Trans-vaccenic acid reprograms CD8+ T cells and anti-tumour immunity.

Diet-derived nutrients are inextricably linked to human physiology by providing energy and biosynthetic building blocks and by functioning as regulatory molecules. However, the mechanisms by which circulating nutrients in the human body influence specific physiological processes remain largely unknown. Here we use a blood nutrient compound library-based screening approach to demonstrate that dietary trans-vaccenic acid (TVA) directly promotes effector CD8+ T cell function and anti-tumour immunity in vivo. TVA is the predominant form of trans-fatty acids enriched in human milk, but the human body cannot produce TVA endogenously1. Circulating TVA in humans is mainly from ruminant-derived foods including beef, lamb and dairy products such as milk and butter2,3, but only around 19% or 12% of dietary TVA is converted to rumenic acid by humans or mice, respectively4,5. Mechanistically, TVA inactivates the cell-surface receptor GPR43, an immunomodulatory G protein-coupled receptor activated by its short-chain fatty acid ligands6-8. TVA thus antagonizes the short-chain fatty acid agonists of GPR43, leading to activation of the cAMP-PKA-CREB axis for enhanced CD8+ T cell function. These findings reveal that diet-derived TVA represents a mechanism for host-extrinsic reprogramming of CD8+ T cells as opposed to the intrahost gut microbiota-derived short-chain fatty acids. TVA thus has translational potential for the treatment of tumours.

Continuous bupivacaine infusion post-iliac crest bone graft harvesting in pediatric cleft surgery: role and comparison with ketorolac.

OBJECTIVE: To investigate the use of intravenous ketorolac and iliac crest bupivacaine infusion in the management of iliac crest donor-site pain in the pediatric cleft population. The null hypothesis was there is no difference with respect to pain scores between ketorolac and iliac crest bupivacaine infusion as analgesic adjuncts to intravenous opioids. METHODS: A total of 54 children and adolescents (27 boys, 27 girls) undergoing alveolar cleft repair or Le Fort I osteotomy were assigned randomly in a prospective, single-blinded fashion to one of three groups: intravenous ketorolac plus iliac crest normal saline infusion, intravenous ketorolac plus iliac crest bupivacaine infusion, or iliac crest bupivacaine infusion alone. Iliac crest infusions and ketorolac were administered for 48 hours or until discharge, whichever occurred first. All patients received morphine via a patient-controlled analgesia device. MAIN OUTCOME MEASURE(S): Primary outcome was pain score, and secondary outcomes were morphine consumption and satisfaction scores. RESULTS: Pain scores, morphine consumption, and satisfaction scores were not significantly different among groups. Estimated costs were significantly higher for bupivacaine infusion than intravenous ketorolac. CONCLUSIONS: Iliac crest donor-site pain is well managed in this patient population. Intravenous ketorolac and iliac crest bupivacaine infusion provide comparable analgesia for iliac crest bone graft donor-site pain in children and adolescents.

The role of protein kinase-C alpha in the activation of particulate guanylate cyclase by 1 alpha,25-dihydroxyvitamin D3 in CaCo-2 cells.

Recent studies have implicated protein kinase-C (PKC) in the regulation of guanylate cyclase in several cell types. In view of prior experiments by our laboratory which have demonstrated that 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25-(OH)2D3] can activate PKC in CaCo-2 cells, it was of interest to determine whether this secosteroid influenced particulate guanylate cyclase and, if so, to determine which isoforms of PKC were involved. To address these issues, CaCo-2 cells were treated with 1 alpha,25-(OH)2D3 or other agents (see below), and crude membranes prepared from these cells were assayed for guanylate cyclase activity. In several experiments, agents were added directly to isolated membranes, and guanylate cyclase activity was then assayed. These studies demonstrated that 1) the addition of 1 alpha,25-(OH)2D3 or 12-O-tetradecanoyl phorbol 13-acetate (TPA), a known activator of PKC, to intact CaCo-2 cells stimulated particulate guanylate cyclase activity in a time- and concentration-dependent manner; 2) these agents induced the translocation of PKC alpha, but not PKC zeta, from the cytosolic to the membrane fraction of these cells; 3) preincubation of cells with staurosporine (50 nM), a PKC inhibitor, or U73122 (10 microM), an inhibitor of phospholipase-C-dependent processes, significantly reduced (P < 0.05) the stimulatory effect of 1 alpha,25-(OH)2D3 (3 nM) on guanylate cyclase; 4) preincubation of isolated membranes with TPA, calcium, and Mg(2+)-ATP increased guanylate cyclase activity, an affect that was augmented by purified rat brain PKC and inhibited by the PKC inhibitor peptide, PKC-(19-36); and 5) selective down-regulation of PKC alpha by treatment of cells with TPA (200 nM) for 24 h concomitantly abolished the activation of guanylate cyclase by 1 alpha,25-(OH)2D3. Taken together, these studies demonstrate that 1 alpha,25-(OH)2D3 activates particulate guanylate cyclase at least in part via a PKC alpha-dependent mechanism.

Vitamin D status modulates rat colonic M3 muscarinic receptor characteristics and coupling to guanylate cyclase.

The present studies were conducted to determine whether [3H]quinuclidinyl benzilate binding in rat colonic membranes and/or carbachol-mediated stimulation of particulate guanylate cyclase were altered by changes in vitamin D status. EC50 values for the stimulation of colonic guanylate cyclase by carbachol were found to be significantly greater in vitamin D-deficient rats compared to their D-sufficient counterparts. Concomitantly, the density of receptors (Bmax) were significantly lower, and dissociation constants (Kd) were significantly higher in D-deficient colonic membranes. In vitamin D-repleted animals, moreover, all of these aforementioned alterations were at least partially corrected.

Relationship between intracranial pressure, mild hypothermia and temperature-corrected PaCO2 in patients with traumatic brain injury.

OBJECTIVE: To study the effects of mild hypothermia and associated changes in temperature-corrected PaCO2 (cPaCO2) on intracranial pressure (ICP), mean velocity of the middle cerebral artery (Vm), and venous jugular saturation in O2 (SjvO2) in patients with severe traumatic brain injury (TBI). DESIGN: Prospective, observational study. SETTING: Intensive care unit. PATIENTS: Severe TBI patients mechanically ventilated, sedated and paralyzed. INTERVENTIONS: Twenty patients were subjected to four consecutive periods: (a) normocapnia-normothermia; (b) hypocapnia-normothermia, where hypocapnia was induced by an increase in minute volume; (c) hypocapnia-hypothermia, where hypocapnia was induced by hypothermia maintaining the ventilatory settings constant; (d) normocapnia-hypothermia, where normocapnia was achieved by a decrease in minute volume. MEASUREMENTS AND RESULTS: cPaCO2 was 41 +/- 8 mmHg in periods 1 and 4, and 31 +/- 7 mmHg in periods 2 and 3. Core temperature was 37.1 +/- 0.8 degrees C in periods 1 and 2, and 34.1 +/- 1.1 degrees C in periods 3 and 4. End-tidal CO2 and cPaCO2 values showed no difference between periods 1 and 4 and periods 2 and 3. ICP and Vm were dependent on cPaCO2 but independent of core temperature values. SjvO2 was related to cPaCO2 and was significantly higher during period 3 than during period 2 (P < 0.05). CONCLUSION: The decrease in ICP was similar when hypocapnia was induced by hyperventilation or as a result of hypothermia alone. The relationship between cPaCO2 and ICP might predict variations in ICP during changes in core temperature. Further studies are needed to confirm the cerebral metabolic effects of moderate hypothermia in TBI patients.

Early SjvO2 monitoring in patients with severe brain trauma.

OBJECTIVE: To investigate early cerebral variables after minimal resuscitation and to compare the adequacy of a cerebral perfusion pressure (CPP) guideline above 70 mmHg, with jugular bulb venous oxygen saturation (SjvO2) monitoring in a patient with traumatic brain injury (TBI). DESIGN: Prospective, observational study. SETTING: Anesthesiological intensive care unit. PATIENTS: 27 TBI patients with a postresuscitation Glasgow Coma Scale score less than 8. INTERVENTION: After initial resuscitation, cerebral monitoring was performed and CPP increased to 70 mmHg by an increase in mean arterial pressure (MAP) with volume expansion and vasopressors as needed. MEASUREMENTS AND RESULTS: MAP, intracranial pressure (ICP), CPP, and simultaneous arterial and venous blood gases were measured at baseline and after treatment. Before treatment, 37% of patients had an SjvO2 below 55%, and SjvO2 was significantly correlated with CPP (r = 0.73, p < 0.0001). After treatment, we observed a significant increase (p < 0.0001) in CPP (78+/-10 vs 53+/-15 mmHg), MAP (103+/-10 vs 79+/-9 mmHg) and SvjO2 (72+/-7 vs 56+/-12), without a significant change in ICP (25+/-14 vs 25+/-11 mmHg). CONCLUSION: The present study shows that early cerebral monitoring with SjvO2 is critical to assess cerebral ischemic risk and that MAP monitoring alone is not sensitive enough to determine the state of oxygenation of the brain. SjvO2 monitoring permits the early identification of patients with low CPP and high risk of cerebral ischemia. In emergency situations it can be used alone when ICP monitoring is contraindicated or not readily available. However, ICP monitoring gives complementary information necessary to adapt treatment.

Human errors in a multidisciplinary intensive care unit: a 1-year prospective study.

OBJECTIVES: To determine the incidence and identify risk factors of critical incidents in an ICU. DESIGN: Prospective observational study of consecutive patients admitted over 1 year to an ICU. Critical incidents were recorded using predefined criteria. Their causes and consequences were analysed. The causes were classified as technical failure, patient's underlying disease, or human errors (subclassified as planning, execution, or surveillance). The consequences were classified as lethal, leading to sequelae, prolonging the ICU stay, minor, or without consequences. The correlation between critical incidents and specific factors including patient's diagnosis and severity score, use of monitoring and therapeutic modalities was analysed by uni- and multivariate analysis. SETTING: An 11-bed multidisciplinary ICU in a non-university teaching hospital. PATIENTS: 1,024 consecutive patients admitted to the ICU. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: The median length of ICU stay by the 1,024 patients was 1.9 days. Of the 777 critical incidents reported 2% were due to technical failure and 67 % to secondary to underlying disease. There were 241 human errors (31%) in 161 patients, evenly distributed among planning (n = 75), execution (n = 88), and surveillance (n = 78). One error was lethal, two led to sequelae, 26 % prolonged ICU stay, and 57 % were minor and 16 % without consequence. Errors with significant consequences were related mainly to planning. Human errors prolonged ICU stay by 425 patient-days, amounting to 15 % of ICU time. Readmitted patients had more frequent and more severe critical incidents than primarily admitted patients. CONCLUSIONS: Critical incidents add morbidity, workload, and financial burden. A substantial proportion of them are related to human factors with dire consequences. Efforts must focus on timely, appropriate care to avoid planning and execution mishaps at the beginning of the ICU stay; surveillance intensity must be maintained, specially after the fourth day.

Determination of bupivacaine in plasma by high-performance liquid chromatography. Levels after scalp infiltration in children.

The local anaesthetic bupivacaine could be very useful for analgesia in pediatric neurosurgery. Since systemic toxic reactions to bupivacaine are correlated with high plasma levels it was important, as an adjunct to clinical evaluation, to measure plasma bupivacaine. This report describes a high-performance liquid chromatography (HPLC) method for the quantitation of plasma bupivacaine. Sample preparation involves extraction into ether followed by back-extraction into HCl. After evaporation, the acid extract is redissolved and separated by reversed-phase chromatography. The assay is linear to 5 mg bupivacaine/L and shows excellent recovery and precision. With samples from children undergoing brain surgery following scalp infiltration with either 0.125% or 0.25% bupivacaine, plasma levels peak within 10 min, then fall rapidly to a plateau by 30 min. This plateau is maintained for at least 120 min. In no case did we find supposed toxic levels of bupivacaine.

Effects of neck position and head elevation on intracranial pressure in anaesthetized neurosurgical patients: preliminary results.

This study reports the collective effect of the positions of the operating table, head, and neck on intracranial pressure (ICP) of 15 adult patients scheduled for elective intracerebral surgery. Patients were anesthetized with propofol, fentanyl, and maintained with a propofol infusion and fentanyl. Intracranial pressure was recorded following 20 minutes of stabilization after induction at different table positions (neutral, 30 degrees head up, 30 degrees head down) with the patient's neck either 1) straight in the axis of the body, 2) flexed, or 3) extended, and in the five following head positions: a) head straight, b) head angled at 45 degrees to the right, c) head angled at 45 degrees to the left, d) head rotated to the right, or e) head rotated the left. For ethical reasons, only patients with ICP < or = 20 mm Hg were included. Intracranial pressure increased every time the head was in a nonneutral position. The most important and statistically significant increases in ICP were recorded when the table was in a 30 degree Trendelenburg position with the head straight or rotated to the right or left, or every time the head was flexed and rotated to the right or left-whatever the position of the table was. These observations suggest that patients with known compromised cerebral compliance would benefit from monitoring ICP during positioning, if the use of a lumbar drainage is planed to improve venous return, cerebral blood volume, ICP, and overall operating conditions.

[From the macroscopic lesion to cellular ischemia]. / De la lésion macroscopique à l'ischémie cellulaire.

Traumatic brain injury (TBI) constitutes a major health and economic problem for developed countries, being one of the main causes of mortality and morbidity in children and young adults. Because of the immense importance and future consequences of TBI, the physician who sees a patient soon after brain injury must have a complete understanding of the pathophysiology and develop a practical knowledge of initial management of such patients. TBI may have intracranial and systemic effects that combine to give overall cerebral ischaemia. Injury to the nervous system is characterised by a stereotypic pattern, irrespective of the primary injury. The primary injury initiates a multitude of inflammatory cascades resulting in secondary brain injury, the effect of which is as important as the primary injury. This period of brain inflammation can last up to three weeks and renders the brain more susceptible to the effects of systemic insults such as hypotension, hypoxia and/or pyrexia. It has been shown in postmortem examination of patients dying from severe TBI that more than 90% had evidence of secondary ischaemic damage. The concept of 'cerebral protection' has been extended to encompass pretreatment of secondary injury. Preventing and treating cerebral ischaemia is the main goal of initial management of head-injured patients. Initial care focuses on achieving oxygenation, airway control and treatment of arterial hypotension.

[The specificity of neurosurgical anesthesia for the child]. / Spécificité de l'anesthésie de l'enfant en neurochirurgie.

Anaesthesia for paediatric neurosurgical procedures presents an interesting challenge to the anaesthesiologist. The child is not simply a small adult. At birth the central nervous system (CNS) development is incomplete and will not be mature until the end of the first year of life. Because of this delay in the maturation of the CNS, several specific pathophysiological and psychological differences ensue. Although one has little control on the child primary lesion, the selection of an anaesthetic technique designed to protect the perilesional area and the recognition of perioperative events and changes may well have a profound effect in the reduction or prevention of significant morbidity. Current neuroanaesthestic practice is based on the understanding of cerebral anatomy and physiology. Paediatric neuroanaesthesiologists must face the added challenge of the physiological differences between developing children and their adult counterparts.

[Cerebral oedema in children compared to cerebral oedema in adults]. / Oedème cérébral chez l'enfant par rapport à l'adulte: quelles sont les différences?

About 50% of deaths, in the pediatric population between 1-15 years of age, are due to trauma. This high mortality rate, associated with the frequent sequelae, leading sometimes to severe handicaps, constitutes a major problem for public health in the developed countries. Pediatric trauma has some particularities, due to anatomic and physiologic differences, and to specific injury mechanisms. In a busy traumatology center, a child will be admitted daily in the emergency department with head trauma injury. The anaesthesiologist must have a complete understanding of the pathophysiology involved in this clinical presentation if one wishes to develop a practical knowledge of initial management of such patients. Traumatic brain injury may have intracranial and systemic effects that combine to give global cerebral ischaemia.

[Biomechanics and intracranial hypertension]. / Biomécanique et hypertension intracrânienne.

Biomechanics can be defined as the physical concepts exploring the effects of mechanical forces in biology. Biomechanics explores the consequences of an alteration in the steady-state normally existing between living tissues and their immediate environment. The application of this science in the field of brain physiopathology and intracranial hypertension is essential to understanding the sequence of events triggered during an alteration of the intracranial volume such as observed with intracranial pathologies. Furthermore, biomechanics allows the development of a logical and rational therapeutic approach, better adapted to the various intracerebral problems anaesthesiologists might be confronted with.

[Traumatic head injury in children: physiopathology and clinical management]. / Les différentes lésions cérébrales traumatiques du nourrisson et du petit enfant: mécanismes et clinique.

Traumatic brain injury (TBI) constitutes a major health and economic problem for developed countries, being one of the main causes of mortality and morbidity in children. In a busy traumatology center, a child will be admitted daily in the emergency department with head trauma injury. The anaesthesiologist must have a complete understanding of the pathophysiology and develop a practical knowledge of initial management of such patients. Traumatic brain injury may have intracranial and systemic effects that combine to give global cerebral ischaemia. Injury to the nervous system, irrespective of the primary injury, initiates a multitude of inflammatory cascades resulting in secondary brain injury. The consequence of these secondary brain injuries is most often as important, if not, more important than the primary injury. This period of brain inflammation can last up to three weeks and renders the brain more susceptible to the effects of systemic insults such as hypotension, hypoxia and or pyrexia. It has been shown in post-mortem examination of patients dying from severe traumatic brain injury that more than 91% had evidence of secondary ischaemic damage. These secondary injuries may be responsible for the clinical presentation of the "child who talk and die". The concept of "cerebral protection" has been extended to encompass the active treatment of secondary injury and the prevention of cerebral ischaemia. Initial care focuses on achieving oxygenation, airway control and treatment of arterial hypotension.

[Intubation conditions: importance of the rate of repetition of the train-of-four]. / Conditions d'intubation: importance de la fréquence de répétition du train de quatre.

OBJECTIVES: To assess that neuromuscular relaxation onset of the adductor pollicis (AP) is related to neuromuscular stimulation rate. To assess that train-of-four (TOF) at 0.05 Hz is a more accurate indicator of optimal tracheal intubation time and conditions, than TOF at 0.08 Hz. STUDY DESIGN: Prospective, comparative, randomized double-blind study. PATIENTS: Forty adults, physical class ASA 1 or 2, undergoing general anaesthesia with tracheal intubation were allocated to two groups (n = 20) according to the sequence of stimulation of the AP: either TOF at 0.05 Hz (test group) or TOF at 0.08 Hz (control group). METHODS: Induction of anaesthesia was achieved with thiopentone, fentanyl and vecuronium (0.1 mg.kg-1). Neuromuscular monitoring was obtained with force displacement transducers attached to each AP. Tracheal intubation was performed once AP muscular response obtained with TOF at 0.05 Hz for test group and TOF at 0.08 Hz for control group was abolished. Results are expressed as mean +/- SEM. Fisher exact test was used for intubation conditions comparison. Curarization time between groups was compared with unpaired Student's t test (P < 0.05 accepted). RESULTS: TOF with 0.05 Hz stimulation significantly increased curarization time: 217 +/- 7 versus 162 +/- 6 s (P < 0.001). Intubation conditions were excellent in 95% and good in 5% of patients in the study group, compared to 15 and 40% in the control group, respectively (P < 0.01) in 45% of the control group patients coughing at intubation occurred. CONCLUSION: Low stimulation rate (TOF at 0.05 Hz) of AP is a reliable technique to determine the appropriate intubation time for patients paralyzed with vecuronium.

[Enhancement of cardiac performance for prevention and treatment of delayed cerebral ischemia caused by vasospasm]. / Augmentation de la performance cardiaque pour la prévention et le traitement de l'ischémie cérébrale retardée par vasospasme.

Following subarachnoid haemorrhage, delayed cerebral ischaemia from cerebral vasospasm remains the most important cause of mortality and morbidity in patients with surgically secured aneurysms. Therapy with haemodilution, hypertension and volume expansion has been recommended to prevent and treat delayed cerebral ischaemia in these patients on the basis of uncontrolled clinical series (level of evidence III to V, grade C recommendation). Despite the lack of controlled studies, the maintenance of a cardiac index > 3.5 L.min-1.m-2 and a systolic arterial pressure between 120 and 150 mmHg before clipping and 160 to 200 mmHg thereafter is recommended as a prophylactic or therapeutic measure for vasospasm. Close monitoring of neurological and cardiorespiratory status is important to avoid neurologic and systemic complications.

[Efficacy of ketanserin on postanesthetic shivering]. / Efficacité de la kétansérine sur le frisson postanesthésique.

OBJECTIVE: To evaluate the clinical and electromyographic (EMG) effects of ketanserin (K), a serotoninergic receptor antagonist (5-HT2), on postoperative shivering (POS). STUDY DESIGN: Prospective, randomised, double-blind study. PATIENTS: Fifty ASA class 1 and 2 patients with major clinical postoperative tremor were studied. METHODS: POS was assessed clinically (0 = nil, 1 = moderate, 2 = severe). Inclusion criterion was a POS of 2 at admission in the recovery room. The mean arterial blood pressure, rectal temperature, SpO2 were recorded at admission (T0) and subsequently at T5, T10, T15, T30 and T60 minutes. Either 10 mg of K (n = 25) or a corresponding volume of a placebo (P) (n = 25) were intravenously injected. The EMG activity of the deltoid and quadriceps muscles was recorded continuously. Blood lactic acid concentration was measured at the end of POS. Results are expressed as mean +/- SEM. Parametric values were analysed with unpaired Student's t-test, and nonparametric values with chi 2 analysis. P < 0.05 was accepted. RESULTS: Demographic data, duration of anaesthesia, postoperative temperature, oxygen saturation, blood pressure and blood lactate concentration were similar between groups. The POS duration in the K group was significantly shorter than in the P group: 8.8 +/- 1.5 min and 15.5 +/- 1.5 min respectively (P < 0.01). The number of patients in the K group experiencing POS at T5 and T10 was significantly lower, when compared with those who had received the P (P < 0.05). CONCLUSION: At a dose of 10 mg, K administered in patients with POS during recovery, reduced significantly the duration and intensity of the shivering without noticeable side effects. This study suggests that this 5-HT2 antagonist is an efficient therapeutic tool for POS in adults.

-The effect of ondansetron on intracranial pressure and cerebral perfusion pressure in neurosurgical patients-. / Effet de l'ondansétron sur la pression intracrânienne et la pression de perfusion cérébrale chez le patient neurochirurgical.

OBJECTIVE: To determine the effect of ondansetron on intracranial pressure (ICP), mean arterial pressure (MAP) and cerebral perfusion pressure (CPP). STUDY DESIGN: Prospective, comparative, randomized double-blind study. PATIENTS: Twenty-six patients undergoing intracranial surgery. METHOD: Induction was obtained with propofol (1-2.5 mg.kg-1), fentanyl (1.5 micrograms.kg-1) and pancuronium (0.1 mg.kg-1), and maintenance was achieved with propofol and fentanyl. Intermittent positive pressure ventilation was used to ensure mild hypocapnia at 35 +/- 2 mmHg. Positioning of the patient was followed by 15 minutes steady-state. Patient received thereafter either 8 mg ondansetron or a placebo intravenously. The ICP was measured using a lumbar malleable spinal needle. CPP was calculated using the formula CCP = MAP-ICP. All variables were measured every minute for 15 minutes. RESULTS: The ICP, MAP and CPP did not differ between the two groups. There were no differences in the highest ICP values in patients receiving either ondansetron or placebo (11 +/- 5 versus 9 +/- 5, mean +/- SD), respectively. CONCLUSION: Intravenous administration of 8 mg ondansetron affects neither cerebral hemodynamics nor ICP.

[Peroperative risks in cerebral aneurysm surgery]. / Risques peropératoires lors de chirurgie cérébrale anévrismale.

The perioperative complications associated with cerebral aneurysm surgery require a specific anaesthetic management. Four major perioperative accidents are discussed in this review. The anaesthetic and surgical management in case of rebleeding subsequent to the re-rupture of the aneurysm is mainly prophylactic. It includes haemodynamic stability assurance, maintenance of mean arterial pressure (MAP) between 80-90 mmHg during stimulation of the patient such as endotracheal intubation, application of the skull-pin head-holder, incision, and craniotomy. The aneurysmal transmural pressure should be adequately maintained by avoiding an aggressive decrease of intracranial pressure. Once the skull is open, the brain must be kept slack in order to decrease pressure under the retractors and avoid the risks of stretching and tearing of the adjacent vessels. If, despite these precautions, the aneurysm ruptures again. MAP should be decreased to 60 mmHg and the brain rendered more slack, in order to allow direct clipping of the aneurysm, or temporary clipping of the adjacent vessels. The optimal agents in this situation are isoflurane (which decreases CMRO2), intravenous anaesthetic agents (inspite their negative inotropic effect, they may potentially protect the brain) and sodium nitroprusside. Vasospasm occurs usually between the 3rd and the 7th day after subarachnoid haemorrhage. It may be seen peroperatively. The optimal treatment, as well as prophylaxis, is moderate controlled hypertension (MAP > 100 mmHg), associated with hypervolaemia and haemodilution, the so-called triple H therapy, with strict control of the filling pressures. Other beneficial therapies are calcium antagonists (nimodipine and nicardipine), the removal of the blood accumulated around the brain and in the cisternae, and possibly local administration of papaverine. Abrupt MAP increases are controlled in order to maintain adequate aneurysmal transmural pressure. Beta-blockers, local anaesthetics administered locally or intravenously, a carefully titrated level of anaesthesia, a maintained volaemia play a protective role. Cerebral oedema is sometimes already present at the opening of the skull or may arise later, due to a high pressure under the retractors, to the surgical manipulations of the brain or to brain ischaemia subsequent to temporary clipping. Its treatment is aggressive, with intravenous agents, mannitol, deep hypocapnia and/or lumbar drainage. Prophylaxis, according to the "brain homeostasis concept", is the preferred method to avoid these four peroperative accidents. It includes normal blood volume, normoglycaemia, moderate hypocapnia, normotension, soft manipulation of the brain and optimal brain relaxation.