Population pharmacokinetics of intravenous and oral ciprofloxacin in children to optimize dosing regimens.

PURPOSE: This study aimed to characterize pharmacokinetics of intravenous and oral ciprofloxacin in children to optimize dosing scheme. METHODS: Children treated with ciprofloxacin were included. Pharmacokinetics were described using non-linear mixed-effect modelling and validated with an external dataset. Monte Carlo simulations investigated dosing regimens to achieve a target AUC0-24 h/MIC ratio ≥ 125. RESULTS: A total of 189 children (492 concentrations) were included. A two-compartment model with first-order absorption and elimination best described the data. An allometric model was used to describe bodyweight (BW) influence, and effects of estimated glomerular filtration rate (eGFR) and age were significant on ciprofloxacin clearance. CONCLUSION: The recommended IV dose of 10 mg/kg q8h, not exceeding 400 mg q8h, would achieve AUC0-24 h to successfully treat bacteria with MICs ≤ 0.25 (e.g. Salmonella, Escherichia coli, Proteus, Haemophilus, Enterobacter, and Klebsiella). A dose increase to 600 mg q8h in children > 40 kg and to 15 mg/kg q8h (max 400 mg q8h, max 600 mg q8h if augmented renal clearance, i.e., eGFR > 200 mL/min/1.73 m2) in children < 40 kg would be needed for the strains with highest MIC (16% of Pseudomonas aeruginosa and 47% of Staphylococcus aureus). The oral recommended dose of 20 mg/kg q12h (not exceeding 750 mg) would cover bacteria with MICs ≤ 0.125 but may be insufficient for bacteria with higher MIC and a dose increase according bodyweight and eGFR would be needed. These doses should be prospectively confirmed, and a therapeutic drug monitoring could be used to refine them individually.

Organ donation by Maastricht-III pediatric patients: Recommendations of the Groupe Francophone de Réanimation et Urgences Pédiatriques (GFRUP) and Association des Anesthésistes Réanimateurs Pédiatriques d'Expression Française (ADARPEF) Part I: Ethical considerations and family care.

The French Transplant Health Authority (Agence de la Biomédecine) has broadened its organ- and tissue-donation criteria to include pediatric patients whose death is defined by circulatory criteria and after the planned withdrawal of life-sustaining therapies (WLST) (Maastricht category III). A panel of pediatric experts convened to translate data in the international literature into recommendations for organ and tissue donation in this patient subgroup. The panel estimated that, among children aged 5 years or over with severe irreversible neurological injury (due to primary neurological injury or post-anoxic brain injury) and no progression to brain death, the number of potential donors, although small, deserves attention. The experts emphasized the importance of adhering strictly to the collegial procedure for deciding to withdraw life support. Once this decision is made, the available data should be used to evaluate whether the patient might be a potential donor, before suggesting organ donation to the parents. This suggestion should be reserved for parents who have unequivocally manifested their acceptance of WLST. The discussion with the parents should include both the pediatric intensive care unit (PICU) team under the responsibility of a senior physician and the hospital organ- and tissue-procurement team. All recommendations about family care during the end of life of a child in the PICU must be followed. The course and potential challenges of organ donation in Maastricht-III pediatric patients must be anticipated. The panel of experts recommended strict compliance with French recommendations (by the Groupe Francophone de Réanimation et Urgences Pédiatriques) about WLST and providing deep and continuous sedation until circulatory arrest. The experts identified the PICU as the best place to implement life-support discontinuation and emphasized the importance of returning the body to the PICU after organ donation. French law prohibits the transfer of these patients from one hospital to another. A description of the expert-panel recommendations regarding the organization and techniques appropriate for children who die after controlled circulatory arrest (Maastricht III) is published simultaneously in the current issue of this journal..

Organ donation by Maastricht-III pediatric patients: Recommendations of the Groupe Francophone de Réanimation et Urgences Pédiatriques (GFRUP) and Association des Anesthésistes Réanimateurs Pédiatriques d'Expression Française (ADARPEF). Part II: Specific organizational and technical considerations.

A panel of pediatric experts met to develop recommendations on the technical requirements specific to pediatric controlled donation after planned withdrawal of life-sustaining therapies (Maastricht category III). The panel recommends following the withdrawal of life-sustaining therapies protocol usually applied in each unit, which may or may not include immediate extubation. The organ retrieval process should be halted if death does not occur within 3 h of life-support discontinuation. Circulatory arrest is defined as loss of pulsatile arterial pressure and should be followed by a 5-min no-touch observation period. Death is declared based on a list of clinical criteria assessed by two senior physicians. The no-flow time should be no longer than 30, 45, and 90 min for the liver, kidneys, and lungs, respectively. At present, the panel does not recommend pediatric heart donation after death by circulatory arrest. The mean arterial pressure cutoff that defines the start of the functional warm ischemia (FWI) phase is 45 mmHg in patients older than 5 years and/or weighing more than 20 kg. The panel recommends normothermic regional perfusion in these patients. The FWI phase should not exceed 30 and 45 min for retrieving the pancreas and liver, respectively. There is no time limit to the FWI phase for the lungs and kidneys. The panel recommends routine sharing of experience with Maastricht-III donation among all healthcare institutions involved in order to ensure optimal outcome assessment and continuous discussion on the potential difficulties, notably those related to the management of normothermic regional perfusion in small children.

[Haemorrhagic shock during cerebrospinal fluid shunt procedure. Reassessment of the anaesthetic or surgical practice?]. / Chocs hémorragiques au cours de dérivation interne du liquide céphalorachidien. Faut-il revoir la pratique anesthésique ou chirurgicale?

We report two cases of perioperative haemorrhagic shock after accidental puncture of trunc vessels, during emergency shunt procedures in children who suffer of severe intracranial hypertension. In both cases it's the peritoneal internalization of the shunt with Portnoy trocar which is responsible of these deep vascular wounds. Evolution was favourable in both cases with cardiovascular resuscitation, transfusion and surgical haemostatic correction. Few days later, an internal shunt was performed in the second patient, while the first patient did not need shunt anymore. These two accidents lead to the discussion of the surgical procedure with surgeons, in order to have a better prevention against this complication. We also discuss our anaesthesiological practice from preoperative to perioperative period of this usually non-haemorrhagic surgical procedure.

Pediatric sinogenic epidural and subdural empyema: The role of endoscopic sinus surgery.

AIM: To analyze the indications and outcomes of open neurosurgical approaches (ONA) and endoscopic transnasal approaches (ETA) in the surgical management of pediatric sinogenic subdural and epidural empyema. MATERIAL AND METHODS: Retrospective single-center study design within a tertiary care referral center setting. Children less than 18 years of age consecutively operated on between January 2012 and February 2014 for drainage of a sinogenic subdural empyema (SE) or epidural (EE) empyema were included. MAIN OUTCOME MEASURES: success of first surgical procedure, persistent symptoms and sequelae at the end of the follow-up period. RESULTS: Nine SE (53%) and 8 EE (47%) were observed. Neurological symptoms, especially seizures, were more frequent in the SE group. Perioperative pus samples were positive in 67% of the SE group and in 75% of the EE group. The most frequently isolated bacteria belonged to the Streptococcus anginosus group. CT or MR imaging showed that most empyema probably originated from the frontal sinus. However, two cases resulted from an ethmoiditis and one case from a Pott's puffy tumor, without any direct contact with the paranasal sinus. In cases of SE, the most effective surgical technique was ONA with craniotomy. Associated endoscopic sinus drainage was useful for the purpose of bacteriological diagnosis. In cases of EE, effectiveness was noted in both ONA and ETA techniques. In two cases of EE, the ETA procedure encompassed direct drainage of the empyema through the posterior wall of the frontal sinus (Draf III approach). The number of patients successfully treated after a single surgical procedure was higher in the EE group (p=0.05). Regarding outcomes, no mortalities were observed. Persistent disorders at the end of the follow-up period, especially headaches, cognitive, concentration or schooling problems, tended to be more frequent in the SE group than in the EE group (67% vs 29%), and were more commonly observed in cases requiring several surgical procedures (75% vs 12.5%) (p=0.05). DISCUSSION: Endoscopic sinus surgery plays a critical role in the surgical management of pediatric sinogenic SE and EE. In cases of small volume EE, the endoscopic approach associated with antibiotherapy may be sufficient to treat the infectious process.

Validity of applying TRISS analysis to paediatric blunt trauma patients managed in a French paediatric level I trauma centre.

OBJECTIVE: Using a weighted combination of the Revised Trauma Score (RTS), the Injury Severity Score (ISS), the type of injury (blunt or penetrating) and patient age, the TRISS method is used to calculate the probability of survival (ps) in trauma patients. The goal of this study was to compare the ability of the American Major Trauma Outcome Study (MTOS) norm for adult blunt trauma patients (ADULT) and the specific norm for paediatric patients (PED) to estimate the ps of injured children using TRISS methodology. DESIGN: Retrospective analysis using a paediatric trauma patient database. SETTING: A French level 1 paediatric trauma centre. PATIENTS: Four hundred seven consecutive paediatric blunt trauma patients, treated over a 3-year period. MEASUREMENTS: The observed and expected survivals were compared, using the M, W and Z scores, with both ADULT and PED. The W score is the number of survivors more or less than expected from the MTOS predictions for 100 patients. A Z score, which measures the significance of W, between -1.96 and +1.96, indicates no significant difference between observed and expected survivors. A value of M less than 0.88 indicates a disparity in the severity match between the study group and the MTOS group. We calculated the standardised W score (Ws), which represents the W score that would have been observed if the case mix of severity was identical to that of the MTOS group. Accordingly, a standardised Z score (Zs) was also calculated. In addition, we calculated the area under the receiver operating curve (aROC) using both norms, while calibration was also assessed by calculation of the Hosmer-Lemeshow goodness-of-fit tests. RESULTS: Using PED, the number of actual survivors (n = 364) was not significantly different from the MTOS (n = 358). The value of M, 0.65, indicated a disparity in the severity match between the study group and the MTOS group, due to a higher proportion of patients with lower ps (TRISS < 0.95, 52 vs 27%). We was +1.06% (95% confidence interval -0.34 to 2.08) and Zs was 1.48, indicating no significant difference from the MTOS. Using ADULT, the number of observed survivors (n = 364) was significantly higher than that expected (n = 354), with a W score of +2.70% (Z = +1.98, p < 0.05). There was a disparity in the severity match (M = 0.67) between the study group and the MTOS group, due to a higher proportion of patients with lower ps. Ws was +1.32% (95% confidence interval -0.12 to 2.37) and Zs = +1.79 (NS), indicating no significant difference from the MTOS. The Hosmer-Lemeshow statistics indicated that ADULT (Cg = 7.24, p = 0.51; Hg = 4.45, p = 0.81) and PED (Cg = 6.08, p = 0.64; Hg = 3.55, p = 0.90) provided sufficient goodness-of-fit. There was no significant difference in the aROC of the TRISS between the two norms (0.935 +/- 0.050 vs 0.936 +/- 0.050; NS). CONCLUSION: Both adult and paediatric norms were equally good predictors of the probability of survival of injured children, provided that Ws and Zs are used when there is a disparity in the severity match between the study group and the MTOS group.

[Anesthetic management for craniosynostosis]. / Prise en charge anesthésique des craniosténoses.

Surgical procedures for correction of craniosynostosis are performed in young infants with a small blood volume and represent major surgery with extensive blood loss. An accurate determination and a precise restoration of blood losses represent the major concern for the anaesthetist during this surgery. The preoperative assessment of these patients is usually simple, except in the cases where the craniosynostosis is associated with other congenital malformations. The anaesthetist should keep in mind that intracranial hypertension may be associated with craniosysnostosis, which modify the anaesthetic management, especially the induction of anaesthesia. Even though the psychological impact of a craniosynostosis should be taken into consideration, surgery is most often indicated for functional considerations, therefore parents should be informed of the risks related to the procedure. During the postoperative period the major concerns are related to the possibility of a persistent bleeding, which usually decreases and disappears over the first 12 hours.

[Effect of a lung contusion on the prognosis of severe head injury in the child]. / Effet de la contusion pulmonaire sur le pronostic du traumatisme crânien grave chez l'enfant.

OBJECTIVES: To assess the effects of a pulmonary contusion (PC) on the outcome of a severe head trauma (SHT) in children less than 15-year-old. STUDY DESIGN: Retrospective study. PATIENTS: The study included 30 severely head injured children with a Glasgow Coma Scale score (GCS) < or = 8, associated with a PC (PC+) diagnosed on a thoracic CT-scan and 30 severely head injured children without PC (PC-). METHODS: Outcome was assessed using the Glasgow Outcome Scale (GOS), on discharge and six months later. Age, body weight, gender, GCS, PTS, ISS, hypoxaemia, arterial hypotension, the results of the cerebral CT-scan, the main treatment administered, complications, the duration of tracheal intubation as well as the duration of stay in the intensive care unit (ICU) and in the hospital were compared between groups. RESULTS: GCS median was lower (6 vs 8, P = 0.001) and ISS median higher (25 vs 23, P = 0.0004) in the PC+ group. Hypoxaemia was more frequent in the PC+ group (n = 12 vs n = 0, P = 0.0001). There was no difference between groups regarding the results of cerebral CT scan. Blood transfusion was more frequently used in the PC+ group (n = 14 vs n = 5, P = 0.03). Median duration of tracheal intubation, and of stay in the ICU and in the hospital were shorter in the PC- group (respectively 8 vs 6 days, P = 0.03; 10 vs 7.5 days, P = 0.008; 13.5 vs 10.5 days, P = 0.01). No difference was observed regarding complications between groups. GOS on discharge was higher in the PC+ group (3 vs 2, P = 0.01). There was an increase in GOS at six months in the two groups, however GOS remained significantly higher in the PC+ group (median values 2 vs 1, P = 0.002). A favourable outcome occurred less frequently in the PC+ group on discharge and at six months (respectively n = 14 vs 25, P = 0.006; n = 20 vs 28, P = 0.02). CONCLUSION: The association of a PC to a severe head trauma is responsible for a poorer outcome in children, probably because, at least in part, a higher incidence of hypoxaemia.

[Acute hemolysis following perioperative blood salvage in chldren operated for the surgical correction of craniosynostosis]. / Hémolyse aiguë au décours d'une chirurgie de correction d'une craniosténose utilisant l'autotransfusion périopératoire chez un nourrisson.

We report the case of a 6-month-old child, who suffered from acute haemolysis following transfusion of salvaged blood. This complication, of favourable outcome, was related to the accidental aspiration of benzalkonium chloride into the cell saver. This case emphasizes that any adjunction of antiseptic solution is contraindicated during blood saving. The use of a cell saver must be associated with written protocols, describing clearly the contraindications, precautions of use, and the different steps of use of this method of autologous blood transfusion.

[Anesthesia and intensive care of craniostenosis and craniofacial dysmorphism in children]. / Anesthésie-réanimation des craniosténoses et dysmorphies craniofaciales de l'enfant.

Craniosynostosis occurs in one out of 2,000 births. It results in primary skull deformations requiring surgical repair, in infants with a body weight of less than 10 kg. Pure craniosynostosis is the most frequent situation, where the risk for cerebral compression during brain development is the lowest. Therefore the aim of surgical correction in this case is mainly cosmetic. Conversely, in syndromic craniosynostosis, associated malformations are more common and cerebral, visual and respiratory consequences of complex facio-craniosynostosis are usually severe. Current surgical techniques consist of a total skull vault reconstruction which carry a high risk of sudden and major blood losses. Intraoperatively, whatever the type of craniosynostosis, mean blood losses corresponding to 90% of estimated red cell mass have to be anticipated. These blood losses vary according to the type of skull deformation and the type of surgery. Accurate evaluation is usually difficult and must be based more on calculation of red cell mass variations than on simple monitoring of surgical drainage. Invasive haemodynamic monitoring is always required. To reduce the amount of homologous blood transfusion, peroperative haemodilution seems to be the most suitable technique, due to unresolved technical difficulties in autotransfusion practice in infants. Severe facial deformities are associated with chronic hypoxaemia and cerebral compression representing major risk for these children in poor condition undergoing such major surgical procedures. With experienced teams, this high-risk surgery carries a low peroperative mortality (less than 1%) and morbidity rate. The latter includes essentially transient peroperative hypotension. The excellent final cosmetic and functional results justify the practice of this surgery in children with a bodyweight of less than 10 kg.

[Antiphospholipid antibody syndrome in pediatric neurosurgery: a hemostasis problem]. / Syndrome des anticorps antiphospholipides en neurochirurgie pédiatrique: un problème d'hémostase.

The case of a 11-year-old boy under anticoagulant therapy for a familial antiphospholipid antibody syndrome (SAAPF), who underwent surgery for a cerebrovascular malformation responsible for an intracerebral haematoma, is reported. Antivitamins K (AVK) were changed for unfractioned heparin (HNF), three days before. Heparin was discontinued two hours prior to surgery to obtain a normal peroperative coagulation. A vascular dural fistula was removed without any haemostatic problem. The neurological status rapidly returned to normal and tomodensitometry at day 1 showed a normal intracranial status. Heparin was readministered at h 16. Thrombocytopenia occurred at day 4 of heparin treatment. The change for a low weight molecular heparinoid, danaparoid (Orgaran), normalized the platelet count. The platelets aggregation tests were negative during thrombopenia. However, the test for antibodies against the PF4-heparin complex with the Elisa technique, was in favour of a heparin induced thrombocytopenia (TIH). In spite of its anecdotic occurrence due to cumulative thrombotic risks from the association of immunologic disorders (TIH and SAAPF), this case report underlines the value but also the risks of anticoagulant therapy in neurosurgery, when patients are at high risk for thrombosis.

[Pulmonary embolism in sclerotherapy for a venous malformation in a child under general anesthesia]. / Embolie pulmonaire au cours de la sclérothérapie percutanée d'un angiome veineux sous anesthésie générale chez un enfant.

We report a case of pulmonary embolism associated with percutaneous sclerotherapy (absolute ethanol: 0.5 mL.kg-1) of a venous angioma, performed under general anaesthesia in a 13 year-old child. The diagnosis of pulmonary embolism, suspected on the clinical setting and symptoms, was supported by the pulmonary scintigraphy obtained 4 hours later, showing 3 minimal pulmonary defects. The outcome was rapidly favourable without sequelae under heparin administration and the pulmonary scintigraphy, performed on day 7, was normal. The role of absolute ethanol, for explaining the apparent contrast between the severity of the symptoms and the minimal obstruction noted on pulmonary scintigraphy is discussed. Also discussed are the prophylactic and curative therapeutic issues of this severe complication.

[Anesthesia-resuscitation for intracranial expansive processes in children]. / Anesthésie-réanimation des processus expansifs intracrâniens de l'enfant.

The most frequent space-occupying cerebral lesions in children are brain tumors, mostly posterior fossa tumors and haematoma resulting from arteriovenous malformation rupture. They result in intracranial hypertension, directly or by compression of the cerebrospinal fluid pathway resulting in hydrocephalus. Their localization and compressive effects are responsible for specific neurological deficits and general problems. Posterior fossa lesions carry a high risk of obstructive hydrocephalus, cranial nerves palsy and brain stem compression, pituitary and chiasmatic tumors a risk of blindness, pituitary deficiency and diabetes insipidus, and cortical tumors a risk of motor deficit and epilepsy. All these parameters must be analyzed before choosing anaesthetic protocols, and surgical techniques. In the presence of life-threatening intracranial hypertension, emergency anaesthetic induction, tracheal intubation and ventilation are life-saving. The specific treatment consists in either hydrocephalus derivation, initial medical treatment with osmotherapy, or rarely surgical removal. In other situations, surgical process requires a highly deep, stable anaesthesia with perfect control of cerebral haemodynamics. Surgical positioning is complex for these long lasting procedures and carries specific risks. The most common is venous air embolism in the sitting position that must be prevented by the use of specific measures. In the postoperative period, the risk of neurological and general complications commands close surveillance, fast track extubation must be adapted on an individual basis.

Intracerebral activity of antibiotics against Listeria monocytogenes during experimental rhombencephalitis.

We used a model of rhombencephalitis in gerbils to test the efficacy of various antibiotics against Listeria monocytogenes. Gerbils were inoculated in the middle ear with strain EGD and treated subcutaneously with various antibiotics alone or in combination. We found that the most active antibiotics on intracerebral bacteria were amoxycillin, co-trimoxazole, rifampicin and imipenem. Vancomycin, gentamicin and ciprofloxacin were weakly or not active. The combinations amoxycillin-co-trimoxazole, amoxycillin-gentamicin and co-trimoxazole-rifampicin were highly active against intracerebral bacteria.

A gerbil model for rhombencephalitis due to Listeria monocytogenes.

Rhombencephalitis due to Listeria monocytogenes is a frequent complication of human listeriosis, inducing a high mortality and severe neurological sequelae despite antibiotic therapy. However, there is no animal model which consistently reproduces clinical rhombencephalitis. Here, we present a model of Listeria rhombencephalitis in gerbils. Animals were inoculated in the middle ears with a low infective dose of L. monocytogenes, thus creating prolonged otitis media with persistent bacteremia. Gerbils developed a severe rhombencephalitis with circling syndrome, paresia, ataxia, rolling movements. The invasion of the central nervous system was visualized on living animals by resonance magnetic imaging and characterized by bacterial growth in the brain, reaching about 10(7) bacteria in the rhombencephalum by day 12 of infection. The histological lesions were mainly located in the brainstem, and consisted in coalescent, necrotic abscesses with perivascular sheaths, mimicking those observed in human rhombencephalitis. Bacteria were detected by electronmicroscopy inside infectious foci, either free in necrotic material or inside inflammatory cells, mainly polymorphonuclear cells. This gerbil model of Listeria rhombencephalitis will be useful to study the molecular mechanisms allowing bacteria to cross the blood-brain barrier, and to evaluate the intracerebral efficacy of antibiotics.