Maternal brain death and somatic support

Brain death is a concept used in situations in which life-support equipment obscures the conventional cardiopulmonary criteria of death, and it is legally recognized in most countries worldwide. Brain death during pregnancy is an occasional and tragic occurrence. The mother and fetus are two distinct organisms, and the death of the mother mandates consideration of the well-being of the fetus. Where maternal brain death occurs after the onset of fetal viability, the benefits of prolonging the pregnancy to allow further fetal maturation must be weighed against the risks of continued time in utero, and preparations must be made to facilitate urgent cesarean section and fetal resuscitation at short notice. Where the fetus is nonviable, one must consider whether continuation of maternal organ supportive measures in an attempt to attain fetal viability is appropriate, or whether it constitutes futile care. Although the gestational age of the fetus is central to resolving this issue, there is no clear upper physiological limit to the prolongation of somatic function after brain death. Furthermore, medical experience regarding prolonged somatic support is limited and can be considered experimental therapy. This article explores these issues by considering the concept of brain death and how it relates to somatic death. The current limits of fetal viability are then discussed. The complex ethical issues and the important variations in the legal context worldwide are considered. Finally, the likelihood of successfully sustaining maternal somatic function for prolonged periods and the medical and obstetric issues that are likely to arise are examined.     

The neurophysiology of pain perception and hypnotic analgesia: implications for clinical practice

Although there remains much to be learned, a great deal is now known about the neurophysiological processes involved in the experience of pain. Research confirms that there is no single focal "center" in the brain responsible for the experience of pain. Rather, pain is the end product of a number of integrated networks that involve activity at multiple cortical and subcortical sites. Our current knowledge about the neurophysiological mechanisms of pain has important implications for understanding the mechanisms underlying the effects of hypnotic analgesia treatments, as well as for improving clinical practice. This article is written for the clinician who uses hypnotic interventions for pain management. It begins with an overview of what is known about the neurophysiological basis of pain and hypnotic analgesia, and then discusses how clinicians can use this knowledge for (1) organizing the types of suggestions that can be used when providing hypnotic treatment, and (2) maximizing the efficacy of hypnotic interventions in clients presenting with pain problems.     

Linking pain and the body: neural correlates of visually induced analgesia

The visual context of seeing the body can reduce the experience of acute pain, producing a multisensory analgesia. Here we investigated the neural correlates of this "visually induced analgesia" using fMRI. We induced acute pain with an infrared laser while human participants looked either at their stimulated right hand or at another object. Behavioral results confirmed the expected analgesic effect of seeing the body, while fMRI results revealed an associated reduction of laser-induced activity in ipsilateral primary somatosensory cortex (SI) and contralateral operculoinsular cortex during the visual context of seeing the body. We further identified two known cortical networks activated by sensory stimulation: (1) a set of brain areas consistently activated by painful stimuli (the so-called "pain matrix"), and (2) an extensive set of posterior brain areas activated by the visual perception of the body ("visual body network"). Connectivity analyses via psychophysiological interactions revealed that the visual context of seeing the body increased effective connectivity (i.e., functional coupling) between posterior parietal nodes of the visual body network and the purported pain matrix. Increased connectivity with these posterior parietal nodes was seen for several pain-related regions, including somatosensory area SII, anterior and posterior insula, and anterior cingulate cortex. These findings suggest that visually induced analgesia does not involve an overall reduction of the cortical response elicited by laser stimulation, but is consequent to the interplay between the brain's pain network and a posterior network for body perception, resulting in modulation of the experience of pain.     

Fetal pain?

During the last few years a vivid debate, both scientifically and emotionally, has risen in the medical literature as to whether a fetus is able to feel pain during abortion or intrauterine surgery. This debate has mainly been inspired by the demonstration of various hormonal or motor reactions to noxious stimuli at very early stages of fetal development. The aims of this paper are to review the literature on development of the pain system in the fetus, and to speculate about the relationship between "sensing" as opposed to "feeling" pain and the number of reactions associated with painful stimuli. While a cortical processing of pain theoretically becomes possible after development of the thalamo-cortical connections in the 26th week of gestation, noxious stimuli may trigger complex reflex reactions much earlier. However, more important than possible painfulness is the fact that the noxious stimuli, by triggering stress responses, most likely affect the development of an individual at very early stages. Hence, it is not reasonable to speculate on the possible emotional experiences of pain in fetuses or premature babies. A clinically relevant aim is rather to avoid and/or treat any possibly noxious stimuli, and thereby prevent their potential adverse effects on the subsequent development.     

Prenatal experience with milk: fetal behavior and endogenous opioid systems.

The existence of organized responses to milk in newborn mammals, which lack experience at the nipple, implies the prenatal development of neural and behavioral systems for recognizing, obtaining, and processing milk. Many components of milk-directed behavior have been identified in the fetus. The stretch response expressed by neonatal rats during milk ejection at the nipple can be elicited before birth by infusing milk into the mouth of the fetus. Milk promotes reorganization of fetal motor behavior, facilitates expression of the stretch response, and alters fetal responsiveness to cutaneous stimulation. Pretreatment of fetuses with opioid agonists and antagonists has confirmed involvement of the mu and kappa opioid systems in mediating the effects of milk. Opioids appear to play a dual role in milk-oriented behavior: Initially, opioids suppress behavioral responses of the fetus and neonate to novelty, permitting ingestion of milk, and secondarily, opioid activity can promote learning at the nipple by functioning as a reinforcer. Study of milk-directed behavior in the fetus may promote better understanding of the special needs of preterm human infants.     

The central cannabinoid receptor type-2 (CB2) and chronic pain

Cannabinoid receptor type-2 (CB2, CB2 receptor or CB2-R) mediates analgesia via two mechanisms. CB2 receptors contained in peripheral immune tissue mediate analgesia by altering cytokine profiles, and thus have little adverse effects on central nervous systems (CNSs). CB2 is also expressed in the neurons and glial cells of the CNS. This neuronal expression may also contribute to pain attenuation. The CB2 receptor has been proposed as a potential target in treating chronic pain of several etiologies.     

Mechanisms of acupuncture analgesia for clinical and experimental pain

There is convincing evidence that acupuncture (AP) is effective for the treatment of postoperative and chemotherapy-induced nausea/vomiting, as well as postoperative dental pain. Less convincing data support AP's efficacy for chronic pain conditions, including headache, fibromyalgia and low back pain. There is no evidence that AP is effective in treating addiction, insomnia, obesity, asthma or stroke deficits. AP seems to be efficacious for alleviating experimental pain by increasing pain thresholds in human subjects and it appears to activate analgesic brain mechanisms through the release of neurohumoral factors, some of which can be inhibited by the opioid antagonist naloxone. In contrast to placebo analgesia, AP-related pain relief takes some time to develop and to resolve. Furthermore, repetitive use of AP analgesia can result in tolerance that demonstrates cross-tolerance with morphine. However, it appears that not all forms of AP are equally effective for providing analgesia. In particular, electro-AP seems to best deliver stimuli that activate powerful opioid and nonopioid analgesic mechanisms. Thus, future carefully controlled clinical trials using adequate electro-AP may be able to provide the necessary evidence for relevant analgesia in chronic pain conditions, such as headache, fibromyalgia, irritable bowel syndrome and low back pain.     

Growth and function of the normal human placenta

The placenta is the highly specialised organ of pregnancy that supports the normal growth and development of the fetus. Growth and function of the placenta are precisely regulated and coordinated to ensure the exchange of nutrients and waste products between the maternal and fetal circulatory systems operates at maximal efficiency. The main functional units of the placenta are the chorionic villi within which fetal blood is separated by only three or four cell layers (placental membrane) from maternal blood in the surrounding intervillous space. After implantation, trophoblast cells proliferate and differentiate along two pathways described as villous and extravillous. Non-migratory, villous cytotrophoblast cells fuse to form the multinucleated syncytiotrophoblast, which forms the outer epithelial layer of the chorionic villi. It is at the terminal branches of the chorionic villi that the majority of fetal/maternal exchange occurs. Extravillous trophoblast cells migrate into the decidua and remodel uterine arteries. This facilitates blood flow to the placenta via dilated, compliant vessels, unresponsive to maternal vasomotor control. The placenta acts to provide oxygen and nutrients to the fetus, whilst removing carbon dioxide and other waste products. It metabolises a number of substances and can release metabolic products into maternal and/or fetal circulations. The placenta can help to protect the fetus against certain xenobiotic molecules, infections and maternal diseases. In addition, it releases hormones into both the maternal and fetal circulations to affect pregnancy, metabolism, fetal growth, parturition and other functions. Many placental functional changes occur that accommodate the increasing metabolic demands of the developing fetus throughout gestation.     

Termination of pregnancy for fetal neurological abnormalities

Introduction Prenatal screening for fetal abnormalities may identify conditions likely to result in perinatal death or in survival with a risk of handicap, for which termination of pregnancy is legal in many countries.Discussion When considering termination of pregnancy, it is crucial that prenatal diagnosis be as accurate as possible and that the prognosis of the condition diagnosed in utero is thoroughly understood by the parents. Our ability to predict postnatal outcome in borderline cases should not be overestimated. Parents should not precipitate their decision, and in some European countries, the absence of a gestational age limit at which a termination may be performed is viewed as a guarantee against hasty terminations. Maternal morbidity potentially associated with termination should be kept as low as possible. This includes maternal analgesia, and avoiding uterine trauma to preserve fertility and to prevent obstetrical complications in subsequent pregnancies. Bereavement should also be taken into account. Tests that could contribute to confirming the diagnosis or to establishing the aetiology of the abnormality, such as fetal karyotype or platelet count, should be implemented when appropriate, since post-termination genetic counselling relies on such data. Post-mortem examination is often crucial for genetic counselling and should include X-rays and gross examination of the fetus as well as brain and spine examination by a neuropathologist with expertise in the field of fetal medicine. Specific post-mortem procedures sometimes need to be planned before termination, for instance, in fetal akinesia sequence. First trimester surgical techniques and second or third trimester medical techniques of termination of pregnancy are reviewed.     

Pain treatment in burn patients

Burn injuries can be causing the most intense and prolonged types of pain. Pain in such patients can also cause psychologic and functional difficulties, and is difficult to predict from wound depth. The fundamental problem of the burn pain treatment is insufficient analgesia. The pain management of the burn patient can be very difficult and necessitate enough experience because of individual differences of the patients and pain that involve different components. The psychological support and treatment is also as important as pharmacological treatment. The success rate of the pain treatment of the burn patient can be increased with the multidisciplinary approach based on the decision of the most appropriate pain treatment modalities for individual patient and the principles of the pain treatment.     

Inferring distinct mechanisms in the absence of subjective differences: Placebo and centrally acting analgesic underlie unique brain adaptations

Development and maintenance of chronic pain is associated with structural and functional brain reorganization. However, few studies have explored the impact of drug treatments on such changes. The extent to which long‐term analgesia is related to brain adaptations and its effects on the reversibility of brain reorganization remain unclear. In a randomized placebo‐controlled clinical trial, we contrasted pain relief (3‐month treatment period), and anatomical (gray matter density [GMD], assessed by voxel‐based morphometry) and functional connectivity (resting state fMRI nodal degree count [DC]) adaptations, in 39 knee osteoarthritis (OA) patients (22 females), randomized to duloxetine (DLX, 60 mg once daily) or placebo. Pain relief was equivalent between treatment types. However, distinct circuitry (GMD and DC) could explain pain relief in each group: up to 85% of variance for placebo analgesia and 49% of variance for DLX analgesia. No behavioral measures (collected at entry into the study) could independently explain observed analgesia. Identified circuitry were outside of nociceptive circuitry and minimally overlapped with OA‐abnormal or placebo response predictive brain regions. Mediation analysis revealed that changes in GMD and DC can influence each other across remote brain regions to explain observed analgesia. Therefore, we can conclude that distinct brain mechanisms underlie DLX and placebo analgesia in OA. The results demonstrate that even in the absence of differences in subjective pain relief, pharmacological treatments can be differentiated from placebo based on objective brain biomarkers. This is a crucial step to untangling mechanisms and advancing personalized therapy approaches for chronic pain.     

Patient-controlled epidural analgesia in labour: the addition of fentanyl or clonidine to bupivacaine

In this study, we studied 45 healthy parturients with singleton vertex presentation. Patients were allocated randomly to receive either 0,125 % bupivacaine with 2 micro g/ml fentanyl or 0,125 % bupivacaine with 1,5 micro g/ml clonidine for epidural labour analgesia. A patient controlled epidural analgesia (PCEA) pump was programmed as follows: basale infusion rate: 6 ml/h, demand bolus: 5 ml, lockout interval: 10 min. Efficacy of analgesia was evaluated using visual analogue scale. Maternal and fetal cardiovascular variables, Apgar scores of the newborn at 1-5 min and umbilical arterial blood gas measurements were recorded. The duration of stages of labour and total analgesic consumption were also noted. Systolic blood pressure decreased significantly at 3rd h in bupivacaine plus fentanyl group. Although all patients experienced a good analgesia, pain scores in bupivacaine plus clonidine group were lower than bupivacaine plus fentanyl group. The analgesic requirement in bupivacaine plus clonidine group was less than the other group. There were no significant differences in fetal heart rate, Apgar scores or umbilical blood gases. In conclusion, the addition of clonidine to epidural bupivacaine for PCEA was superior to bupivacaine plus fentanyl for analgesia and analgesic requirement during labour.     

Hypnosis as an intervention in pain management: A brief review

While there is a consensus that psychosocial factors play an important role in the experience of pain, clinical interventions for acute and chronic pain remain primarily biomedical. This pattern persists despite a body of recent empirical work supporting the effectiveness of a number of behavioral and relaxation interventions for these problems. One of these interventions is hypnosis. We briefly discuss hypnotic analgesia and describe how hypnosis can be integrated into biomedical treatment for acute and chronic pain. Special attention is given to indications and contraindications, preparation of patients, and technique.     

Réactivité à la douleur dans les schizophrénies : un phénomène spécifique ou lié au fonctionnement psychique des patients ?

Medical practitioners do not for a long time pay enough attention to patient's pain. This approach is in the line of society feelings. Pain was long consider to be a contingency to withstand as showed in Christian's bible or Stoicism's principle. Changes in mentality appear in present times. It seems obvious that for sociological and scientific reasons pain's care in medical and psychiatric disorders is now an important subject. Recent research in autistic disorders suggest that insensitivity observed in autism is not an analgesic phenomenon but a different behavioral reactivity to pain. Prevalence of schizophrenic disorder is from 0.5 to 1%. It is also a complex disorder that has defied decades of concerted efforts to uncover its origins and attenuate its symptoms. The most promising hypotheses suggest that neurodevelopmental impairment increases the risk of later schizophrenia. Most of recent researches in this topic did focus to trait or state markers. According to the vulnerability models of schizophrenia, trait markers are clinical, psychological, physiological, anatomical or cognitive impairments found in patients with schizophrenia during all the course of the illness and even before the onset. Several lines of evidence (case report, epidemiological studies, experimental studies) suggest that patients with schizophrenia show a relative insensitivity to physical pain. We will review and critic the scientific literature in this specific topic. We will see if data are relevant with the neurodevelopmental hypothesis and vulnerability models. Articles are separated in 2 groups, first are clinical or epidemiological studies, and second are experimental studies. Clinical and experimental data strongly suggest a decrease of behavioural reactivity to pain (BRP) but there is a lack of argument to prove a real analgesia. Because schizophrenia is a severe decease with impairment in communication and social skills, it may be very difficult to affirm that the insensitivity to pain does really exist for patients. It seems inappropriate at this point to speak about insensitivity or analgesia. We could hypothesis that the decrease of BRP is less a consequence of analgesia than a different way to express emotion in general and pain in particular. It is well known that patients with schizophrenia show communication and thinking impairment, not adapted social skills and also a lack of body representation. However, this decrease of behavioral response seems to be frequent and may be explored by objective research protocol to understand if patients don’t feel pain or probably don’t express pain by adapted social skills. Furthermore, decrease of BRP may take place in a comprehensive theory of schizophrenia in the line of stress-vulnerability model. Impairment or lack of behavioral pain reactivity could induce an increasing anxiety level for patient with vulnerability to schizophrenia and a higher risk of onset of the pathology. We may argue that pain stimuli would conduct to a nociceptive stress witch couldn’t discharge by usual ways of regulation and behavioral expression of pain. Recent research regarding empathy in patients with schizophrenia may be a relevant approach for understanding the un-specificity of pain reactivity impairment in these patients.     

Fetal neurologic consultations

The pediatric neurologist can fulfill a useful role as a subspecialty consultant concerning the fetus with a suspected brain disorder, given that neurologic disease may occur before the intrapartum period. Brain disorders detected in the neonatal period may also reflect fetal brain damage before dysfunction is first documented. Medical conditions during the antepartum or intrapartum periods can alternatively predispose the fetus or neonate to express brain dysfunction at a later period, with either de novo or compounded brain injury. The pediatric neurologist must, therefore, consider maternal, placental, and fetal diseases on which a neonatal encephalopathy may be superimposed. This review article provides the neurologist with an integrative approach to fetal neurology, emphasizing perspectives from other subspecialties concerning maternal-fetal medicine, pathology, and neonatology, as well as other pediatric subspecialties. Evaluation of future strategies for either fetal or neonatal brain resuscitation will need to consider the developmental context in which a suspected brain injury occurred during the antepartum, intrapartum, and neonatal periods.     

Social conflict analgesia: Inhibition of early non-opioid component by diazepam or Flumazepil fails to affect appearance of late opioid component

Two forms of analgesia (opioid and non-opioid) are associated with social conflict in mice. The non-opioid form is seen in response to the scent of an aggressive conspecific or defeat experience, whilst the opioid form occurs in response to extended conspecific attack. Recently, it has been reported that the non-opioid reaction is dose-dependently blocked by diazepam and by Flumazepil (Ro15-1788; a benzodiazepine receptor antagonist). In view of the temporal relationship between these two reactions, the present study was conducted to determine whether activation of non-opioid substrates is a necessary precursor to the development of opioid analgesia. Results indicate that inhibition of non-opioid analgesia by diazepam (2-4 mg/kg), or by Flumazepil (20-40 mg/kg), does not alter the opioid analgesic reaction to conspecific attack. Findings are discussed in relation to the presumed adaptive significance of these biologically-meaningful forms of pain inhibition.     

Footshock induced analgesia in dependent neither on pituitary nor sympathetic activation

A variety of environmental stimuli have been demonstrated to produce potent behavioral analgesia. Of these, footshock has been shown to be capable of differentially eliciting opiate or non-opiate analgesia dependent upon the body region shocked; front paw and hind paw shock produce opiate and non-opiate analgesia, respectively. In addition, footshock can be used as a conditioned stimulus to elicit classically conditioned opiate analgesia. A question which arises is whether such pain inhibition is mediated by neural or hormonal pathways. Evidence exists which suggests that endogenous opioids in the pituitary and adrenal medulla may be involved in the production of environmentally induced analgesia. Furthermore, epinephrine administration has previously been shown to produce pronounced pain inhibition. However, the present series of experiments demonstrate that the pituitary-adrenal cortical and sympathetic-adrenal medullary axes are neither necessary nor sufficient for the production of footshock induced analgesia (FSIA). Hypophysectomy failed to attenuate front paw FSIA, hind paw FSIA or classically conditioned analgesia indicating that pituitary β-endorphin or other pituitary factors are not necessary for the production of analgesia. Adrenal opioids and peripheral catecholamines are also not critical since front paw FSIA was potentiated by adrenalectomy or total sympathetic blockade. Furthermore, pituitary and sympathetic activation are not sufficient for the production of analgesia since low thoracic spinalization allows normal hormonal response to front paw shock yet abolishes shock-induced inhibition of the spinally mediated tail flick reflex. These results provide strong evidence that front paw FSIA, hind paw FSIA and classically conditioned analgesia are mediated by neural, rather than hormonal, pathways and provide further parallels between these forms of environmental analgesia, morphine analgesia and brain stimulation produced analgesia.     

Pain perception during self-reported distress and calmness in patients with borderline personality disorder and self-mutilating behavior

Self-mutilation occurs in 70-80% of patients who meet DSM-IV criteria for borderline personality disorder. Approximately 60% of these patients report that they do not feel pain during acts of self-mutilation such as cutting or burning. Findings of recent studies measuring pain perception in patients with BPD are difficult to interpret since variables such as distress, dissociation or relevant psychotropic medication have not been controlled. The Cold Pressor Test (CPT) and the Tourniquet Pain Test (TPT) were administered to 12 female patients with BPD who reported analgesia during self-mutilation and 19 age-matched healthy female control subjects. All subjects were free of psychotropic medication. The patients were studied on two occasions: during self-reported calmness and during intensive distress (strong urge to cut or burn themselves). Even during self-reported calmness, patients with BPD showed a significantly reduced perception of pain compared to healthy control subjects in both tests. During distress, pain perception in BPD patients was further significantly reduced as compared with self-reported calmness. The present findings show that self-mutilating patients with BPD who experience analgesia during self-injury show an increased threshold for pain perception even in the absence of distress. This may reflect a state-independent increased pain threshold which is further elevated during stress. Interpretation of these findings is limited by their reliance upon self-reports.     

Prenatal ontogeny of substance P-like immunoreactivity in the nucleus tractus solitarii and dorsal motor nucleus of the vagus nerve of the human fetus: an immunocytochemical study

By using immunocytochemical method, the prenatal ontogeny of substance P-like immunoreactivity (SP-LI) was demonstrated in the dorsal motor nucleus of the vagus nerve (nX) and the nucleus tractus solitarii (nTS) of the human fetus at fetal age (menstruation age) of 11.5 weeks to 40 weeks. The time of initial appearance of SP-LI in the human brainstem nTS was between the fetal age 11.5 weeks and 16 weeks. At fetal age 16 weeks, the nTS showed moderate density of SP-LI fibers and terminals in subnucleus dorsalis of the nTS and nX. While the fetus grew, the density of SP-LI in the human fetus brainstem nTS and nX increased gradually from fetal age 16 weeks to 40 weeks. According to the Nissl staining, at fetal age 23 weeks, the nTS of human fetus can be subdivided into dorsal, medial, dorsolateral, ventrolateral and ventral gelatinosus subnuclei. The cytoarchitectonic subdivisions of human fetus nTS is in good agreement with the results obtained by immunocytochemical staining. These findings indicated that substance P (SP) might play an important role in the development of human brainstem nX, nTS, their related cranial nerves, and in their functional establishment during the pranatal period.