PEDIATRICS Vol. 119 No. 5 May 2007, pp. e1071-e1078 (doi:10.1542/peds.2006-2841)
ARTICLE |
Randomized Clinical Trial of Prevention of Hydrocephalus After Intraventricular Hemorrhage in Preterm Infants: Brain-Washing Versus Tapping Fluid
a Department of Clinical Science at North Bristol
d South Bristol, University of Bristol, Bristol, United Kingdom
b Neonatal Intensive Care Unit, Southmead Hospital, Bristol, United Kingdom
c Department of Neurosurgery, Frenchay Hospital, Bristol, United Kingdom
e Department of Neonatal Intensive and Special Care
f Division of Pediatric Neurosurgery, Medical University of Silesia, Katowice, Poland
g Neonatal Intensive Care Unit, Queen Mother's Hospital, Glasgow, United Kingdom
h Department of Surgical Paediatrics, Royal Hospital for Sick Children, Glasgow, United Kingdom
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVE. Hydrocephalus is a serious complication of intraventricular hemorrhage in preterm infants, with adverse consequences from permanent ventriculoperitoneal shunt dependence. The development of hydrocephalus takes several weeks, but no clinical intervention has been shown to reduce shunt surgery in such infants. The aim of this study was to test a new treatment intended to prevent hydrocephalus and shunt dependence after intraventricular hemorrhage.
METHODS. We randomly assigned 70 preterm infants who had gestational ages of 24 to 34 weeks and were progressively enlarging their cerebral ventricles after intraventricular hemorrhage to either (1) drainage, irrigation, and fibrinolytic therapy to wash out blood and cytokines or (2) tapping of cerebrospinal fluid by reservoir as required to control excessive expansion and signs of pressure (standard treatment). We evaluated outcomes at 6 months of age or hospital discharge (if later).
RESULTS. Of 34 infants who were assigned to drainage, irrigation, and fibrinolytic therapy, 2 died and 13 underwent shunt surgery (dead or shunt: 44%). Of 36 infants who were assigned to standard therapy, 5 died and 14 underwent shunt surgery (dead or shunt: 50%). This difference was not significant. Twelve (35%) of 34 infants who received drainage, irrigation, and fibrinolytic therapy had secondary intraventricular hemorrhage compared with 3 (8%) of 36 in the standard group. Secondary intraventricular hemorrhage was associated with an increased risk for subsequent shunt surgery and more blood transfusions.
CONCLUSIONS. Despite its logical basis and encouraging pilot data, drainage, irrigation, and fibrinolytic therapy did not reduce shunt surgery or death when tested in a multicenter, randomized trial. Secondary intraventricular hemorrhage is a major factor that counteracts any possible therapeutic effect from washing out old blood.
Key Words: hydrocephalus • randomized prospective trial • neurosurgery • intraventricular hemorrhage
Abbreviations: IVH—intraventricular hemorrhage • PHVD—posthemorrhagic ventricular dilation • CSF—cerebrospinal fluid • ICP—intracranial pressure • rTPA—recombinant tissue plasminogen activator • DRIFT—drainage, irrigation, and fibrinolytic therapy • LP—lumbar puncture
Hemorrhage into the ventricles of the brain is 1 of the most serious complications of preterm birth despite improvements in the survival of preterm infants. Large intraventricular hemorrhage (IVH) has a high risk for neurologic disability, and >50% of these children go on to develop progressive ventricular dilation.1 Increasing survival of extremely preterm infants is associated with posthemorrhagic ventricular dilation (PHVD) with high morbidity and considerable mortality.2,3 Multiple blood clots may obstruct the ventricular system or channels of cerebrospinal fluid (CSF) 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.4,5 There is evidence that transforming growth factor ß is likely to be a mediator of this process, which probably takes weeks,5 although this was not confirmed in 1 study that found that vascular endothelial growth factor was elevated in the CSF of infants with PHVD.6 Intraventricular blood and ventricular expansion may have adverse effects on the immature periventricular white matter by a variety of mechanisms, including physical distortion, raised intracranial pressure (ICP),7 free radical generation facilitated by free iron,8 and inflammation.9
Treatment is more difficult than other types of hydrocephalus, because the large amount of blood and protein level in the CSF combined with the small size and instability of the patient makes an early ventriculoperitoneal shunt operation impossible. There is a considerable complication rate throughout the child's life from such surgery, and the child is permanently dependent on the shunt system.10 Neither treatment by repeated lumbar or ventricular tapping nor the use of acetazolamide and furosemide to reduce CSF production prevents the need for shunt surgery or improves neurologic outcome, and both have appreciable adverse effects.11,12 Death or shunt surgery occurred in 67% and 52% of infants, respectively, in these 2 trials.11,12 Phase 1 clinical trials of intraventricular fibrinolytic therapy treatment13,14 and a small randomized trial15 have not given encouraging results.
The standard treatment varies, and few centers have built up large series for analysis. The standard arms of the Ventriculomegaly Trial and the PHVD Drug Trial both used selective tapping of CSF to control signs of pressure or excessive head enlargement.11,12 The practice of inserting a ventricular access device, such as an Ommaya reservoir, to facilitate repeated tapping of adequate volumes is widely practiced without having been tested by randomized trial.16
Adults with IVH have been treated by early ventricular drainage combined with intraventricular recombinant tissue plasminogen activator (rTPA), and these studies reported mortality that was much lower than historical controls.17,18 Clearly, IVH in adults is very different from IVH in preterm infants with respect to etiology and also likelihood of raised ICP, but the adult experience and our previous research on this topic suggested that there might be a critical period of days or weeks during which removing as much blood, cytokine, and free iron as possible in preterm infants with large IVH might stop the progression of pathology before irreversible hydrocephalus is established.
We have piloted a procedure, drainage, irrigation, and fibrinolytic therapy (DRIFT), that aims to remove intraventricular blood and the cytokines that are associated with hydrocephalus before hydrocephalus becomes established.19 Twenty-5 preterm infants with ventricular enlargement after a large IVH were enrolled. Eighteen (75%) of 24 survivors did not require a ventriculoperitoneal shunt. Two infants developed reservoir-associated infection, and 2 infants had a second IVH. Shunt surgery or death (28%) was reduced compared with historical controls with similar treatment criteria.11,12 Although this technique irrigates and drains the lateral ventricles, we had ultrasound evidence that blood clot was also removed from the third ventricle. The primary object of this study was to test the hypothesis that treatment by DRIFT reduces ventriculoperitoneal shunt or death when compared with standard treatment for PHVD.
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METHODS |
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Study Infants
The study was approved by the research ethics board of each institution that took part: Southmead Hospital (Bristol, United Kingdom), Royal Hospital for Sick Children (Glasgow, United Kingdom), Medical University of Silesia (Katowice, Poland), and Haukeland Hospital (Bergen, Norway). Written informed consent was obtained from the mother of each infant. In all 4 centers, preterm infants who required intensive care or showed neurologic abnormalities had daily cranial ultrasound scans for the first 3 days and then at least weekly for 4 weeks. When IVH was diagnosed, ultrasound scanning was then done twice weekly. Ventricular measurements were made when there was any visible enlargement, and head circumference was then measured daily. Cranial ultrasound continued twice weekly until resolution of ventricular enlargement and more frequently when enlargement was progressive.
Inclusion criteria were (1) IVH documented on ultrasound; (2) age no more than 28 days; and (3) progressive dilation of the both lateral ventricles with each side: (a) ventricular width 4 mm over the 97th centile18; (b) all of the following: anterior horn diagonal width 4 mm (1 mm over 97th centile19), thalamo-occipital distance 26 mm (1 mm over 97th centile19), and third ventricle width 3 mm (1 mm over 97th centile19); or (c) measurements above a or b on 1 side combined with obvious midline shift indicating a pressure effect. Exclusion criteria were a prothrombin time of >20 seconds or accelerated partial thromboplastin time of >50 seconds or platelets <50000/mL.
Randomization
A computer-generated randomization scheme was used to assign the infants to treatment groups in a 1:1 ratio. Randomization was stratified by study center and in blocks of 8, 10, or 12. Each infant was allocated to treatment using sequentially numbered, double-opaque envelopes (1 envelope inside the other for security) that each contained a "DRIFT" or "standard treatment" card.
Treatment
DRIFT
A detailed description of this technique was published previously.17 Under anesthesia, 2 ventricular catheters were inserted (right frontal and left occipital). A Codman external ventricular drainage system (Johnson & Johnson, Piscataway, NJ) was connected. The connections are shown in Fig 1. rTPA (Actilyse, Boehringer Ingelheim Int, Ingelheim, Germany) 0.5 mg/kg was injected intraventricularly. After 8 hours, artificial CSF (Torbay Pharmaceutical Manufacturing Unit, Kemmings Close, Paignton, United Kingdom; and the Biochafa Production Plant, Sosnowiec, Poland) with 10 mg of vancomycin and 5 mg/500 mL intrathecal gentamicin was infused at 20 mL/hour into the right frontal ventricular catheter with a pressure transducer on the in-going line. Simultaneously, fluid was allowed to drain from the left occipital ventricular catheter, the height of the drainage reservoir being raised or lowered to maintain the ICP below 7 mm Hg. It was usually necessary to drain 60 to 100 mL/24 hours more than the infused volume to maintain normal pressure. The drainage fluid was usually cola-colored initially and then gradually cleared. When the drainage fluid became colorless, infusion of artificial CSF was stopped and both catheters were removed after a median of 3 days (range: 2–7 days).
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Standard Treatment
The infant was observed daily for raised ICP (irritability, apnea, reduced consciousness, bulging fontanelle, or loss of diastolic velocities on cerebral arteries) or excessive head enlargement over time. When neither of these applied, no intervention was conducted. This policy followed logically from the previous randomized trial data on PHVD.4,5 Head circumference enlarges by
1 mm/day between 26 weeks of gestation and 32 weeks and by 0.7 mm/day between 32 and 40 weeks.20 Excessive head enlargement was defined as 2 mm/day. Suspected raised ICP or excessive head expansion prompted a lumbar puncture (LP) with the object of removing 10 to 20 mL/kg over 10 to 20 minutes. When the LP was successful, the infant continued to be observed to determine whether a repeat LP would be necessary. When the head circumference increased by 2 mm/day after LP, additional tapping was conducted.
Criteria for Insertion of Ventricular Reservoir
When >2 LPs were necessary or when the LP failed to drain enough to normalize head growth to <2 mm/day, a ventricular reservoir was indicated. When there was a delay in surgical insertion of a reservoir and the clinical situation seemed urgent, a ventricular tap was conducted to drain 10 to 20 mL/kg over 10 to 20 minutes at a frequency to ensure that head growth was <2 mm/day, preferably 1 mm/day.
Failed DRIFT and Crossover to Standard Treatment
When DRIFT was followed by persistent enlargement of ventricles and excessive head growth (2 mm/day), management changed to standard treatment with LPs and ventricular reservoir. Infants were not switched from conventional therapy to DRIFT.
Criteria for Shunt Surgery
When an infant was having repeated reservoir taps to control head growth, this was continued until weight reached 2500 g and CSF protein fell to <1.5 g/L. Tapping was stopped and the head circumference was measured daily. When the head circumference increased by 2 mm/day, ultrasound was used to confirm that expansion was CSF and not brain growth. A ventriculoperitoneal shunt was indicated when the excessive growth persisted over several days after the described procedures.
Outcomes
In this study, follow-up was until 6 months of age or discharge from hospital, when later. The primary outcome is a composite of ventriculoperitoneal shunt surgery and death. This was documented from the hospital clinical records and by our own contact with the family.
Secondary IVH was diagnosed on the basis of ultrasound appearance of new intraventricular echodensities (Fig 2) within 1 week of randomization combined with a fall in hemoglobin of at least 2 g/dL in 2 days. The ultrasound diagnosis was always confirmed by at least 2 examiners. Diagnosis of secondary CSF infection required a positive culture of bacteria and a raised white cell count in the CSF after randomization. Neurodevelopmental outcome at 2 years past term will be the subject of a separate report.
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Statistical Analysis
On the basis of previous trials, the inclusion criteria predicted that 50% to 60% of the infants would need a shunt operation or die. Our initial power calculation (using a 5% level of significance) indicated that 60 infants in each group would give 91% power of detecting a reduction from 60% in primary outcome to 30% and a 79% power of detecting a reduction from 55% to 30%.21
The trial was closed early after an interim analysis of the first 50% of infants (30 DRIFT and 30 standard treatment) conducted for the Data Monitoring and Safety Group. "Conditional" power was calculated for the primary outcome (ie, the probability of obtaining a significant difference in the rate of shunt/death given the results that had been obtained up to the half-way point).22,23 The estimate of power under the alternative trial hypothesis (30% DRIFT versus 55% standard) was only 15%. The Data Monitoring and Safety Group made a recommendation to the Trial Steering Group in March 2006 to cease recruitment, by which time an additional 10 infants had been treated. The statistical analysis presented here is for all 70 infants.
Analysis was by intention to treat. Standard statistical tests were used throughout. Proportions were compared using continuity-corrected 
2 tests, a Student's t test was used to compare the mean minimum hemoglobin concentration, and a Mann-Whitney U test was used to compare the number of transfusions.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Recruitment started in Bristol in February 2003 and finished in April 2006 (38 months). Seventy infants were recruited to the DRIFT trial: 47 in Bristol, 20 in Katowice, 2 in Glasgow, and 1 in Bergen. The great majority of infants who were recruited in Bristol and Katowice were transferred from other cities for neurosurgical assessment. Seventy of 74 parents of the infants who met trial criteria gave consent when asked, and none of the recruited infants was lost to follow-up. Patient flow is shown in Fig 3.
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Table 1 shows the characteristics of the infants at randomization. The 2 treatment groups were similar with respect to gender, gestation, birth weight, age at randomization, and presence of parenchymal hemorrhagic infarction at entry.
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Table 2 shows the main outcomes at discharge. Of 34 infants who were assigned to DRIFT, 2 died and 13 underwent shunt surgery (dead or shunt: 44%). Of 36 infants who were assigned to standard therapy, 5 died (1 with a shunt) and 13 survived shunt operation (dead or shunt: 50%). This difference was not significant (P = .80). The causes of death were not directly related to brain injury or neurosurgical intervention but were necrotizing enterocolitis, septicemia, and chronic lung disease.
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Infants who required shunt surgery in the DRIFT group were slightly younger when they received this than the corresponding infants in the standard treatment group (median [range]: 72 [40–221] vs 99 [42–147] days; P = .25).
Infants in the standard group were almost twice as likely to have a ventricular reservoir inserted (38% vs 75%; P = .004). Within the standard group, 15 (56%) of 27 infants who received a reservoir subsequently required a shunt. None of the infants in the standard group without a reservoir needed a shunt. In the DRIFT group, 6 of 21 infants who did not receive a reservoir eventually needed a shunt. They avoided a reservoir because of repeated LPs or because enlargement was late enough for shunt surgery to be possible.
Secondary IVH was an important secondary outcome because this occurred in the pilot study of DRIFT. Twelve (35%) of 34 infants who received DRIFT had secondary IVH, compared with 3 (8%) of 36 in the standard treatment group, and this difference was statistically significant (difference 27%; 95% confidence interval: 9% to 45%; P = .014). It was not possible to time secondary IVH precisely because infants were usually scanned once a day, but most occurred within 24 hours of catheter insertion. Because secondary IVH was accompanied by a fall in hemoglobin, there often was a requirement for replacement blood transfusion. The mean number of blood transfusions that were received in the first 7 days after randomization was 1.7 (range: 0–4) in the DRIFT group and 0.8 (range: 0–2) in the standard group (P < .001). Within the DRIFT group, the mean number received was 2.2 (range: 1–4) when there was secondary IVH and 1.4 (range: 0–4) if there was no secondary IVH (P = .055). The mean of the lowest hemoglobin was 8.9 (SD: 1.3) g/dL in the DRIFT group and 9.7 (SD: 1.3) g/dL in the standard group (P = .012). In only 1 case was the secondary IVH clinically apparent. This infant was undergoing DRIFT when he acutely developed thrombocytopenia. There was no significant difference between centers in the frequency of secondary IVH.
Additional evidence that secondary IVH is of clinical importance is provided by 8 (67%) of 12 infants in the DRIFT group who had secondary IVH that required shunt surgery, whereas only 5 (23%) of 22 in the DRIFT group without secondary IVH required shunt surgery (P = .032). Table 3 shows that the infants who bled were not different from those who did not bleed with respect to age at randomization, initial coagulation status, presence of parenchymal hemorrhagic infarction, gestational age, birth weight, or gender. Secondary infection in the CSF was rare, with none in the DRIFT group and 1 in 36 of the standard group (coagulase-negative Staphylococci in an infant with a reservoir), which resolved with standard intravenous antibiotic therapy.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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This trial arose from the negative results of previous trials of therapies for posthemorrhagic ventricular dilation and from progress in understanding the pathophysiology of this condition. Available evidence suggested the possibility that progression of hydrocephalus might be halted by removing as much of the blood and cytokines as possible before irreversible hydrocephalus. Ventricular drainage and irrigation are established techniques, and the rTPA was added to increase mobilization of old blood clot and to reduce catheter blockage. A single-center pilot study of DRIFT had shown promising results with low rates of secondary hemorrhage (<10%), infection (<10%), and shunt surgery or death (28%) when compared with historical controls. There was considerable interest in the pilot study, and we were strongly advised to test DRIFT in a multicenter, randomized, clinical trial.
Much thought had to be given to the inclusion criteria and what constituted "standard treatment" for PHVD because of important variation among centers. Because all invasive interventions for PHVD have the potential to cause infection and hemorrhage, we used entry criteria that have predicted a high rate of shunt surgery and disability. On the basis of the evidence that raised ICP reduces cerebral perfusion and can adversely affect neurophysiology,23,24 our standard therapy involved tapping off fluid when there was suspicion of raised ICP or excessive head enlargement.
Strengths of this trial are that (1) the 2 treatment groups were well matched, (2) no infants were lost to follow-up, and (3) all infants received the allocated treatment. A weakness is the limited number of infants, but this was a consequence of the power calculation, the planned interim analysis, and subsequent intervention of the Data Monitoring and Safety Group.
The trial showed that there was no significant difference between the 2 treatment groups in the primary outcome, shunt surgery or death. Even if recruitment were to continue to 120, the trial was highly unlikely to demonstrate a significant advantage for the DRIFT group. An important finding was the significantly increased secondary IVH in the DRIFT group. Although these events were clinically silent in all but 1 case and revealed only by careful examination of daily ultrasound scans and daily hemoglobin measurements, they were associated with increased need for blood transfusion and shunt surgery. Because the central objective of DRIFT as a treatment was to remove as much blood as possible, secondary IVH would directly counteract the planned therapeutic process; therefore, it is understandable that secondary IVH was followed by an increased risk for permanent hydrocephalus. It is not possible from our data to predict which infants are at particularly high risk for secondary IVH.
It must be remembered that, unlike the use of rTPA after clipping an aneurysm with subarachnoid hemorrhage, the original site of intraventricular bleeding in the infants in the DRIFT trial had not been repaired surgically, and it may be that the injection of TPA uncovered the original bleeding site or facilitated bleeding from 1 of the puncture sites that were necessary to place the ventricular catheters. However, we had previously found that omitting rTPA when the CSF was bloody sometimes resulted in the blocking of ventricular catheters with clots.
A multicenter trial of a new technique depends on effective teaching and dissemination. The pilot DRIFT study involved only 1 pediatric neurosurgeon, 2 neonatologists, and a small group of neonatal nurses. In contrast, the multicenter, randomized DRIFT trial involved a much larger number of neurosurgeons, neonatologists, and nurses. Despite that considerable time was devoted to training, there may have been variation in practice and technique that translated into more variable outcomes.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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DRIFT did not reduce ventriculoperitoneal shunt surgery or death in preterm infants with ventricular dilation after IVH when compared with tapping of CSF to control excessive head expansion or raised ICP. Tapping a ventricular reservoir was relatively safe and effective in controlling hydrocephalus even in extremely small infants. It may be that earlier use of a reservoir for tapping can improve outcome, and we understand that this is being tested prospectively in the Netherlands.16 Preventing permanent hydrocephalus in this group of high-risk infants is still inhibited by a limited knowledge of the pathogenesis.
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ACKNOWLEDGMENTS |
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This study was supported by Cerebra and the James and Grace Anderson Trust and North Bristol NHS Trust, which was the sponsor in England.
The following investigators participated in the DRIFT trial: A. Whitelaw, I. Pople, M. Carter, D. Evans, and M. Thoresen (Bristol, United Kingdom); J. Wroblewska, M. Mandera, J. Swietlinski, and E. Musialik-Swietlinska (Katowice, Poland); J. Simpson, A. Watt, R. Carachi, and C. Hajivassilou (Glasgow, United Kingdom); and H. Reigstad (Bergen, Norway); the Trial Steering Group consisted of N. Marlow, A. Whitelaw, I. Pople, D. Evans, J. Wroblewska, J. Simpson, C. Hajivassilou, L. Hunt, S. and R. Walker-Cox (parents of a child in the DRIFT pilot study); the Data Monitoring and Safety Group was made up by A. Wilkinson (Chair), S. Gates, and A. Hockley; and hospitals that referred infants to the DRIFT trial were University College London Hospital, Singleton Hospital (Swansea), Cheltenham General Hospital, Gloucestershire Royal Hospital, Hammersmith Hospital (London), Hillingdon Hospital (London), University Hospital of Wales (Cardiff), Birmingham Maternity Hospital, Dudley Road Hospital (Birmingham), Royal Sussex County Hospital (Brighton), St Mary's Hospital (Portsmouth), Basildon General Hospital, Royal Gwent Hospital (Newport), Musgrove Park Hospital (Taunton), Royal Exeter and Devon Hospital, and Royal Cornwall Hospital. Infants were referred to Katowice from the hospitals at Zabrze, Bielsko-Biala, Opole, Gdansk, and Lomza.
We are grateful to the nursing and medical staff at the trial centers, especially Chrissie Israel and Sue Lamburne in Bristol and Dr Ewa Musialik-Swietlinska and Prof Florian Ryszka in Katowice, and the hospitals that referred infants to the trial centers. We thank the parents of all of the infants in the DRIFT trial for their trust and commitment.
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FOOTNOTES |
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Accepted Oct 31, 2006.
Address correspondence to Andrew Whitelaw, MD, Neonatal Medicine, University of Bristol Medical School, Southmead Hospital, Bristol BS10 5NB, United Kingdom. E-mail: andrew.whitelaw{at}bristol.ac.uk
The authors have indicated they have no financial relationships relevant to this article to disclose.
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