Tuesday March 9 2010
Very premature babies can have brain bleeds
“A technique that ‘washes out’ the brains of severely ill premature babies may aid survival,” says the BBC. The article says that the treatment, called DRIFT (drainage, irrigation and fibrinolytic therapy), could help around 100 babies per year.
The research behind the news looked at whether DRIFT could reduce the risk of death and disability in premature infants that had a type of bleeding that enlarged the fluid-filled spaces in the centre of the brain. This condition is very serious and can lead to death or severe disabilities such as cerebral palsy. Although DRIFT was associated with more secondary bleeding than standard care, subsequent follow-up showed that DRIFT reduced the proportion of infants that died or had severe disabilities by the age of two. The researchers suggest that modifications to the DRIFT process used in the trial could reduce the risk of second bleeds.
Overall, this study suggests that the DRIFT technique could help premature babies with this very serious condition. Further studies should look at whether modifications to the technique can, as claimed, reduce the risk of second bleeds while maintaining the benefits seen in this study.
Where did the story come from?
Dr Andrew Whitelaw and colleagues from the University of Bristol, Frenchay Hospital in Bristol, and research centres in Poland carried out this research. The study was funded by the Cerebra charity and the James and Grace Anderson Trust. The study was published in the peer-reviewed journal Pediatrics.
The Daily Mail, Daily Express and BBC News have covered this study. The BBC provides the most detailed coverage of the study, and reports the findings accurately. The Mail and Express concentrate on the story of one boy who took part in the trial.
What kind of research was this?
This was a randomised controlled trial comparing DRIFT (drainage, irrigation and fibrinolytic therapy) with the standard care for premature infants with a dangerous condition called posthemorrhagic ventricular dilatation (PHVD).
PHVD is caused by bleeding into the fluid-filled spaces in the centre of the brain (ventricles) that causes them to expand, putting pressure on the brain. Bleeding occurs due to the fragile, immature blood capillaries in the premature baby’s brain being unable to withstand changes in blood flow and pressure in the brain following birth. Babies at the greatest risk of PHVD are those who are more severely premature (born at less than 32 weeks) or of very low birth weight.
Developing PHVD as a baby can lead to serious cognitive, motor, and sensory disability, for example the development of cerebral palsy. The DRIFT technique is designed to reduce the excess pressure and build-up of leaked blood in the ventricles soon after bleeding, and aims to reduce the chances of brain damage and death from PHVD. The technique involves draining excess fluid and replacing it with artificial cerebrospinal fluid containing antibiotics while maintaining a steady, normal pressure in the ventricles.
This was a randomised controlled trial, the best way of comparing the effects of two treatments. Randomly assigning individuals into groups (randomisation) is the best way to ensure that the groups are well balanced for factors that could affect results. However, when the numbers of individuals randomised is small, such as in this study, randomisation may not work that well. In these situations researchers should check key factors to make sure that they are balanced, a step that was performed in this study.
What did the research involve?
The researchers recruited 77 preterm infants with bleeding into their ventricles: 54 from Bristol, 20 from Katowice in Poland, two from Glasgow and one from Bergen in Norway. Eligible infants whose parents agreed to participate were randomly assigned to receive either DRIFT or standard care (39 in DRIFT group, 38 in standard care). The infants were then followed up for two years to determine if they survived and whether they had any cognitive, motor or sensory disabilities.
Infants were eligible if they were no more than 28 days old, had been diagnosed with bleeding into their ventricles with ultrasound and showed progressive enlargement of the ventricles in both hemispheres of the brain.
Standard care was to not offer any intervention unless the infant showed signs of having raised pressure within the brain (such as irritability, persistent vomiting or reduced consciousness), or if the infant showed excessive head enlargement (over 2mm expansion in a day). If infants showed these signs, they were given a lumbar puncture to release cerebrospinal fluid and reduce pressure in the brain. The process was repeated as needed.
Treatment with DRIFT involved inserting tubes (catheters) into the ventricles and injecting an anticlotting agent to prevent blockage of the catheters with blood clots. The catheters were used to drain bloody fluid from ventricles and replace it with artificial cerebrospinal fluid containing antibiotics, while maintaining a steady normal pressure in the ventricles. Treatment with DRIFT was administered until the fluid being drained became clear, indicating that all leaked blood had been removed. Treatment with DRIFT continued for an average (median) of three days. If enlargement of the ventricles and excessive head growth did not stop in infants who had received DRIFT, they also received lumbar puncture.
In clinical trials such as this, there is often an external safety monitoring group that looks at the ongoing results of the trial to determine if the treatments being administered are safe. If they judge that the treatments are not safe, they can stop the trial. The safety monitoring group stopped the DRIFT trial because there was an increase in secondary bleeding into the ventricles in the DRIFT group. While DRIFT treatment was discontinued, the children in the study were still followed up to see what their outcomes were.
The children were assessed at an average of 25 months after their expected delivery date. The researcher assessing them did not know whether they had received DRIFT or standard care. The assessment used a standard scale to assess cognitive ability and development. Severe sensory and motor disabilities were defined as:
- inability to walk
- inability to walk unaided
- inability to sit without support
- inability to control head without support
- inability to use hands to feed self
- blindness or only light perception
- hearing loss uncorrected by hearing aid
- inability to communicate by speech
The researchers then compared the overall rate of death or severe disability between the group that received DRIFT and the group that received standard care. They carried out unadjusted analyses, as well as analyses that took into account how child gender, birth weight and severity of bleeding may have affected the results.
What were the basic results?
The researchers found that the DRIFT group and standard care group were similar, except that:
- there were more boys in the DRIFT group than the standard care group (29% vs. 24%)
- the DRIFT group had slightly lower birth weight (1050g vs. 1130g)
- babies in the drift group were born slightly earlier (27 weeks vs. 28 weeks)
- the DRIFT group had a greater proportion with the most severe bleeds, which have a very high mortality and complication rate (grade IV bleeds: 20% vs. 18%)
The researchers were able to assess what happened to all 77 children enrolled in the trial.
- Three children in the DRIFT group and five children in the standard care group had died before the age of two.
- Eighteen of the DRIFT group and 22 children in the standard care group had severe disabilities (cognitive, motor or sensory) by the age of two.
- This equated to 51% of the DRIFT group and 71% of the standard care group either dying or becoming severely disabled by the age of two. This difference was statistically significant once gender, birth weight and severity of bleeding into their ventricles were taken into account (odds ratio 0.25, 95% confidence interval 0.08 to 0.82).
Survivors in the DRIFT group were less likely than those in the standard care group to have severe cognitive disabilities at the age of two (31% vs. 59%). There was a trend for lower rates of individual sensory/motor disabilities in the DRIFT group, but this difference did not reach statistical significance.
How did the researchers interpret the results?
The researchers concluded that, “despite an increase in secondary intraventricular bleeding, DRIFT reduced severe cognitive disability in survivors and overall death or severe disability”.
This small study suggests that, compared to standard care, DRIFT reduces the risk of the combined outcome of death or severe disability in premature infants with enlargement of the ventricles in the brain due to bleeding. There are a number of points to note:
- The study was relatively small, with 39 children in the DRIFT group and 38 in the standard care group. The trial was also stopped early due to safety concerns. The researchers note that these factors mean the results should therefore be interpreted cautiously.
- While larger studies are preferable, the severity of the condition, its relatively uncommon nature and the difficulties associated with carrying out trials in infants mean that larger studies may not be feasible.
- There were some differences between the groups at the start of the study, but the researchers took these into account in their analyses. However, there could be other unmeasured differences between the groups that could have affected the results.
- The researchers believe that the increase in secondary bleeds into the ventricles with DRIFT treatment was likely to be caused by the use of an anticlotting agent called tPA. They say that if DRIFT is used in future that they would not recommend using this anticlotting agent routinely, but would only use it if there was a need to clear a clot blocking the drainage tubes.