Shifting from open surgical cut down to ultrasound-guided percutaneous central venous catheterization in children: learning curve and related complications.

PURPOSE: Tunneled indwelling central venous catheters (CVC) are essential in the management of children with cancer, hematological, nephrological disorders and for parenteral nutrition. The aim of this study is to present the experience of a single center of the transition from traditional open surgical cut down procedure (OSC) to ultrasound (US)-guided percutaneous CVC insertion, focusing on learning curve and related complications. METHODS: All CVCs inserted between April 2008 and November 2009 in children at the Gaslini Children Hospital were revised, and data on methods of cannulation, intraoperative and device-related complications and re-intervention were recorded. RESULTS: 194 CVCs were positioned in 188 patients. 128 out of 194 CVCs were positioned through an OSC technique, whereas the remaining 66 CVCs were inserted percutaneously with US guidance. Of the 27 recorded complications, 15 were mechanical events, 7 cases developed infection, whereas the remaining 5 (2.6%) were classified as intraoperative complications. A second surgical procedure was described in 23 (11.8%) cases. CONCLUSION: Shifting from OSC to US-guided percutaneous CVC insertion inevitably involves a challenging learning curve which is generally associated with high complication rates. Complications progressively decrease once a good experience in US guidance and percutaneous technique has been obtained.

Forum on: the role of recombinant factor VIII in children with severe haemophilia A.

The development of recombinant FVIII (rFVIII) products, fuelled by the need for improved safety of treatment arising from the dramatic widespread blood-borne virus transmission in the 1970-1980s revolutionized the care of children with haemophilia A over the last two decades. The larger availability of perceived safer replacement therapy associated with the introduction of rFVIII products reassured the haemophilia community and there was a strong push in some Western countries to treat haemophilic children only with rFVIII. Moreover, this significantly contributed in the 1990s to the diffusion outside Northern Europe of prophylactic regimens implemented at an early age to prevent bleeding and the resultant joint damage (i.e. primary prophylaxis), together with the possibility of home treatment. These changes led to a substantial improvement of the quality of life of haemophilic children and of their families. The general agreement that primary prophylaxis represents the first-choice treatment for haemophilic children has been recently supported by two randomized controlled trials carried out with rFVIII products, providing evidence on the efficacy of early prophylaxis over on-demand treatment in preserving joint health in haemophilic children. However, the intensity and optimal modalities of implementation of prophylaxis in children, in particular with respect to the issue of the venous access, are still debated. A number of studies also supports the role of secondary prophylaxis in children, frequently used in countries in which primary prophylaxis was introduced more recently. With viral safety now less than an issue and with the more widespread use of prophylaxis able to prevent arthropathy, the most challenging complication of replacement therapy for children with haemophilia remains the risk of inhibitor development. Despite conflicting data, there is no evidence that the type of FVIII concentrate significantly influences the complex multifactorial process leading to anti-FVIII alloantibodies, whereas other treatment-related factors are likely to increase (early intensive treatments due to surgery or severe bleeds) or reduce (prophylaxis) the risk. Although the optimal regimen is still uncertain, eradication of anti-FVIII antibodies by immune tolerance induction (ITI), usually with the same product administered at inhibitor detection, should be the first-choice treatment for all patients with recent onset inhibitors. This issue applies particularly to children, as most patients undergo ITI at an early age, when inhibitors usually appear. The availability of a stable and long-lasting venous access represents a leading problem also in this setting. These and other topics concerning rFVIII treatment of haemophilic children were discussed in a meeting held in Rome on 27 February 2008 and are summarized in this report.

Management and investigation of neonatal thromboembolic events: genetic and acquired risk factors.

Newborns comprise the largest group of children developing thromoboembolic events (TE(S)), due to the peculiarities of their developmental hemostatic system. Moreover, in the sick newborn, especially preterm, numerous acquired perinatal and iatrogenic conditions might result in a disturbance between coagulation and fibrinolysis, leading to thrombus formation. Nevertheless, the contribution of acquired prothrombotic disorders in the pathogenesis of thromboembolic disease in newborns remains poorly defined. Few data are currently available regarding the influence of maternal or fetal genes on thrombotic risk in the fetus and neonate. Ongoing National and International registries are partially answering these questions. The purpose of this review is to evaluate the current knowledge about the role of inherited, acquired perinatal and maternal prothrombotic risk factors in neonatal cerebral nervous system (CNS) thrombotic events and non-CNS thrombotic events.

Incidence of indwelling central venous catheter-related complications using the Sri Paran technique for device fixation in children with cancer.

PURPOSE: Mechanical complications in tunneled indwelling central venous catheters (CVCs) often involve a risk of displacement. Fixation procedures are, therefore, of primary importance. We prospectively evaluated the incidence of CVC-related mechanical and infectious complications observed in devices fixated with the Sri Paran technique. METHODS: All CVCs inserted in children with cancer at our Institution from October 2005 to January 2007 were prospectively monitored for device-related mechanical and infectious complications. The Sri Paran fixation technique was used in all cases. The complication rate per 1,000 days was calculated as 1,000 times the number of complications divided by the total number of catheter days. RESULTS: Ninety-five CVCs were positioned in 84 children. The overall length of observation ranged between 41 and 482 days for a total of 18,618 catheter days. Mechanical complications occurred in 5% of the devices (specific rate 0.27); infections were observed in 6% of the devices (specific rate 0.32). No complications were observed during the first 30 days after CVC insertion. CONCLUSIONS: The results, we obtained with the Sri Paran technique are extremely encouraging. Yet, randomized studies are required to prove these preliminary data.

Caspofungin associated with liposomal amphotericin B or voriconazole for treatment of refractory fungal pneumonia in children with acute leukaemia or undergoing allogeneic bone marrow transplant.

Caspofungin, in association with other antifungal drugs, was administered as rescue therapy in two cases of documented and one case of possible invasive fungal infection in children with acute leukaemia or undergoing allogeneic bone marrow transplant. The combined therapy was well-tolerated and seemed to be effective in all three patients. A combination antifungal therapy including caspofungin could represent an effective therapy for children with invasive mycoses refractory to single-agent antifungal therapy.

[Platelet hyperaggregation induced by an antiplatelet monoclonal antibody in a female patient with essential thrombocythemia of childhood]. / Iperaggregazione piastrinica indotta da un anticorpo monoclonale anti-piastrine in una paziente con trombocitemia essenziale in età pediatrica.

Essential thrombocythemia (ET) is a chronic myeloproliferative disease, rarely observed in pediatric age, characterized by a persistently increased platelet count. Abnormalities of platelet function observed in ET patients may be, at least in part, responsible for the thrombohemorrhagic complications. The authors report about a pediatric patient affected by ET, showing an abnormal platelet response following stimulation by anti-platelet monoclonal antibody. Such finding may be attributable to a structural abnormality of the platelet fibrinogen receptor or to post-receptor alterations.

[Evaluation of auditory function in homozygous beta-thalassemia]. / Valutazione della funzione uditiva nella beta-talassemia omozigote.

We examined the auditory function of 29 subjects affected by homozygous beta-thalassemia, managed with an high transfusion scheme and regularly treated with 40-60 mg/kg/day of desferrioxamine. A group of 29 healthy subjects is studied as control. We found conductive hearing defect in 8 thalassemics (6 bilateral) and sensory-neural hearing loss at high frequencies in 4. Thalassemic patients showed more auditory impairment than controls, an higher incidence of tonsillar hypertrophy, adenotonsillitis and submandibular lymph-node enlargement.

[Diagnostic usefulness and predictive value of laboratory tests in disseminated vascular coagulation]. / Utilità diagnostica e valore predittivo di alcuni tests di laboratorio nella coagulazione intravasale disseminata.

The laboratory tests of 38 patients in pediatric age with Disseminated Intravascular Coagulation (DIC) were retrospectively evaluated. In all patients were performed PT, aPTT, platelets count, FDP dosage and biological assay of Fibrinogen. In most of them the activity of FII, FV, FVII, FX and FVIII was assaied. According to the diagnostic criteria of FSP greater than 8 micrograms/ml, Platelets less than 150 10(9)/1 and Fibrinogen less than 150 ml/dl, in 16 patients the diagnosis of DIC was possible since first examination, while in 9 patients it became possible within 2-4 days; in 13 patients we never could diagnose DIC, although it was reasonably present, since the criteria above mentioned were never simultaneously satisfied. Looking back in our experience, we confirm that the platelets count and the quantitation of plasmatic Fibrin Degradation Products (FDP) are the most useful tests for the diagnosis of full blown DIC, and that the biological assay of plasmatic fibrinogen helps to follow the disorder. A low level of FVIII:C seems to be a forecast of failure. None of the other test performed give any useful information for diagnosis when it is not possible with the above mentioned tests.

[Splenectomy and infection in homozygous beta-thalassemia. The uselessness of penicillin prophylaxis]. / Splenectomia ed infezioni nella beta-talassemia omozigote. Inutilità della profilassi penicillinica.

To investigate the effective usefulness of penicillin prophylaxis in splenectomized patients, we retrospectively focused on a group of sixty-two splenectomized patients affected by thalassemia major. Thirty-six out of 62 has been receiving monthly 1.200.000 Us. of benzathine-penicillin as prophylaxis. The remaining 26 did not receive prophylaxis, but was treated with antibacterial drugs as soon as symptoms of upper respiratory tract infection occurred. During a total period of eleven years of observation we did not observe any pneumococcal sepsis; the incidence of bacterial infections within the two groups is not different. We conclude for the uselessness of penicillin prophylaxis in splenectomized beta-thalassemic patients.

[Normotest in the early neonatal period]. / Ii normotest nel periodo neonatale precoce.

The aim of this study is the behavior of Normotest (NT) values in newborns in the first 4 days of life. The study has been carried out between January, 1982, and December, 1984, at the Department of Child Health and Neonatal Medicine - School of Medicine - University of Genoa. The number of infants tested was 1320. 694 were males and 626 females, 529 preterm (G.A. less than 37 weeks) and 791 full term babies. Infants have been tested from one to five times in the first four days of life, with the first evaluation within 12 hours of life. 1215 newborns (92%) presented NT values greater than 20%, 105 babies (8%) had NT below 20% in at least one evaluation, and received Vitamin K1 (0.5 mg/kg i.m.) as prophylaxis, being thereafter excluded from this study. Among the neonate with NT greater than 20%, 426 babies have been considered, who had, at least, three evaluations in the first four days of life. 288 (68%) of the 426 newborns, had not important disease, while 138 (32%) were sick neonates; of these babies 88 (64%) had respiratory distress syndrome and 50 (36%) had an infectious condition. The mean of NT values of the 426 newborns decreased from the first (33.84%) to the 2nd day (32.72%), with a following increment in 3rd (35.29%) and 4th day of life (39.01%). Newborns with gestational age (G.A.) less than 34 weeks showed significantly lower values than newborns with G.A. between 34-37 weeks and those with G.A. greater than 37 weeks. No newborn with NT values greater than 20% either received vitamin K or showed symptoms of haemorrhagic disease in early or later neonatal period.

Management of bleeding and of invasive procedures in patients with platelet disorders and/or thrombocytopenia: Guidelines of the Italian Society for Haemostasis and Thrombosis (SISET).

The optimal management of bleeding or its prophylaxis in patients with disorders of platelet count or function is controversial. The bleeding diathesis of these patients is usually mild to moderate: therefore, transfusion of platelet concentrates may be inappropriate, as potential adverse effects might outweigh its benefit. The availability of several anti-hemorrhagic drugs further compounds this problem, mainly because the efficacy/suitability of the various treatment options in different clinical manifestations is not well defined. In these guidelines, promoted by the Italian Society for Studies on Haemostasis and Thrombosis (Società Italiana per lo Studio dell'Emostasi e della Trombosi [SISET]), we aim at offering the best available evidence to help the physicians involved in the management of patients with disorders of platelet count or function. Literature review and appraisal of available evidence are discussed for different clinical settings and for different available treatments, including platelet concentrates (PC), recombinant activated factor VII, desmopressin, antifibrinolytics, aprotinin and local hemostatic agents.

[Neurologic emergency in children's hospital. Stroke]. / Emergenza neurologica in pediatria: lo stroke.

AIM: The results may be related to the relative delay in diagnosis and thus in treatment. The authors hope that their paper will help make physicians who work in emergency rooms more aware of the increase in stroke in children. METHODS AND RESULTS: The study a departmental study in the Children's Hospital, carried out at the Giannina Gasslini Children's Hospital of Genoa, Italy. The authors report on 23 children with stroke who were admitted at onset to the pediatric emergency department. The incidence of patients with stroke at the Institute between 2001 and 2005, was 0.8% among neurology patients and 0.02% among all pediatric patients. This incidence would appear to be lower than the rates reported in the literature. This is most likely due to the fact that patients who presented at the Emergency Department at onset of the stroke were not taken in consideration. In the last few years, children with stroke have been treated empirically by anticoagulant or antiplatelet therapy. Patients with sickle cell disease, with venous stroke, or with heart disease are all treated in a rather homogeneous manner. CONCLUSIONS: These cases represent the different types of presentation of stroke in children and also clearly display the different therapeutic strategies that have been applied. In fact, the patients were treated on the basis of an individual protocol which was decided case by case but a critical review of these cases establishes a necessary multidisciplinary protocol.

von Willebrand factor, von Willebrand factor-cleaving protease, and shear stress.

von Willebrand factor (VWF) is a multimeric plasma glycoprotein (GP) involved in platelet adhesion at the site of vascular damage, which acts as a bridge between the injured subendothelium and the platelet receptors. The multimeric structure of VWF allows it to support multiple interactions with platelets and endothelial components under high shear stress. Rapid flow conditions induce a conformational transition of the VWF molecule, thus allowing its functional binding domains to be exposed. A specific VWF-cleaving protease (ADAMTS-13) physiologically down regulates the multimeric size of newly released and circulating VWF in order to prevent unwanted platelet thrombus formation. The occurrence of microvascular platelet aggregation in thrombotic thrombocytopenic purpura, which is caused by an ADAMTS-13 deficiency, well-demonstrates the important role of the protease in regulating the adhesive activity of VWF. Better knowledge of VWF function would contribute to the development of novel anti-thrombotic strategies based on the selective inhibition of the VWF interaction with platelet receptors and endothelial components in areas of the circulation characterised by elevated fluid dynamic forces.

Insight into molecular changes of the FIX protein in a series of Italian patients with haemophilia B.

Deficiency or dysfunction of factor IX FIX leads to haemophilia B (HB), an X-linked, recessive, bleeding disorder. On a molecular basis, HB is due to a heterogeneous spectrum of mutations spread throughout the F9 gene. In several instances, a cause-effect relation has been elucidated, in others predicted possibilities have been offered by crystallography inspection and by software-constructed models of the protein. The aim of this study was to contribute to the understanding of HB molecular pathology. The F9 missense mutations we identified in 21 unrelated Italian HB patients by direct sequencing of the whole F9 coding regions were inspected for the causative effect they provoked on the ensuing transcript, and on the protein structure. Each alteration was studied in order to: (i) characterize the defect on the basis of the nature of the mutation; (ii) identify the predicted defect that is induced in the gene and (iii) speculate about the potential, detrimental effects which upset the protein functionality through an idealized FIX model. The resulting data may further contribute to the comprehension of the mechanisms underlying the disease.

Metabolic and genetic risk factors for migraine in children.

Migraine can induce ischaemic stroke, and is considered an independent risk factor for stroke in the young. To date, the nature of the link between migraine and stroke is essentially unknown. Forty-five children were studied. Homocysteine levels (fasting and post methionine load), vitamin B12 and plasma folate levels, factor V Leiden, factor II G20210A, methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C mutations were examined. Compared with controls, patients with migraine had higher levels of post-methionine load homocysteine values (19.5 +/- 4.9 vs. 16.9 +/- 1.9; P = 0.025) and significantly lower folate levels (5.8 +/- 2.6 vs. 7.5 +/- 2.1; P = 0.002). We found a trend toward an increased risk of migraine in subjects carrying a homozygous mutant genotype for MTHFR C677T and MTHFR A1298C polymorphisms. Genetic prothrombotic conditions do not seem to be related to migraine in the young, whereas the biochemical differences between migrainous patients and controls are an appealing topic for further investigation.

Central venous catheter-related complications in children with oncological/hematological diseases: an observational study of 418 devices.

BACKGROUND: The use of indwelling central venous catheters (CVCs) has become commonplace in the management of children undergoing anticancer treatment. Several types of CVC are available, while information on complications observed in children is scarce. We describe the experience of two tertiary care centers in Italy that prospectively followed up three types of CVC used at both institutions over a 30-month period. PATIENTS AND METHODS: Between January 2000 and May 2002, double-lumen (DL) or single-lumen (SL) Hickman-Broviac (HB) catheters, and single-lumen pressure-activated safety valve (PASV) catheters were used and prospectively evaluated. Four types of possible complication were defined a priori: mechanical, thrombotic, malfunctioning and infectious. RESULTS: Four hundred and eighteen CVCs (180 SL-HB, 162 DL-HB and 76 PASV) were inserted in 368 children, for a total of 107 012 catheter days at risk of complication. At least one complication occurred while using 169 of the devices (40%): 46% of the DL-HB, 46% of the PASV and 33% of the SL-HB (P=0.02) catheters. Subjects with hematological malignancies or non-malignant diseases had significantly more complications than those with solid tumors (P <0.0001). Overall, 234 complications were documented: 93 infectious [complication rate per 1000 catheter days at risk (CR)=0.87], 84 malfunctioning (CR=0.78), 48 mechanical (CR=0.45) and nine thrombotic (CR=0.08). SL-HB had statistically fewer infectious complications, while PASV had more mechanical complications. In a multivariate regression model, the most significant risk factors for having a CVC complication were hematological disease [relative risk (RR)=3.0; 95% confidence interval (CI) 1.8-4.8] and age <6 years at CVC insertion (RR=2.5; 95% CI 1.5-4.1). As for the type of CVC, compared with SL-HB, the DL-HB catheter had a statistically significant two-fold increased risk of any complication (RR=2.1; 95% CI 1.2-3.6), while the PASV catheter had a borderline RR of 1.8 (95% CI 1.0-3.6). Analysis by tumor type showed a higher risk of any kind of complication in patients with solid malignancies who had received a DL-HB catheter as compared with an SL-HB catheter (RR=7.2; 95% CI 2.8-18.7). CONCLUSIONS: CVCs may cause complications in up to 40% of patients, with type of CVC, underlying disease and patient age being the three main factors that affect the incidence of CVC-related complications. SL-HB catheters have the best performance.