The DRIFT Trial
The DRIFT Trial
Drainage, irrigation and fibrinolytic therapy for post-hemorrhagic hydrocephalus in newborn infants
Trial Protocol Version 1.8 January 12th 2005
Andrew Whitelaw, Professor of Neonatal Medicine, University of Bristol
Ian Pople, Consultant Paediatric Neurosurgeon, Frenchay Hospital, Bristol
Dr David Evans, Consultant Neonatologist, Southmead Hospital, Bristol
Dr Martin Simmonds, Consultant Neonatologist, Southmead Hospital, Bristol.
Dr Neil Stoodley, Consultant Paediatric Neuroradiologist, Frenchay Hospital
Dr Jolanta Wroblewska (Neonatologist) and Dr Marek Mandera, (Paediatric Neurosurgeon), Upper Silesian Maternal & Child Health Centre, Katowice, Poland.
Dr Judith Simpson (Neonatologist), Mr Robert Carachi, Mr Alasdair Fyfe and Mr Constantinos Hajivassiliou (Paediatric Surgeons), Dr Andrew Watt (Paediatric Radiologist) Royal Hospital for Sick Children, Glasgow.
Statistical adviser: Dr Linda Hunt, Clinical Science (South Bristol), University of Bristol.
Professor Andrew Whitelaw, Department of Clinical Science North Bristol, University of Bristol Medical School, Southmead Hospital, Bristol BS10 5NB.
+44 117 959 5699
Fax +44 117 959 6105
We gratefully acknowledge grant support from Cerebra and the James and Grace Anderson Trust.
Hemorrhage into the ventricles of the brain is one of the most serious complications of premature birth despite improvements in the survival of premature infants. Large intraventricular hemorrhage (IVH) has a high risk of neurological disability and over 50 % of these children go on to develop progressive ventricular dilatation1. Murphy et al 2 have provided evidence that posthemorrhagic ventricular dilatation (PHVD) in the 1990s has a more aggressive course than previously with appreciable mortality and morbidity in extremely premature infants. Treatment is much more difficult than other types of hydrocephalus because the large amount of blood in the ventricle combined with the small size and instability of the patient make an early ventriculoperitoneal shunt operation impossible. A period of repeated lumbar or ventricular reservoir tapping may be followed after many weeks by shunt surgery. There is a considerable complication rate from such surgery and the child is permanently dependent on the shunt system. Treatment by repeated lumbar or ventricular tapping and the use of acetazolamide and furosemide to reduce CSF production do not reduce the need for shunt surgery, do not improve neurological outcome and have appreciable adverse effects 3, 4.
We have documented that tissue plasminogen activator (tPA) 5 and fibrin degradation products 6 are present in post-hemorrhagic CSF but we have also demonstrated that plasminogen concentrations are very low 7 and plasminogen activator inhibitor - 1 (PAI-1) is present in high concentrations 8. Phase 1 clinical trials of intraventricular fibrinolytic therapy treatment 9-11 and a small randomised trial 12 have not given encouraging results when intraventricular fibrinolytic therapy is started 2 - 4 weeks after the IVH by which time the infant is already developing hydrocephalus.
Multiple blood clots may obstruct the ventricular system or channels of reabsorption initially, but lead to a chronic arachnoiditis of the basal cisterns involving deposition of extracellular matrix proteins in the foramina of the fourth ventricle and the subarachnoid space 13. Transforming growth factor beta (TGFb) is likely to be a key mediator of this process as TGFb is involved in the initiation of wound healing and fibrosis 14. TGFb elevates the expression of genes encoding fibronectin, various types of collagen 15, 16 and other extracellular matrix components 17.
TGFb is elevated in the CSF of adults with hydrocephalus after subarachnoid hemorrhage and intrathecal administration of TGFb to mice resulted in hydrocephalus 18, 19. We have demonstrated that CSF from infants with posthemorrhagic ventricular dilatation has TGFb concentrations which are 10 to 20 times those of non-hemorrhagic CSFs and that the concentration of TGFb in CSF is predictive of later shunt surgery 20. Intraventricular blood may have adverse effects on the immature periventricular white matter by a variety of mechanisms including elevated CSF pressure 21, free radical generation facilitated by free iron 22 and inflammation 23.
Adults with intraventricular hemorrhage have been treated by early ventricular drainage combined with intraventricular recombinant tPA 24, 27. The most recent published study 27 describes 20 adult patients with IVH and impaired consciousness or coma. In 9 patients hemorrhage was from a ruptured aneurysm, in 5 there was hypertensive brain hemorrhage, in 4 there was arteriovenous malformation and in 2 the aetiology was unknown. Continuous ventricular external drainage was established through a frontal approach. 2 to 5 mg of tPA was injected via the ventricle and the drain was then clamped for two hours. The ventricular catheter was then opened to drain with no resistance. The intraventricular tPA was repeated every 24 hours until there was a reduction in haematoma size and the third and fourth ventricles were clear of blood on CT scan. The ventriculostomy drain was removed after a mean duration of 23 days. One died and eleven of the 20 eventually needed a ventriculoperitoneal shunt. All four of the anecdotal reports of intraventricular fibrinolytic therapy in adults have described mortality much lower than historical controls ( e.g. 5 % v 60 - 91 %).
Clearly IVH in adults is very different from IVH in premature infants with respect to aetiology and also likelihood of raised intracranial pressure but the adult experience and our previous research on this topic suggested that early drainage together with intraventricular fibrinolytic therapy should be tried in premature infants with large IVH. In order to try and remove as much blood and cytokine as possible we have combined this treatment approach with irrigation of the ventricular system with a protein-free artificial CSF.
We have piloted a new treatment aimed at removing intraventricular blood and the cytokines associated with hydrocephalus. Twenty five infants were enrolled with ventricular width enlarged to 4 mm over the 97th centile after a large intraventricular hemorrhage (IVH). Sixteen had parenchymal brain lesions before treatment. Median gestation was 28 weeks and birthweight 1150g. At a median postnatal age 17 days, two ventricular catheters (one right frontal, one left occipital) were inserted with 13 infants also having a reservoir frontally. Tissue Plasminogen Activator
0.5 mg/kg was given intraventricularly 8 hours before the ventricles were irrigated with artificial cerebrospinal fluid at 20 ml/hour for a median of 72 hours.
Eighteen of 24 survivors (75%) did not require a ventriculoperitoneal shunt. One infant (of 23 weeks gestation) died. Two infants developed reservoir-associated infection and two infants had a second IVH. Of the 19 survivors aged >12months post term, 8 were normal, 7 had single disability (37%) and 4 (21%) had multiple disabilities.
Shunt surgery was reduced compared to historical controls with similar treatment criteria. Mortality and single and multiple disability rates all showed downward trends. Reducing pressure, free iron and pro-inflammatory and pro-fibrotic cytokines may reduce periventricular brain damage and permanent hydrocephalus. Now is the time to test this treatment approach in a controlled trial.
i) In newborn infants with post-haemorrhagic ventricular dilatation, treatment by drainage, irrigation and fibrinolytic therapy (DRIFT) reduces the percentage of infants die or who require a permanent ventriculoperitoneal shunt.
ii) In newborn infants with post-haemorrhagic ventricular dilatation, treatment by drainage, irrigation and fibrinolytic therapy (DRIFT) reduces disability at 2 years (corrected age) when compared to conventional therapy with lumbar puncture and selective use of ventricular tapping. Disability is defined as cerebral palsy, Mental development index <70, epilepsy (recurrent seizures despite regular anticonvulsant therapy), blindness (visual acuity < 0.3) or deafness (bilateral sensorineural hearing loss not corrected by hearing aids)
iii) DRIFT, when compared to conventional therapy, does not increase the percentage of infants with secondary intraventricular haemorrhage or CNS infection.
iv) DRIFT decreases feeding problems and poor growth (weight < 2SD) at 24 months.
v) DRIFT reduces the number of shunt revisions and the number of admissions for shunt problems before 24 months.
vi) DRIFT reduces visual problems at 2 years. The definition of visual disability at 2 years includes subnormal acuity (<0.3), abnormal refraction, strabismus and any field defect detectable at 2 years.
vii) DRIFT reduces hearing loss which is defined as bilateral sensorineural deafness requiring hearing aids at 2 years or profound hearing loss which cannot be corrected by hearing aids.
viii) DRIFT reduces the need for long-term anticonvulsant therapy.
ix) DRIFT, when compared to conventional therapy, increases white matter and grey matter volume at term (measured by MRI). This will only be possible on a subset of infants because not all centres can carry out this investigation.
1. Inclusion criteria:
i) Intraventricular haemorrhage documented on ultrasound.
ii) Age less than 28 days.
iii) Progressive dilatation of the each lateral ventricle defined as:
i) ventricular width 4 mm over the 97th centile of Levene28.
OR ALL THREE OF THE FOLLOWING:
ii) anterior horn diagonal width 4 mm (1 mm over 97th centile of Davies29).
iii) thalamo-occipital distance 26 mm ( 1 mm over 97th centile of Davies29)
iv) third ventricle width 3 mm ( 1 mm over 97th centile of Davies29).
v) measurements above one of the above criteria on one side combined with obvious midline shift indicating a pressure effect.
2. Exclusion criteria:
Generalised bleeding tendency:
PT > 20 seconds
APTT > 50 seconds
Platelets < 50
An infant may become eligible if the above abnormalities are corrected.
Infants of less than 32 weeks should have at least one cranial ultrasound scan by 72 hours of age and this should be repeated weekly for 4 weeks. More frequent scanning is indicated if there are abnormal neurological signs. Infants with gestational age > 32 weeks should be scanned if there is any abnormal neurological sign e.g. seizure, hypotonia, hypertonia, poor responsiveness, bulging fontanelle, large head. Large intraventricular haemorrhage (grade III on the Papille scale) should prompt particular vigilance with regard to ventricular enlargement.
A indicates the anterior horn diagonal measurement which qualifies the infant if the measurement is 4 mm or more on each side.
B indicates the thalamo-occiptal dimension which qualifies the infant if the measurement is 26 mm or more on each side.
Information to the parents and consent.
The parents should receive a sympathetic explanation of the infant’s diagnosis and prognosis. The written information sheet approved by the Research Ethics committee must be given and can be supplemented with other relevant material if it would be helpful. This may include pictures, posters, the paper on DRIFT in Pediatrics30 and can include this protocol. If the parents are married, either parent can sign the consent form. If the parents are not a married couple, only the mother can give valid consent in the UK until the birth is registered. If the unmarried father is on the birth registration, he can then give legal consent. In our experience, it is most satisfactory for both parents to sign as this indicates that both have understood and are sharing the responsibility. There is no extreme urgency about obtaining consent. Giving information one day and reviewing the information the following day is appropriate. On the basis of our 25 pilot infants, we suspect that 28 days may be too late for DRIFT to influence the process of posthaemorrhagic hydrocephalus and that 21 days of age may be a desirable age limit. However, this is based on very limited information and 28 days remains the limit for randomisation. One copy of the signed consent should be filed in the patient’s notes, one given to the parents and one kept by the research team.
Sequentially numbered double envelopes (one envelope inside the other for security) are prepared in blocks of 8,10 or 12 with randomly allocated small sheets (one identical pair in each numbered envelope) stating “DRIFT” or “standard treatment”. Thus envelope number 1 contains a second envelope number 1 and inside the inner envelope are two small sheets giving the treatment allocation. These blocks of envelopes are obtainable from Prof Whitelaw but they can be made locally. After parental consent has been given, the infant is allocated the next number in the recruitment series and the sealed double envelope with that number is opened. These numbered envelopes are in the DRIFT randomisation file which is kept in a secure place on the NICU in each participating centre. The two identical numbered paper sheets in the envelope will state “DRIFT” or “standard treatment”. The infant’s name and hospital number should be added to the randomisation sheets. One copy of the randomisation sheet will be kept in the patient’s notes and one will be kept by the research team.
The infant’s clinical status and scans are reviewed with Mr Ian Pople or an equivalent neurosurgeon. A time for the insertion of ventricular catheters is agreed. The infant is moved to an open incubator about one hour before the agreed time. If not already intubated, this is done and intravenous anaesthesia is achieved. In Bristol 400 micrograms/kg morphine is normally used and has proved satisfactory. An equivalent dose of fentanyl may be used according to local experience and practice. This is followed by muscle relaxation with pancuronium 100 micrograms/kg. An equivalent muscle relaxation regime may be used if a particular centre has experience and confidence with it. Blood pressure, oxygenation and CO2 are normalised after muscle relaxation.
Equipment required :
Umbilical artery catheter (or equivalent) cut down pack
Size 8 sterile gloves (2 sets) and a sterile gown
4/0 nylon suture on a curved needle
Two size 5 and two size 6 side hole feeding tubes.
One 2 ml syringe, two orange skin needles,
0.5 % or more dilute lignocaine in adrenaline.
Chlorhexidine 0.5% in alcohol
Two Tegaderm patches
A disposable razor
Two 3-way taps
Prior to any surgical approach, the infant must have a pCO2 in the range 35 to 55 mm Hg (4.7 to 7.3 kPa) with SaO2 88 – 95%, temperature 36.5 – 37.0 axillary and adequate blood pressure for age. Haemoglobin should be at least 10g/dl if the infant is >14 days of age and if under 14 days or unstable, a Hb of 12 g/dl is preferable.
Ultrasound is used to estimate the depth from skin to the base of the anterior horn of the right ventricle and from the skin to the middle of the occipital horn of the left ventricle.
Hair is shaved from the right frontal area lateral to the fontanelle and over the left lambdoid suture. Chlorhexidine in spirit is applied to the planned insertion sites. Lignocaine is injected into the skin 1 cm later to the anterior fontanelle and along the left lambdoid suture
The skin is sterilised with chlorhexidine again. A very small hole in the skin is made with a scalpel blade and the arterial dilator is then inserted to the pre-estimated depth. A feeding tube is then inserted along this track using sterile forceps until CSF comes along the catheter. A 3 way tap is attached to the end of the catheter. The feeding tube is stitched in and then a loop is stitched to the skin. These procedures are shown on the digital video. The left occipital catheter is inserted in a similar way. Gauze is applied between the catheter and the skin and Tegaderm is then applied over the whole site.
The above list of equipment and description are not meant to discourage further improvement and refinement. The principles are stabilising and anaesthetising the infant and then inserting and securing two ventricular catheters with sterile technique. Anaesthetic and surgical techniques are usually improved with experience and fresh minds and we look forward to this. The choice of catheter should be up to the surgeon. We believe that the largest convenient catheter with the largest single hole is preferable.
After catheter insertion has been completed and the infant is stable, 5 ml of CSF is withdrawn into sterile containers for microbiology and protein. 2 ml of CSF should be deep frozen for future analysis or rechecking (with name and date). A Codman external ventricular drainage system (Johnson & Johnson, Piscataway, NJ, USA) is connected. This is a closed system which allows sampling and up to 70 ml to be collected in a small reservoir held on a level with the infant’s head. Below this is a larger collecting bag that can take 500 ml. All the bungs and taps in the system must be secure and water-tight.
Irrigation and tPA administration
After 1- 2 hours postoperative stabilisation, 0.5 mg/kg of human recombinant tPA (Actilyse, Boehringer Ingelheim International GmbH, Ingelheim, Germany) is injected via the 3 way tap and anterior ventricular catheter into the cerebral ventricles and left for eight hours before irrigation is started. If the CSF is already heavily blood stained, TPA may be omitted and only given later if there is catheter blockage. However, our experience is that virtually all the infants where TPA was initially omitted for that reason, blocked the drainage catheter and TPA had to be given to unblock it.
Artificial Cerebrospinal Fluid (CSF) (Torbay Pharmaceutical Manufacturing Unit, Kemmings Close, Long Road, Paignton, Devon TQ4 7TW, United kingdom) contains : Glucose 5 mmol/l, Sodium 148 mmol/l, Potassium 4.02 mmol/l, Magnesium 1.22 mmol/l, Calcium 1.36 mmol/l, Chloride 133.8 mmol/l, Phosphate 0.58 mmol/l, Sulphate 1.22 mmol/l, Bicarbonate 22 mmol/l. Vancomycin 10mg and Intrathecal Gentamicin 5mg are added to each bottle. This is infused at 20 ml/hour through a filter into the anterior ventricular catheter. The drainage reservoir marker is set initially to be at the same level as the centre of the head.
A pressure transducer is connected via a three-way tap to the input line as in the above diagram. This is carefully zeroed by opening to air at the level of the centre of the infant’s head. It is very important that the nurse understands the principles of pressure measurement. True intracranial pressure (ICP) is measured by turning the 3 way tap so that the transducer is OFF to the infusion pump and connected the head. This is the value recorded every 30 minutes. However, the fluid will not infuse with this position of the 3 way tap and therefore for infusion, the 3 way tap is turned so that the pump, transducer and head are all connected to each other. This means that the infusion pump pressure adds to the true ICP by 1-2 mm Hg. The value is displayed continuously on the monitor with the alarm set to sound if the intracranial pressure exceeded 6 mm Hg.
The volumes of fluid infused and drained are measured and written down every 30 minutes. The height of the drainage catheter is lowered or raised in order to maintain the output of fluid greater than the input and the intracranial pressure below 7 mm Hg. If the rate of drainage decreases or ICP remains above 6 mm Hg despite this, the infusion is stopped and the cause investigated. Clots in the line may cause temporarily and these can often be flushed out. Try flushing distally first before flushing proximally. Clots can be flushed back into the infant if necessary. Bubbles of air are not harmful in the cerebral ventricles. If this does not restore drainage, then the direction of DRIFT can be reversed with the IN line going in the occipital catheter and the OUT line coming from the frontal catheter. Usually a negative deficit of 50 to 100 ml per day is necessary to maintain normal CSF pressure. A sample of drainage fluid is taken every day for protein, bacteriology and microscopy.
Suspected or confirmed CSF infection with coagulase negative staphylococci is treated with intravenous vancomycin and cefotaxime while DRIFT is continued.
This may reveal itself as the infant becoming pale and starting to have abnormal movements. The fontanelle becomes tenser and ultrasound shows the ventricular lumen has become white. The haemoglobin drops after some hours. Management is to normalise pressure by drainage. Give 10 mg/kg of tranexamic acid iv to block fibrinolysis. Give a blood transfusion as necessary. As the object of the DRIFT is to mobilise blood clot within the ventricle, it can sometimes be alarming to see an increased amount of blood draining. This may mean that DRIFT is succeeding in mobilising old blood rather than provoking new bleeding. With this in mind, we have been conservative with our use of tranexamic acid as this drug blocks fibrinolysis.
Sedation during DRIFT
As ICP is maintained constant during DRIFT and the brain itself is not as sensitive to pain as most structures, we do not believe DRIFT is a painful procedure. However, we suspect that very active movement of the head while the two catheters are in place probably increases the risk of re-bleeding. Therefore we have used a continuous infusion of morphine sufficient to keep the baby sedated, but not unconscious, during DRIFT. We respect the experience of skilled nurses in assessing stress and discomfort in babies and delegate to them the decision as to whether more or less intervention is required. The nurse may find non-pharmacological means of relieving stress or discomfort in these babies. For small prematures in Bristol, DRIFT has usually meant keeping the baby intubated throughout. For larger babies, extubation has been considered before the end of DRIFT.
Irrigation is normally carried out for 72 hours but can be continued for up to a week if the CSF has not cleared from the appearance of cola to that of white wine. After stopping the infusion, leave the OUT line to drain for 1-2 hours so that you leave the ventricles small and reduce the risk of leakage after the catheters are removed. Both ventricular catheters are then removed. Insert one stitch across each insertion hole.
The infant is observed to see if there is suspicion of raised intracranial pressure or excessive head enlargement over time. If neither of these events occur, no intervention is carried out. This is the policy which follows logically from the previous randomised trial data on PHVD. Normal head growth at this age is approximately 1 mm per day.
Excessive head enlargement is defined as 2 mm per day.
If there is a bulging fontanelle, deteriorating neurology, increased irritability, absent cerebral diastolic velocity (not explained by a patent ductus arteriosus), or head expansion of 2 mm/day (e.g.1.4 cm over 7 days) (without symptoms), then a lumbar puncture is carried out with the object of removing 10 – 20 ml/kg over 10 – 20 minutes. If the lumbar puncture is successful, the infant continues to be observed to see if a repeat lumbar puncture (LP) becomes necessary. If the head circumference increases by 2 mm per day post-lumbar puncture, a further puncture is carried out.
Criteria for insertion of ventricular reservoir
If more than two LPs appear to be necessary or if the lumbar puncture fails to drain enough to normalise head growth to <2 mm/day, in Bristol, a ventricular reservoir is indicated. If there will be some delay in arranging surgical insertion of a reservoir and the clinical situation appears urgent, then a ventricular tap is carried out draining 10 – 20 ml/kg over 10 – 20 minutes31.
When to tap the reservoir
Following surgical insertion of a ventricular reservoir it has been our experience that it is important to avoid raised pressure in the early post-operative period as this may lead to leakage from the suture line and subsequent infection. Thus we suggest carrying out daily taps of 10 – 20 ml/kg from the ventricular reservoir for the first 5 days post insertion. After this period, the frequency and volume of the ventricular taps are governed to avoid excessive head growth and absence of signs of raised pressure. Up to a maximum of 20 ml/kg over 20 minutes can be removed at one tap and the frequency should be such that head growth is <2 mm/day, preferably 1 mm/day.
Repeated ventricular tapping as alternative to a reservoir
An equivalent approach to ventricular reservoir tapping is to carry out repeated ventricular taps as required for the same indications. The advantage of repeated ventricular taps is that the infant avoids the journey to the operating theatre, general anaesthetic and the risk of infection from having a foreign body in place. However, ventricular taps require a higher level of skill than tapping a reservoir and this usually means that the infant has to remain in the specialist centre and cannot return to a district hospital. In Glasgow, ventricular tapping is only done by experienced surgeons. If ventricular tapping is done for the same indications as reservoir tapping (to control excessive head enlargement and pressure) we regard this as an equivalent approach to the same end.
Failed DRIFT and crossover to standard treatment
If DRIFT is followed by persistent enlargement of ventricles and excessive head growth (2 mm/day) then management changes to “standard treatment” with LPs and ventricular reservoir. Infants are not, however, switched from conventional therapy to DRIFT. Analysis will be by intention to treat.
Criteria for shunt surgery
Ventriculoperitoneal shunting is carried out if there is persistent need for tapping to maintain normal head growth or if there is persistent excessive head enlargement. If an infant has had a reservoir inserted and is having repeated taps to maintain normal head growth, continue until CSF protein < 1.5g/l and the infant is free from infection with an acceptable weight (2.5 kg usually in Bristol but could be lower in individual cases). When these conditions are met, stop tapping and measure the head circumference daily. If the head circumference increases by 2 mm/day, use ultrasound to confirm that the increase is CSF and not brain growth. Insertion of a ventriculo-peritoneal shunt is indicated if the excessive growth persists over several days in the above circumstances. Occasionally, infants demonstrate raised intracranial pressure without expanding the head at 2 mm/day and shunting is required. Similarly, some infants grow at a rate just below 2 mm/day but do so persistently and cross all the centiles eventually developing an inappropriately large head for the body. If there is some intra-abdominal pathology such as necrotising enterocolitis which contra-indicates a VP shunt, carry on tapping the reservoir until the abdomen normalises. Very rarely, another type of surgical shunt may have to be considered. Usually, a low-pressure valve system is used in shunting babies with PHVD. Whether the shunt valve is low, medium or high pressure will be recorded on the patient data sheets.
At Southmead, infants under 32 weeks are routinely imaged with magnetic resonance at term. It is planned to incorporate volumetric measurements of white matter and grey matter and gyrification as it is theoretically possible that the intervention may improve these important indicators of brain growth and development 32, 33. Because this technique is not up and running at the beginning of the trial and not at all in one centre, it will only be possible to examine a sub-population of infants. Nevertheless, we feel this is of considerable interest and importance and will give spin-off information relating MRI volumes to outcome. Prof Whitelaw, Dr Stoodley and Dr Watt will be conferring on the specification of the volume sequences and the methods of volume calculation. Auditory evoked potential screening (part of universal hearing screening) should be done before the infants leave hospital in the UK centres. The infants in the trial will be followed up every 3 –6 months or more often if indicated. For trial purposes the important assessment is at a corrected age of 24 months when neurological examination and Bayley Scales of Infant Development II 34 will be carried out as well as assessments of growth, feeding and hospitalisation history. The parents will be asked to consent to follow-up around school entry. At 24 months, vision will be assessed (visual acuity and strabismus) and hearing will be assessed if it has not been thoroughly examined before.
An overall assessment as to single or multiple disability will be made as described by Amiel-Tison and Stewart 35.
On the basis of previous trials, the inclusion criteria predict that 50 – 60 % of the infants will need a shunt operation or die. To reduce the percentage of death or shunt infants from 55 % to 30% with conventional levels of statistical power would require about 120 infants to be enrolled (60 + 60) (two sided) 36.
To demonstrate at conventional levels of statistical power, a difference of 0.5 standard deviation in Mental Development Index a trial populations of 128 would be required36The trial has been established in Bristol with the intention of discussing the collaboration of other centres with a motivated neonatologist and neurosurgeon. It is much easier to teach staff from other centres with the trial already established in Bristol. 25 infants have been recruited in Bristol over 24 months. With two more large centres now taking part (Glasgow and Katowice) a target of 120 over the next 2 years becomes realistic. With a fourth centre taking part, a target of 128 would be more realistic.
A part time research nurse is needed to take care of the documentation, equipment and general education of staff about the trial. It will be important for participants (neonatal medical and nursing and neurosurgical) to travel between centres to teach and learn. Supplies of Artficial CSF will need to be secured for the trial. In the case of hospitals outside the UK, an alternative such as Hartmann’s solution with glucose might be suitable but the cost of Artificial CSF is modest. The Trial Steering Group chairman is Professor Neil Marlow (Nottingham University). The data safety monitoring group will be chaired by Professor Andrew Wilkinson (Oxford University) and will include Dr Simon Gates (statistician) and Mr Tony Hockley (paediatric neurosurgeon).
1. Volpe, JJ. Neurology of the Newborn. 4th ed. Philadelphia : Saunders; 2001: 428-493.
2. Murphy, BP, Inder, TE, Rooks, V, Taylor, GA, Anderson, NJ, Mogridge, N, Horwood LJ, Volpe, JJ. Posthemorrhagic ventricular dilatation in the premature infant: natural history and predictors of outcome. Arch Dis Child 2002; 87: F37-41.
3. Ventriculomegaly Trial Group. Randomised trial of early tapping in neonatal post-
hemorrhagic ventricular dilatation. Arch Dis Child 1990; 65: 3-10.
4. Kennedy, CR, Ayers, S, Campbell, MJ, Elbourne, D, Hope, P, Johnson, A.
Randomized, Controlled Trial of Acetazolamide and Furosemide in Posthemorrhagic Ventricular Dilatation in Infancy: Follow-up at 1 year. Pediatrics 2001; 108: 597-607.
5.Whitelaw, A, Mowinckel, MC, Fellman, V, Abildgaard, U. Endogenous tissue
plasminogen activator in neonatal cerebrospinal fluid. Eur J Pediatr 1996; 155: 117-9.
6. Whitelaw, A, Mowinckel, MC, Larsen, M, Røkas, E, Abildgaard, U. Intraventricular streptokinase increases cerebrospinal D dimer in preterm infants with posthemorrhagic ventricular dilatation. Acta Paediatrica 1994; 83: 270-2.
7. Whitelaw, A, Mowinckel, MC, Abildgaard, U. Low levels of plasminogen in
cerebrospinal fluid after intraventricular hemorrhage: a limiting factor for clot lysis?
Acta Paediatrica 1995; 84: 933-6.
8. Hansen, A, Whitelaw, A, Lapp C, Brugnara, C. Cerebrospinal Fluid Plasminogen
Activator Inhibitor-1 : A Prognostic Factor In Posthemorrhagic Hydrocephalus. Acta
Paediatrica 1997; 86: 995-8.
9. Whitelaw, A, Rivers, RPA, Creighton, L, Gaffney, P. Low dose intraventricular
fibrinolytic treatment to prevent posthemorrhagic hydrocephalus. Arch Dis Child 1992; 67: 12-4.
10. Whitelaw, A, Saliba, E, Fellman,V, Mowinckel, M-C, Acolet, D, Marlow, N. A phase 1 study of intraventricular recombinant tissue plasminogen activator for the treatment of posthemorrhagic hydrocephalus. Arch Dis Child 1996; 75: F20-6.
11. Hansen, A, Volpe, JJ, Goumnerova, LC, Madsen, JR. Intraventricular urokinase for the treatment of posrhemorrhagic hydrocepahlus. Pediatric Neurology 1997; 17: 213-7.
12. Luciano, R, Velardi, F, Romagnoli, C, Papacci, P, De Stafano, V, Tortorolo, G. Failure of fibrinolytic endoventricular treatment to prevent neonatal post-hemorrhagic
hydrocephalus. Child's Nervous System 1997; 13: 73-6.
13. Larroche, JC. Posthemorrhagic hydrocephalus in infancy. Biology of the Neonate 1972; 20: 287-99.
14. Beck, LS, Chen, TL, Amman, AJ et al. Accelerated healing of ulcer wounds in the
rabbit ear by recombinant human transforming growth factor beta-1. Growth Factors 1990; 2: 273-82.
15. Ignotz, RA, Massague, J. Transforming growth factor beta stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. J Biol Chem 1986; 261: 4337-45.
16. Roberts, AB, Sporn, MB, Assoian, RK et al. Transforming growth factor type rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci USA 1986; 83: 4167-71.
17. Massague, J, Boyd, FT, Andres, JL, Chefetz, S. mediators of TGF-beta action: TGF- receptors and TGF--binding proteoglycans. Ann NY Acad Sci. 1990; 593: 59-72.
18. Kitazawa, K, Tada, T. Elevation of transforming growth factor beta-1 level in
cerebrospinal fluid of patients with communicating hydrocephalus after subaracnoid
hemorrhage. Stroke 1994; 25: 1400-1404.
19. Tada, T, Kanaji, M, Kobayashi, S. Induction of communicating hydrocephalus in mice by intrathecal injection of human recombinant transforming growth factor beta-1. J Neuroimmunol 1994; 50: 153-8.
20. Whitelaw, A, Christie, S, Pople, I. Transforming growth factor b-1: a possible signal molecule for post-hemorrhagic hydrocephalus? Pediatr Res 1999; 46: 576-80.
21. Kaiser, A, Whitelaw, A. Cerebrospinal fluid pressure during posthemorrhagic ventricular dilatation in newborn infants. Arch Dis Child 1985; 60: 920-3.
22. Savman, K, Nilsson, UA, Blennow, M, Kjellmer, I, Whitelaw, A. Non-protein-bound iron is elevated in cerebrospinal fluid from preterm infants with posthemorrhagic ventricular dilatation. Pediatr Research 2001; 49: 208-12.
23. Savman, K, Blennow, M, Hagberg, H, Tarkowski, E, Thoresen, M, Whitelaw, A.
Cytokine response in cerebrospinal fluid from preterm infants with posthaemorrhagic ventricular dilatation. Acta Paediatrica 2002; 91: 1357-63.
24. Findlay, JM, Weir, BKA, Stollery, DE. Lysis of intraventricular hematoma with tissue plasminogen activator. Case report. J Neurosurg 1991; 74: 455-64.
25. Mayfrank, L, Lippitz, B, Groth, M et al. Effect of recombinant tissue plasminogen
activator on clot lysis and ventricular dilatation in the treatment of severe intraventricular hemorrhage. Acta Neurochir 1993; 122: 32-8.
26. Shen, PH, Matsuoka, Y, Kawajiri, K. et al. Treatment of intraventricular hemorrhage using urokinase. Neurol Med Chir (Tokyo) 1990; 30: 329-30.
27. Rohde, V, Schaller, C, Hassler, WE. Intraventricular recombinant tissue plasminogen activator for lysis of intraventricular hemorrhage. J Neurol, Neurosurg, Psychiatry 1995; 58: 447-51.
28. Levene, M. Measurement of the growth of the lateral ventricle in preterm infants with real-time ultrasound. Arch Dis Child 1981; 56: 900-4.
29. Davies et al Reference ranges for linear dimensions of Intracranial ventricles in
Preterm neonates. Arch Dis Child 2000; 82: F218-23.
30. Whitelaw A, Pople I, Cherian S, Evans D, Thoresen M. Phase 1 trial of prevention of hydrocephalus after intraventricular hemorrhage in newborn infants by DRIFT (Drainage, Irrigation and Fibrinolytic Therapy) Pediatics 2003; 111: 759-65.
31. De Vries, LS, Liem, KD, van Dijk, K, Smit, BJ, Sie, L, Rademaker, KJ, Gavilanes, AWD. Early versus late treatment of posthaemorrhagic ventricular dilatation: results of a retrospective study from five neonatal intensive care units in the Netherlands. Acta Paediatr 2002; 91: 212-7.
32. Inder TE, Huppi PS, Warfield S, Kikinis R, Zientara GP, Barnes PD, Jolesz F,
Volpe JJ. Periventricular white matter injury in the premature infant is followed by
reduced cerebral cortical gray matter volume at term. Ann Neurol 1999 Nov;46(5):755-60.
33. Ajayi-Obe M, Saeed N, Cowan FM, Rutherford MA, Edwards AD. Reduced development of cerebral cortex in extremely preterm infants. Lancet 2000 Sep 30;356(9236):1162-3
34. Bayley N. Bayley Scales of Infant Development II. Psychological Corporation. Oxford. 1993.
35. Amiel-Tison, C, Stewart, AL. Follow-up studies in the first five years of life: a pervasive assessment of neurological function. Arch Dis Child 1989; 64: 496-502.
36. Machin D, Campbell MJ, Fayers PM, Pinol A. Sample size tables for clinical studies. 1997. Blackwell. Oxford.