Efficacy and safety of lidocaine for treatment of neonatal seizures.

AIM: Treatment of neonatal seizures still relies primarily on phenobarbital, despite an estimated efficacy of less than 50% and concern over neurodegenerative side effects. The objective of this study was to evaluate the efficacy and safety of lidocaine as second-line treatment of neonatal seizures in infants following benzodiazepine treatment but without previous treatment with phenobarbital. METHODS: In a 10-year cohort, a retrospective chart review was conducted for all infants (gestational age ≥ 37 w, age ≤ 28 days) who had received lidocaine as second-line treatment of neonatal seizures prior to treatment with phenobarbital between January 2000 and June 2010. Infants were included if they had electroencephalographic seizures. RESULTS: Cessation of seizure activity was seen in 16 of 30 infants based on clinical and electroencephalographic features, and a probable response was seen in an additional 3 of 30 patients. Suspected adverse effects were seen in only one patient, who developed a transient bradycardia. CONCLUSION: Lidocaine has a moderate efficacy as second-line therapy following benzodiazepines for treating neonatal seizures and is not frequently associated with cardiovascular adverse effects. Lidocaine should therefore be considered in the treatment of seizures in the neonatal period to a higher extent than is the case today.

Hypoxic ventilatory response in Tac1-/- neonatal mice following exposure to opioids.

Morphine is the dominating analgetic drug used in neonates, but opioid-induced respiratory depression limits its therapeutic use. In this study, we examined acute morphine effects on respiration during intermittent hypoxia in newborn Tac1 gene knockout mice (Tac1-/-) lacking substance P and neurokinin A. In vivo, plethysmography revealed a blunted hypoxic ventilatory response (HVR) in Tac1-/- mice. Morphine (10 mg/kg) depressed the HVR in wild-type animals through an effect on respiratory frequency, whereas it increased tidal volumes in Tac1-/- during hypoxia, resulting in increased minute ventilation. Apneas were reduced during the first hypoxic episode in both morphine-exposed groups, but were restored subsequently in Tac1-/- mice. Morphine did not affect ventilation or apnea prevalence during baseline conditions. In vitro, morphine (50 nM) had no impact on anoxic response of brain stem preparations of either strain. In contrast, it suppressed the inspiratory rhythm during normoxia and potentiated development of posthypoxic neuronal arrest, especially in Tac1-/-. Thus this phenotype has a higher sensitivity to the depressive effects of morphine on inspiratory rhythm generation, but morphine does not modify the reactivity to oxygen deprivation. In conclusion, although Tac1-/- mice are similar to wild-type animals during normoxia, they differed by displaying a reversed pattern with an improved HVR during intermittent hypoxia both in vivo and in vitro. These data suggest that opioids and the substance P-ergic system interact in the HVR, and that reducing the activity in the tachykinin system may alter the respiratory effects of opioid treatment in newborns.

Increased morphine analgesia and reduced side effects in mice lacking the tac1 gene.

BACKGROUND AND PURPOSE: Although morphine is a very effective analgesic, its narrow therapeutic index and severe side effects limit its therapeutic use. Previous studies indicated that the pharmacological responses of opioids are modulated by genetic and pharmacological invalidation of tachykinin receptors. Here we address the role of substance P and neurokinin A, which are both encoded by the tachykinin 1 (tac1) gene, as modulators of opioid effects. EXPERIMENTAL APPROACH: The analgesic and side effect potential of morphine was compared between wild-type and tac1 null mutant mice. KEY RESULTS: Morphine was a more potent analgesic in tac1 null mutant mice, that is, in the absence of substance P/neurokinin A signalling. Interestingly, the most serious side effect of acute morphine, that is respiratory depression, was reduced in tac1(-/-) animals. Comparing the addictive potential of morphine in wild-type and knockout animals we found that morphine preference was similar between the genotypes. However, the aversive effect of withdrawal precipitated by naloxone in morphine-dependent animals was significantly reduced in tac1 knockout mice. Behavioural sensitization, the underlying mechanism of addiction, was also significantly lower in tac1(-/-) mice. CONCLUSION AND IMPLICATIONS: The analgesic potential of morphine was increased in tac1 knockout mice. In contrast, both the ventilatory suppressing effect and the addictive potential of morphine were reduced. These results suggest that reducing activity of the tachykinin system may be a possible strategy to improve the pharmacological potential of morphine.

Childhood encephalitis in Sweden: etiology, clinical presentation and outcome.

Acute encephalitis is a relatively uncommon but potentially harmful CNS inflammation usually caused by infection. The diagnosis is difficult to establish and the etiology often remains unclear. Furthermore, the long-term prognosis of acute encephalitis in children is poorly described. In this study, we characterize childhood encephalitis from a Swedish perspective in regard to etiology, clinical presentation and sequele. We retrospectively studied all children (n=93) who were admitted for acute encephalitis at Karolinska University Hospital in Stockholm during 2000-2004. A confirmed etiological agent was identified in eight cases and a probable one in 37; in 48 cases no etiological agent could be found. Tick-borne encephalitis virus, enterovirus, respiratory syncytial virus, varicella zoster virus and influenza virus predominated and represented 67% of all the confirmed or probable etiologies. Encephalopathy was present in 80% of the children, 81% had fever, 44% had focal neurological findings, and seizures occurred in 40%. EEG abnormalities were seen in 90% and abnormal neuroimaging was present in 30%. The cerebrospinal fluid showed pleocytosis in 55%. There was no mortality, but 60% of the children had persisting symptoms at the time of discharge, 41% of which were moderate to severe. We conclude that the etiology of encephalitis among Swedish children is at large the same as in other European countries with similar vaccination programs. Fever and encephalopathy were seen in a majority of children and the most sensitive tool for making the diagnosis was EEG examination. Furthermore, many children display persisting sequele at discharge for which the strongest predictive factor was focal neurological findings at presentation.

Altered respiratory pattern and hypoxic response in transgenic newborn mice lacking the tachykinin-1 gene.

Substance P is known to be involved in respiratory rhythm and central pattern-generating mechanisms, especially during early development. We therefore studied respiratory responses in transgenic newborn mice (Tac1(-/-)) lacking substance P and neurokinin A (NKA). In vivo, the effects of intermittent isocapnic hypoxia (IH) and hypercapnia were studied using whole body flow plethysmography at P2-3 and P8-10. In vitro, anoxic responses and the effects of hypocapnic and hypercapnic conditions were studied in brain stem-spinal cord preparations (C4 activity) at P2. Hypoxic challenge considerably modified the respiratory activity in transgenic mice displayed in vivo as an attenuated increase in tidal volume during IH. Transgenic mice also showed a more prominent posthypoxic frequency decline in vivo, and posthypoxic neuronal arrests appeared more often in vitro. We recognized two types of sigh activity: with or without a following pause. During IH, the amount of sighs with a pause decreased and those without increased, a redistribution that became stronger with age only in controls. Intermittent anoxia induced long-term facilitation effects in controls, but not in Tac1(-/-) animals, manifested as an increase in burst frequency in vitro and by an augmentation of ventilation during posthypoxic periods in vivo. Thus our data demonstrate that a functional substance P/NKA system is of great importance for the generation of an adequate respiratory response to hypoxic provocation in newborn mice and during early maturation. It also indicates that substance P (and/or NKA) is involved in the development of the plasticity of the respiratory system.

Effects of nicotine during pregnancy: human and experimental evidence.

Prenatal exposure to tobacco smoke is a major risk factor for the newborn, increasing morbidity and even mortality in the neonatal period but also beyond. As nicotine addiction is the factor preventing many women from smoking cessation during pregnancy, nicotine replacement therapy (NRT) has been suggested as a better alternative for the fetus. However, the safety of NRT has not been well documented, and animal studies have in fact pointed to nicotine per se as being responsible for a multitude of these detrimental effects. Nicotine interacts with endogenous acetylcholine receptors in the brain and lung, and exposure during development interferes with normal neurotransmitter function, thus evoking neurodevelopmental abnormalities by disrupting the timing of neurotrophic actions. As exposure to pure nicotine is quite uncommon in pregnant women, very little human data exist aside from the vast literature on prenatal exposure to tobacco smoke.The current review discusses recent findings in humans on effects on the newborn of prenatal exposure to pure nicotine and non-smoke tobacco. It also reviews the neuropharmacological properties of nicotine during gestation and findings in animal experiments that offer explanations on a cellular level for the pathogenesis of such prenatal drug exposure. It is concluded that as findings indicate that functional nAChRs are present very early in neuronal development, and that activation at this stage leads to apoptosis and mitotic abnormalities, a total abstinence from all forms of nicotine should be advised to pregnant women for the entirety of gestation.

Perinatal distribution of galanin and galanin receptor-1 mRNA in the rat hindbrain.

In situ hybridisation was used to determine the distribution and levels of mRNA for galanin precursor preprogalanin (ppGAL) and galanin receptor-1 (GAL-R1) in the rat hindbrain before and after birth. Quantification of mRNA levels was performed from E21. Also, immunohistochemistry was used to study GAL-like immunoreactivity (GAL-LI) prenatally. On E16, no expression of ppGAL mRNA could be detected in any areas examined, whereas on E19 low transcript levels were observed. GAL-LI, however, was seen at relatively high levels in nerve fibres already on E16, mainly in the areas receiving primary afferents. Also, GAL-R1 mRNA was expressed at high levels in discrete areas of the hindbrain on E16. On E21 ppGAL mRNA was found in the locus coeruleus (LC), the nucleus of the solitary tract, the dorsal motor nucleus of the vagus (nX), the lateral reticular nucleus (LRn) and superficially along the ventral medullary surface. Expression increased postnatally in all these areas except in nX and LRn. GAL-R1 mRNA, on the other hand, was found to be expressed at high levels on E21 in the LC, where levels then decreased on P1. Expression of GAL-R1 mRNA was also found in other areas of the brainstem, but here no changes were detected around birth. These findings demonstrate that ppGAL and GAL-R1 mRNAs, as well as GAL-LI, are present in the brainstem in the rat fetus and that the changes in expression after birth could be of importance for the newborn in the transition from pre- to postnatal life.

A review of physical exercises recommended for VDT operators.

This paper presents an evaluation of exercises that have been recommended for the prevention of musculoskeletal discomfort among VDT/office workers. 127 individual exercises were analysed for their suitability for performance in VDT workplaces. Additionally, each exercise was judged in terms of its safety and its compliance with principles of physiotherapy. Results showed that, in the majority of cases, the prepared instructions for the exercises were satisfactory and the exercises could be readily performed at the workstation. However, over a third of the exercises were conspicuous and potentially embarrassing to perform, and half would significantly disrupt the work routine. Additionally, a number of the exercises posed potential safety hazards, exacerbated biomechanical stresses common to VDT work, or were contraindicated for persons with certain health problems. These findings suggest a need for greater attention to both the practical and the therapeutic aspects of exercises promoted for VDT users.

Effect of work load and respirator wear on postural stability, heart rate, and perceived exertion.

The effects on postural stability (sway) were investigated for different work loads under conditions of wearing a full facepiece respirator and not wearing any respiratory protection device. Fifteen subjects accomplished light (40 W), moderate (85 W), and heavy (125 W) work loads under the two conditions. Measurements of postural sway were made immediately after each load by using a multicomponent, strain gage-type force platform. Changes in each subject's movement pattern of the center of pressure were quantitated and compared to their initial baseline sway tests. Each subject's heart rate and perceived exertion were also recorded during each condition. A statistically significant effect (p = 0.007) caused by work load was observed for total length of sway with or without a respirator. An interaction approaching statistical significance (p = 0.056) between work load and respirator use was found. This indicated that sway increased more quickly and in a more consistently linear fashion with increasing work load under the respirator condition (p = 0.02) compared to the nonrespirator condition. The results from the respirator condition showed linear increases in postural sway length across the entire range of work loads, but sway length in the nonrespirator condition showed an increase only at 125-W work loads. The greater increase in sway during the postural balance test could be attributable to the increasing work load-induced proprioceptive fatigue effect on the nervous system's ability to process signals from proprioception systems incongruent with body sway. The heart rate was significantly higher during respirator wear (an increase in heart rate averaging 5.62 beats/min).(ABSTRACT TRUNCATED AT 250 WORDS)