Filippia Aroni

Pharmacological Aspects and Potential New Clinical Applications of Ketamine: Reevaluation of an Old Drug

Ketamine, the phencyclidine derivative described in 1965, is an intravenous anesthetic with a variety of applications. The enthusiasm following its initial release subsided due to side effects from the central nervous system. New anesthetics limited the role of ketamine in anesthetic practice. However, its hemodynamically stable profile, along with its beneficial respiratory properties and analgesic potency, rendered the drug invaluable in battlefield medicine, sedation of the uncooperative child, analgesia, and sedation in burn units. Reevaluation, though, of analgesic properties of ketamine resulted in new interest regarding its use in perioperative and chronic pain management. Moreover, recent studies in the effects of the substance on intracranial pressure and cerebral blood flow led to revising the recommendation against its use in brain injury. Furthermore, the bronchodilating effects of the substance led to increasing interest for potential use in asthma treatment. In addition, separation of the 2 enantiomers and subsequent separate studies indicated beneficial results of the S(+) one. Thus, new controlled multicentered clinical trials are to be conducted to justify approval for new uses of ketamine and take advantage of its unique range of applications.

A metabolomic approach in an experimental model of hypoxia-reoxygenation in newborn piglets: urine predicts outcome

Perinatal asphyxia is one of the leading causes of morbidity and mortality in the neonatal period. Response to oxygen treatment is unpredictable and the optimum concentration of oxygen in neonatal resuscitation is still a matter of debate among neonatologists. A metabolomic approach was used to characterize the metabolic profiles of newborn hypoxic-reoxygenated piglets. Urine samples were collected from newborn piglets (n = 40) undergoing hypoxia followed by resuscitation at different oxygen concentrations (ranging from 18% to 100%) and analyzed by 1H NMR spectroscopy. Despite reoxygenation 7 piglets, out of 10 which became asystolic, did not respond to resuscitation. Profiles of the 1H NMR spectra were submitted to unsupervised (principal component analysis) and supervised (partial least squares-discriminant analysis) multivariate analysis. The supervised analyses showed differences in the metabolic profile of the urine collected before the induction of hypoxia between survivors and deaths. Metabolic variations were observed in the urine of piglets treated with different oxygen concentrations comparing T0 (basal value) and end of the experiment (resuscitation). Some of the individual metabolites discriminating between these groups were urea, creatinine, malonate, methylguanidine, hydroxyisobutyric acid. The metabolomic approach appears a promising tool for investigating newborn hypoxia over time, for monitoring the response to the treatment with different oxygen concentrations, and might lead to a tailored management of the disorder.

The role of novel biomarkers in early diagnosis and prognosis of acute kidney injury in newborns.

Acute kidney injury (AKI) refers to the rapid loss of renal function. In clinical practice, AKI is common among hospitalized patients of all age groups including neonates and remains an important cause of morbidity and mortality due to its late diagnosis and therefore delayed therapeutic intervention. Although the precise incidence of AKI in newborn is unknown, several studies have reported that 8 to 24% of all critically ill newborns in neonatal intensive care units may develop the condition. We aim at reviewing the existing literature on novel serum and urinary biomarkers and discuss their role in the early diagnosis and prognosis of AKI in newborns. Specifically, this review will focus on cystatin C (CysC), neutrophil gelatinase-associated lipocalin (NGAL) and interleukin-18 (IL-18) in serum and on CysC, NGAL, kidney injury molecule-1, and IL-18 in urine.

Conventional Direct Laryngoscopy versus Videolaryngoscopy with the GlideScope®: A Neonatal Manikin Study with Inexperienced Intubators

We hypothesized that because the view of the glottis is better with videolaryngoscopes, successful intubation in neonates would be accomplished in a shorter time with the GlideScope (®) (Verathon, Inc., Bothell, WA) videolaryngoscope (GVL). Forty-five students of the University of Athens, inexperienced in both techniques, participated in the study (21 medical students and 24 nursing students, crossover randomized study). Following a brief educational session, each participant practiced and attempted intubation on a neonatal manikin using conventional laryngoscope and GVL, as many times as required to secure the airway. The time required to successful intubation and the number of attempts with each device were recorded. No significant difference was observed between the number of attempts required for successful intubation with either laryngoscope. The time required for the first successful intubation with the conventional laryngoscope was significantly shorter compared with that required with the GVL ( P = 0.0013). There was no difference regarding the time required for the successful intubation between medical and nursing students, using the conventional laryngoscope or the GVL. The number of attempts to successful intubation with either device did not differ. The time required for intubation with the GVL was longer, and this is probably due to a design flaw.

Hypoxia/reoxygenation-induced myocardial lesions in newborn piglets are related to interindividual variability and not to oxygen concentration

OBJECTIVE: Evaluation of myocardial histological changes in an experimental animal model of neonatal hypoxia-reoxygenation. METHODS: Normocapnic hypoxia was induced in 40 male Landrace/Large White piglets. Reoxygenation was initiated when the animals developed bradycardia (HR <60 beats/min) or severe hypotension (MAP <15 mmHg). The animals were divided into four groups based on the oxygen (O2) concentration used for reoxygenation; groups 1, 2, 3, and 4 received 18%, 21%, 40%, and 100% O2, respectively. The animals were further classified into five groups based on the time required for reoxygenation: A: fast recovery (<15 min); B: medium recovery (15-45 min); C: slow recovery (45-90 min); D: very slow recovery (>90 min), and E: nine deceased piglets. RESULTS: Histology revealed changes in all heart specimens. Interstitial edema, a wavy arrangement, hypereosinophilia and coagulative necrosis of cardiomyocytes were observed frequently. No differences in the incidence of changes were observed among groups 1-4, whereas marked differences regarding the frequency and the degree of changes were found among groups A-E. Coagulative necrosis was correlated with increased recovery time: this condition was detected post-asphyxia in 14%, 57%, and 100% of piglets with fast, medium, and slow or very slow recovery rates, respectively. CONCLUSIONS: The significant myocardial histological changes observed suggest that this experimental model might be a reliable model for investigating human neonatal cardiac hypoxia-related injury. No correlation was observed between the severity of histological changes and the fiO2 used during reoxygenation. Severe myocardial changes correlated strictly with recovery time, suggesting an unreported individual susceptibility of myocardiocytes to hypoxia, possibly leading to death after the typical time-sequence of events.

An experimental model of neonatal normocapnic hypoxia and resuscitation in Landrace/Large White piglets

Objective: The aim of this study is to describe and evaluate an experimental model of neonatal normocapnic hypoxia and resuscitation. Methods: Ten male Landrace/Large White neonatal piglets were studied. Following anaesthesia and intubation, the animals were mechanically ventilated. Surgical procedures included catheterization of the right internal jugular vein and the carotid artery. After stabilization with 21% O2, normocapnic hypoxia was induced by decreasing the inspired O2 to 6–8%. When piglets developed bradycardia (heart rate < 60 beats/min), reoxygenation was initiated by administering 21% O2. Arterial blood samples were taken during baseline, hypoxia and reoxygenation in order to measure interleukine-6 and interleukine-8. Results: Nine out of ten animals were successfully resuscitated (one of these required chest compressions and a dose of adrenaline) and one died despite resuscitation efforts. After returning to baseline haemodynamic values, euthanasia was performed using thiopental overdose. Conclusions: Haemodynamic fluctuations at baseline, during normocapnic hypoxia and reoxygenation in Landrace/Large White piglets are comparable to that in human neonates, making the breed a favorable model of human neonatal hypoxia investigation.

Histopathology of renal asphyxia in newborn piglets: Individual susceptibility to tubular changes

AIM To analyze the effects on the kidney of hypoxia-reoxygenation in an experimental model of normocapnic asphyxia. METHODS To this end, 40 newborn Landrace/Large-White piglets aged 1-4 d were studied in this work. Hypoxia was induced by decreasing the inspired fiO2 to 0.06-0.08. Animals were resuscitated with different fiO2 and subdivided into 4 groups: group 1, 2, 3 and 4 received 18%, 21%, 40% and 100% O2 respectively. Macroscopic examination was carried out to evidence possible pathological features. Tissue sample were obtained from both kidneys. Four or five micron paraffin sections were stained with H-E and PAS stain and examined under an optical microscope. RESULTS Pathological changes, mainly affecting tubular cells, were observed in the vast majority of kidneys of asphyxiated piglets. The most frequent tubular changes were: tubular casts (95%), tubular dilatation (87.5%), tubular vacuolization (70%), tubular eosinophilia (52.5%), sloughing (50%), fragmentation of the brush border (50%), oedema (32.5%), apoptosis (15%) and glomerular changes (meningeal cell proliferation, capsular adhesion between the flocculus and Bowmans capsule, glomerulosclerosis and fibrous or cellular crescents associated with collapse of the glomerular tuft). Statistical analysis was carried out on changes observed when the animals were allocated in the 4 groups (χ(2)-test 0.05). The statistical analysis showed no evidence of differences regarding kidney lesions among the animals groups. CONCLUSION Our data show that renal pathology in newborn piglets is characterized by interindividual variability to hypoxia and is not associated with oxygen concentration.

The role of Levosimendan in cardiopulmonary resuscitation

Although initial resuscitation from cardiac arrest (CA) has increased over the past years, long term survival rates remain dismal. Epinephrine is the vasopressor of choice in the treatment of CA. However, its efficacy has been questioned, as it has no apparent benefits for long-term survival or favorable neurologic outcome. Levosimendan is an inodilator with cardioprotective and neuroprotective effects. Several studies suggest that it is associated with increased rates of return of spontaneous circulation as well as improved post-resuscitation myocardial function and neurological outcome. The purpose of this article is to review the properties of Levosimendan during cardiopulmonary resuscitation (CPR) and also to summarize existing evidence regarding the use of Levosimendan in the treatment of CA.

Inflammation and oxidative stress biomarkers in neonatal brain hypoxia and prediction of adverse neurological outcome: a review

Despite advances in perinatal care, the outcome of newborns with hypoxic-ischemic encephalopathy is poor and the issue still remains challenging in neonatology. The use of an easily approachable and practical biomarker not only could identify neonates with severe brain damage and subsequent adverse outcome, but could also target the group of infants that would benefit from a neuroprotective intervention. Recent studies have suggested interleukin-1b, interleukin-6, tumour necrosis alpha (TNF-a) and neuron specific enolase (NSE) to be potential biomarkers of brain damage in asphyxiated newborns. S100B, lactate dehydrogenase, nitrated albumin-nitrotyrosine, adrenomedullin, activin-A, non protein bound iron, isoprostanes, vascular endothelial growth factor and metalloproteinases have also been proposed by single-centre studies to play a similar role in the field. With this review we aim to provide an overview of existing data in the literature regarding biomarkers for neonatal brain damage.

S100B immunoreactivity: a new marker of hypoxia-related cardiac damage in newborn piglets.

Abstract Objective: The evaluation of the expression of S100B protein, in the swine heart in an experimental model of hypoxia - reoxygenation. Methods: Normocapnic hypoxia was induced in 40 male Landrace/Large White neonatal piglets by decreasing the inspired concentration of oxygen to 6–8%. When animals developed bradycardia or severe hypotension, reoxygenation was initiated. Piglets were allocated in four groups of 10, according to the oxygen concentration they were reoxygenated with: Group 1, 2, 3 and 4 resuscitated with 18%, 21%, 40% and 100% oxygen, respectively. The animals were further classified into 4 groups according with the time required for reoxygenation: group A (<15 min); group B (16–60 min); group C (>60 min); group D (deceased animals). Results: Immunostaining for S100B protein was detected in 14 out of the 40 heart samples (35%), both inside the cytoplasm of cardiomyocytes and as globular deposits in the interstitial spaces. Significant differences were observed among groups 1–4 regarding S100B expression. Reactivity for S100B in cardiac cells was detected in 50%, 50%, 10% and 33% of animals in groups 1 and 2, 3 and 4, respectively. Marked differences were also observed among groups A–D: 75%, 33%, 12% and 22% of the animals in group 1, 2, 3 and 4, respectively, showed reactivity for S100B in the heart. Conclusions: Expression of S100B protein occurred in the heart of some of newborn piglets following severe hypoxia. S100B storage in cardiomyocytes correlates with the different oxygen concentration used during reoxygenation, being higher in piglets reoxygenated with 18% and 21%, and lower in animals reoxygenated with 40% oxygen. Intermediate levels of S100B expression were found in 100% O2-treated animals. The finding of a higher percentage of S100B-immunoreactive hearts in piglets with a fast recovery and the detection of a decreased reactivity in animals with a slow and a very slow recovery clearly indicates S100B protein as an early protective factor with a positive prognostic value in asphyxiated newborn piglets.