Progressive posthämorrhagische Ventrikelerweiterung des Frühgeborenen Inzidenz, Prognose und Therapie

Background. 35% of preterm infants with intraventricular hemorrhage develop ventricular dilatation. The posthemorrhagic ventricular dilatation can persist, be transient or be progressive. Finally 1–2% of all very low birthweight (VLBW <1500 g) infants require shunt placement for the treatment of the posthemorrhagic hydrocephalus. Outcome. The neurodevelopmental outcome is extremely poor in children surviving progressive posthemorrhagic ventricular dilatation. Therapy. There are no uniform guidelines for the treatment of preterm infants with progressive posthemorrhagic ventricular dilatation. Randomised multicenter trials demonstrated, that inhibition of cerebrospinal fluid production with acetazolamide and furosemide or early cerebrospinal fluid tapping did not reduce the need for shunt placement and may worsen the outcome or can be associated with adverse side-effects. Preterm infants with posthemorrhagic ventricular dilatation should be treated by standard therapy with uniform guidelines for cerebrospinal fluid tapping and shunt placement.     

Low levels of plasminogen in cerebrospinal fluid after intraventricular haemorrhage: a limiting factor for clot lysis?

The aim of this study was to measure plasminogen in the cerebrospinal fluid (CSF) of control neonates with no infection or haemorrhage and in infants who had suffered intraventricular haemorrhage (IVH). A chromogenic substrate method was used. The 16 reference infants had a median CSF plasminogen level of 0.74% of that of normal adult plasma (range 0.17-1.1%). The 11 infants with IVH had a median CSF plasminogen level of 0.55% of normal adult plasma (range 0-4.4%). Six of the IVH infants went on to develop permanent hydrocephalus despite the use of intraventricular plasminogen activators. Endogenous fibrinolysis and the potential for fibrinolytic treatment in the CSF may be limited by low concentrations of plasminogen, and administration of recombinant plasminogen may assist attempts to clear intraventricular blood clots. Cerebrospinal fluid, hydrocephalus, intraventricular haemorrhage, newborn infant, plasminogen
A Whitelaw, Department of Paediatrics, Aker University Hospital, 0514 Oslo, Norway     

Endogenous tissue plasminogen activator in neonatal cerebrospinal fluid

Tissue type plasminogen activator (tPA) plays a role in differentiation of neurones and activity-dependent structural changes in neurones. We hypothesised that tPA would also be present in CSF during fibrinolysis after intraventricular haemorrhage. We measured tPA antigen in CSF from 13 normal newborn infants and 14 infants with posthaemorrhagic ventricular dilation (PHVD). tPA was undetectable or at the limit of detection (1 g/l) in normal CSF. The CSF tPA concentration ranged from 1.3 to 3.5 g/l in the infants with PHVD. Serial tapping in one infant showed persistence of tPA in the CSF from 3 to 8 weeks of age. We conclude that endogenous tPA may be part of the physiological response to intraventricular haemorrhage or may be present as a result of passive diffusion into the CSF.     

Cerebrospinal fluid plasminogen activator inhibitor-1: a prognostic factor in posthaemorrhagic hydrocephalus

Intraventricular fibrinolytic enhancement with plasminogen activators is an experimental treatment for posthaemorrhagic hydrocephalus, but some infants do not respond. The objectives of this study were to investigate whether plasminogen activator inhibitor-1 is detectable in normal or posthaemorrhagic neonatal cerebrospinal fluid and whether higher neonatal cerebrospinal fluid concentrations of plasminogen activator inhibitor-1 are associated with failure of fibrinolytic therapy. Cerebrospinal fluid samples from 7 controls and 16 infants with posthaemorrhagic hydrocephalus (15 treated with exogenous fibrinolytic agents) were analysed for plasminogen activator inhibitor-1. Plasminogen activator inhibitor-1 was not detectable in any of the control samples but was detectable in all but one of the posthaemorrhagic samples, and at significantly higher levels in the treatment failures (median 94 ng ml^-1) than in the treatment successes (median 25 ng ml^-1). High levels of plasminogen activator inhibitor-1 in the cerebrospinal fluid are predictive of, and provide a plausible biological explanation for, failure of intraventricular fibrinolytic therapy.     

Intraventricular and parenteral gentamicin therapy for ventriculitis in children

Five children with intraventricular shunts developed ventriculitis due to organisms resistant to multiple antimicrobial agents but sensitive to gentamicin sulfate. No gentamicin was detected in ventricular CSF of four patients at a time when gentamicin was being administered only intravenously. The intraventricular administration of 1 mg of gentamicin resulted in ventricular CSF concentrations greater than 20 microgram/ml one hour and 5 to 14 microgram/ml 36 hours after administration. Patients were treated with intraventricularly given gentamicin for an average of 16 days, with no apparent complications or relapses during the 12- to 24-month follow-up period. Intraventricularly administered gentamicin sulfate (1 mg every 24 to 36 hours) in conjunction with complete shunt removal was an effective means of therapy of ventriculitis caused by bacteria resistant to antibiotics that readily penetrate the blood-brain barrier.     

Posthaemorrhagic ventricular dilatation: new mechanisms and new treatment

Post haemorrhagic ventricular dilatation is associated with a high rate of disability, multiple impairments and adverse effects of shunt surgery for hydrocephalus. Post haemorrhagic ventricular dilatation results initially from multiple small blood clots throughout the cerebrospinal fluid channels impeding circulation and re-absorption. Transforming growth factor beta is released into the cerebrospinal fluid and there is evidence that this cytokine stimulates the laying down of extracellular matrix proteins which produce permanent obstruction to the cerebrospinal fluid pathways. Prolonged raised pressure, pro-inflammatory cytokines and free radical damage from iron may contribute to periventricular white matter damage and subsequent disability. Interventions such as early lumbar punctures, diuretic drugs to reduce cerebrospinal fluid production and intraventricular fibrinolytic therapy have been tested and, not only fail to prevent shunt dependence, death or disability, but have significant adverse effects. Surgical interventions such as subcutaneous reservoir, external drain, choroid plexus coagulation and third ventriculostomy have not been subject to controlled trial. Ventriculoperitoneal shunt is not feasible in the early phase after intraventricular haemorrhage but, despite the problems with blockages and infections, remains the only option for infants with excessive head expansion over periods of weeks. We have piloted drainage, irrigation and fibrinolytic therapy as a way of removing blood early enough to stop the progressive deposition of matrix proteins, permanent hydrocephalus and shunt dependence.     

Posthaemorrhagic ventricular dilatation: new mechanisms and new treatment

Post haemorrhagic ventricular dilatation is associated with a high rate of disability, multiple impairments and adverse effects of shunt surgery for hydrocephalus. Post haemorrhagic ventricular dilatation results initially from multiple small blood clots throughout the cerebrospinal fluid channels impeding circulation and re-absorption. Transforming growth factor β is released into the cerebrospinal fluid and there is evidence that this cytokine stimulates the laying down of extracellular matrix proteins which produce permanent obstruction to the cerebrospinal fluid pathways. Prolonged raised pressure, pro-inflammatory cytokines and free radical damage from iron may contribute to periventricular white matter damage and subsequent disability. Interventions such as early lumbar punctures, diuretic drugs to reduce cerebrospinal fluid production and intraventricular fibrinolytic therapy have been tested and, not only fail to prevent shunt dependence, death or disability, but have significant adverse effects. Surgical interventions such as subcutaneous reservoir, external drain, choroid plexus coagulation and third ventriculostomy have not been subject to controlled trial. Ventriculoperitoneal shunt is not feasible in the early phase after intraventricular haemorrhage but, despite the problems with blockages and infections, remains the only option for infants with excessive head expansion over periods of weeks. We have piloted drainage, irrigation and fibrinolytic therapy as a way of removing blood early enough to stop the progressive deposition of matrix proteins, permanent hydrocephalus and shunt dependence.     

Serial lumbar punctures in prevention of post-hemorrhagic hydrocephalus in preterm infants

We studied 47 infants with either grade 3 or grade 4 intraventricular hemorrhage, to assess the efficacy of intermittent lumbar punctures in the prevention of post-hemorrhagic hydrocephalus in a prospective controlled trial. The control group received supportive care only, whereas the treatment group additionally underwent intermittent spinal taps. The spinal taps were started at postnatal age 11 +/- 5 days and continued for 20 +/- 16 days, with the removal of 67 +/- 101 ml cerebrospinal fluid using 16 +/- 12 taps. The two groups were comparable with regard to birth weight, gestational age, race, sex, Apgar score, and severity of hemorrhage. Three infants in the control group died, compared with two infants in the study group. Nine infants in the control group and 10 infants in the study group developed hydrocephalus requiring a ventriculoperitoneal shunt or a ventricular catheter reservoir. These differences in the outcome in the two groups are not statistically significant. We conclude that serial lumbar punctures were unsuccessful in prevention of hydrocephalus in this group of preterm infants with intraventricular hemorrhage.     

Early administration of indomethacin to preterm infants.

Indomethacin (0.2 mg/kg) or saline was given intravenously during the first 24 hours to 50 preterm infants in a double blind controlled trial. Eight of the control group later required treatment with indomethacin for clinical signs of left to right shunt, but only one in the treatment group (p = 0.03). Treatment with indomethacin prolonged bleeding time, raised serum creatinine concentrations, and was associated with gastrointestinal haemorrhage in seven infants. Five of these had a serum indomethacin concentration greater than 1.0 microgram/ml. There was a significant reduction of the stable metabolite of prostacyclin, 6-ketoprostaglandin F1 alpha, commencing six hours after treatment and lasting for four days. There was no significant difference in the incidence of intraventricular haemorrhage, days of treatment with oxygen or ventilation, or mortality between the two groups.     

Transforming growth factor-beta1: a possible signal molecule for posthemorrhagic hydrocephalus?

Posthemorrhagic hydrocephalus remains a complication of preterm birth for which we lack a clear understanding and a curative therapy. Transforming growth factor beta (TGF-beta) is a cytokine that upregulates the production by fibroblasts of extracellular matrix proteins. We hypothesized that TGF-beta might be released into cerebrospinal fluid (CSF) after intraventricular hemorrhage and play a role in posthemorrhagic hydrocephalus. Total TGF-beta1 and TGF-beta2 were measured by immunoassay in CSF samples from 12 normal preterm infants, nine preterm infants with transient posthemorrhagic ventricular dilation, and 10 infants who subsequently developed permanent hydrocephalus. Five infants received intraventricular tissue plasminogen activator, and two infants were treated by drainage irrigation and fibrinolytic therapy. Median TGF-beta1 in normal CSF was 0.495 ng/mL. In infants with transient posthemorrhagic ventricular dilation, median initial CSF TGF-beta1 was 2.1 ng/mL. Infants who subsequently had permanent hydrocephalus had median initial CSF TGF-beta1, 9.7 ng/mL (differences between groups p < 0.01). Intraventricular recombinant tissue plasminogen activator was followed by a rise in CSF TGF-beta1 (p = 0.0007). Drainage irrigation and fibrinolytic therapy was followed by a fall in CSF TGF-beta1. TGF-beta2 was detected in CSF and showed similar trends, but the CSF concentration of TGF-beta1 was more than 20 times higher. These findings support the hypothesis that TGF-beta1 is released into CSF after intraventricular hemorrhage and may play an important part in hydrocephalus. The results help to explain the failure of intraventricular fibrinolytic therapy.     

Alternative uses for the subgaleal shunt in pediatric neurosurgery

The subgaleal shunt has been used for the temporary bypass of the normal cerebrospinal fluid (CSF) pathways. We retrospectively reviewed all subgaleal shunts placed at the Children's Hospital, Birmingham, Ala., USA, from 1997 to the present and examined all uses (e.g. indication, length of follow-up) of the subgaleal shunt outside its use for temporary CSF diversion in premature infants with intraventricular hemorrhage and subsequent hydrocephalus. The average length of survival of the primary subgaleal shunt in this population was 32.2 days. We have had good success with subgaleal shunts in children with malignant brain tumors, intraventricular abscesses, chronic truncal wounds, chronic subdural hygromas and meningitis. However, the greatest utility has been in those scenarios in which the peritoneal cavities were not currently, but with time would be, candidates for distal shunt implantation. Examples of these instances are patients with hydrocephalus and necrotizing enterocolitis or hydrocephalus and preoperative abdominal wall pathology such as omphalocele.     

Treatment of purulent meningitis in the child using Cefotaxime

Cefotaxime has a good meningeal diffusion and is effective at low concentrations on many bacteria, especially ampicillin resistant Enterobacteriaceae and Hemophilus influenzae. We have therefore used cefotaxime (150 mg/kg/24 h, continuous infusions lasting 30 minutes q. 6 h.) in meningitis due to gram negative bacilli. Twenty eight infants and children have been treated within 4 years. The 13 Hemophilus influenzae meningitis (including 2 beta-lactamase producers) have been cured without immediate sequelae. The duration of treatment could be reduced from 3 weeks to 2 weeks. The 7 infants with Enterobacteria meningitis (6 E. coli and 1 Serratia) have been cured of their infection with a 21 to 28 days treatment. The C.S.F. was sterile 2-3 days after treatment except a case of E. coli persisting during 7 days in C.S.F. contrasting with a normal ventricular fluid. A case of relapse with E. coli remaining sensitive was cured with a new course of the same treatment. Five meningitis complicated with hydrocephalus needed external drainage: the fluid was sterile 1 day after treatment in 4 of them. Two superinfections of ventriculo-peritoneal shunt due to Enterobacteriaceae have been cured. To obtain a good result, the need for a careful drug monitoring must be emphasized.     

Early high-dose phenobarbital treatment for prevention of hypoxic-ischemic brain damage in very low birth weight infants

In a randomized prospective trial, we studied the effect of early high-dose phenobarbital treatment on the early (intraventricular hemorrhage) and late (neurodevelopmental abnormalities) manifestations of hypoxic-ischemic encephalopathy in preterm infants weighing 1500 g or less at birth. The first intravenous dose of 15 mg/kg was given at a mean age of 110 minutes, followed by 15 mg/kg after 4 hours and then by 5 mg/kg at 24-hour intervals for 5 days. The overall incidence of intraventricular hemorrhage was 32% in treated and 46% in control infants, a nonsignificant difference. An ultrasound brain scan at 9 months old revealed no significant difference in the incidence of ventricular dilatation between treated (19%) and control (29%) infants. At 27 months, a similar incidence of mild (10%) and severe (10%) neurodevelopmental handicaps was found in both treated and control groups. Since beneficial effects could not be documented by any of the criteria used, we conclude that routine administration of phenobarbital to low birth weight infants is not justified.     

Cerebrospinal fluid shunt infections in children

Infections of cerebrospinal fluid shunts continue to be a substantial source of mortality and morbidity in children with hydrocephalus. Although several therapeutic modalities are currently used for the treatment of shunt infections, there are no clear guidelines for treatment. The purpose of this study was to determine the common pathogens of cerebrospinal fluid shunt infections and evaluate the success of our management. Thirty-five children treated for ventriculoperitoneal shunt infections over the past 9 years were reviewed. The management protocol consisted of the removal of the infected shunt, the application of ventricular taps or reservoir placement, intraventricular antibiotic treatment, and the placement of a new shunt when cerebrospinal fluid sterility was achieved. Four patients were treated with antibiotics alone. Most episodes occurred within 4 months of shunt placement. The most common causative microorganism identified was Staphylococcus epidermidis, followed by S. aureus, and S. warneri. Three patients died from complications of shunt infections, 2 patients had a recurrent shunt infection, while the remaining 29 patients remained free from shunt-related complications. In agreement with the evidence published in the literature, our findings suggest that the above management protocol is effective for the treatment of cerebrospinal fluid shunt infections.     

Prostacyclin concentrations and transitional circulation in preterm infants requiring mechanical ventilation.

AIM: To describe the association between early postnatal prostacyclin concentrations in preterm infants; echocardiographic measurements of ductal diameter and ventricular output and clinical outcomes of intraventricular haemorrhage (IVH) and patent ductus arteriosus (PDA). METHODS: Forty nine preterm infants born before 30 weeks of gestational age (median birthweight 980 g, median gestational age 27 weeks) underwent echocardiographic studies at 5, 12, 24 and 48 hours of postnatal age. Measurements included ventricular outputs and the ductal shunt diameter as a measure of the shunt size. Simultaneous measurements of blood pressures, mean airway pressure and inspired fraction of oxygen (FIO2) were recorded. A blood sample for the prostacyclin metabolite 6-ketoprostaglandin F1-alpha (6KPGF1 alpha) was taken at the 5 and 24 hour echocardiogram. RESULTS: The mean 6KPGF1 alpha concentrations were higher than adult concentrations at 5 (515 pg/ml) and 24 (255 pg/ml) hours. There was no association with gestational age. Raised 6KPGF1 alpha concentrations were related to increased need for mechanical ventilation and severity of respiratory disease. At 5 hours, increased 6KPGF1 alpha concentrations were associated with larger PDA and at 24 hours with larger PDA and higher left ventricular output. Infants with higher 6KPGF1 alpha concentrations were more likely to develop clinically significant PDA. There was no association between early measurements of 6KPGF1 alpha and IVH. CONCLUSIONS: Early postnatal prostacyclin concentrations are markedly raised in preterm infants, particularly in those with more severe lung disease. Raised 6KPGF1 alpha concentrations were associated with an increased ductal diameter and subsequent PDA, but not IVH.     

Outpatient treatment of febrile infants 28 to 89 days of age with intramuscular administration of ceftriaxone.

STUDY OBJECTIVE: To determine the outcome of outpatient treatment of febrile infants 28 to 89 days of age with intramuscular administration of ceftriaxone. DESIGN: Prospective consecutive cohort study. SETTING: Urban emergency department. PATIENTS: Five hundred three infants 28 to 89 days of age with temperatures greater than or equal to 38 degrees C who did not appear ill, had no source of fever detected on physical examination, had a peripheral leukocyte count less than 20 x 10(9) cells/L, had a cerebrospinal fluid leukocyte count less than 10 x 10(6)/L, did not have measurable urinary leukocyte esterase, and had a caretaker available by telephone. Follow-up was obtained for all but one patient (99.8%). INTERVENTION: After blood, urine, and cerebrospinal fluid cultures had been obtained, the infants received 50 mg/kg intramuscularly administered ceftriaxone and were discharged home. The infants returned for evaluation and further intramuscular administration of ceftriaxone 24 hours later; telephone follow-up was conducted 2 and 7 days later. RESULTS: Twenty-seven patients (5.4%) had a serious bacterial infection identified during follow-up; 476 (94.6%) did not. Of the 27 infants with serious bacterial infections, 9 (1.8%) had bacteremia (8 of these had occult bacteremia and 1 had bacteremia with a urinary tract infection), 8 (1.6%) had urinary tract infections without bacteremia, and 10 (2.0%) had bacterial gastroenteritis without bacteremia. Clinical screening criteria did not enable discrimination between infants with and those without serious bacterial infections. All infants with serious bacterial infections received an appropriate course of antimicrobial therapy and were well at follow-up. One infant had osteomyelitis diagnosed 1 week after entry into the study, received an appropriate course of intravenous antimicrobial therapy, and recovered fully. CONCLUSIONS: After a full evaluation for sepsis, outpatient treatment of febrile infants with intramuscular administration of ceftriaxone pending culture results and adherence to a strict follow-up protocol is a successful alternative to hospital admission.     

Posthaemorrhagic ventricular dilatation in the premature infant: natural history and predictors of outcome

OBJECTIVE: To investigate the natural history and predictors of outcome of posthaemorrhagic ventriculomegaly in the very low birthweight (VLBW) infant. METHODS: All VLBW infants admitted between September 1994 and September 1997 to the neonatal intensive care units of Brigham and Women's Hospital (Boston), Children's Hospital (Boston), and Christchurch Women's Hospital (New Zealand) with germinal matrix intraventricular haemorrhage (IVH) were identified. All charts and ultrasound scans were reviewed to define the natural history and perinatal and/or postnatal factors of value in prediction of the course of posthaemorrhagic ventriculomegaly. Progressive ventricular dilatation (PVD) was defined from the results of serial cranial ultrasound scans. RESULTS: A total of 248 VLBW infants had evidence of IVH (22% of all VLBW infants, mean (SD) gestational age 26.8 (2.6) weeks). A quarter of the infants exhibited PVD. Spontaneous arrest of PVD occurred without treatment in 38% of infants with PVD. Of the remaining 62% with persistent PVD, 48% received non-surgical treatment only (pharmacological and/or drainage of cerebrospinal fluid by serial lumbar punctures), 34% received surgical treatment with insertion of a ventriculoperitoneal reservoir and/or shunt, and 18% died. The development of PVD after IVH and adverse short term outcome, such as the requirement for surgery, were predicted most strongly by the severity of IVH. CONCLUSIONS: These data reflect the natural history of PVD in the 1990s and show that, despite a slight reduction in its overall incidence, there appears to be a more aggressive course, with appreciable mortality and morbidity in the extremely premature infant. The major predictor of adverse short term outcome, defined as death or need for surgical intervention, was the severity of IVH. These findings may be valuable for the management of very small premature infants.     

Randomized low-dose indomethacin trial for prevention of intraventricular hemorrhage in very low birth weight neonates

We admitted 36 preterm neonates (600 to 1250 gm birth weight) with normal 6-hour echoencephalograms to a randomized, placebo-controlled prospective trial to determine whether a low dose of indomethacin would prevent germinal matrix or intraventricular hemorrhage and permit adequate urinary output. Between the sixth and tenth postnatal hours, indomethacin (0.1 mg/kg) or placebo was administered intravenously every 24 hours for a total of three doses. Cardiac ultrasound studies to assess the status of the ductus arteriosus were performed at 6 postnatal hours and on day 5. Urinary output, serum electrolytes, serum indomethacin levels, and renal and clotting functions were monitored. No differences in birth weight, gestational age, or Apgar scores were noted between the two groups of infants. Two indomethacin-treated infants and three infants given placebo had significant urinary output difficulties, requiring that the study medication be withheld. Of 19 infants given indomethacin, two had germinal matrix or intraventricular hemorrhage, in comparison with 8 of 17 infants given saline solution (p = 0.02). Of the infants who had a left-to-right patent ductus arteriosus shunt before treatment, 64% of the indomethacin-treated and 33% of the saline solution-treated infants no longer had a patent ductus arteriosus on day 5. Ductal status appeared unrelated to the development of germinal matrix or intraventricular hemorrhage.     

Soluble Fas (CD95/Apo-1), soluble Fas ligand,and activated caspase 3 in the cerebrospinal fluid of infants with posthemorrhagic and nonhemorrhagic hydrocephalus

Hydrocephalus may result in loss of tissue associated with neuronal degeneration, axonal damage, and reactive gliosis. The soluble form of the anti-apoptotic regulator Fas (sFas) and the pro-apoptotic factors soluble FasL (sFasL) and activated caspase 3 were studied in the cerebrospinal fluid of infants with hydrocephalus. Fifteen preterm infants with posthemorrhagic hydrocephalus undergoing serial reservoir puncture and seven term or near-term infants with nonhemorrhagic hydrocephalus and shunt surgery were included in the study. Twenty-four age-matched patients with lumbar puncture for the exclusion of meningitis served as controls. Elevated levels of sFas were observed in infants with posthemorrhagic hydrocephalus [median (range), 131 ng/mL (51-279 ng/mL)] and in nonhemorrhagic hydrocephalus [127 ng/mL (35-165 ng/mL)]. sFas concentrations were highest in a subgroup of eight patients with posthemorrhagic hydrocephalus developing periventricular leukomalacia [164 ng/mL (76-227 ng/mL)]. In contrast, in 24 control infants, sFas was low, in 15 cases below detection limit (0.5 ng/mL) and in nine cases, 24 ng/mL (20-43 ng/mL). sFasL and activated caspase 3 did not differ from control infants in all groups of patients. Increased intrathecal release of sFas in the cerebrospinal fluid of infants with hydrocephalus may serve as an indicator of brain injury from progressive ventricular dilatation.     

Factors influencing mortality and morbidity after clinically apparent intraventricular haemorrhage.

Twenty newborn infants with clinically apparent intraventricular haemorrhage were studied in order to determine the factors associated with mortality and morbidity. Ten survived, 4 without handicap and 2 with only moderate handicap. Maturity and not size of haemorrhage appeared to be the main factor affecting mortality and morbidity at 1 year. Coma longer than 24 hours after intraventricular haemorrhage distinguished survivors with handicap from those without and may be a useful prognostic sign.