Propranolol 0.1% eye micro-drops in newborns with retinopathy of prematurity: a pilot clinical trial.

BACKGROUND: Oral propranolol reduces retinopathy of prematurity (ROP) progression, although not safely. This study evaluated safety and efficacy of propranolol eye micro-drops in preterm newborns with ROP. METHODS: A multicenter open-label trial, planned according to the Simon optimal two-stage design, was performed to analyze safety and efficacy of propranolol micro-drops in newborns with stage 2 ROP. To this end, hemodynamic and respiratory parameters were monitored, and blood samples were collected weekly, for 3 wk. Propranolol plasma levels were also monitored. The progression of the disease was evaluated with serial ophthalmologic examinations. RESULTS: Twenty-three newborns were enrolled. Since the fourth of the first 19 newborns enrolled in the first stage of the study showed a progression to stage 2 or 3 with plus, the second stage was prematurely discontinued. Even though the objective to complete the second stage was not achieved, the percentage of ROP progression (26%) was similar to that obtained previously with oral propranolol administration. However, no adverse effects were observed and propranolol plasma levels were significantly lower than those measured after oral administration. CONCLUSION: Propranolol 0.1% eye micro-drops are well tolerated, but not sufficiently effective. Further studies are required to identify the optimal dose and administration schedule.

Oral propranolol for retinopathy of prematurity: risks, safety concerns, and perspectives.

OBJECTIVE: To evaluate safety and efficacy of oral propranolol administration in preterm newborns affected by an early phase of retinopathy of prematurity (ROP). STUDY DESIGN: Fifty-two preterm newborns with Stage 2 ROP were randomized to receive oral propranolol (0.25 or 0.5 mg/kg/6 hours) added to standard treatment or standard treatment alone. To evaluate safety of the treatment, hemodynamic and respiratory variables were continuously monitored, and blood samples were collected weekly to check for renal, liver, and metabolic balance. To evaluate efficacy of the treatment, the progression of the disease (number of laser treatments, number of bevacizumab treatments, and incidence of retinal detachment) was evaluated by serial ophthalmologic examinations, and plasma soluble E-selectin levels were measured weekly. RESULTS: Newborns treated with propranolol showed less progression to Stage 3 (risk ratio 0.52; 95% CI 0.47-0.58, relative reduction of risk 48%) or Stage 3 plus (relative risk 0.42 95% CI 0.31-0.58, relative reduction of risk 58%). The infants required fewer laser treatments and less need for rescue treatment with intravitreal bevacizumab (relative risk 0.48; 95% CI 0.29-0.79, relative reduction of risk 52 %), a 100% relative reduction of risk for progression to Stage 4. They also had significantly lower plasma soluble E-selectin levels. However, 5 of the 26 newborns treated with propranolol had serious adverse effects (hypotension, bradycardia), in conjunction with episodes of sepsis, anesthesia induction, or tracheal stimulation. CONCLUSION: This pilot study suggests that the administration of oral propranolol is effective in counteracting the progression of ROP but that safety is a concern.

A novel RRM2B mutation associated with mitochondrial DNA depletion syndrome.

Mitochondrial DNA (mtDNA) depletion syndromes are disorders characterized by infantile-onset, severe progression, and the drastic loss of mtDNA content in affected tissues. In a patient who showed severe hypotonia, proximal tubulopathy and sensorineural hearing loss after birth, we observed severe mtDNA depletion and impaired respiratory chain activity in muscle due to heterozygous variants c.686G > T and c.551-2A > G in RRM2B, encoding the p53R2 subunit of the ribonucleotide reductase.

Study protocol: safety and efficacy of propranolol in newborns with Retinopathy of Prematurity (PROP-ROP): ISRCTN18523491.

BACKGROUND: Despite new therapeutic approaches have improved the prognosis of newborns with retinopathy of prematurity (ROP), an unfavourable structural and functional outcome still remains high. There is high pressure to develop new drugs to prevent and treat ROP. There is increasing enthusiasm for anti-VEGF drugs, but angiogenic inhibitors selective for abnormal blood vessels would be considered as an optimal treatment.In an animal experimental model of proliferative retinopathy, we have recently demonstrated that the pharmacological blockade of beta-adrenoreceptors improves retinal neovascularization and blood retinal barrier breakdown consequent to hypoxia. The purpose of this study is to evaluate the propranolol administration in preterm newborns suffering from a precocious phase of ROP in terms of safety and efficacy in counteracting the progression of retinopathy. METHODS/DESIGN: Preterm newborns (gestational age at birth lower than 32 weeks) with stage 2 ROP (zone II-III without plus) will be randomized, according to their gestational age, to receive propranolol added to standard treatment (treatment adopted by the ETROP Cooperative Group) or standard treatment alone. Propranolol will be administered until retinal vascularization will be completely developed, but not more than 90 days. Forty-four participants will be recruited into the study. To evaluate the safety of propranolol administration, cardiac and respiratory parameters will be continuously monitored. Blood samplings will be performed to check renal, liver and metabolic balance. To evaluate the efficacy of propranolol, the progression of the disease, the number of laser treatments or vitrectomies, the incidence of retinal detachment or blindness, will be evaluated by serial ophthalmologic examinations. Visual function will be evaluated by means of behavioural standardized tests. DISCUSSION: This pilot study is the first research that explores the possible therapeutic role of beta blockers in ROP. The objective of this research is highly ambitious: to find a treatment simple, inexpensive, well tolerated and with few adverse effects, able to counteract one of the major complications of the prematurity. Any favourable results of this research could open new perspectives and original scenarios about the treatment or the prevention of this and other proliferative retinopathies. TRIAL REGISTRATION: Current Controlled Trials ISRCTN18523491; ClinicalTrials.gov Identifier NCT01079715; EudraCT Number 2010-018737-21.

Dramatic effect of levetiracetam in early-onset epileptic encephalopathy due to STXBP1 mutation.

BACKGROUND: Syntaxin Binding Protein 1 (STXBP1) mutations determine a central neurotransmission dysfunction through impairment of the synaptic vesicle release, thus causing a spectrum of phenotypes varying from syndromic and non-syndromic epilepsy to intellectual disability of variable degree. Among the antiepileptic drugs, levetiracetam has a unique mechanism of action binding SV2A, a glycoprotein of the synaptic vesicle release machinery. PATIENT DESCRIPTION: We report a 1-month-old boy manifesting an epileptic encephalopathy with clonic seizures refractory to phenobarbital, pyridoxine and phenytoin that presented a dramatic response to levetiracetam with full epilepsy control and EEG normalization. Genetic analysis identified a novel de novo heterozygous mutation (c.[922A>T]p.[Lys308(∗)]) in the STXBP1 gene that severely affects the protein. CONCLUSIONS: The observation of a dramatic efficacy of levetiracetam in a case of STXBP1 epileptic encephalopathy refractory to other antiepileptic drugs and considerations regarding the specific mechanism of action of levetiracetam modulating the same system affected by STXBP1 mutations support the hypothesis that this drug may be able to reverse specifically the disease epileptogenic abnormalities. Further clinical observations and laboratory studies are needed to confirm this hypothesis and eventually lead to consider levetiracetam as the first choice treatment of patients with suspected or confirmed STXBP1-related epilepsies.

Considerations and approaches in determining the protein and energy composition of preterm infant formulas.

Optimal early nutritional support is considered a crucial issue in the care of the preterm infant, particularly of those with very low- or extremely low-brithweight. Unfortunately, this goal is seldom satisfactorily attained. Several conditions such as hypoxia, acidosis, patent ductus arteriosus, drug therapy, reduced intestinal motility may interfere with an adequate nutritional delivery in the early neonatal period. Moreover, there is still concern about metabolic and intestinal tolerance of the currently suggested intakes and a lack of uniformity in the nutritional program among different NICUs. Finally, the vast majority of the available preterm formulas are not fully adequate to the real nutritional needs of these infants. Inadequate protein content and inappropriate protein energy ratio of most preterm formulas represent a matter of major concern, since there is a strict relationship between formula composition and the quantity and quality of weight gain. As a consequence there is a need of at least two milk formulas for different preterm infants: one for LBW and VLBW infants, the other for preterm infants weighing >1500 g.

The pathophysiology of retinopathy of prematurity: an update of previous and recent knowledge.

Retinopathy of prematurity (ROP) is a disease that can cause blindness in very low birthweight infants. The incidence of ROP is closely correlated with the weight and the gestational age at birth. Despite current therapies, ROP continues to be a highly debilitating disease. Our advancing knowledge of the pathogenesis of ROP has encouraged investigations into new antivasculogenic therapies. The purpose of this article is to review the findings on the pathophysiological mechanisms that contribute to the transition between the first and second phases of ROP and to investigate new potential therapies. Oxygen has been well characterized for the key role that it plays in retinal neoangiogenesis. Low or high levels of pO2 regulate the normal or abnormal production of hypoxia-inducible factor 1 and vascular endothelial growth factors (VEGF), which are the predominant regulators of retinal angiogenesis. Although low oxygen saturation appears to reduce the risk of severe ROP when carefully controlled within the first few weeks of life, the optimal level of saturation still remains uncertain. IGF-1 and Epo are fundamentally required during both phases of ROP, as alterations in their protein levels can modulate disease progression. Therefore, rhIGF-1 and rhEpo were tested for their abilities to prevent the loss of vasculature during the first phase of ROP, whereas anti-VEGF drugs were tested during the second phase. At present, previous hypotheses concerning ROP should be amended with new pathogenetic theories. Studies on the role of genetic components, nitric oxide, adenosine, apelin and ß-adrenergic receptor have revealed new possibilities for the treatment of ROP. The genetic hypothesis that single-nucleotide polymorphisms within the ß-ARs play an active role in the pathogenesis of ROP suggests the concept of disease prevention using ß-blockers. In conclusion, all factors that can mediate the progression from the avascular to the proliferative phase might have significant implications for the further understanding and treatment of ROP.

Heart Rate and Arterial Pressure Changes during Whole-Body Deep Hypothermia.

Whole-body deep hypothermia (DH) could be a new therapeutic strategy for asphyxiated newborn. This retrospective study describes how DH modified the heart rate and arterial blood pressure if compared to mild hypothermia (MH). Fourteen in DH and 17 in MH were cooled within the first six hours of life and for the following 72 hours. Hypothermia criteria were gestational age ≥36 weeks; birth weight ≥1800 g; clinical signs of moderate/severe hypoxic-ischemic encephalopathy. Rewarming was obtained in the following 6-12 hours (0.5°C/h) after cooling. Heart rates were the same between the two groups; there was statistically significant difference at the beginning of hypothermia and during rewarming. Three babies in the DH group and 2 in the MH group showed HR < 80 bpm and QTc > 520 ms. Infant submitted to deep hypothermia had not bradycardia or Qtc elongation before cooling and after rewarming. Blood pressure was significantly lower in DH compared to MH during the cooling, and peculiar was the hypotension during rewarming in DH group. Conclusion. The deeper hypothermia is a safe and feasible, only if it is performed by a well-trained team. DH should only be associated with a clinical trial and prospective randomized trials to validate its use.

Does pulmonary function change during whole-body deep hypothermia?

Whole-body deep hypothermia (DH) could be a new therapeutic strategy for asphyxiated newborn. Aim of this study was to describe how DH (core temperature 30-33°C) modifies the respiratory function if compared with mild hypothermia (MH; core temperature 33-34°C). This is an observational study. Results were obtained from a pilot study of safety of DH and topiramate in neonatal hypoxic-ischaemic encephalopathy. Fifty-seven newborns were enrolled: 29 patients in DH and 28 in MH. Recruitment criteria were moderate-severe hypoxic-ischaemic encephalopathy and gestational age ≥36 weeks. Mechanical ventilation was set to maintain SaO(2) between 92% and 95%. Nineteen patients in DH and 18 in MH required mechanical ventilation. Of these patients, 10 and 12, respectively, did not required oxygen. No significant differences were observed in hours of oxygen and ventilation support, respiratory rate and PaCO(2). Maximum FiO(2), peak inspiratory pressure, positive end-expiratory pressure, minute ventilation and tidal volume during hypothermia were similar. Pulmonary function with different levels of hypothermia was similar.

Safety of deep hypothermia in treating neonatal asphyxia.

BACKGROUND: Several studies have demonstrated the efficiency and safety of mild hypothermia (33 degrees C) used for treating moderate encephalopathy. In animal models, deep hypothermia proved to be neuroprotective. OBJECTIVES: To determine the safety of whole-body deep hypothermia between 30 and 33 degrees C in moderate-severe hypoxic-ischemic encephalopathy in newborn term infants. METHODS: Mortality rates, incidence of brain damage detected by magnetic resonance imaging (MRI) and neurological outcomes of 39 term asphyxiated infants were retrospectively compared. A first group of patients (control group C) was treated with routine standard methods, a second group (MH) was treated with mild whole-body hypothermia (32-34 degrees C) and a third group (DH) was treated with deep whole-body hypothermia (30-33 degrees C), for 72 h. Mean arterial pH, basic excess (BE) and lactic acid in the blood were measured. Laboratory and clinical side effects of hypothermia were investigated. A conventional brain MRI was performed after the second week of life. RESULTS: 39 term asphyxiated newborns were enrolled in the study: 11 in group C, 10 in group MH, and 18 in group DH. During the first 72 h, disseminated intravascular coagulation was recorded in 2 cases (18%) in group C, pulmonary hypertension in 2 patients (20%) in group MH, and pneumonia in 3 cases (16%) in group DH. Severe cerebral lesions and poor neurological outcome were observed in 4 cases (36%) in group C, 1 case (10%) in group MH, and 1 case (5%) in group DH. A statistically significant difference in brain damage and major clinical neurological abnormalities was observed between group C and groups MH and DH, whereas no differences were demonstrated between asphyxiated infants treated with mild or deep hypothermia. CONCLUSIONS: The results support the safety of deep hypothermia. Further studies are needed to confirm these results and the neuroprotective effect of this approach.