Barbiturate Administration Research Articles

An overview of management of intracranial hypertension in the intensive care unit.

Intracranial hypertension (IH) is a clinical condition commonly encountered in the intensive care unit, which requires immediate treatment. The maintenance of normal intracranial pressure (ICP) and cerebral perfusion pressure in order to prevent secondary brain injury (SBI) is the central focus of management. SBI can be detected through clinical examination and invasive and non-invasive ICP monitoring. Progress in monitoring and understanding the pathophysiological mechanisms of IH allows the implementation of targeted interventions in order to improve the outcome of these patients. Initially, general prophylactic measures such as patient’s head elevation, fever control, adequate analgesia and sedation depth should be applied immediately to all patients with suspected IH. Based on specific indications and conditions, surgical resection of mass lesions and cerebrospinal fluid drainage should be considered as an initial treatment for lowering ICP. Hyperosmolar therapy (mannitol or hypertonic saline) represents the cornerstone of medical treatment of acute IH while hyperventilation should be limited to emergency management of life-threatening raised ICP. Therapeutic hypothermia could have a possible benefit on outcome. To control elevated ICP refractory to maximum standard medical and surgical treatment, at first, high-dose barbiturate administration and then decompressive craniectomy as a last step are recommended with unclear and probable benefit on outcomes, respectively. The therapeutic strategy should be based on a staircase approach and be individualized for each patient. Since most therapeutic interventions have an uncertain effect on neurological outcome and mortality, future research should focus on both studying the long-term benefits of current strategies and developing new ones.

La cura de sueño en la historia

A finales del siglo XIX comenzaron a utilizarse sustancias tales como los bromuros para inducir sueño profundo en personas con trastornos mentales. El uso de barbitúricos con el mismo fin fue reportado por Epifanio en 1913, pero fue Kläsi quien difundió con más éxito la administración de aquellos medicamentos, particularmente el Somnifen, y la denominó “cura de sueño prolongado” o “narcosis prolongada” (dauernarkose), a partir de la década de 1920. En 1934 se introdujo el Cloettal, una mezcla de barbitúricos y otros compuestos, en reemplazo del Somnifen. El uso de este procedimiento declinó con la aparición de otros métodos terapéuticos, pero continuó por varias décadas. En la Unión Soviética, la cura de sueño estuvo influida por la doctrina pavloviana, y se usó tanto para trastornos mentales como para padecimientos considerados psicosomáticos. El mayor desprestigio del método se dio en el Hospital de Chelmsford, en Australia, donde se reportaron 25 muertes asociadas a su uso durante el periodo 1963-1979. En el 2009, el Colegio Real de Psiquiatras de Australia y Nueva Zelanda concluyó que “la terapia de sueño profundo y la administración de barbitúricos endovenosos no tiene lugar en el tratamiento de trastornos psiquiátricos”. Aun cuando en la actualidad no forma parte de ningún tratamiento convencional, la cura de sueño sigue siendo ofrecida y solicitada.

Thiopental Does Not Produce Hyperalgesia: A Laboratory Study Using Two Human Experimental Pain Models.

Past investigations assessing the effects of thiopental on pain are conflicting. Although several studies demonstrate hyperalgesia as a result of barbiturate administration, others show analgesia. Our objective was to assess the effects of an infusion of the GABAA agonist thiopental, compared with placebo, in healthy participants on two subjective experimental pain paradigms: noxious electrical stimulation and intradermal capsaicin. For electrical stimulation, the milliamps required to achieve pain threshold and tolerance were recorded, and the percent change from baseline was determined for each infusion condition. In the intradermal capsaicin condition, the area of hyperalgesia was determined by von Frey technique pre- and postinfusion, and the percent change in the area of hyperalgesia was calculated. Though thiopental infusion resulted in an increase in the electrical stimulation current required to elicit pain threshold or reach pain tolerance when compared with baseline, this finding was not statistically significant. In the intradermal capsaicin condition, there was a statistically significant difference in overall pre- and postinfusion pain interpretation, as measured by the McGill Pain Questionnaire (P < 0.05), but there was no significant difference in area of hyperalgesia. In this human study of thiopental's effects on two experimental pain models, our results show that thiopental does not induce hyperalgesia.

Absence and reappearance of N20 response after thiopental withdrawal in postanoxic coma.

I read with interest the case report by Coppo et al.1 After coma was induced in the patient by high-dose barbiturate (thiopental) administration to combat refractory nonconvulsive status epilepticus, median nerve somatosensory evoked potential (SSEP) N20 responses elicited from the primary somatosensory cortex were bilaterally absent but responses from brainstem-cervical components were present. Continuous EEG recording at that time showed an isoelectric pattern. N20 responses reappeared after the barbiturate was …

Refractory Intracranial Hypertension in Posterior Reversible Encephalopathy Syndrome

Posterior reversible encephalopathy syndrome (PRES) is a largely reversible disease with long-term favorable outcome. A minority of patients, however, may develop progressive cerebral edema and ischemia resulting in severe disability or death. We report a case of severe intracranial hypertension associated with PRES that was successfully treated according to intracranial pressure (ICP)- and cerebral perfusion pressure (CPP)-driven therapy. Case report. A 42-year-old woman underwent bilateral lung transplantation for severe bronchiectasis. Her immunosuppressive regimen consisted of azathioprine, prednisone, and tacrolimus. She acutely developed an aggressive form of PRES that rapidly resulted in severe refractory intracranial hypertension despite discontinuation of potentially causative medications and adequate supportive therapy. Accordingly, second-tier therapies, including barbiturate infusion, were instituted and immunosuppression was switched to anti-thymocyte globulin followed by mycophenolate mofetil. Within 10 h of barbiturate administration, ICP dropped to 20 mmHg. Thiopental was administered for two days and then rapidly tapered because of severe urosepsis. Six months after discharge from the intensive care unit the patient returned to near-normal life, her only complaint being short-term amnesia. The decision to undertake ICP monitoring in medical conditions in which no clear recommendations exist greatly relies on physicians' judgment. This case suggests that ICP monitoring may be considered in the setting of acute PRES among selected patients, when severe intracranial hypertension is suspected, provided that a multidisciplinary team of neurocritical care specialists is readily available.

Chapter 11. Barbiturates

Chapter 11. Barbiturates

Chapter 15. Analgesics, sedatives, and neuromuscular blockade

Chapter 15. Analgesics, sedatives, and neuromuscular blockade

Response to intracranial hypertension treatment as a predictor of death in patients with severe traumatic brain injury

The normalization of increased intracranial pressure (ICP) in patients with severe traumatic brain injury (TBI) is assumed to limit secondary brain injury and improve outcome. Despite evidence-based recommendations for monitoring and treatment of elevated ICP, there are few studies that show an association between response to ICP-directed therapeutic regimens and adjusted mortality rate. This study utilizes a large prospective database to examine the effect of response to ICP-lowering therapy on risk of death within the first 2 weeks of injury in patients who sustained TBI and are older than 16 years. The current study is based on 1426 patients with severe TBI (Glasgow Coma Scale [GCS] score < 9) of whom 388 were treated for elevated ICP (> 25 mm Hg) between 2000 and 2008 at 22 trauma centers enrolled in a New York State quality improvement program. This prospectively collected database also contains information including age, admission GCS score, pupillary status, CT scanning parameters, and hypotension, which are all known early prognostic indicators of death. Treatment of elevated ICP consisted of administration of mannitol, hypertonic saline, barbiturates, and/or drainage of CSF or decompressive craniectomy. The factors predicting ICP response to treatment and predicting death at 2 weeks were evaluated using logistic regression analyses. Increasing age and fewer hours of elevated ICP on Day 1 were found to be significant predictors (p = 0.001 and 0.0003, respectively) of a positive response to treatment. Response to ICP-lowering therapy (p = 0.03), younger age (p < 0.0001), fewer hours of elevated ICP (p < 0.0001), and absence of arterial hypotension on Day 1 (p = 0.001) significantly predicted reduced risk of death. Patients who responded to ICP-lowering treatment had a 64% lower risk of death at 2 weeks than those who did not respond after adjusting for factors that independently predict risk of death.

What to do when a competent ICU patient does not want to live anymore but is dependent on life-sustaining treatment? Experience from The Netherlands

If patients on the intensive care unit (ICU) are awake and life-sustaining treatment is suspended because of the patients’ request, because of recovering from the disease, or because independence from organ function supportive or replacement therapy outside the ICU can no longer be achieved, these patients can suffer before they inevitably die. In The Netherlands, two scenarios are possible for these patients: (1) deep palliative (terminal) sedation through ongoing administration of barbiturates or benzodiazepines before withdrawal of treatment, or (2) deliberate termination of life (euthanasia) before termination of treatment. In this article we describe two awake patients who asked for withdrawal of life-sustaining measures, but who were dependent on mechanical ventilation. We discuss the doctrine of double effect in relation to palliative sedation on the ICU. Administration of sedatives and analgesics before withdrawal of treatment is seen as normal palliative care. We conclude that the doctrine of the double effect is not applicable in this situation, and mentioning it criminalised the practice unnecessarily and wrongfully.

Acute encephalitis with refractory, repetitive partial seizures (AERRPS): a peculiar form of childhood encephalitis

We conducted a nationwide multicenter study in Japan to elucidate the clinical and laboratory characteristics of acute encephalitis with refractory, repetitive partial seizures (AERRPS). Clinical and laboratory features, treatment, and outcome were assessed using a structured questionnaire. Twenty-nine children were enrolled in the study. Refractory and repetitive partial seizures accompanied by fever were the cardinal clinical features. Partial seizures consisted principally of eye deviation or facial twitching, being periodically repeated during the acute phase. These seizures were refractory to conventional anticonvulsants and were only suppressed by high-dose intravenous barbiturate administration. Rhythmic activities on electroencephalography and non-specific cerebral atrophy on neuroimaging were common. Serum or cerebrospinal antibodies against GluRepsilon2 were positive in six patients. General prognosis was unfavorable due to intractable epilepsy and cognitive deficits. Based on the peculiar and homogenous features, AERRPS can be regarded as a distinct clinical entity.

Phenobarbital blockade of the preovulatory luteinizing hormone surge: association with phase-advanced circadian clock and altered suprachiasmatic nucleus Period1 gene expression

The suprachiasmatic nucleus (SCN) controls the timing of the preovulatory luteinizing hormone (LH) surge in laboratory rodents. Barbiturate administration during a critical period on proestrus delays the surge and prolongs the estrous cycle 1 day. Because a nonphotic timing signal (zeitgeber) during the critical period that phase advances activity rhythms can also induce the latter effect, we hypothesized that barbiturates delay the LH surge by phase-advancing its circadian timing signal beyond the critical period. In experiment 1, locomotor rhythms and estrous cycles were monitored in hamsters for 2-3 wk preinjection and postinjection of vehicle or phenobarbital and after transfer to darkness at zeitgeber time (ZT) 6 on proestrus. Phenobarbital delayed estrous cycles in five of seven hamsters, which exhibited phase shifts that averaged twofold greater than those exhibited by vehicle controls or phenobarbital-injected hamsters with normal cycles. Experiment 2 used a similar protocol, but injections were at ZT 5, and blood samples for LH determination were collected from 1200 to 1800 on proestrus and the next day via jugular cannulae inserted the day before proestrus. Phenobarbital delayed the LH surge 1 day in all six hamsters, but it occurred at an earlier circadian time, supporting the above hypothesis. Experiment 3 investigated whether phenobarbital, like other nonphotic zeitgebers, suppresses SCN Period1 and Period2 transcription. Two hours postinjection, phenobarbital decreased SCN expression of only Period1 mRNA, as determined by in situ hybridization. These results suggest that phenobarbital advances the SCN pacemaker, governing activity rhythms and hormone release in part by decreasing its Period1 gene expression.

Intraoperative use of somatosensory-evoked potentials: is general anaesthesia comparable to awake condition?

Editor, We have read with great interest the article by Fielmuth and Uhlig [1] on the role of somatosensory-evoked potentials (SSEPs) in detecting cerebral ischaemia during carotid endarterectomy. The authors made an assessment of the validity of SSEP monitoring during carotid endarterectomy in awake patients under locoregional anaesthesia. They correctly reported the current substantial variety of SSEP parameters and thresholds related to these SSEP parameters used to detect critical deterioration in cerebral blood flow (CBF). Their study was designed to compare SSEP tracings with the objective clinical–neurological examination in order to evaluate the reliability of the different SSEP-generated criteria. They referred to Shapiro and Aidinis [2], who developed a model, which can be seen as the methodological basis for current neuromonitoring during carotid surgery. This model correlates neuronal integrity and electrical activity with CBF. Using this approach to interpret changes in SSEP tracing as a perfusion-dependent neuronal metabolic situation, different parameters and values have been established to detect a relevant reduction in CBF.

Varialibility of Neurological Complications in the Treatment of Acute Lymphoblastic Leukemia:Experience of a Single Pediatric Institution

Intensive chemotherapy significantly improves the outcome of pediatric acute lymphoblastic leukemia (ALL) but unfortunately increases the incidence and severity of acute adverse events. The current study analyses the incidence of central nervous system (CNS) complications during ALL treatment in a single pediatric institution. CNS leukemic infiltration at diagnosis, therapy-related peripheral neuropathy and leukoencephalopathy and neurocognitive defects after treatment were excluded by the study. From September 2000 to July 2008, two hundred and forty ALL patients (pts) were treated in our Institution according to BFM-AIEOP ALL 2000 protocol. Twenty-four out of 240 patients (10 %) (15 females and 9 males, median age at the event 7.7 years, range 2–16 years) developed CNS complications during treatment. Thirteen presented tonic-clonic seizures, four showed dyskinesia and dyslalia, one presented visual impairment and enuresis, and six had loss of consciousness. In 18 pts a rapid resolution of the event was obtained by administration of benzodiazepines or barbiturates; 6 pts required admission in intensive care unit, instead. Only two out of twenty-four patients presented neurological sequelae (one pts with recurrent seizures and one pts with right limb disability). Co-morbidity at the time of neurological accident included: blood pressure increase (6 pts), electrolytes imbalance (4 pts), LDH increase (4 pts), coagulation disorders (6 pts), hepatic enzyme increase (2 pts), severe anemia (1 pts), severe thrombocytopenia (4 pts), renal failure (1 pts), and Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) (1 pts). Radiological scanning (either CT or MRI) and electroencephalography (EEG) performed within 48 hr from the onset of the clinical symptoms revealed different etiologies: 8 posterior reversible leukoencephalopathies (PRES), 3 cerebral bleedings, 2 ischemic cerebral diseases, 2 methotrexate toxicity, 1 SIADH, 2 temporal lobe epilepsy and 6 unidentified problems. In conclusion this retrospective study on CNS complications during ALL treatment shows that the most frequent neurological accident (33%) is the PRES.

Phenomenology and Emotional Impact of Neuropsychiatric Symptoms in Orthotopic Liver Transplant for Hepatocellular Carcinoma

Background Few studies have focused on neuropsychiatric symptoms like hallucinations or delusions occurring in the early posttransplant period. The aim of this study was to estimate the percentage of patients reporting neuropsychiatric symptoms in the immediate postoperative phase, to describe the phenomenology, and to evaluate the emotional impact of such disorders. Method We studied 94 consecutive patients who underwent orthotopic liver transplant (OLT) for hepatocellular carcinoma at least 30 days prior. The presence of neuropsychiatric symptoms were retrospectively evaluated through a semistructured interview. Results Overall 49 patients (52%) reported various postoperative neuropsychiatric symptoms. None of the demographic and clinical variables showed significant associations, except for barbiturate administration; patients using barbiturates showed a lower percentage of neuropsychiatric symptoms. It was a time-limited phenomenon that in most cases resolved by day 7 after transplantation. Interestingly, the most frequent emotion perceived was surprise and not fear; a nontrivial amount of patients reported happiness, while many patients reported no emotion. Conclusions The results of this study suggested the usefulness of a registry of the neurological and psychiatric complications after OLT that may help to clarify the pathogenic mechanisms of such complications and implement uniform protocols of prevention and treatment. In fact, better knowledge of the phenomenology of neuropsychiatric symptoms in OLT recipients could allow easier symptom recognition and therapy adjustments on the basis of the emotional impact of such symptoms on patients, family, and caregivers, as well as increase patients’ awareness and capability to face this experience.

重症くも膜下出血の治療―ニカルジピン徐放剤を用いて―

Nicardipine prolonged-release pellets (NP) are made for implantation during surgery to prevent cerebral vasospasm. We retrospectively analyzed patients with a poor-grade subarachnoid hemorrhage (SAH) between October 1999 and September 2004. Among 125 surgically treated SAH patients, 34 belonged to WFNS grades 4 and 5 (male/female 13/21, the average age was 63, the ratio craniotomy/coil 26/8). Four to 12 NPs (16-48 mg of nicardipine) were placed along the respective artery (IC, A1, A2, A3, M1, M2, and M3) after clipping the aneurysm, where there was thick clot and therefore subsequent vasospasm was highly likely. The intracranial pressure was monitored and treated with glycerin, ventricular drainage, external decompression, and/or barbiturate administration. Neither induced hypervolemia nor induced hypertension was used. A delayed ischemic neurological deficit was seen in 1 patient, but there were no cerebral infarctions due to cerebral vasospasm. Angiography performed on days 7-12 revealed no vasospasm in any arteries close to where the NPs were placed. The outcome after 3 months was good in 7, moderately disabled in 13, severely disabled in 7, vegetative state in 2, and 5 patients had deceased. The NP is an effective, simple, and safe prophylactic treatment to prevent vasospasm when a surgical procedure is chosen to treat ruptured aneurysms of poor-grade SAH patients.

Computed tomographic angiography for diagnosis of brain death.

The authors report two patients with suspected brain death who required confirmatory tests other than clinical examination because of prolonged barbiturate administration for intracranial hypertension. Absence of intracranial blood flow was documented on CT angiography and confirmed by CT perfusion images. Cerebral angiography confirmed the findings consistent with brain death. CT angiography with CT perfusion may represent a rapid noninvasive method for diagnosis of brain death.

Conversation with Conan Kornetsky.

Conversation with Conan Kornetsky.

The effect of four anesthetic protocols on the spleen in dogs

Splenic enlargement following administration of barbiturates has been well described in dogs; other agents have not been investigated. This study aimed to compare the effects of four anesthetic protocols on splenic size. Twenty-four fasted Beagle dogs scheduled for laparotomy were allocated to one of the four groups. Group 1: acepromazine and butorphanol followed by induction with thiopental; Group 2: acepromazine and butorphanol followed by induction with propofol; Group 3: medetomidine and butorphanol followed by induction with propofol; Group 4: medetomidine and butorphanol followed by induction with ketamine and diazepam. Anesthesia was maintained with halothane in oxygen, intravenous fluids were administered. Splenic length, width and height were measured once when the abdomen was opened and again just prior to closure. Spleens were also traced, the image was digitized, and the area was calculated. PCV and total solids were measured before and after pre-medication, after induction, and each time the spleen was measured. Data were analyzed using a Repeated Measures anova with splenic variables indexed by body surface area and dose of induction agent as a covariate. Area and width of the spleens were less in the dogs of Groups 2 and 3 than in those of the other groups. Splenic area and length did not change significantly during surgery. Dosage of propofol was not significantly different between Groups 2 and 3. Baseline PCV was not significantly different among groups and decreased significantly in all dogs, but at different times. In Groups 1 and 2, the decrease occurred after pre-medication, in Group 3 at induction, and in Group 4 during surgery. A significant decrease in TS occurred in all groups during surgery. We concluded that the use of propofol resulted in smaller spleen size during surgery than that following the use of thiopental. Multiple factors influenced the PCV.

Cyclosporine can increase isoflurane MAC.

Previous reports indicate that cyclosporine increases sleeping time from barbiturate administration, and analgesia from fentanyl administration, suggesting a possible contribution of cyclosporine to anesthesia. Accordingly, we determined whether cyclosporine pretreatment decreases isoflurane MAC (the minimum alveolar concentration of anesthetic required to eliminate movement in response to noxious stimulation in 50% of subjects) in rats, and whether cyclosporine changes the hindpaw withdrawal latency (HPWL) test to thermal nociceptive stimulation. We assigned rats to receive vehicle (control; n = 18), 7.5 mg. kg(-1). d(-1) cyclosporine (n = 10), or 15 mg. kg(-1). d(-1) cyclosporine (n = 20). MAC was determined before and immediately after 3 days of treatment. HPWL was determined after 3 days of treatment in controls (vehicle) and cyclosporine (15 mg. kg(-1). d(-1)) treated animals. Cyclosporine 7.5 and 15 mg. kg(-1). d(-1) increased MAC by 10.4% +/- 7.3% and 23.1% +/- 17.1% (mean +/- SD) (P < 0.05), respectively. The changes in isoflurane MAC correlated significantly with cyclosporine blood concentrations. Cyclosporine did not significantly increase HPWL. Contrary to our hypotheses, cyclosporine increases rather than decreases MAC, but does not confer appreciable analgesia. The immunosuppressive drug, cyclosporine, which is frequently used after organ transplantation, increases the amount of a commonly used anesthetic (isoflurane) necessary to avoid movement to painful stimuli in the rat.

Neuronal activity and stress differentially regulate hippocampal and hypothalamic corticotropin-releasing hormone expression in the immature rat

Corticotropin-releasing hormone, a major neuromodulator of the neuroendocrine stress response, is expressed in the immature hippocampus, where it enhances glutamate receptor-mediated excitation of principal cells. Since the peptide influences hippocampal synaptic efficacy, its secretion from peptidergic interneuronal terminals may augment hippocampal-mediated functions such as learning and memory. However, whereas information regarding the regulation of corticotropin-releasing hormone’s abundance in CNS regions involved with the neuroendocrine responses to stress has been forthcoming, the mechanisms regulating the peptide’s levels in the hippocampus have not yet been determined. Here we tested the hypothesis that, in the immature rat hippocampus, neuronal stimulation, rather than neuroendocrine challenge, influences the peptide’s expression. Messenger RNA levels of corticotropin-releasing hormone in hippocampal CA1, CA3 and the dentate gyrus, as well as in the hypothalamic paraventricular nucleus, were determined after cold, a physiological challenge that activates the hypothalamic pituitary adrenal system in immature rats, and after activation of hippocampal neurons by hyperthermia. These studies demonstrated that, while cold challenge enhanced corticotropin-releasing hormone messenger RNA levels in the hypothalamus, hippocampal expression of this neuropeptide was unchanged. Secondly, hyperthermia stimulated expression of hippocampal immediate-early genes, as well as of corticotropin-releasing hormone. Finally, the mechanism of hippocampal corticotropin-releasing hormone induction required neuronal stimulation and was abolished by barbiturate administration. Taken together, these results indicate that neuronal stimulation may regulate hippocampal corticotropin-releasing hormone expression in the immature rat, whereas the peptide’s expression in the hypothalamus is influenced by neuroendocrine challenges.