High doses of benzodiazepine predict analgesic and sedative drug withdrawal syndrome in paediatric intensive care patients.

AIM: Critically ill children can develop withdrawal syndrome after prolonged analgesia and sedation in a paediatric intensive care unit (PICU), when treatment is stopped abruptly or reduced quickly. The aim of this study was to evaluate the incidence of withdrawal syndrome in patients after three or more days of analgesic or sedative drug therapy, using a validated scale. We also analysed the association between withdrawal syndrome and the patients' outcome and factors related to analgesia and sedation treatment. METHODS: This prospective observational study analysed 89 periods of weaning from analgesia and sedation in 60 children between October 2010 and October 2011. Of these, 65% were less than six months old and 45% were admitted to the PICU after heart surgery. Withdrawal syndrome was assessed using the Withdrawal Assessment Tool-1 (WAT-1) scale. RESULTS: The incidence of withdrawal syndrome was 37%, and the only variable that predicted its presence was the highest administered dose of benzodiazepine. The duration of weaning, Sophia Observational Withdrawal Symptom scale score and nurse judgment were also associated with positive WAT-1 scores. CONCLUSION: Withdrawal syndrome should be considered after three or more days of analgesic or sedative treatment. A high dose of benzodiazepine increases the risk of developing withdrawal symptoms.

Practice of analgesia and sedation in Italian Paediatric Intensive Care Units: did we progress?

BACKGROUND: No strong recommendation was reported in management analgesia and sedation of critically ill children. The present study was performed to describe the current practice of analgesia and sedation in Pediatric Italian Intensive Care Units, in order to evaluate the adherence to last published pediatric guidelines. METHODS: A questionnaire was sent to 24 Italian Paediatric Intensive Care Units during 2010. RESULTS: One Hundred percent of contacted centers returned the filled form. All Pediatric Italian Intensive Care Units used the same combination (opioid plus benzodiazepine); 50% of centers referred to regularly monitor the level of sedation, but only 37% of them used validate tools. Withdrawal syndrome was regularly monitored in 25% of contacted Pediatric Italian Intensive Care Units; Finnegan scale was the only adopted scale. CONCLUSION: National pediatric intensivists identified the same drug strategy to obtain analgesia and sedation in their patients, according to last published guidelines. Assessment of analgesia and sedation was more diffuse but not regularly performed and different methods were used. Withdrawal syndrome was monitored in a minority of contacted centres. Considering our data the practice of analgesia and sedation in Italian Pediatric Intensive Care Units is improved but not yet completely adherent to last international recommendations.

Assessing sedation in a pediatric intensive care unit using Comfort Behavioural Scale and Bispectral Index: these tools are different.

BACKGROUND: The aim of this paper was to monitor comfort in pediatric critical ill patients which is necessary to adequate analgesic and sedative therapy. The primary objective of this prospective observational study was to measure the level of sedation in a Pediatric Intensive Care Unit (PICU) of a tertiary care Hospital, using Comfort Behavioural Scale (CBS) and Bispectral Index (BIS), evaluating the agreement between these tools; secondly we analyzed the correlation of an adequate level of sedation and patient's outcome. METHODS: We enrolled 46 patients, mechanically ventilated for almost 12 hours, monitored at a basal level and during a stimulus (tracheal suctioning). As outcome variables we analyzed: length of ventilation and PICU stay, duration of sedative therapy and weaning, time between beginning of sedative administration and start of weaning, presence of infection. RESULTS: Twenty-six percent (doctor CBS score), 34.8% (nurse CBS score) and 73.9% (BIS) of our population were found adequately sedated; none state of undersedation was reported. During the stimulus the percentage of adequately sedated patients according to CBS became 78.2%. CBS level of agreement versus BIS was weak. No significative difference was found between doctor and nurse CBS score. Length of PICU stay and duration of sedative administered were significant shorter in patients adequately sedated at Bispectral Index monitoring; no outcome variable resulted significant looking at CBS score. CONCLUSION: Our data support the risk of oversedation in critically ill patients and the difference between CBS and BIS, especially in evaluating light oversedation state. The presence of an excessive level of sedation evaluated by BIS was associated with duration of hospitalization and sedative administration.

[Use of protein C concentrate in critical conditions: clinical experience in pediatric patients with sepsis]. / Il concentrato di proteina C negli stati critici: l'esperienza clinica nei pazienti pediatrici settici.

The coagulation disturbance, typical of septic conditions, is associated to a reduction of clotting factors in plasma with an "acquired" deficiency (from consumption) of protein C. As observed with "purpura fulminans" in neonates affected by congenital protein C deficiency, administration of protein C concentrate has proved to reduce thrombotic manifestations and to improve morbidity and mortality of children with septic shock. The Protein C concentrate is presently utilized as a therapy for patients with a congenital deficiency of protein C and several papers in the literature support the efficacy of protein C concentrate in the treatment of children with meningococcus septicemia, with the aim of correcting the acquired protein C deficiency often seen in septic conditions and shown to be strongly correlated to a higher morbidity and mortality. Protein C, given as a plasma concentrate, can exert its therapeutic actions only after activation once in the blood stream: clinical trials with the use of protein C concentrate failed to show any increased risk of bleeding or related disorders. At our PICU 8 children, with sepsis, septic shock and purpura have been treated with protein C concentrate (Ceprotin); because the plasma protein C level was lower than the normal range (mean value 0.32 IU/ml, range 0.11-0.6 IU/ml). Six children have shown a rapid response to all therapeutic efforts and survived without sequelae and two are died. No adverse reaction was observed during and after Ceprotin administration to all patients.

Amiodarone inhibits lung degradation of SP-A and perturbs the distribution of lysosomal enzymes.

Amiodarone may induce lung damage by direct toxicity or indirectly through inflammation. To clarify the mechanism of direct toxicity, we briefly exposed rabbit alveolar macrophages to amiodarone and analyzed their morphology, synthesis, and degradation of dipalmitoylphosphatidylcholine (DPPC); distribution of lysosomal enzymes; and uptake of diphtheria toxin and surfactant protein (SP) A used as tracers of the endocytic pathway. Furthermore, in newborn rabbits, we studied the clearance of DPPC and SP-A instilled into the trachea together with increasing amounts of amiodarone. We found that in vitro amiodarone decreases the surface density of mitochondria and lysosomes while increasing the surface density of inclusion bodies, increases the incorporation of choline into DPPC, modifies the distribution of lysosomal enzymes, and does not affect the uptake and processing of diphtheria toxin but inhibits the degradation of SP-A. In vivo amiodarone inhibits the degradation of SP-A but not of DPPC. We conclude that the acute exposure to amiodarone perturbs the endocytic pathway acting after the early endosomes, alters the traffic of lysosomal enzymes, and interferes with the turnover of SP-A.

Functional approach to infants and young children with noisy breathing: validation of pneumotachography by blinded comparison with bronchoscopy.

Flow-volume loop evaluation yields considerable diagnostic information about adult patients with upper airway obstruction. No conclusive data support the reliability of this method in young children with noisy breathing. We used analysis of flow-volume loops at tidal breathing (TB-FV) as a first diagnostic approach to young children presenting with persistent noisy breathing (chronic stridor and/or wheezing). Flexible fiberoptic bronchoscopy was performed to establish a conclusive diagnosis and was used to verify the accuracy of the preliminary functional localization of the airway obstruction causing noisy breathing. The physician conducting pneumotachography was blinded to the bronchoscopic findings in the study, and the investigators conducting bronchoscopy were blinded to the pneumotachographic findings. Through a 6-yr period, 113 consecutive young children (ranging in age from 15 to 48 mo) with noisy breathing were enrolled in the study. Three morphologically abnormal TB-FV patterns, as compared with the normal round-shaped TB-FV loops obtained with 15 healthy children, were identified in 110 patients. A TB-FV pattern of inspiratory fluttering was found in 26 subjects and in the first 3 yr of the study was always associated with an endoscopic diagnosis of isolated laryngomalacia. Subsequently, this pattern was used to diagnose isolated laryngomalacia in 18 other infants, in whom endoscopy was avoided. Of infants with endoscopic evidence of airway obstruction ranging from the glottis to the mainstem bronchi (49 subjects), all but three showed a TB-FV loop pattern characterized by expiratory-limb flattening. A concave expiratory loop, with early expiratory peak flow and low flow at low volume, was invariably associated with peripheral bronchoconstriction, without endoscopic evidence of anatomic abnormalities (20 cases). In conclusion, TB- FV loop analysis is a noninvasive, accurate method of establishing the site of airway obstruction in young children with recurrent stridor and/or wheezing. Clinical use of this method may provide interesting pathophysiologic information and may be useful in addressing the diagnostic management of such children.

Polyethylenimine shows properties of interest for cystic fibrosis gene therapy.

Before being considered for a cystic fibrosis (CF) gene therapy trial, any gene delivery agent must be able to show that it produces low levels of toxicity as well as being able to protect the DNA from nuclease degradation. Here we show that complexes of linear polyethylenimine (L-PEI) and DNA can repeatedly be administered to animals (up to 21 consecutive days) without eliciting an immune response against PEI/DNA particles or inducing toxic side effects due to accumulation of PEI in the lungs. However, the host response to the exogenous protein resulted in some decrease of expression. PEI-mediated transfection was unaffected by treatment of the complexes with DNase (frequently used to reduce the viscosity of lung secretions in CF patients). Taken together, these properties make L-PEI a valuable vector for gene therapy of CF.

Uptake and degradation of Curosurf after tracheal administration to newborn and adult rabbits.

This paper examines the removal from the airways of Curosurf, a commercial surfactant derived from porcine lungs, administered at pharmacological concentrations to newborn or adult animals. Curosurf was labelled by the addition of radioactive dipalmitoyl phosphatidylcholine (DPPC) and administered intratracheally to newborn and adult rabbits at a dose of 200 mg x kg(-1) body weight. The disappearance of DPPC from the airways and its appearance in alveolar macrophages, lung parenchyma, lamellar bodies, serum, liver, kidneys and brain was then studied for 24-48 h. The in vitro degradation of Curosurf DPPC by alveolar macrophages was also studied. During the first 3 h after instillation, large amounts of Curosurf left the airways and became associated with tissue, indicating that it mixed rapidly with the endogenous pools of surfactant. A fraction of administered DPPC became associated with the lamellar bodies, suggesting that Curosurf can be recycled. Curosurf administration did not stop the secretion of endogenous surfactant. Very little intact radioactive DPPC could be recovered at any time in alveolar macrophages, however, macrophages have the ability, in vitro, to degrade Curosurf. Newborn rabbits lose Curosurf from the lungs at a slower rate than adult rabbits. One and two days after instillation, organic extracts from the liver, kidney, brain and serum contained small but measurable amounts of radioactivity. These results indicate that Curosurf rapidly enters the pathways of surfactant metabolism and that alveolar macrophages may play an important role in the catabolism of Curosurf.

Inhaled nitric oxide in hypoxaemic newborns who are candidates for extracorporeal life support.

The aim of this study was to evaluate the effect of inhaled nitric oxide (NO) in newborns with acute hypoxaemic respiratory failure and the impact of this NO therapy on survival and the need for extracorporeal membrane oxygenation (ECMO). A cohort of newborns with a gestational age of > or = 34 weeks and an oxygenation index (OI) > 25 were prospectively evaluated. Patients were given NO at an initial dose of 10 parts per million (ppm). Oxygenation parameters were evaluated prior and during NO inhalation. From January 1994 to December 1996, 20 infants were enrolled in the study. Based upon their outcome, patients were divided into two groups: survivors with no need for ECMO, group A (n=8) and survivors requiring ECMO or nonsurvivors, group B (n=12). All infants approached or met ECMO criteria before NO inhalation. Eight patients (40%) were successfully managed with NO and conventional treatment (group A). Newborns in this group showed a rapid and sustained improvement of systemic oxygenation during NO inhalation. Mean arterial oxygen tension (Pa,O2) increased significantly from 4.5 kPa (34 mmHg) (95% confidence interval (95% CI) 1.9-7.1 kPa (14.4-53.7 mmHg)) to 10.1 kPa (75.7 mmHg) (95% CI 6.5-13.6 kPa (49.1-1023 mmHg)) after 1 h and was 9.0 kPa (67.7 mmHg) (95% CI 7.1-11.0 kPa (53.1-82.4 mmHg)) at 24 h. Conversely, none of the oxygenation parameters improved in the 12 patients who ultimately required ECMO or died (group B). The results indicate that inhaled nitric oxide can improve systemic oxygenation in newborns with acute respiratory failure and may reduce the need for extracorporeal membrane oxygenation support in candidates. Lack of a rapid response to nitric oxide may be an early predictor of unfavourable short-term outcome, prompting a move towards alternative treatments.

ExGen 500 is an efficient vector for gene delivery to lung epithelial cells in vitro and in vivo.

Nonviral vectors might represent a safe alternative to adenovirus for gene therapy of lung disorders, in particular cystic fibrosis (CF). Cationic lipids have been shown to correct the CF defect both in vitro and in vivo, but more efficient vectors are needed to improve the low gene transfer efficiency. Here, we show that the cationic polymer ExGen 500, a linear polyethylenimine derivative, is more efficient than cationic lipids in transferring reporter genes to lung epithelial cells in vitro. In vivo ExGen 500 was able to mediate gene transfer into both newborn and adult rabbit lungs with comparable efficiencies. The best levels of transfection were obtained using neutral complexes. Under such conditions, luciferase activities corresponding to about 10(3) RLU/10 s/mg of protein were reproducibly obtained 2 days after transfection throughout the four lung lobes of newborn and adult rabbits. A nlslacZ reporter gene showed transfected cells around the lumen of large and small bronchi. No signs of acute toxicity (inflammation, cellular infiltration etc) were detected by direct histopathological analysis. Within 1 week after instillation, transgene expression decreased by two orders of magnitude.

[The evolution of care for the critical child: pediatric intensive care]. / L'evoluzione dell'assistenza al bambino critico: la terapia intensiva pediatrica.

Pediatric intensive care units (PICUs) have been developed to provide intensive care for children between post-neonatal age and adolescence. These units have largely been developed in North America, mainly in tertiary hospitals. In Italy, critically ill children are still often nursed on adult ICU's, where medical and nursing staff often lack pediatric training. Here we report the first 5-year experience of the multidisciplinary PICU developed at the Department of Pediatrics, University of Padua, focusing on PICU and patients characteristics, as well as on the evaluation of outcome by means of the Pediatric Risk of Mortality (PRISM) score.

[Extracorporeal membrane oxygenation (ECMO) in the newborn infant and the child with intractable respiratory failure]. / Ossigenazione extracorporea a membrana (ECMO) nel neonato e nel bambino con insufficienza respiratoria intrattabile.

Extracorporeal membrane oxygenation (ECMO) has become a nearly standard treatment for neonates with refractory hypoxemic respiratory failure due to various disease. Even though in the non-neonatal age the experience is less extensive, an increased widespread interest on the possible applications in children with severe life-threatening respiratory or cardiovascular insufficiency is well documented in the literature. General contraindications include presence of active bleeding, underlying lethal disease, congenital malformations, or severe brain damage. Whilst in the neonatal population common entry criteria have been widely accepted, the identification of precise parameters capable to predict mortality and thus indicating an ECMO support in older patients are still lacking. At present, nonetheless, more than 10.000 newborns and 1.000 children with severe respiratory insufficiency at high mortality risk have received an ECMO treatment, with a survival rate of more than 80% and 50%, respectively. The initial results of our ECMO program for both neonatal and pediatric patients with refractory respiratory failure are encouraging, both in terms of mortality and morbidity, and they will be briefly discussed.

[Transportation of the critical newborn infant and child]. / II trasporto del neonato e del bambino critico.

Advance in the science and technology of neonatal and pediatric critical care have resulted in improved outcome for high risk newborn and children. Effective interhospital transport programmes are necessary for the appropriate use of resources and has become an integral component of regionalized perinatal care. It is now well established that use of an organized neonatal and pediatric transport team results in a fall in mortality and morbidity of infant. The American College of Obstetrician and Gynecologist and, recently, American Academy of Pediatrics published guidelines and recommendations for safe interhospital transfer of neonates, infants and children. Training of personnel, selection of equipment, organization and communication between hospitals are critical elements of a successful transport system. We present an overview of the role, principles and operating procedures of such neonatal-pediatric transport team and the basis of clinical stabilization before and during transfer. We also discuss data of the first 17 month experience of the Neonatal-Pediatric Transport Service of the Department of Pediatrics, University of Padua.

[Nitric oxide via inhalation in the newborn infant and the child with acute hypoxemic respiratory failure]. / Ossido nitrico per via inalatoria nel neonato e nel bambino con insufficienza respiratoria ipossiemica acuta.

Inhaled nitric oxide (NO) has been recently proposed as a new treatment in newborns and children with severe hypoxemic respiratory failure. Differently from other vasodilators, inhaled nitric oxide selectively lowers pulmonary vascular resistance and pulmonary arterial pressure, and improves the ventilation/perfusion matching by directing pulmonary blood flow toward better ventilated areas, ultimately improving systemic oxygenation. In our experience, we have observed that inhaled NO may acutely ameliorate gas exchange in patients with severe respiratory failure. This may allow a reduction of both ventilatory parameters and fraction of inspired oxygen, thus limiting further damage to the lungs. Nonetheless, the underlying disease and the clinical conditions before NO treatment seem to maintain a crucial role in the ultimate prognosis of these patients. Further studies are needed in order to better define indications, dosages, and safety of nitric oxide treatment, and to verify its authentic prognostic value in neonates and children with acute respiratory failure.

[Congenital diaphragmatic hernia: the use of ECMO and other modern therapeutic strategies]. / Ernia congenita diaframmatica: impiego dell'ECMO e di altre moderne strategie terapeutiche.

Congenital diaphragmatic hernia (CDH) with severe respiratory failure is still associated with significant mortality. Modern treatment of CDH is now widely accepted to be delayed repair after stabilization. Availability of Extracorporeal Membrane Oxygenation (ECMO) led up to real improvement in survival. Several others modalities have been recently used in attempting to reduce the need for ECMO or, otherwise, to improve outcome. Multicenter controlled trial of high-frequency oscillatory ventilation (HFOV), exogenous surfactant replacement, nitric oxide (NO) inhalation and, more recently, liquid ventilation have been reported. We describe four cases of CDH treated in our ECMO-centre from 1993 to date, 25% surviving. One patient died by pulmonary hypertension and multiorgan failure while on ECMO; one by pulmonary hypertension and cardiac failure and one by sepsis, both ones far from effective ECMO weaning. All patients underwent extracorporeal bypass because of Oxygenation Index (OI) ranging 65-215. Venovenous has been always made but one patient needed early switching on venoarterial. Several trials with surfactant and nitric oxide were performed during extracorporeal bypass. In survived patient, diaphragmatic defect was repaired out of ECMO. Patients survived to the weaning underwent vascular reconstruction. Our ECMO data confirm worse prognosis for CDH rather than other ECMO requiring diseases (we report 66.7% surviving in overall ECMO application); we underline real improvement by using alternative therapies together with extracorporeal bypass and primary role of OI as predicting index for ECMO.

SP-A, SP-B, and SP-C in surfactant subtypes around birth: reexamination of alveolar life cycle of surfactant.

Transformations of surfactant after secretion are incompletely understood. To clarify them, we lavaged lungs in fetuses and in newborn rabbits, fractionated the lavage fluid by differential and density gradient centrifugation, and analyzed the distribution of surfactant protein (SP) phospholipids, SP-A, SP-B, and SP-C. Furthermore, we administered into trachea of newborn rabbits labeled surfactant and compared the alveolar clearance of SP-A, SP-B, SP-C and saturated phosphatidylcholine. We found that, in the fetus, secreted lamellar bodies contain all components of surfactant, except a small amount of SP-A. As breathing starts and new surfactant subtypes are generated, the proteins are mostly associated with dense subtypes, but SP-B and SP-C are especially concentrated in dense materials that contain minor amounts of phospholipids and SP-A. Furthermore, we found that, during breathing, alveolar surfactant is degraded into more than one type of remnant, that the lavage fluid contains a pool of SP-A not associated with membranes, and that SP-A, SP-B, and SP-C are all turned over at a faster rate than saturated phosphatidylcholine.

Primary occlusion of the iliac and femoral artery in two newborn infants: efficacy of medical treatment.

Arterial occlusion not associated with umbilical artery catheterization is a rare condition in the newborn period. Two neonates with femoral and iliac artery occlusion in the first days of life are presented. While almost all the cases described in the literature underwent surgical treatment, these two infants received only pharmacological treatment with good results. Although angiography remains the examination of choice for the diagnosis, noninvasive angiologic evaluations such as oscillometry and Doppler flow examination have been used for both diagnosis and follow-up. The etiology in these two cases remains unknown. The results obtained with these two neonates suggest that with prompt recognition of this disorder and an aggressive medical treatment, a complete recovery could be achieved.

Rapid improvement of static compliance after surfactant treatment in preterm infants with respiratory distress syndrome.

Respiratory mechanics were measured in 20 preterm infants before and in the 24-hr period after treatment with surfactant. All infants were enrolled in the rescue clinical trial with Curosurf carried out in the Neonatal Intensive Care Unit. They received a dose of 200 mg/kg lipid surfactant intratracheally after birth. Static compliance of the respiratory system (Crs) was measured by the single breath occlusion technique during both spontaneous and mechanical ventilation. Resistance of the respiratory system (Rrs) and expiratory time constant (Trs) were also measured. As early as 3 hr after surfactant administration a significant improvement of 45% in Crs measured during mechanical ventilation (CrsV) was noted (0.40 +/- 0.14 vs 0.58 +/- 0.17 mL/cm H2O/kg, P < 0.001), together with a significant improvement of the arterial/alveolar O2 tension ratio (Pa/AO2) (0.12 +/- 0.03 vs 0.30 +/- 0.16, P < 0.01). The improvement of CrsV and Pa/AO2 was confirmed 24 hr later (0.55 +/- 0.15 mL/cm H2O/kg and 0.33 +/- 0.18, respectively). A significant correlation was found between Crs and Pa/AO2 ratio (r = 0.56, P < 0.001). Time constant values were significantly higher after surfactant treatment (0.15 +/- 0.07 vs 0.09 +/- 0.03 sec; P < 0.01). Rrs remained unchanged. These data indicate that Curosurf given intratracheally after birth determines a rapid improvement of respiratory mechanics as soon as 3 hr after dosing, together with the improvement of oxygenation. From the findings obtained with the present study we show evidence that respiratory system mechanics may be a useful physiological measure to guide ventilatory strategy following surfactant therapy.

A placebo-controlled crossover trial using trazodone in pediatric migraine.

An 8-month, double-blind, placebo-controlled cross-over trial was carried out on the use of trazodone in pediatric migraine prophylaxis. It involved 40 patients aged 7 to 18 years old and suffering from migraine without aura, randomly divided into 2 groups. After a 4-week run-in period, Group A received oral trazodone (1 mg/kg a day divided into 3 doses) for 12 weeks, while Group B received a placebo. After a further 4-week washout period, Group A was given the placebo and Group B was treated with trazodone for a further 12 weeks. The trial was completed by 35 patients, the number of drop-outs being comparable in the two groups. During the first treatment period, both the frequency and the duration of the migraine episodes were significantly reduced in both groups. During the second, a significant further improvement in both parameters was only observed in Group B. No side-effects were observed at any time. Our results showed that, like other antidepressants, trazodone is a valid prophylactic agent for juvenile migraine.