Randomized trial of dobutamine versus dopamine in preterm infants with low systemic blood flow

OBJECTIVE: Our purpose was to determine if dobutamine or dopamine results in greater improvements in systemic blood flow in very preterm infants with low flow during the first 24 hours of life. STUDY DESIGN: A 2-center, randomized, double-blind study. Infants (n = 42) with low superior vena cava (SVC) flow (<41 mL/kg/min) in the first 12 hours were randomly assigned to receive 10 mL/kg normal saline solution, followed by 10 microg/kg/minute of dobutamine or dopamine. If low flow persisted or recurred, the inotrope was increased to 20 microg/kg/minute, with crossover to the other inotrope if treatment failed to maintain flow. RESULTS: Volume produced a more significant increase in SVC flow than dopamine (+43%). At the highest dose, dobutamine resulted in a significantly greater increase in SVC flow than dopamine (mean, +9.9 vs -3.2 mL/kg/min, P =.02). Dopamine resulted in a significantly greater increase in blood pressure. Infants receiving dobutamine only at 24 hours had a greater right ventricular output than infants receiving dopamine (mean, 295 vs 167 mL/kg/min, P <.001). Forty percent failed to increase or maintain SVC flow in response to either inotrope. No significant differences in mortality or morbidity were found. CONCLUSIONS: Dobutamine produced a greater increase in blood flow than dopamine.     

Extensive experience with dural sinus thrombosis

OBJECTIVE: Dural sinus thrombosis (DST) is an uncommon cause of stroke. The safest and most effective therapy for DST has not been conclusively identified. METHODS: A retrospective chart review of data for 31 patients who were treated for DST at our institution between 1992 and 2001 was performed. Four treatment strategies were identified, i.e., 1). medical observation only, 2). systemic anticoagulation (AC) therapy with heparin, 3). endovascular chemical thrombolysis with urokinase or tissue plasminogen activator and concurrent systemic AC therapy, and 4). mechanical endovascular clot thrombolysis with concurrent systemic AC therapy. Complications and clinical outcomes were assessed for each group. RESULTS: Patients treated solely with medical observation fared the worst; four of five patients experienced intracranial hemorrhagic complications, and only two of five exhibited clinical improvement. Patients who received systemic AC therapy experienced no hemorrhagic complications, even when pretreatment hemorrhage was present; 75% (six of eight patients) exhibited improvement with AC therapy alone. Chemical thrombolysis was very effective in restoring sinus patency (90% of patients); however, 30% of patients (3 of 10 patients) experienced hemorrhagic complications. Sixty percent of patients (6 of 10 patients) who underwent chemical thrombolysis exhibited clinical improvement. Patients who underwent mechanical thrombectomies demonstrated a low hemorrhagic complication rate, and most (88%) made good recoveries. CONCLUSION: Therapy directed at the underlying clot in DST must begin without delay. Our results suggest that supportive medical management of DST, without therapy directed at the clot or clotting process, is not effective. Systemic AC therapy, even in the presence of intracerebral hemorrhage, seems to be safe. Heparin can be safely titrated to yield partial thromboplastin times of 60 to 70 seconds. Chemical clot thrombolysis is efficacious in opening occluded sinuses but may cause intracranial hemorrhage. We currently recommend either systemic AC therapy or systemic AC therapy in conjunction with mechanical clot thrombectomy as a safe effective treatment for DST.     

Outcome of very premature infants with necrotising enterocolitis cared for in centres with or without on site surgical facilities

OBJECTIVE: To determine if the presence of a neonatal surgical facility on site has any effect on mortality and morbidity of very premature infants with necrotising enterocolitis (NEC). DESIGN AND SETTING: Retrospective review of infants of less than 29 weeks gestation cared for in the seven perinatal centres in New South Wales. PATIENTS: Between 1992 and 1997, 605 infants were cared for in two centres with in house surgical facilities (group 1) and 1195 in five centres where transfers were required for surgical management (group 2). RESULTS: Although use of antenatal steroids was significantly lower in group 1 centres than group 2 centres (74% v. 85% respectively), and the incidence of hyaline membrane disease, pneumothorax, and NEC was higher, mortality was identical (27%). Fifty two (9%) infants in group 1 and 72 (6%) in group 2 of comparable perinatal characteristics and CRIB (Clinical Risk Index for Babies) scores developed radiologically or pathologically proven NEC. The overall mortality of infants with NEC in group 1 was lower but this was not statistically significant (27% v. 35%). Significantly more infants with NEC in group 1 had surgery (69% v. 39%). There were fewer postoperative deaths in group 1 and more deaths without surgery in group 2. The duration of respiratory and nutritional support and hospital stay for the survivors were similar in the two groups. In a multivariate analysis, shorter gestation was the only factor associated with mortality in infants with NEC; the presence of in house surgical facilities was not. CONCLUSIONS: There were no significant differences in outcome of premature infants with NEC managed in perinatal centres with or without on site surgical facilities. Early transfers should be encouraged. This finding may have implications for future planning of facilities for neonatal care.     

Psychiatric research: what ethical concerns do LRECs encounter? A postal survey. Local research ethics committees

BACKGROUND AND METHODS: Psychiatric research can occasionally present particular ethical dilemmas, but it is not clear what kind of problems local research ethics committees (LRECs) actually experience in this field. We aimed to assess the type of problems that committees encounter with psychiatric research, using a postal survey of 211 LRECs. RESULTS: One hundred and seven (51%) of those written to replied within the time limit. Twenty eight (26%) experienced few problems with psychiatric applications. Twenty six (24%) emphasised the value of a psychiatric expert on the committee. The most common issues raised were informed consent (n=64, 60%) and confidentiality (n=17, 16%). The use of placebos (and washout periods) (n=18, 17%), the validity of psychiatric questionnaires (n=16, 15%) and overuse of psychiatric "jargon" (n=14, 13%) in psychiatric applications also raised concern. CONCLUSIONS: Our results suggest that LRECs have specific concerns regarding methodology, consent, and confidentiality in psychiatric research, and that they find psychiatric input invaluable.     

DRG analysis reveals potential problems, trends

Specific DRGs are frequently the targets of review if they are connected to errors. But documentation review alone to identify problems may not be sufficient. The author describes a strategy to review aggregate data for two tricky DRGs.     

Prevalence and nature of connexin 26 mutations in children with non-syndromic deafness

OBJECTIVE: To determine (1) the prevalence and nature of connexin 26 mutations in a cohort of Australian children with non-syndromic hearing loss, and (2) the carrier frequency of the common connexin 26 mutation (35delG) in the general population. DESIGN: A cohort, case-finding study. Mutation analysis was performed on DNA extracted from white blood cells, buccal cells, or Guthrie blood spots. SETTING: A hearing loss investigation clinic and a deafness centre in two Australian capital cities, 1 January 1998 to 31 October 2000. PARTICIPANTS: (1) 243 children (age range, 4 weeks to 16 years; median, 4 years), attending hearing loss clinics in Sydney and Melbourne; (2) 1000 blood samples obtained from anonymous Guthrie card blood spots collected in 1984 [corrected] by the Victorian Clinical Genetics Service as part of the newborn screening program. MAIN OUTCOME MEASURES: (1) The prevalence and types of connexin 26 mutations in a cohort of children with prelingual deafness; (2) the carrier frequency of the common connexin 26 mutation, 35delG, in the general population. RESULTS: Connexin 26 mutations were identified and characterised in 52 (21%) of the 243 children; 14 different mutations, including four previously unreported mutations (135S, C53R, T123N and R127C), were identified. The common 35delG mutation was found in 56 of the 104 alleles (ie, 86 of the connexin 26 alleles in which a mutation was positively identified). The mutations V371 and M34T were also relatively common. The carrier frequency of connexin 26 mutations and of the common 35delG connexin 26 mutation in the Victorian population was estimated to be 1 in 54 and 1 in 100, respectively. CONCLUSIONS: Mutations in the connexin 26 gene (especially the 35delG mutation) are a common cause of prelingual hearing loss in Australia.     

The development of the bradykinin agonist labradimil as a means to increase the permeability of the blood-brain barrier: from concept to clinical evaluation

Labradimil (Cereport; also formerly referred to as RMP-7) is a 9-amino-acid peptide designed for selectivity for the bradykinin B2 receptor and a longer plasma half-life than bradykinin. It has been developed to increase the permeability of the blood-brain barrier (BBB) and is the first compound with selective bradykinin B2 receptor agonist properties to progress from concept design through to tests of efficacy in patients. In vitro studies demonstrate that labradimil has a longer half-life than bradykinin and selectively binds to bradykinin B2 receptors, initiating typical bradykinin-like second messenger systems, including increases in intracellular calcium and phosphatidylinositol turnover. Initial proof of principle studies using electron microscopy demonstrated that intravenous labradimil increases the permeability of the BBB by disengaging the tight junctions of the endothelial cells that comprise the BBB. Autoradiographic studies in rat models further demonstrated that labradimil increases the permeability of the BBB in gliomas. Intravenous or intra-arterial labradimil increases the uptake of many different radiolabelled tracers and chemotherapeutic agents into the tumour in a dose-related fashion. These effects are selective for the tumour and for the brain surrounding the tumour, and are particularly robust in tumour areas that are normally relatively impermeable. The increased chemotherapeutic concentrations are maintained for at least 90 minutes, well beyond the transient effects on the BBB. The increase in permeability with labradimil occurs rapidly but is transient, in that restoration of the BBB occurs very rapidly (2 to 5 minutes) following cessation of infusion. Even with continuous infusion of labradimil, spontaneous restoration of the barrier begins to occur within 10 to 20 minutes. Collectively, these data demonstrate that the B2 receptor system that modulates permeability of the BBB is highly sensitive and autoregulated and that careful attention to the timing of labradimil and the chemotherapeutic agent is important to achieve maximal effects. Survival studies in rodent models of both gliomas and metastatic tumours in the brain demonstrate that the enhanced uptake observed with the combination of labradimil and water-soluble chemotherapeutics enhances survival to a greater extent than achieved with chemotherapy alone. Finally, preliminary clinical trials in patients with gliomas provide confirmatory evidence that labradimil permeabilises the blood-brain tumour barrier and might, therefore, be used to increase delivery of agents such as carboplatin to tumours without the toxicity typically associated with dose escalation.     

Prenatal diagnosis of fetal heart failure in twin reversed arterial perfusion syndrome

Diagnosis of twin reversed arterial perfusion (TRAP) syndrome is a rare fetal anomaly that can be misdiagnosed on prenatal ultrasound. We confirmed the use of colour-flow Doppler for prenatal diagnosis of TRAP syndrome and used serial fetal echocardiography for non-invasive evaluation of the fetus. A patient with twin intrauterine pregnancy was referred to our centre with suspected intrauterine fetal demise following a 16 week ultrasound. Serial colour-flow Doppler ultrasonography demonstrated retrograde arterial flow in an acardiac twin. Following diagnosis of TRAP syndrome, serial fetal echocardiography was employed to follow the normal twin for signs of heart failure, including right atrial dilation, tricuspid regurgitation and pericardial effusion. When early signs of fetal heart failure were suspected a viable female infant was delivered at 32 weeks' gestation. We suggest that serial fetal echocardiography represents a non-invasive approach that can be used to follow fetal cardiac function of the normal twin in TRAP syndrome.     

Intravenous thrombolytic therapy for stroke: a review of recent studies and controversies.

STUDY OBJECTIVES: To review the randomized, controlled, multicenter trials of intravenous thrombolytic therapy for ischemic stroke. METHODS: Studies of ischemic stroke confirmed by computed tomography (CT) and randomization of more than 100 patients are reviewed. Streptokinase studies are the MAST-I, the MAST-E, and the ASK Trial. Studies using tissue plasminogen activator (tPA) are the NINDS Stroke Study, ECASS I, ECASS II, and ATLANTIS. One study using ancrod is STAT. We discuss significant factors common to each study, including thrombolytic agent used, CT scan interpretation, time of therapy administration in relation to stroke onset, thrombolytic dose, ancillary medication administration, safety, and neurologic outcomes. RESULTS: All streptokinase studies were stopped early because of increased mortality in the treated groups. Initial results of the STAT study are promising; publication of full study details is awaited. The ATLANTIS study was terminated early because of nonstatistical efficacy at interim analysis. The NINDS and the ECASS trials were completed; only the NINDS study demonstrated significant increase in the percentage of patients with complete recovery or minimal deficit at 3 months, without significant difference in mortality in the treated group. CONCLUSION: This review supports the use of intravenous thrombolytic therapy for ischemic stroke using tPA at a dose of.9 mg/kg body weight and a "golden window" treatment time of 3 hours. Administration without strict adherence to protocol, even within this time frame, may shift the benefit/risk profile of tPA. We recommend the treating physician have rapid access to CT scanning and to collaboration with individuals experienced in the evaluation of stroke and CT interpretation.