Including Intracranial Hemorrhage Research Articles

Two important factors affecting the transition to breastfeeding in preterm infants: corrected age and periventricular leukomalacia.

Dear Editor, I have read the article of Aytekin et al. (1) titled “The effect of feeding with spoon and bottle on the time of switching to full breastfeeding and sucking success in preterm babies” with interest. In this study, spoon feeding and bottle feeding methods which are used as assistive methods in the period of transition from enteral feeding to breastfeeding were compared. It was found that the time for transition to full breastfeeding was significantly shorter in preterm babies who were spoon-fed compared to the ones who were bottle-fed (p<0.05). Sufficient sucking occurs in the 32–33rd week at the earliest in preterm babies (2). This is related with brain development and central nervous system myelinization (2, 3). In the study of Aytekin et al. (1), the gestational week as corrected age at which the transition from enteral feeding to oral feeding occured was not reported. Instead, it was reported that the body weights were similar in both study groups at the time of onset of breastfeeding and thus both groups had similar maturational behaviors. In preterm babies, increase in body weight may vary depending on addition of fortifiers, development of oral intolerance in the baby and daily amounts of intake of calorie, protein, fat, carbohydrate and other elements (4). Therefore, corrected gestational age should be reported as an indicator of neurological maturation instead of body weight (2, 3). In preterm babies, detection of pathological conditions including intracranial hemorrhage (ICH) and periventricular leukomalacia (PVL) which may occur while development of the brain continues is important in terms of follow-up and treatment (3). In previous years, transfontanel ultrasonography (TFUS) screening was recommended for babies born before the 30th gestational week, whereas it has been recommended that this screening should be performed in all babies up to the 36th gestational week in recent years (5). In a study performed by Ballardini et al. (5), the TFUS findings of babies born at the 33–36th gestational age were examined retrospectively. Pathological TFUS finding (PVL, ICH, subependimal cyst, sinus vein thrombosis) was detected in 13% of a total of 724 babies. The most common finding was reported as PVL. It was reported that 78 (83%) of these patients who were found to have pathology were asymptomatic and 19 (20%) had no risk factor. In the study of Aytekin et al. (1), it was reported that babies who had no congenital malformation which would lead to asphyxia and affect respiration, who had spontaneous respiration and who had no cranial hemorrhage or hyperbilirubinenia which would require exchange transfusion were included in the study. However, it was not reported if TFUS was performed or not. Considering that PVL can develop even in patients whithout risk factors or marked neurological finding, it is not clear if the patient group of Aytekin et al. (1) had PVL which could interrupt development of sucking ability. In conclusion, it should be kept in mind that the sucking ability in preterm babies is related with gestational age and each baby should be evaluated according to his/her own gestational week. In addition, it should be kept in mind that brain imaging should be performed in order to detect pathological conditions including PVL which would disrupt the natural process in neurological maturation in preterm babies.

Why so little progress in therapeutic thrombolysis? The current state of the art and prospects for improvement.

Thrombosis is a major contributor to disability and mortality worldwide and is estimated to be the cause of one in four deaths [1]. It is the pathology responsible for triggering acute myocardial infarction (AMI) and ischemic stroke, and is the primary cause of venous thromboembolism. The pathogenesis has been well-studied starting with Virchow more than 150 years ago [2], and its prevention by anti-thrombotic drugs has made much progress, culminating most recently in the approval of new oral anticoagulants which are specific inhibitors of thrombin or factor Xa. By contrast, treatment by thrombolysis, the only pharmacological means available, has remained at a near standstill since Genentech first applied for FDA approval of tissue plasminogen activator (tPA) in 1983. A replacement for streptokinase (SK) had been long-sought, but after early successes in AMI, tPA use has since been on the decline. Instead, percutaneous coronary intervention (PCI) has become the treatment of choice in AMI, despite its technical, time-consuming, and costly demands. Pre-treatment with tPA to hasten coronary reperfusion, so-called facilitated PCI, was found to increase PCI complications including intracranial hemorrhage (ICH) making the two incompatible [3]. In ischemic stroke, tPA has been estimated to be used in only 2–5 % of patients over-all [4], and in pulmonary embolism, bleeding and stroke complications limited its use to the minority of patients with hemodynamic decompensation [5]. The recent trend in stroke has also begun to favor the use of endovascular devices with three major trials in ischemic stroke published in the first 2 months of 2015 in the NEJM [6–8]. In this same period, a clinical trial of catheter-directed ultrasound was also published which showed a significant acceleration of the thrombolysis rate by this method [9]. These device reperfusion techniques require bringing the patient to a qualified facility which inevitably consumes precious time for conditions in which “minutes are myocardium or neurons.” An optimal treatment for these time-sensitive conditions can only be one that can be brought to the patient and is easily and safely administered. The resort to alternative methods is a reflection on the inadequacy of current thrombolysis, a problem that was foretold by the results with tPA in major clinical trials.

Severe Hemorrhage in Chinese Children With Immune Thrombocytopenia.

To better understand the clinical features, therapy, and clinical outcome of Chinese patients with immune thrombocytopenia (ITP) who suffered severe hemorrhage, we retrospectively analyzed 663 children with ITP diagnosed in our hospital during the last 10 years. Of the total 663 patients enrolled in our study, 520 were eligible for bleeding severity assessment, of which 20 children (3.8%) had severe bleeding, including intracranial hemorrhage (ICH) (n = 9), gastrointestinal hemorrhage (n = 6), massive epistaxis (n = 3), urinary tract hemorrhage (n = 1), and pulmonary hemorrhage (n = 1). The age at diagnosis of severe hemorrhage ranged from 47 days to 14 years. Thirteen patients were newly diagnosed with ITP, 3 had persistent ITP, and 4 had chronic ITP. The latency between the onset of ITP and severe bleeding ranged from 6 hours to 10 years. The median platelet count at the time of severe hemorrhage was 6.5 × 10/L (range, 0 to 32 × 10/L). Most patients with severe hemorrhage were treated with intravenous immunoglobulin (90%), corticosteroids (65%), or both (60%). Two patients (10%) died because of ICH and pulmonary hemorrhage, respectively. Four patients (20%) recovered from thrombocytopenia. Our observation showed that severe hemorrhage is rare but can occur anywhere and at any time during the course of ITP. The majority of children with ITP in China should be observed rather than treated.

Abstract W P417: A Common Variant in a TGFβ Modifier Locus Is Associated with Intracranial Hemorrhage Presentation of Brain Arteriovenous Malformation in Hereditary Hemorrhagic Telangiectasia

Introduction: Hereditary hemorrhagic telangiectasia (HHT) is caused by mutations in TGFβ/BMP9 pathway genes, most commonly ENG or ALK1. HHT patients have arteriovenous malformations (AVM) in brain, lung and liver, leading to severe complications including intracranial hemorrhage (ICH) from brain AVM. ICH presentation of brain AVM in HHT is a marker of high ICH risk. The clinical heterogeneity of HHT suggests a potential role for genetic modifier effects. Common genetic variants in loci that modify phenotype severity in Tgfb knockout mice have been reported to be associated with pulmonary AVM in HHT. We sought to replicate these associations and investigate whether these variants are also associated with brain AVM and ICH presentation of brain AVM in HHT patients. Methods: We genotyped 3 variants (PTPN14 rs2936018, USH2A rs700024 and ADAM17 rs10495565) in 665 Caucasian HHT patients enrolled by the Brian Vascular Malformation Consortium (BVMC). Association of genotype with pulmonary AVM, brain AVM and ICH presentation was evaluated by multivariate logistic regression adjusted for age, gender and family clustering, and also stratified by HHT mutation (ALK1 or ENG). Results: Of 665 Caucasian HHT patients analyzed, 51% had pulmonary AVM and 20% had brain AVM, of whom 17% presented with ICH. None of the 3 SNPs was significantly associated with pulmonary or brain AVM. Among 130 brain AVM patients, USH2A rs700024 was associated with ICH presentation (OR=3.34, 95% CI=1.22-9.15, p=0.019). The effect size was similar in HHT patients with ALK1 and ENG mutations, but only reached statistical significance among the latter (OR=6.77, p=0.014). Conclusions: A common variant in USH2A, rs700024, previously reported to be associated with pulmonary AVM in HHT, was associated with ICH presentation of brain AVM, but not with brain or pulmonary AVM, in the BVMC HHT cohort. Association of the same USH2A variant with different HHT severity phenotypes in different cohorts suggests that it may act as a genetic modifier of HHT phenotype severity in concert with other genetic and environmental factors. Once validated, such genetic modifiers may improve our understanding of the phenotypic heterogeneity of HHT and aid in ICH risk prediction in HHT brain AVM.

Reversing the effects of antiplatelet agents in the setting of intracranial hemorrhage: a look at the literature.

Patients are increasingly being prescribed antiplatelet agents (APAs) for a growing number of medical and surgical conditions. These agents are associated with an increased risk of hemorrhage, including intracranial hemorrhage (ICH). In the setting of warfarin use and ICH, strategies to reverse the drug effects have improved outcomes. No such strategy exists for APAs, and these patients continue to have poor posthemorrhage outcomes. One strategy is the use of platelet transfusions to provide functional, circulating platelets. Studies have shown mixed results regarding the benefit of this practice. Other strategies include the use of desmopressin and recombinant factor VIIa. More studies are necessary to delineate the effectiveness of the various strategies.

New antithrombotics for secondary prevention of acute coronary syndrome.

Patients with acute coronary syndrome (ACS) usually receive acetylsalicylic acid plus an adenosine diphosphate (ADP) receptor inhibitor to reduce the long‐term risk of recurrent events. However, patients receiving standard antiplatelet prophylaxis still face a substantial risk of recurrent events. Strategies involving 3 antithrombotic agents with different modes of action have now been tested. In Thrombin Receptor Antagonists for Clinical Event Reduction (TRA‐CER), compared with standard care alone, bleeding complications including intracranial hemorrhage (ICH) were increased with the addition of vorapaxar, without efficacy benefit. In Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Atherosclerosis (TRA 2°P–TIMI 50), the addition of vorapaxar reduced recurrent events compared with standard care in stable patients with prior myocardial infarction. This study was terminated early in patients with prior stroke owing to excess ICH, though an increased risk of ICH or fatal bleeding was not detected in patients with prior myocardial infarction. The Apixaban for Prevention of Acute Ischemic and Safety Events 2 (APPRAISE‐2) trial of standard‐dose apixaban added to standard care in patients with ACS was also stopped early owing to excess serious bleeding. However, in Rivaroxaban in Combination With Aspirin Alone or With Aspirin and a Thienopyridine in Patients With Acute Coronary Syndromes (ATLAS ACS 2 TIMI 51), fatal bleeding or fatal ICH did not increase with low‐dose rivaroxaban added to low‐dose acetylsalicylic acid‐based standard care compared with standard care alone. In that trial, a significant reduction of recurrent vascular events was shown with 3 antithrombotic regimens compared with standard care. Therefore, depending on drug dose and patient population, further reductions in recurrent vascular events after ACS may be possible in future clinical practice, with a favorable benefit‐risk profile.

Adrenocorticotropic Hormone for the Treatment of West Syndrome in Children

To review the current literature on the efficacy and safety of low- versus high-dose adrenocorticotropic hormone (ACTH) regimens, low-dose ACTH regimens, and comparison of ACTH with oral corticosteroids or vigabatrin for the treatment of West syndrome. A literature search was performed using MEDLINE, PubMed, and Inter national Pharmaceutical Abstracts (1975-November 2012) to identify studies for inclusion. In addition, reference citations from identified publications were reviewed. The following search terms were used: infantile spasms, West syndrome, adrenocorticotropic hormone, corticotropin, symptomatic West syndrome, cryptogenic West syndrome, pediatric, children, infant, adolescent, and neonate. Studies included in this article evaluated low-dose versus high-dose ACTH, low-dose ACTH, and ACTH compared with vigabatrin and oral corticosteroids. Data reporting the efficacy and adverse effects of ACTH, vigabatrin, and oral corticosteroids were extracted from each publication. Only English-language publications were included. We initially reviewed 20 studies, and 14 were included: 5 prospective randomized clinical trials and 9 chart reviews. West syndrome is an age-specific epileptic disorder that occurs in infancy and early childhood. It is characterized by the triad of infantile spasms, neurodevelopmental regression or delay, and hypsarrhythmia on electroencephalogram (EEG). The efficacy and adverse events of ACTH with different dosage regimens were reviewed and analyzed. ACTH compared with vigabatrin and oral corticosteroids was also evaluated. Based on this review, low-dose ACTH is probably as effective as high-dose ACTH. Compared with other agents, ACTH is suggested to be more effective than oral corticosteroids, and compared with vigabatrin, it has improved outcomes in the cessation of spasms. However, studies evaluating the efficacy of ACTH are limited by small sample size, inconsistent dosage regimens, and the use of synthetic or natural ACTH products. Serious adverse events, including intracranial hemorrhage, brain atrophy, Cushing syndrome, infection, weight gain, and hypertension, may deter the use of ACTH. Short-term therapy is recommended to reduce the risk of adverse effects. The current literature suggests that short-term, low-dose ACTH should be considered first-line treatment of infantile spasms.

Aminocaproic acid decreases the incidence of intracranial hemorrhage and other hemorrhagic complications of ECMO

Since the inception of extracorporeal membrane oxygenation (ECMO), hemorrhage has been a major complication often limiting its usefulness. This study was undertaken to evaluate the effect of aminocaproic acid (AMICAR), an inhibitor of fibrinolysis, on all hemorrhagic complications of ECMO including intracranial hemorrhage (ICH). In 1990, 49 neonates and 5 older children received ECMO therapy. None of these patients received AMICAR. In 1991, 51 neonates and 5 older children received ECMO. Forty-two of these patients who were considered to be at high risk for bleeding complications (preexisting or anticipated surgical procedures, preexisting ICH, or profound hypoxia, acidosis, coagulopathy, or prematurity) were given AMICAR. The remaining 14 low-risk neonates did not receive AMICAR, and for purposes of analysis were combined with the 1990 group. AMICAR was administered just prior to or after cannulation (100 mg/kg, intravenously) and was infused continuously at 30 mg/kg/h until decannulation. Except for the addition of AMICAR, the ECMO protocol was identical for these two patient groups. Patients who received AMICAR had significantly less bleeding while on ECMO ( P = .03) and required fewer blood transfusions ( P = .01) than patients not receiving AMICAR. This difference was most significant in the congenital diaphragmatic hernia and cardiac subgroups ( P = .0001) and was not significant in the meconium aspiration subgroup ( P = .1). The incidence of ICH in the neonatal subgroup was also significantly reduced with no patient on AMICAR developing a new or extending a preexisting ICH ( P = .007). Reexploration of the cannulation site for bleeding was also reduced in the AMICAR-treated group but the difference failed to reach statistical significance. A slight increase in thrombotic circuit and patient complications did occur in the AMICAR group but the difference was neither statistically nor clinically significant. We conclude: (1) AMICAR is effective in decreasing the incidence of ICH and other hemorrhagic complications associated with ECMO; (2) AMICAR appears to be safe and is associated with a low incidence of thrombotic complications; and (3) the use of AMICAR should be considered for patients thought to be at high risk for hemorrhagic complications on ECMO.