Doxapram versus placebo in preterm newborns: a study protocol for an international double blinded multicentre randomized controlled trial (DOXA-trial).

BACKGROUND: Apnoea of prematurity (AOP) is one of the most common diagnoses among preterm infants. AOP often leads to hypoxemia and bradycardia which are associated with an increased risk of death or disability. In addition to caffeine therapy and non-invasive respiratory support, doxapram might be used to reduce hypoxemic episodes and the need for invasive mechanical ventilation in preterm infants, thereby possibly improving their long-term outcome. However, high-quality trials on doxapram are lacking. The DOXA-trial therefore aims to investigate the safety and efficacy of doxapram compared to placebo in reducing the composite outcome of death or severe disability at 18 to 24 months corrected age. METHODS: The DOXA-trial is a double blinded, multicentre, randomized, placebo-controlled trial conducted in the Netherlands, Belgium and Canada. A total of 396 preterm infants with a gestational age below 29 weeks, suffering from AOP unresponsive to non-invasive respiratory support and caffeine will be randomized to receive doxapram therapy or placebo. The primary outcome is death or severe disability, defined as cognitive delay, cerebral palsy, severe hearing loss, or bilateral blindness, at 18-24 months corrected age. Secondary outcomes are short-term neonatal morbidity, including duration of mechanical ventilation, bronchopulmonary dysplasia and necrotising enterocolitis, hospital mortality, adverse effects, pharmacokinetics and cost-effectiveness. Analysis will be on an intention-to-treat principle. DISCUSSION: Doxapram has the potential to improve neonatal outcomes by improving respiration, but the safety concerns need to be weighed against the potential risks of invasive mechanical ventilation. It is unknown if the use of doxapram improves the long-term outcome. This forms the clinical equipoise of the current trial. This international, multicentre trial will provide the needed high-quality evidence on the efficacy and safety of doxapram in the treatment of AOP in preterm infants. TRIAL REGISTRATION: ClinicalTrials.gov NCT04430790 and EUDRACT 2019-003666-41. Prospectively registered on respectively June and January 2020.

Propofol in neonates causes a dose-dependent profound and protracted decrease in blood pressure.

AIM: To analyse the effects of different propofol starting doses as premedication for endotracheal intubation on blood pressure in neonates. METHODS: Neonates who received propofol starting doses of 1.0 mg/kg (n = 30), 1.5 mg/kg (n = 23) or 2.0 mg/kg (n = 26) as part of a previously published dose-finding study were included in this analysis. Blood pressure in the 3 dosing groups was analysed in the first 60 minutes after start of propofol. RESULTS: Blood pressure declined after the start of propofol in all 3 dosing groups and was not restored 60 minutes after the start of propofol. The decline in blood pressure was highest in the 2.0 mg/kg dosing group. Blood pressure decline was mainly dependent on the initial propofol starting dose rather than the cumulative propofol dose. CONCLUSION: Propofol causes a dose-dependent profound and prolonged decrease in blood pressure. The use of propofol should be carefully considered. When using propofol, starting with a low dose and titrating according to sedative effect seems the safest strategy.

Propofol for endotracheal intubation in neonates: a dose-finding trial.

OBJECTIVE: To find propofol doses providing effective sedation without side effects in neonates of different gestational ages (GA) and postnatal ages (PNA). DESIGN AND SETTING: Prospective multicentere dose-finding study in 3 neonatal intensive care units. PATIENTS: Neonates with a PNA <28 days requiring non-emergency endotracheal intubation. INTERVENTIONS: Neonates were stratified into 8 groups based on GA and PNA. The first 5 neonates in every group received a dose of 1.0 mg/kg propofol. Based on sedative effect and side effects, the dose was increased or decreased in the next 5 patients until the optimal dose was found. MAIN OUTCOME MEASURES: The primary outcome was the optimal single propofol starting dose that provides effective sedation without side effects in each age group. RESULTS: After inclusion of 91 patients, the study was prematurely terminated because the primary outcome was only reached in 13% of patients. Dose-finding was completed in 2 groups, but no optimal propofol dose was found. Effective sedation without side effects was achieved more often after a starting dose of 2.0 mg/kg (28%) than after 1.0 mg/kg (3%) and 1.5 mg/kg (9%). Propofol-induced hypotension occurred in 59% of patients. Logistic regression analyses showed that GA and PNA did not predict effective sedation or the occurrence of hypotension. CONCLUSIONS: Effective sedation without side effects is difficult to achieve with propofol and the optimal dose in different age groups of neonates could not be determined. The sedative effect of propofol and the occurrence of hypotension are unpredictable and show large inter-individual variability in the neonatal population.

Evaluation of an Intubation Readiness Score to Assess Neonatal Sedation before Intubation.

BACKGROUND: Premedication for neonatal intubation facilitates the procedure and reduces stress and physiological disturbances. However, no validated scoring system to assess the effect of premedication prior to intubation is available. OBJECTIVE: To evaluate the usefulness of an Intubation Readiness Score (IRS) to assess the effect of premedication prior to intubation in newborn infants. METHODS: Two-center prospective study in neonates who needed endotracheal intubation. Intubation was performed using a standardized procedure with propofol 1-2 mg/kg as premedication. The level of sedation was assessed with the IRS by evaluating the motor response to a firm stimulus (1 = spontaneous movement; 2 = movement on slight touch; 3 = movement on firm stimulus; 4 = no movement). Intubation was proceeded if an adequate effect, defined as an IRS of 3 or 4, was reached. IRS was compared to the quality of intubation measured with the Viby-Mogensen intubation score. RESULTS: A total of 115 patients, with a median gestational age of 27.7 weeks (interquartile range 5.3) and a median birth weight of 1,005 g (interquartile range 940), were included. An adequate IRS was achieved in 105 patients, 89 (85%) of whom also had a good Viby-Mogensen intubation score and 16 (15%) had an inadequate Viby-Mogensen intubation score. The positive predictive value of the IRS was 85%. CONCLUSIONS: Preintubation sedation assessment using the IRS can adequately predict optimal conditions during intubation in the majority of neonates. We suggest using the IRS in routine clinical care. Further research combining the IRS with other parameters could further improve the predictability of adequate sedation during intubation.

Assessment of sedation level prior to neonatal intubation: A systematic review.

BACKGROUND: Adequate premedication before neonatal endotracheal intubation reduces pain, stress, and adverse physiological responses, diminishes duration and number of attempts at intubation, and prevents traumatic airway injury. Therefore, intubation should not be started until an adequate level of sedation is reached. It is not clear how this should be measured in the clinical situation. OBJECTIVES: The aim of this study is to provide a systematic review of the usability and validity of scoring systems or other objective parameters to evaluate the level of sedation before intubation in neonates. Secondary aims were to describe parameters that are used to determine the level of sedation and criteria on which the decision to proceed with intubation is based. METHODS: Literature was searched (January 2017) in the following electronic databases: Embase, Medline, Web of Science, Cochrane Central Registrar of Controlled Trials, Pubmed Publisher, and Google Scholar. RESULTS: From 1653 hits, 20 studies were finally included in the systematic review. In 7 studies, intubation was started after a predefined time period; in 1 study, preoxygenation was the criterion to start with intubation; and in 12 studies, intubation was started in case of adequate sedation and/or relaxation. Only 4 studies described the use of 3 different objective scoring system, all in the neonatal intensive care unit, which are not validated. CONCLUSION: No validated scoring systems to assess the level of sedation prior to intubation in newborns are available in the literature. Three objective sedation assessment tools seem promising but need further validation before they can be implemented in research and clinical settings.

Insufficient Sedation and Severe Side Effects after Fast Administration of Remifentanil during INSURE in Preterm Newborns.

BACKGROUND: Neonatal intubation is stressful and should be performed with premedication. In the case of an INSURE (intubation/surfactant/extubation) procedure a short duration of action of the premedication used is needed to facilitate fast extubation. Given its pharmacological profile, remifentanil seems a suitable candidate. OBJECTIVES: The aim here was to evaluate the effect and side effects of remifentanil as a premedication for preterm neonates undergoing INSURE. METHODS: A prospective, single-center study in a level III neonatal intensive care unit was conducted. The quality of sedation was assessed in preterm infants receiving remifentanil prior to intubation for the INSURE procedure. Intravenous remifentanil was administered quickly and followed by a saline flush in approximately 30 s. The quality of sedation was defined by a combination of adequate sedation score, good intubation conditions and absence of side effects. RESULTS: The study was terminated after the inclusion of 14 patients because of the high rate of side effects and the poor intubation conditions. Adequate sedation was achieved in only 2 patients (14%). Six patients (43%) needed additional propofol to obtain adequate sedation. Chest wall rigidity occurred in 6 patients (43%). CONCLUSIONS: The rapid administration of remifentanil provides insufficient sedation and is associated with a high risk of chest wall rigidity in preterm neonates.

Double-blind placebo-controlled food challenges in children with alleged cow's milk allergy: prevention of unnecessary elimination diets and determination of eliciting doses.

BACKGROUND: Children with cow's milk allergy (CMA) need a cow's milk protein (CMP) free diet to prevent allergic reactions. For this, reliable allergy-information on the label of food products is essential to avoid products containing the allergen. On the other hand, both overzealous labeling and misdiagnosis that result in unnecessary elimination diets, can lead to potentially hazardous health situations. Our objective was to evaluate if excluding CMA by double-blind placebo-controlled food challenge (DBPCFC) prevents unnecessary elimination diets in the long term. Secondly, to determine the minimum eliciting dose (MED) for an acute allergic reaction to CMP in DBPCFC positive children. METHODS: All children with suspected CMA under our care (Oct'05-Jun'09) were prospectively enrolled in a DBPCFC. Placebo and verum feedings were administered on two randomly assigned separate days. The MED was determined by noting the 'lowest observed adverse effect level' (LOAEL) in DBPCFC-positive children. Based on the outcomes of the DBPCFC a dietary advice was given. Parents were contacted by phone several months later about the diet of their child. RESULTS: 116 children were available for analysis. In 76 children CMA was rejected. In 60 of them CMP was successfully reintroduced, in 2 the parents refused introduction, in another 3 the parents stopped reintroduction. In 9 children CMA symptoms reappeared. In 40 children CMA was confirmed. Infants aged ≤ 12 months in our study group have a higher cumulative distribution of MED than older children. CONCLUSIONS: Excluding CMA by DBPCFC successfully stopped unnecessary elimination diets in the long term in most children. The MEDs form potential useful information for offering dietary advice to patients and their caretakers.

Sedation of newborn infants for the INSURE procedure, are we sure?

BACKGROUND: Neonatal intubation is a stressful procedure that requires premedication to improve intubation conditions and reduce stress and adverse physiological responses. Premedication used during the INSURE (INtubation, SURfactant therapy, Extubation) procedure should have a very short duration of action with restoration of spontaneous breathing within a few minutes. AIMS: To determine the best sedative for intubation during the INSURE procedure by systematic review of the literature. METHODS: We reviewed all relevant studies reporting on premedication, distress, and time to restoration of spontaneous breathing during the INSURE procedure. RESULTS: This review included 12 studies: two relatively small studies explicitly evaluated the effect of premedication (propofol and remifentanil) during the INSURE procedure, both showing good intubation conditions and an average extubation time of about 20 minutes. Ten studies reporting on fentanyl or morphine provided insufficient information about these items. CONCLUSIONS: Too little is known in the literature to draw a solid conclusion on which premedication could be best used during the INSURE procedure. Both remifentanil and propofol are suitable candidates but dose-finding studies to detect effective nontoxic doses in newborns with different gestational ages are necessary.

Long-term subcutaneous protein C replacement in neonatal severe protein C deficiency.

We describe here the case of a boy who presented 2 days after birth with purpura fulminans on his feet and scalp. Laboratory investigations revealed signs of disseminated intravascular coagulation. An underlying coagulation disorder was suspected, and therapy with recombinant tissue plasminogen activator, fresh-frozen plasma, and unfractionated heparin was started. On the basis of plasma protein C activity and antigen levels of 0.02 and 0.03 IU/mL, respectively, after administration of fresh-frozen plasma, a diagnosis of severe protein C deficiency was established, and therapy with intravenous protein C concentrate (Ceprotin [Baxter, Deerfield, IL]) was started. Because of difficulties with venous access, we switched to subcutaneous administration after 6 weeks. The precise dosing schedule for subcutaneously administered protein C concentrate is unknown. In the literature, a trough level of protein C activity at >0.25 IU/mL is recommended to prevent recurrent thrombosis. During 1 year of follow-up our patient frequently had protein C activity levels at <0.25 IU/mL. Clinically, however, there was no recurrent thrombosis, and we kept the dosage unchanged. This report highlights 2 important points: (1) subcutaneously administered protein C concentrate is effective in treating severe protein C deficiency; and (2) in accordance with previous studies, after the acute phase trough levels of protein C activity at >0.25 IU/mL may not be necessary to prevent recurrent thrombosis. However, further research on the dosing, efficacy, and safety of protein C concentrate for prophylaxis and treatment of severe protein C deficiency is needed.