1987; 3:103–105

9. Kretschmer H: Prognosis of severe head inju-ries in childhood and adolescence. Neuropedi-atrics 1983; 14:176–181

W ith the lack of

sufficient evi-

dence for bene-

ficial effect and the potential

for increased complications

and suppression of adrenal

production of cortisol, the

routine use of steroids is not

recommended for children

following severe traumatic

brain injury.

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APPENDIX: LITERATURE SEARCH STRATEGIES

SEARCHED MEDLINE AND HEALTHSTAR FROM 1966 TO 2001

Chapter 16. Steroids

1. exp craniocerebral trauma/2. head injur$.tw.3. brain injur$.tw.4. 1 or 2 or 35. exp steroids/ or “steroids”.mp.6. glucocorticoics, synthetic/ or “synthetic glucocorticoids”.mp.7. 5 or 68. 4 and 79. limit 8 to (newborn infant �birth to 1 month� or infant �1 to 23 months� or preschool child �2 to 5 years� or

child �6 to 12 years� or adolescence �13 to 18 years�)

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