Although we have a great group of ENT surgeons at my hospital, we do have one bone of contention; at least, there is just one bone left since they have agreed that you cannot diagnose reflux by performing a laryngoscopy! See my post : you-cant-diagnose-reflux-with-a-laryngoscope/ The other issue is that when they see a patient at high risk for post-extubation laryngeal oedema and re-intubation risk they often request that we administer dexamethasone, and usually in industrial doses.
I have numerous questions about this practice,
- do steroids have clinical benefit in neonatal patients at risk of post-extubation stridor and re-intubation?
- is dexamethasone preferable to other steroids?
- what dose should we use?
Although this is a frequent practice, there are very few good data. A Cochrane review from 2009 (Khemani RG, et al. Corticosteroids for the prevention and treatment of post-extubation stridor in neonates, children and adults. Cochrane Database Syst Rev) by the Cochrane Airways Group found 6 adult (n=2000), 3 paediatric (n=206), and 2 neonatal trials (n=104), with variable steroid doses. A more recent systematic review in adults found another 6 trials, and a recently published protocol for a paediatric RCT refers to 2 more recent small paediatric trials. I haven’t found any more recent neonatal trials, but the Cochrane review from the neonatal group included additional data from an earlier trial, for which the extubation data were only ever published as an abstract, and which included an additional 52 babies.
The steroid types and doses that were used in the adult studies vary between 100 mg of hydrocortisone, to two 40 mg doses of methylprednisolone, to a single 5 mg dose of dexamethasone to a maximum of 5 mg of dexamethasone every 6 h, 4 times. The latter of the adult systematic reviews divided the trials into those among high-risk patients (determined by a cuff leak test), and unselected patients. They showed a reduction in re-intubation among high-risk patients and performed a meta-regression to examine the effects of steroid dose, which they counted according to “hydrocortisone equivalents”. That analysis showed no impact of the dose of steroid on their efficacy in reducing the need for re-intubation, the lower doses were just as effective as the highest dose.
The studies in children (after the neonatal period) again used different doses, all of dexamethasone, the doses varied from 0.5 mg/kg one dose (maximum of 8 mg), 0.5 mg/kg one dose (maximum of 10 mg), 0.5 mg/kg given q6h for 3 or for 6 doses, all those studies were in children without identified increased risk. The only study in high-risk paediatric patients used 0.5 mg/kg q6h x 3, and doesn’t state a maximum dose, it actually showed no major benefit of dexamethasone in a small RCT (n=23).
The 3 neonatal trials used doses of 0.25 mg/kg once, 0.5 mg/kg once and o.25 mg/kg 3 times q8h. In terms of our discussion for today, only one of those trials is relevant; two of them were in larger preterm infants with no airway concerns and were studying the routine use of dexamethasone for prevention of re-intubation after at least 48 to 72 hours of intubation. The only relevant study is from 1992, studied 50 preterm infants considered at high risk for airway compromise, and showed a reduction in re-intubation from 0/27 to 4/23, (RR=0.1, 95% 0.01-1.7) that study used the highest of the 3 cumulative doses.
What then is the scientific evidence-based answer to our 3 questions?
- Do steroids have clinical benefit in neonatal patients at risk of post-extubation stridor and re-intubation?
For neonatal patients specifically, and in those whom you would consider treating, i.e. with previous extubation failures and/or known airway problems, the answer has to be “not proven”. The tiny amount of directly relevant data precludes an evidence-based answer. In older children there is similarly very little data.
2. Is dexamethasone preferable to other steroids?
Neonatology: only dexamethasone ever studied. Paediatrics: only dexamethasone ever studied. In adults dexamethasone and methylprednisolone have been studied in higher-risk patients, hydrocortisone only studied in standard-risk patients. The answer then is
3. what dose should we use?
Again the evidence-based answer is that there is no evidence, but in adults lower doses are as effective as higher doses.
The doses used in neonatal studies, and suggested for ENT use in clinical practice in my experience, are enormously higher than those shown to be effective in adults. A 5 mg total dose for an adult could be anywhere between 0.1 mg/kg and 0.02 mg/kg, to use a reasonable range of adult weights. The highest dose regime ever studied in adults gave 20 mg/day of dexamethasone, or a maximum of 0.5 mg/kg/day in a tiny 40 kg adult. The average per kg dose of this extremely high dose regime would be about 0.25 mg/kg/day divided into 4 doses if your adults average 80kg. In adults the variety of doses studied, all much lower than neonatal doses, showed no correlation between dose given and efficacy. Indeed among trials studying high-risk adults, the relative benefit was almost identical regardless of the dose used.
There is very little surveillance for adverse effects reported in the RCTs. Some of the adult trials have reported low rates of hyperglycaemia and of GI bleeding, but those, of course, used much lower doses.
The data from adult studies suggests a benefit of steroids for post-extubation laryngeal oedema; if I were to put money on it, I think it is likely there is some benefit in reducing post-extubation laryngeal oedema in neonates and probably reducing some clinical impacts, whether they are effective enough to prevent some re-intubations is impossible to say.
Many of the babies that I see who have serious upper airway problems, and for whom we consider dexamethasone for extubation, have already received steroids, sometimes more than one course and occasionally over a prolonged period. Adding another blast of extremely high doses of this medication, associated with significant long term worse outcomes, is often very worrying. Dose matters (Wilson-Costello D, et al. Impact of Postnatal Corticosteroid Use on Neurodevelopment at 18 to 22 Months’ Adjusted Age: Effects of Dose, Timing, and Risk of Bronchopulmonary Dysplasia in Extremely Low Birth Weight Infants. Pediatrics. 2009:peds.2008-1928), this study from the NICHD network showed the following, referring to postnatal dexamethasone use in very preterm babies:
Each 1 mg/kg dose was associated with a 2.0-point reduction on the Mental Developmental Index and a 40% risk increase for disabling cerebral palsy.
In summary, there is very little good relevant evidence, but to give my best-guess clinical implications of this review:
- steroids might be effective in reducing upper airway oedema after extubation in newborn infants at high risk of airway compromise, and could possibly reduce extubation failures,
- any steroid with glucocorticoid action might be equally as effective,
- there is no evidence to support the enormous doses that are often prescribed.
I would suggest that a dose similar to the DART starting dose of 0.15 mg/kg/day of dexamethasone is still well within the range of doses shown to be effective in adults, and can be stopped very quickly after extubation if there are few signs of airway compromise.
The less we give the better: reducing the dose, shortening the duration, and targeting the babies most likely to benefit are essential.
Could not agree more with the last sentence – thank you for tackling another gray area of practice with no good evidence!