I was searching through the lyrics of ELVIS songs for a quote that might be more apt for this new blog post than “It’s now or ever”, which I have used previously, when I realized that I am a loser, and I should spend more time with my kids!
The 2 year neurological and developmental outcomes of the ELVIS trial (Early vs Late Ventricular Intervention Study) have been published. Cizmeci MN, et al. Randomized Controlled Early versus Late Ventricular Intervention Study (ELVIS) in Posthemorrhagic Ventricular Dilatation: Outcome at 2 Years. The Journal of Pediatrics. 2020. Hopefully, you will remember (surely as a result of my previous ELVIS blog post) that this was a much-needed RCT comparing 2 strategies for intervening for post-haemorrhagic ventricular dilatation in preterm infants. You can imagine the importance of this study when you note that Linda de Vries, Floris Groenendaal, and Andy Whitelaw were all three involved in organizing and performing this trial. Post-haemorrhagic hydrocephalus (PHH, as I will call it from now on) has become less frequent over the years, as severe IVH has become less common, but it remains a major problem for a small number of babies.
In ELVIS, preterm infants under 35 weeks gestation who had an acute IVH with ventricular dilatation followed by progressive ventricular dilatation, were randomized to either of 2 approaches; in the early group:
treatment was started after the Ventricular Index had crossed p97 (97th percentile) but before crossing the p97+4 mm line, the Anterior Horn Width was >6 mm but <10 mm and/or the Thalamo-Occipital Distance was >25 mm. Intervention started with LPs (max 3), and if necessary, followed by insertion and taps from a Ventricular Reservoir, aiming for VI<p97 over the next 7–10 days.
In the late treatment group, the same sorts of interventions were performed, but they started when the ventricular index was greater than the 97th percentile + 4 mm, and the anterior horn width was over 10mm. This later threshold was based on old observational data, from Malcolm Levine I believe, that showed that once you passed this threshold progressive hydrocephalus was frequent. It had become a sort of default standard of care without any good data that it was the best indication for intervention.
In both groups, if a reservoir was inserted, it was tapped regularly
Ten mL/kg were removed once or twice a day, the volume adjusted according to cranial US. When taps from a reservoir were still needed 28 days after insertion to keep the ventricular index well below the p97+4 mm, one or two ‘challenges’ were performed with discontinuation of taps. Reservoir taps were resumed in case of expanding ventricles, clinical symptoms and/or excessive head growth. Taps were continued until infant’s weight reached 2000–2500 g and according to unit protocol, the protein had decreased to <1.5 g/L and erythrocytes <100/mm3, at which stage the infant became eligible for a VP shunt.
The primary outcome for the early phase of the study was whether or not you survived without needing a shunt.
As you might imagine, the early treatment group had many more LPs; and needed many more reservoirs, 40/64 compared to 27/62. They did not, however, need more VP shunts, in fact, slightly fewer shunts were needed with early treatment, 12 vs 14.
Of course what we really want to know is the long term outcomes, if they had been similar, then less intervention could be considered to always be a good thing, but if there was a difference between groups, then the increased need for intervention in the early group should be weighed against the outcomes. The 2 year follow up study analyzed outcomes from about 90% of survivors, so is a reliable indication of what outcomes to expect with these approaches.
Bayley scores were better with earlier intervention, and there was less cerebral palsy; there was a relatively small sample size, and therefore the differences shown may have been random effects. This figure suggests that, among those needing shunts, the differences were greater than could be expected by random variation.
Adjusted analyses showed that early intervention seemed to be associated with a decreased risk of an adverse outcome after correcting for gestational age, the severity of intraventricular haemorrhage and cerebellar haemorrhage (adjusted odds ratio: 0.24, 95% confidence interval [CI], 0.07 to 0.87. In this situation, I think adverse outcome means death, or cerebral palsy, or a Bayley version 3 motor or cognitive composite score more than 2 SD below the mean.
It is interesting that in the early treatment group 94% of the cognitive scores were above -2SD with early treatment, and 87% with later treatment. The large majority of preterm infants with PHH who were enrolled in this trial, therefore, did NOT have cognitive delay! There is obviously a great deal of selection that goes on before an infant would be randomized in a trial such as this, but good outcomes of PHH are not rare! Motor scores were more severely affected than cognitive scores, but were also somewhat better in the early treatment group.
The clinical implications of this trial to me are that PHH should be treated according to the early intervention thresholds in ELVIS. The differences in outcomes are not enormous, but all favour earlier intervention. The only advantage of waiting until the later thresholds are crossed is that there are fewer lumbar punctures and fewer reservoirs, but no reduction in permanent shunts. I also think the study confirms that the Levine thresholds from many years ago were reasonable, and, I think should now be considered to be late treatment. Once the late treatment thresholds are reached intervention becomes urgent and should not be further delayed, unless there is an understanding with the parents that interventions will be limited. If we are aiming for the best possible long term outcomes, then the early treatment thresholds of ELVIS should be followed.
Otherwise, we may be accompanying ELVIS singing “Maybe its too late, I sometimes even hate myself…”