Comparison of "IN-REC-SUR-E" and LISA in preterm neonates with respiratory distress syndrome: a randomized controlled trial (IN-REC-LISA trial).

BACKGROUND: Surfactant is a well-established therapy for preterm neonates affected by respiratory distress syndrome (RDS). The goals of different methods of surfactant administration are to reduce the duration of mechanical ventilation and the severity of bronchopulmonary dysplasia (BPD); however, the optimal administration method remains unknown. This study compares the effectiveness of the INtubate-RECruit-SURfactant-Extubate (IN-REC-SUR-E) technique with the less-invasive surfactant administration (LISA) technique, in increasing BPD-free survival of preterm infants. This is an international unblinded multicenter randomized controlled study in which preterm infants will be randomized into two groups to receive IN-REC-SUR-E or LISA surfactant administration. METHODS: In this study, 382 infants born at 24+0-27+6 weeks' gestation, not intubated in the delivery room and failing nasal continuous positive airway pressure (nCPAP) or nasal intermittent positive pressure ventilation (NIPPV) during the first 24 h of life, will be randomized 1:1 to receive IN-REC-SUR-E or LISA surfactant administration. The primary outcome is a composite outcome of death or BPD at 36 weeks' postmenstrual age. The secondary outcomes are BPD at 36 weeks' postmenstrual age; death; pulse oximetry/fraction of inspired oxygen; severe intraventricular hemorrhage; pneumothorax; duration of respiratory support and oxygen therapy; pulmonary hemorrhage; patent ductus arteriosus undergoing treatment; percentage of infants receiving more doses of surfactant; periventricular leukomalacia, severe retinopathy of prematurity, necrotizing enterocolitis, sepsis; total in-hospital stay; systemic postnatal steroids; neurodevelopmental outcomes; and respiratory function testing at 24 months of age. Randomization will be centrally provided using both stratification and permuted blocks with random block sizes and block order. Stratification factors will include center and gestational age (24+0 to 25+6 weeks or 26+0 to 27+6 weeks). Analyses will be conducted in both intention-to-treat and per-protocol populations, utilizing a log-binomial regression model that corrects for stratification factors to estimate the adjusted relative risk (RR). DISCUSSION: This trial is designed to provide robust data on the best method of surfactant administration in spontaneously breathing preterm infants born at 24+0-27+6 weeks' gestation affected by RDS and failing nCPAP or NIPPV during the first 24 h of life, comparing IN-REC-SUR-E to LISA technique, in increasing BPD-free survival at 36 weeks' postmenstrual age of life. TRIAL REGISTRATION: ClinicalTrials.gov NCT05711966. Registered on February 3, 2023.

Establishment of an Italian chronic migraine database: a multicenter pilot study.

To optimize chronic migraine (CM) ascertainment and phenotype definition, provide adequate clinical management and health care procedures, and rationalize economic resources allocation, we performed an exploratory multicenter pilot study aimed at establishing a CM database, the first step for developing a future Italian CM registry. We enrolled 63 consecutive CM patients in four tertiary headache centers screened with face-to-face interviews using an ad hoc dedicated semi-structured questionnaire gathering detailed information on life-style, behavioral and socio-demographic factors, comorbidities, and migraine features before and after chronicization and healthcare resource use. Our pilot study provided useful insights revealing that CM patients (1) presented in most cases symptoms of peripheral trigeminal sensitization, a relatively unexpected feature which could be useful to unravel different CM endophenotypes and to predict trigeminal-targeted treatments' responsiveness; (2) had been frequently admitted to emergency departments; (3) had undergone, sometime repeatedly, unnecessary or inappropriate investigations; (4) got rarely illness benefit exemption or disability allowance only. We deem that the expansion of the database-shortly including many other Italian headache centers-will contribute to more precisely outline CM endophenotypes, hence improving management, treatment, and economic resource allocation, ultimately reducing CM burden on both patients and health system.

Serotonin receptor targeted therapy for migraine treatment: an overview of drugs in phase I and II clinical development.

INTRODUCTION: Research has focused on serotonin (5-HT) 5-HT1D and 5-HT1F receptors to develop drugs acting through non-vasoconstrictive mechanisms for treating acute migraine and those targeting 5-HT2B and 5-HT7 receptors for preventing migraine. Areas covered: This paper reviews antimigraine drugs targeting 5-HT receptors in one phase I trial (sumatriptan iontophoretic transdermal system, TDS) and five phase II clinical trials (PNU-142633, LY334370, lasmiditan, NOX-188). Expert opinion: Data from our overview on investigational drugs in phase I and II clinical trials using the 5-HT1B/1D receptor agonist (sumatriptan TDS), 5-HT1D receptor agonist (PNU-142633), 5-HT1F receptor agonists (LY334370, lasmiditan) and a combined 5-HT1B/1D receptor agonist with nNOS inhibition (NOX-188) provided encouraging data for sumatriptan TDS and lasmiditan, disappointing results for PNU-142633, and promising findings for NOX-188. The 5-HT1F receptor agonist lasmiditan, a drug acting through non-vasoconstrictive mechanisms, represents a promising safe, effective and tolerated acute migraine therapy also for patients at cardiovascular risk. Upcoming phase III trials should clarify the optimal lasmiditan dose and eventual clinical advantages over triptans. The negative results for the PNU-142633 trial prompt further studies using specific compounds more precisely targeting 5-HT1D receptors. Antagonism at 5-HT2B and 5-TH7 receptors, a promising strategy to prevent migraine, is still limited to experimental migraine models.

The phenotype of migraine with unilateral cranial autonomic symptoms documents increased peripheral and central trigeminal sensitization. A case series of 757 patients.

BACKGROUND: Migraine with unilateral cranial autonomic symptoms (UAS) is a putative migraine endophenotype with convincing response to trigeminal-targeted treatments that still needs a thorough characterization. OBJECTIVE: The objective of this article is to carefully investigate the clinical phenotype of migraine with UAS in a large group of patients for more accurate migraine diagnoses, improved clinical management, and better outcome prediction. METHODS: We studied 757 consecutive episodic and chronic migraineurs in a tertiary headache clinic with face-to-face interviews, detailing in depth their lifestyle, sociodemographic and headache characteristics. RESULTS: Migraineurs with UAS (37.4%) differed from the general migraine population with respect to longer attack duration (OR = 2.47, p < 0.02, having >72-hour long attacks), more strictly unilateral (OR = 3.18, p < 0.001) and severe headache (OR = 1.72, p = 0.011), more frequent allodynia (OR = 3.03, p < 0.001) and photophobia (OR = 1.87, p = 0.019). CONCLUSIONS: Migraine patients with UAS are characterized not only by symptoms due to intense peripheral trigeminal activation but also to central sensitization. Our study broadens the knowledge on the clinical and phenotypic characteristics of migraine with UAS, suggests pathophysiological implications, and supports the need for future prospective clinical studies.

Rationale for use of onabotulinum toxin A (BOTOX) in chronic migraine.

Chronic migraine is a severely disabling headache evolving from episodic migraine as a result of different transforming factors and characterized by atypical pain modulation and peripheral and central sensitization. Discovered by serendipity, onabotulinum toxin A (BoNT-A) represents the only drug specifically approved for CM prophylaxis. According to the dominant opinion, BoNT-A acts peripherally, impairing the exocytosis of neuropeptide and neurotransmitter and the delivery of receptors and ion channels on the cell surface of peripheral trigeminal endings, thereby indirectly reducing central sensitization. However, it is not excluded that BoNT-A has also a central antinociceptive action, probably associated with an enhanced opioidergic and GABA-ergic transmission. This review discusses the rationale for use of BoNT-A in CM including its mechanisms of action and molecular targets and provides suggestions for a more tailored BoNT-A prophylaxis in patients with CM.

Lung recruitment strategies and surfactant in neonatal intensive care unit.

Several studies in the lamb model have shown that hyperinflation of the lungs early in life may cause a blunted response to surfactant with signs of lung injury and any attempt to recruit lung volume in the surfactant deficient preterm infant by large lung inflations at birth should be potentially dangerous. As regards the situation when surfactant is given later, as rescue treatment for established RDS, the evidence for a clinically beneficial effect of a recruitment maneuver is yet insufficient and, hopefully, future studies will gather more data on this aspect.

Treatment of tension-type headache: from old myths to modern concepts.

Tension-type headache (TTH) is the second most common human disease, accounting for intense disability, high costs and numerous workdays lost. Tension-type headache is less simple and easy-to-treat than commonly thought. Antidepressants, despite their poor tolerability, are still the first-choice drugs for preventing TTH. The most widely studied non-pharmacological approach to TTH, cognitive-behavioral techniques, effectively relieve pain only in selected patients. The most frequently used and recommended treatments for acute TTH, NSAIDs and paracetamol have scarce efficacy as documented by their low therapeutic gain over placebo in the 2-h pain-free response. Their effectiveness may be increased by a more proper use and by the adjunction of caffeine, antiemetics, myorelaxants or tranquillizers but the risk of medication-overuse headache must be considered. Hence, the need for more effective and tailored treatments in TTH remains.

Dopaminergic symptoms in migraine.

Migraine pain is often preceded, accompanied and followed by dopaminergic symptoms (premonitory yawning and somnolence, accompanying nausea and vomiting, postdromal somnolence, euphoria and polyuria). After reviewing evidence from pharmacological, biochemical, genetic and animal experimental studies on the relationship between dopamine and migraine, and matching these data with patients' clinical features, we postulate that migraine attacks could be characterized by an ictal dopamine release in a subject with dopamine receptor hypersensitivity due to a chronic dopaminergic deficit synergistic to serotoninergic impairment. Our review suggests that when the attack begins, a low dopamine plasma concentration stimulates hypersensitive central presynaptic dopamine receptors thus causing prodromal symptoms such as yawning and somnolence. Increasing dopamine levels, though still insufficient to stop trigeminovascular activation, stimulate postsynaptic dopamine receptors thus inducing nausea, vomiting and hypotension. Finally, dopamine levels slowly return to baseline, giving rise to somnolence and fatigue, but, in some cases, continue to rise triggering postdromal symptoms such as euphoria and polyuria.

Effectiveness of treatment with surfactant in premature infants with respiratory failure and pulmonary infection.

INTRODUCTION: Surfactant inactivation is present in neonatal pneumonia. MATERIALS AND METHODS: One hundred thirty-nine preterm babies with Birth Weight (BW) < or = 1250 grams were studied and subdivided in two groups: RDS Group, with a diagnosis of "simple" RDS (N 80) and RDS with Pneumonia Group, consisting of babies with a diagnosis of RDS and a positive BALF culture in the first 24-48 h of life (N 59). OUTCOMES: Surfactant administration seems less effective in the latter group, because a significantly higher number of infants needed a second dose of surfactant, compared to the patients suffering from RDS alone. (www.actabiomedica.it).

Target fraction of inspired oxygen during open lung strategy in neonatal high frequency oscillatory ventilation: a retrospective study.

BACKGROUND: There is no agreement to define the target FiO2 to adopt in the lung recruitment phase during HFOV in preterm infants. We report our experience of an optimal lung volume strategy (OLVS), defined as FiO2≤0.25 during the recruitment phase, in a cohort of neonates with gestational age (GA) ≤27 weeks treated with elective HFOV for respiratory distress syndrome (RDS) between July 2006 and September 2008. METHODS: FiO2 used during the recruitment phase was different according to physician' evaluation. 51 newborns were then divided into two groups: patients reaching FiO2≤0.25 (OLVS Group, N.=28), and patients reaching FiO2>0.25 (No-OLVS Group, N.=23). RESULTS: Prior to surfactant administration OLVS Group, respect to No-OLVS Group, received a significantly higher continuous distending pressure (CDP): 12.8±1.1 cmH2O vs 11.2±1.3 cmH2O (P<0.0001) and a significantly lower FiO2: 0.25±0.01 vs 0.35±0.06 (P<0.0001). A multivariate modeling approach confirmed that OLVS was significantly associated to the need for less surfactant doses (OR 0.19[95% CI 0.05-0.84]), a decreased risk of ductus arteriosus surgically ligated (OR 0.13[95% CI 0.02-0.86]) and to a lower number of ventilation hours before extubation: -152 (95% CI -284- -20). CONCLUSION: OLVS to fully recruit the lungs achieving FiO2≤0.25 during elective HFOV is associated with better short-term pulmonary outcomes respect to a strategy where the patients received a FiO2>0.25 during the recruitment phase. Utilizing HFOV in this way provides a more effective means to recruit and protect acutely injured lungs.

Migraine prophylaxis: what is new and what we need?

A wide array of options are now available for migraine prophylaxis. Conventional treatments include beta-blockers, anticonvulsants, antidepressants, calcium antagonists and antiserotoninergic drugs. Emerging medications such as ACE inhibitors, sartans and nutritional supplements are gaining favour for migraine prophylaxis. Botulinum toxin type A is a promising therapeutic tool for chronic migraine. Tonabersat is likely to be a step forward for the treatment of migraine with aura. However, much work is needed to identify predictive clinical features of successful responsiveness and to better define the duration of prophylaxis.

Proteomics and neonatal infection.

Antimicrobial peptides plays an important role in the host innate defence network, even in humans. Recent studies demonstrated the capacity of human airways epithelial cells to synthesize antimicrobial peptides, and their multifunctional role in the primary immunity. The presence of ct-defensins in bronchoalveolar lavage fluid (BALF) was investigated in a cohort of preterm newborns with gestational age (GA) < or =30 weeks. BALF samples were analysed by High Performance Liquid Chromatography Electrospray Ionization Mass Spectrometer. Our data show that preterm newborns, also at the lower GA, are able to produce defenses, underlining that their innate defence system is already active before the at-term delivery date.

Hypertension as a risk factor for migraine chronification.

Progression of episodic migraine to chronic migraine may be related to comorbid medical conditions. In this study, we focused on the role played by arterial hypertension in migraine transformation. Several studies reveal that hypertension is associated with chronic migraine and may induce migraine chronification. Hypertension probably amplifies the effects of migraine on the vascular wall further enhancing the endothelial dysfunction in cerebral vasculature. Consequently, monitoring of blood pressure is recommended in migraineurs showing an otherwise unexplained increase in attack frequency. Studies are needed to verify if prophylactic treatment with drugs improving endothelial function (e.g. calcium channel blockers, beta blockers, calcium inhibitors, ACE inhibitors and sartans) may selectively ameliorate the course of migraine in these patients.

A case-control study on excessive daytime sleepiness in episodic migraine.

Migraine patients often complain of sleepiness, a problem that manifests both during and outside an attack, may impair the quality of life and can lead to potentially harmful situations. Findings from an uncontrolled study suggest that a high percentage of migraineurs experience excessive daytime sleepiness (EDS). We investigated EDS in a case-control study on 100 patients with episodic migraine and 100 age- and sex-matched healthy controls and also assessed sleep quality, anxiety and depression. Although it was found that EDS was more frequent in migraineurs than in controls (14% vs. 5%; odds ratio 3.1; 95% confidence interval 1.1-8.9), the frequency was lower than previously reported. EDS correlated with migraine disability, sleep problems and anxiety. EDS in patients with migraine probably stems from the full constellation of headache-sleep-affective symptoms resulting from the complex clinical burden of the disease.

Excessive daytime somnolence in Parkinson's disease. Follow-up after 1 year of treatment.

Excessive daytime somnolence (EDS) and quality of sleep were studied in 25 parkinsonian patients at baseline, when they had not yet received any antiparkinsonian medication, and after 1 year of treatment with dopaminergic drugs. EDS was measured by the Epworth Sleepiness Scale (ESS) and sleep quality by the Pittsburgh Sleep Quality Index (PSQI). At baseline, the ESS score was not different from that of age-matched healthy controls. The mean ESS score increased significantly after 1 year of follow-up, being more than 10 in 12 patients. The mean PSQI also increased significantly after 1 year of treatment, but there were no differences in the number of "bad sleepers" at baseline and at follow-up. In conclusion, EDS seems to emerge during the course of the illness, at least in a proportion of PD patients, and could represent another clinical correlate of the interaction between the ongoing neurodegenerative process and the side effects of drugs.

Donepezil in the treatment of hallucinations and delusions in Parkinson's disease.

As cholinergic mechanisms may be at least partially responsible for hallucinations and delusions in Parkinson's disease (PD), we conducted an open study in 8 PD patients to assess the efficacy and tolerability of the cholinesterase inhibitor donepezil, 5 mg at bedtime for two months, in the treatment of these complications. Hallucinations and delusions improved significantly in all patients. Donezepil was overall well tolerated, but a deterioration in motor disability was noted in 2 out of 8 patients.

Tardive dyskinesias in the elderly.

The progressive ageing of the population will produce an increase of those neuropsychiatric disturbances (late onset psychosis, behavioural disturbances of dementia, psychosis in Parkinson's disease) which may require treatment with antipsychotics. However, aged individuals are at higher risk for the development of adverse events from these drugs, namely extrapyramidal disturbances and tardive dyskinesias (TD). TD are a complex disorder, and despite much work done both in basic science and in clinical studies, many issues are still unresolved, such as risk factors, natural history and response to treatment. Although TD may be a mild disorder, it may become debilitating in a proportion of patients. As treatment is often quite disappointing, efforts are directed to its prevention. In this respect, atypical antipsychotics, with their peculiar mixed dopamine-serotonin antagonism, present a clear advantage over classic neuroleptics in young schizophrenic patients, with a lower incidence of TD during chronic treatment. Data are accumulating to show that this is likely to be true also in older patients.