Efficacy and safety of switching from intravenous to oral antibiotics (amoxicillin-clavulanic acid) versus a full course of intravenous antibiotics in neonates with probable bacterial infection (RAIN): a multicentre, randomised, open-label, non-inferiority trial.

BACKGROUND: Switching from intravenous antibiotic therapy to oral antibiotic therapy among neonates is not yet practised in high-income settings due to uncertainties about exposure and safety. We aimed to assess the efficacy and safety of early intravenous-to-oral antibiotic switch therapy compared with a full course of intravenous antibiotics among neonates with probable bacterial infection. METHODS: In this multicentre, randomised, open-label, non-inferiority trial, patients were recruited at 17 hospitals in the Netherlands. Neonates (postmenstrual age ≥35 weeks, postnatal age 0-28 days, bodyweight ≥2 kg) in whom prolonged antibiotic treatment was indicated because of a probable bacterial infection, were randomly assigned (1:1) to switch to an oral suspension of amoxicillin 75 mg/kg plus clavulanic acid 18·75 mg/kg (in a 4:1 dosing ratio, given daily in three doses) or continue on intravenous antibiotics (according to the local protocol). Both groups were treated for 7 days. The primary outcome was cumulative bacterial reinfection rate 28 days after treatment completion. A margin of 3% was deemed to indicate non-inferiority, thus if the reinfection rate in the oral amoxicillin-clavulanic acid group was less than 3% higher than that in the intravenous antibiotic group the null hypothesis would be rejected. The primary outcome was assessed in the intention-to-treat population (ie, all patients who were randomly assigned and completed the final follow-up visit on day 35) and the per protocol population. Safety was analysed in all patients who received at least one administration of the allocated treatment and who completed at least one follow-up visit. Secondary outcomes included clinical deterioration and duration of hospitalisation. This trial was registered with ClinicalTrials.gov, NCT03247920, and EudraCT, 2016-004447-36. FINDINGS: Between Feb 8, 2018 and May 12, 2021, 510 neonates were randomly assigned (n=255 oral amoxicillin-clavulanic group; n=255 intravenous antibiotic group). After excluding those who withdrew consent (n=4), did not fulfil inclusion criteria (n=1), and lost to follow-up (n=1), 252 neonates in each group were included in the intention-to-treat population. The cumulative reinfection rate at day 28 was similar between groups (one [<1%] of 252 neonates in the amoxicillin-clavulanic acid group vs one [<1%] of 252 neonates in the intravenous antibiotics group; between-group difference 0 [95% CI -1·9 to 1·9]; pnon-inferiority<0·0001). No statistically significant differences were observed in reported adverse events (127 [50%] vs 113 [45%]; p=0·247). In the intention-to-treat population, median duration of hospitalisation was significantly shorter in the amoxicillin-clavulanic acid group than the intravenous antibiotics group (3·4 days [95% CI 3·0-4·1] vs 6·8 days [6·5-7·0]; p<0·0001). INTERPRETATION: An early intravenous-to-oral antibiotic switch with amoxicillin-clavulanic acid is non-inferior to a full course of intravenous antibiotics in neonates with probable bacterial infection and is not associated with an increased incidence of adverse events. FUNDING: The Netherlands Organization for Health Research and Development, Innovatiefonds Zorgverzekeraars, and the Sophia Foundation for Scientific Research.

Lidocaine response rate in aEEG-confirmed neonatal seizures: Retrospective study of 413 full-term and preterm infants.

OBJECTIVE: To investigate the seizure response rate to lidocaine in a large cohort of infants who received lidocaine as second- or third-line antiepileptic drug (AED) for neonatal seizures. METHODS: Full-term (n = 319) and preterm (n = 94) infants, who received lidocaine for neonatal seizures confirmed on amplitude-integrated EEG (aEEG), were studied retrospectively (January 1992-December 2012). Based on aEEG findings, the response was defined as good (>4 h no seizures, no need for rescue medication); intermediate (0-2 h no seizures, but rescue medication needed after 2-4 h); or no clear response (rescue medication needed <2 h). RESULTS: Lidocaine had a good or intermediate effect in 71.4%. The response rate was significantly lower in preterm (55.3%) than in full-term infants (76.1%, p < 0.001). In full-term infants the response to lidocaine was significantly better than midazolam as second-line AED (21.4% vs. 12.7%, p = 0.049), and there was a trend for a higher response rate as third-line AED (67.6% vs. 57%, p = 0.086). Both lidocaine and midazolam had a higher response rate as third-line AED than as second-line AED (p < 0.001). Factors associated with a good response to lidocaine were the following: higher gestational age, longer time between start of first seizure and administration of lidocaine, lidocaine as third-line AED, use of new lidocaine regimens, diagnosis of stroke, use of digital aEEG, and hypothermia. Multivariable analysis of seizure response to lidocaine included lidocaine as second- or third-line AED and seizure etiology. SIGNIFICANCE: Seizure response to lidocaine was seen in ~70%. The response rate was influenced by gestational age, underlying etiology, and timing of administration. Lidocaine had a significantly higher response rate than midazolam as second-line AED, and there was a trend for a higher response rate as third-line AED. Both lidocaine and midazolam had a higher response rate as third-line compared to second-line AED, which could be due to a pharmacologic synergistic mechanism between the two drugs.

Lidocaine-Associated Cardiac Events in Newborns with Seizures: Incidence, Symptoms and Contributing Factors.

BACKGROUND: Lidocaine is an effective therapy for neonatal seizures; however, it is not widely used, presumably due to the risk of cardiac events. OBJECTIVE: To investigate the incidence of cardiac events in full-term and preterm infants receiving lidocaine for seizures. METHODS: Full-term (n = 368) and preterm (n = 153) infants, admitted to a level 3 neonatal intensive care unit from 1992 to 2012, who received lidocaine for seizures were retrospectively studied. The causal relation between reported cardiac events and lidocaine administration was evaluated based on expected plasma concentrations, symptoms and relevant interactions during cardiac events. RESULTS: Cardiac events were reported in 11/521 infants (2.1%; 9 full-term, 2 preterm). In 7/11 infants the causal relation was considered plausible, in 3/11 questionable and in 1/11 implausible. The incidence was calculated to be 1.3-1.9% (n = 7-10/521), but was only 0.4% (n = 1/246, p = 0.02) when using reduced-dose regimens. Important risk factors for cardiac events were unstable potassium, (congenital) cardiac dysfunction and concurrent phenytoin use. CONCLUSIONS: Lidocaine-associated cardiac events were rare in our cohort, especially since the introduction of new reduced-dose regimens. This indicates that lidocaine is safe to use as an antiepileptic drug in full-term and preterm infants.

Neuroimaging in neonatal seizures.

Seizures are the most common sign of neurological dysfunction in full-term neonates, with an incidence estimated at 0.15-3.5/1,000 live births. Neonatal seizures often reflect severe underlying brain injury and are associated with high rates of mortality and morbidity. Prognosis is primarily determined by the nature, site and extent of the underlying aetiology, making accurate diagnosis and identification of associated brain lesions essential. Data on neuroimaging in newborns presenting with seizures is limited and most studies report on MRI findings in infants with a specific underlying problem, such as hypoxic-ischaemic encephalopathy, stroke or metabolic disorders. The aim of this review is to discuss the spectrum of neuroimaging findings in full-term newborns presenting with seizures, divided into subgroups with different underlying aetiologies. A standard neonatal MRI protocol is presented.

The aetiology of neonatal seizures and the diagnostic contribution of neonatal cerebral magnetic resonance imaging.

AIM: The aim of this study was to delineate aetiologies and explore the diagnostic value of cerebral magnetic resonance imaging (MRI) in addition to cranial ultrasonography (cUS) in infants presenting with neonatal seizures. METHOD: This retrospective cohort study comprised infants (gestational age 35.0-42.6wks) with seizures, confirmed by either continuous amplitude-integrated electroencephalography (aEEG) or standard EEG and admitted during a 14-year period to a level three neonatal intensive care unit (n=378; 216 males, 162 females; mean [SD] birthweight 3334g [594]). All infants underwent cUS and MRI (MRI on median of 5 days after birth, range 0-58d) within the first admission period. RESULTS: An underlying aetiology was identified in 354 infants (93.7%). The most common aetiologies identified were hypoxic-ischaemic encephalopathy (46%), intracranial haemorrhage (12.2%), and perinatal arterial ischaemic stroke (10.6%). When comparing MRI with cUS in these 354 infants MRI showed new findings which did not become apparent on cUS, contributing to a diagnosis in 42 (11.9%) infants and providing additional information to cUS, contributing to a diagnosis in 141 (39.8%). cUS alone would have allowed a diagnosis in only 37.9% of infants (134/354). INTERPRETATION: Cerebral MRI contributed to making a diagnosis in the majority of infants. In 11.9% of infants the diagnosis would have been missed if only cUS were used and cerebral MRI added significantly to the information obtained in 39.8% of infants. These data suggest that cerebral MRI should be performed in all newborn infants presenting with EEG- or aEEG-confirmed seizures.

Treatment of neonatal seizures.

Seizures occur more often during the neonatal period than at any other period of life. Precise incidence is difficult to delineate and depends on study population and criteria used for diagnosis of seizures. Controversy exists as to whether neonatal seizures themselves cause damage to the developing brain, or if the damage is primarily due to the underlying cause of the seizures. As a result of this controversy there is an ongoing discussion as to whether all seizures (both clinical and subclinical) should be treated. When (sub)clinical seizures are treated, there is no consensus about the most appropriate treatment for neonatal seizures and how to assess the efficacy of treatment. Current therapeutic options to treat neonatal seizures (i.e. primarily first generation antiepileptics) are relatively ineffective. There is an urgent need for prospective, randomized, controlled trials for efficacy and safety of these second-generation antiepileptic drugs in neonates. The aim of this review is to survey current knowledge regarding treatment of neonatal seizures in both term and preterm infants.

Clinical management of seizures in newborns : diagnosis and treatment.

Neonatal seizures can be classified as tonic, clonic, myoclonic, and subtle. A clinical diagnosis is not easy as seizures are usually subtle in neonates. In the majority of newborn infants seizures are subclinical. On the other hand, not all abnormal movements identified by clinicians as clinical seizures are accompanied by electroencephalographic seizure discharges in the EEG. Precise incidence is difficult to delineate and depends on study population and criteria used for diagnosis of seizures. Controversy exists as to whether neonatal seizures themselves cause damage to the developing brain, or if the damage is primarily due to the underlying cause of the seizures. As a result of this controversy there is ongoing discussion whether all seizures (both clinical and subclinical) should be treated. In addition, when (sub)clinical seizures are treated, there is no consensus about the most appropriate treatment for neonatal seizures and how to assess the efficacy of treatment. Current therapeutic options to treat neonatal seizures (i.e. primarily first-generation antiepileptic drugs [AEDs]) are relatively ineffective. In practice, phenobarbital still remains the drug of first choice for EEG confirmed or suspected seizures. Benzodiazepines are also used in (phenobarbital) refractory cases. Several (small) studies indicate that lidocaine is an effective drug for refractory seizures as second- or third-line treatment. Although data are scarce, some AEDs with a wide acceptance in adult and pediatric neurology practice are being used to treat neonatal seizures (i.e. second-generation AEDs). These drugs are chemically different from all first-generation AEDs and they have an effect on other pathways so they provide new pharmacological targets for controlling seizures in newborns. Levetiracetam, topiramate, felbamate, bumetanide, lamotrigine and vigabatrin are examples of these second-generation AEDs. There is an urgent need for prospective, randomized, controlled trials to assess the efficacy and safety of these second-generation AEDs in neonates. The aim of this review is to provide an overview of the current knowledge of diagnosis, the effect on brain injury, and the treatment of neonatal seizures.

Effect of treatment of subclinical neonatal seizures detected with aEEG: randomized, controlled trial.

OBJECTIVES: The goals were to investigate how many subclinical seizures in full-term neonates with hypoxic-ischemic encephalopathy (HIE) would be missed without continuous amplitude-integrated electroencephalography (aEEG) and whether immediate treatment of both clinical and subclinical seizures would result in a reduction in the total duration of seizures and a decrease in brain injury, as seen on MRI scans. METHODS: In this multicenter, randomized, controlled trial, term infants with moderate to severe HIE and subclinical seizures were assigned randomly to either treatment of both clinical seizures and subclinical seizure patterns (group A) or blinding of the aEEG registration and treatment of clinical seizures only (group B). All recordings were reviewed with respect to the duration of seizure patterns and the use of antiepileptic drugs (AEDs). MRI scans were scored for the severity of brain injury. RESULTS: Nineteen infants in group A and 14 infants in group B were available for comparison. The median duration of seizure patterns in group A was 196 minutes, compared with 503 minutes in group B (not statistically significant). No significant differences in the number of AEDs were seen. Five infants in group B received AEDs when no seizure discharges were seen on aEEG traces. Six of 19 infants in group A and 7 of 14 infants in group B died during the neonatal period. A significant correlation between the duration of seizure patterns and the severity of brain injury in the blinded group, as well as in the whole group, was found. CONCLUSIONS: In this small group of infants with neonatal HIE and seizures, there was a trend for a reduction in seizure duration when clinical and subclinical seizures were treated. The severity of brain injury seen on MRI scans was associated with a longer duration of seizure patterns.

Additional value of two-channel amplitude integrated EEG recording in full-term infants with unilateral brain injury.

BACKGROUND: Amplitude integrated electroencephalography (aEEG) is a valuable tool for evaluating neonatal encephalopathy and identifying electrographic seizures. OBJECTIVE: To compare seizure activity and background pattern (BGP) between one-channel and two-channel aEEG recordings in full-term neonates. METHODS: The two-channel aEEG recordings (F3-P3; F4-P4) of 34 neonates with seizures were compared with single-channel recordings (P3-P4). RESULTS: All 34 infants with unilateral (n=14), diffuse (n=18) or without (n=2) brain injury had seizure patterns on one-channel and two-channel recordings, with 18% more seizure patterns detected with two-channel recording. In 79% of infants with unilateral injury more seizures were noted on the ipsilateral side compared to the contralateral side. In 39% of the infants with diffuse brain damage more seizures were found with two-channel recordings. A sensitivity of 65% was found when using the automatic seizure detection algorithm. In 4/14 (29%) infants with unilateral injury a more severely affected BGP was seen on the ipsilateral side compared to the BGP on one-channel recording. In infants with diffuse injury differences in BGP pattern were seen in 6-17% of the infants depending on the system used for scoring. CONCLUSION: Although there were no major differences found between seizure detection with one-channel or two-channel aEEG, in a subgroup of infants with a predominantly unilateral brain lesion, two-channel recording did provide additional information with identification of more seizure patterns on the affected side, sometimes also associated with a difference in BGP. To improve early diagnosis of unilateral lesions and improve seizure detection in these infants, routine use of two-channel recordings is recommended.

The use of amplitude integrated electroencephalography for assessing neonatal neurologic injury.

Amplitude-integrated electroencephalography (aEEG) plays an important role in integrated care of the full-term infant with neonatal encephalopathy. The three main features that are provided with aEEG are the background pattern on admission and the rate of recovery seen during the first 24 to 48 hours after birth, the presence of most electrographic discharges, and the effect of antiepileptic drugs.

Neurodevelopmental outcome in term infants with status epilepticus detected with amplitude-integrated electroencephalography.

OBJECTIVES: This study evaluated seizure, patient characteristics, and neurodevelopmental outcome of term newborns with amplitude-integrated electroencephalography-detected status epilepticus. METHODS: Fifty-six term infants with status epilepticus were identified during a 12.5-year period. The time of onset of status epilepticus, background pattern before and after status epilepticus, success of controlling status epilepticus with antiepileptic drugs, and neurodevelopmental outcome were studied. RESULTS: The incidence of status epilepticus in our population was 18%. Forty-two infants (75%) had a poor outcome and 14 were normal at follow-up. When all infants were studied as a single group, we found that not the duration, but the background pattern was correlated with neurodevelopmental outcome. In 50% of the infants with a poor outcome, the background pattern was abnormal before the status epilepticus and in 71% after the status epilepticus. Among infants with a good outcome, background pattern was normal in 14% before and 7% after the status epilepticus. In a subgroup of 48 infants with hypoxic-ischemic encephalopathy, there was a significant difference in background pattern, as well as in duration of the status epilepticus between infants with a poor outcome, compared with those with a good outcome. In 48% of the infants with a poor outcome, the background pattern was abnormal before, and in 75% after the status epilepticus, compared with 25% and 13%, respectively, for those with a good outcome. In 57% of the infants with a hemorrhage or perinatal arterial stroke, the status epilepticus was not controlled with antiepileptic drugs, compared with 21% in infants with hypoxic-ischemic encephalopathy (not significant). CONCLUSIONS: The background pattern at the onset of status epilepticus was the main predictor of neurodevelopmental outcome. The duration of the status epilepticus was only of predictive value in the infants with hypoxic-ischemic encephalopathy. No association was found between the ability to control status epilepticus and subsequent neurodevelopmental outcome.

Development of an optimal lidocaine infusion strategy for neonatal seizures.

INTRODUCTION: Lidocaine is an effective drug for the treatment of neonatal convulsions not responding to traditional anticonvulsant therapy. However, one of the side-effects is a risk of cardiac arrhythmias. The aim of this study was to develop an optimal dosing strategy with minimal risk of cardiac arrhythmias. MATERIALS AND METHODS: As a first step, we studied 20 neonates during routine treatment of neonatal seizures with lidocaine. All were given a loading dose of 2 mg/kg in 10 min, followed by the continuous infusion of 6 mg/kg per hour for 12 h, 4 mg/kg per hour for 12 h and finally 2 mg/kg per hour for 12 h. Effectiveness, cardiac toxicity and lidocaine plasma concentrations were then determined. RESULTS: No cardiac arrhythmias were observed, and lidocaine was effective in 76% of the treatments. In most of the treatments (13 out of 20) maximal lidocaine plasma concentrations were >9 mg/L. Plasma levels >9 mg/L have been related to cardiac toxicity when used as an anti-arrhythmic drug in adults. It was of interest that all preterm infants showed high lidocaine plasma levels. Secondly, we developed the optimal dosing regimen, which was defined as an infusion regimen at which maximal lidocaine plasma concentrations are <9 mg/L. Simulations with the developed pharmacokinetic model indicated a reduction in the infusion duration of lidocaine at 6 mg/kg per hour from 12 to 6 h. Thirdly, the new lidocaine dosing regimen was evaluated. Fifteen neonates (16 treatments) were studied. No cardiac arrhythmias were observed, and lidocaine was effective in 78% of the treatments. In most of the treatments (11 out of 16) maximal lidocaine plasma concentrations were <9 mg/L. Again preterm infants showed relatively high lidocaine plasma levels. CONCLUSION: A new lidocaine dosing schedule was developed. This new regimen should have a lower risk of cardiac arrhythmias and appears to be as effective in term infants. For preterm infants the optimal regimen needs to be determined.

Sleep-wake cycling on amplitude-integrated electroencephalography in term newborns with hypoxic-ischemic encephalopathy.

OBJECTIVE: The objective of this amplitude-integrated electroencephalography (aEEG) study was to evaluate the influence of perinatal hypoxia-ischemia on sleep-wake cycling (SWC) in term newborns and assess whether characteristics of SWC are of predictive value for neurodevelopmental outcome. METHODS: From a consecutive series of newborns born during a 10-year period, the aEEG tracings of 171 term newborns with hypoxic-ischemic encephalopathy were assessed for the presence, time of onset, and quality of SWC. SWC patterns were categorized with regard to the background pattern on which they presented, as normal or abnormal SWC. RESULTS: SWC was seen in 95.4% of the surviving newborns and in 8.1% of those who died. The median time intervals from birth to onset of SWC were significantly different in newborns with hypoxic-ischemic encephalopathy grades I, II, and III (7, 33, and 62 hours, respectively). Newborns with seizure discharges developed SWC with a delay of 30.5 hours. Good outcome was associated with earlier onset of SWC and normal SWC pattern. The difference in the median Griffiths' developmental quotients in newborns who started SWC before/after 36 hours was 8.5 points. The good/poor neurodevelopmental outcome was predicted correctly by the onset of SWC before/after 36 hours in 82% of newborns. CONCLUSIONS: The presence, time of onset, and quality of SWC reflected the severity of the hypoxic-ischemic insult to which newborns were exposed. The time of onset of SWC has a predictive value for neurodevelopmental outcome.

Cardiac arrhythmias in neonates receiving lidocaine as anticonvulsive treatment.

UNLABELLED: Lidocaine has been used in neonates as an effective drug in controlling neonatal seizures not responding to traditional anticonvulsant therapy. Little is known about the effect of lidocaine on heart rate or occurrence of cardiac arrhythmias in neonates. The purpose of the present study was to assess the incidence of cardiac arrhythmias associated with lidocaine use for neonatal seizures. A retrospective review was performed in 207 neonates who received lidocaine for treatment of neonatal seizures. All were given a loading dose of 2 mg/kg in 10 min followed by a continuous infusion of 6 mg/kg per h, tailed off over the next 48 h. A total of ten (4,8%) infants developed cardiac arrhythmias during lidocaine infusion. In five infants a bradycardia developed, associated with a prolonged QRS complex in one. In one infant a tachycardia was seen following the bolus administration. In the other four an irregular heart rate was noted. In eight infants the arrhythmias disappeared immediately following discontinuation of lidocaine. In two infants, with severe encephalopathy, who died, the association was not so clear. CONCLUSION: The present study demonstrates that continuous cardiac monitoring of neonates who receive lidocaine for neonatal seizures is indicated, as there is a risk to develop cardiac arrhythmias. Lidocaine should be discontinued immediately when a cardiac arrhythmia occurs. Lidocaine should not be given to patients with a congenital heart disease and to infants who have already been treated with diphantoine.