BACKGROUNDPlethysmographic variability index (PVI) is an accurate predictor of fluid responsiveness in mechanically ventilated patients. However, the site of measurement of the plethysmographic waveform impacts its morphology and its respiratory variation. The goal of this study was to investigate the ability of PVI to predict fluid responsiveness at three sites of measurement (the forehead, ear, and finger) in mechanically ventilated patients under general anaesthesia.METHODSWe studied 28 subjects after induction of general anaesthesia. Subjects were monitored with a pulmonary artery catheter and three pulse oximeter sensors (the finger, ear, and forehead). Pulse pressure variation, central venous pressure, cardiac index (CI), and PVI measured at the forehead, ear, and finger (PVI(forehead), PVI(ear), and PVI(finger)) were recorded before and after fluid loading (FL). Subjects were responders to volume expansion if CI increased >15% after FL.RESULTSAreas under the receiver-operating curves to predict fluid responsiveness were 0.906, 0.880, and 0.836 for PVI(forehead), PVI(ear), and PVI(finger), respectively (P<0.05). PVI(forehead), PVI(ear), and PVI(finger) had a threshold value to predict fluid responsiveness of 15%, 16%, and 12% with sensitivities of 89%, 74%, and 74% and specificities of 78%, 74%, and 67%, respectively.CONCLUSIONSPVI can predict fluid responsiveness in anaesthetized and ventilated subjects at all three sites of measurement. However, the threshold values for predicting fluid responsiveness differ with the site of measurement. These results support the use of this plethysmographic dynamic index in the cephalic region when the finger is inaccessible or during states of low peripheral perfusion.

Boron Neutron Capture Therapy (BNCT) is a radiotherapic technique still under development that could become crucial in the fight against some types of cancer (extended ones, located near vital organs or radioresistant). This binary technique requires the administration to the patient of a boron delivery agent and the irradiation with a thermal neutron beam. The high LET particles produced in the B-10(n, alpha)Li-7 reaction are exploited to destroy the tumour cells. This work presents a new system based on neutron autoradiography with a non-depleted self-triggering microstrip silicon detector, using a neutron beam produced by a hospital Linac. The system is fast, real time and allows the detection of B-10 contents down to 25 ng. The main results on the study of B-10 uptake in biological samples will be described in terms of kinetic curves (B-10 uptake as a function of time).

Boron Neutron Capture Therapy (BNCT) is an experimental radiotherapy technique exploiting the reaction 10B(n,α)7Li to deliver a dose to the tumor sparing the healthy tissues: dedicated molecules are used to introduce the boron selectively in the tumor cells, which are irradiated with a thermal-epithermal neutron beam. There are two main limitations preventing BNCT from becoming a large-scale therapy: the availability of the neutron sources (that for their intensity and energy spectrum are strictly limited to nuclear reactors) and the specificity of the drugs used as boron carriers (i.e. their ability to concentrate only in the cancer cells and not in the bloodstream or in the healthy tissues).

Boron Neutron Capture Therapy (BNCT) is a radiotherapic technique exploiting the α particles produced after the irradiation of the isotope 10 of boron with thermal neutrons in the capture reaction B(n,α)710Li. It is used to treat tumours that for their features (radioresistance, extension, localization near vital organs) cannot be treated through conventional photon-beams radiotherapy. One of the main limitations of this technique is the lack of specificity (i.e. the ability of localizing in tumour cells, saving the healthy tissues) of the compounds used to carry the 10B isotope in the organs to be treated. This work, developed in the framework of the INFN PhoNeS project, describes the possibility of boron imaging performed exploiting the neutrons photoproduced by a linac (the Clinac 2100C/D of the S. Anna Hospital Radiotherapy Unit in Como, Italy) and detecting the αs with a non-depleted microstrip silicon detector: the result is a 1D scan of the boron concentration. Several boron doped samples have been analysed, from solutions of H3BO3 (reaching a minimum detectable amount of 25ng of 10B) to biological samples of urine containing BPA and BSH (the two molecules currently used for the clinical trials in BNCT) in order to build kinetic curves (showing the absolute 10B concentration as a function of time). Further measurements are under way to test the imaging system with 10BPA–Fructose complex perfused human lung samples.

The ability to selectively hit the tumour cells is an essential characteristic of an anti-tumour therapy. In boron neutron capture therapy (BNCT) this characteristic is based on the selective uptake of 10B in the tumour cells with respect to normal tissues. An important step in the BNCT planning is the measurement of the boron concentration in the tissue samples, both tumour and healthy. When the tumour is spread through the healthy tissue, as in the case of metastases, the knowledge of the different kinds of tissues in the sample being analysed is crucial. If the percentage of tumour and normal tissues cannot be evaluated, the obtained concentration is a mean value depending on the composition of the different samples being measured. In this case an imaging method that could give information both on the morphology and on the spatial distribution of boron concentration in the sample would be a fundamental support. In this paper, the results of the boron uptake analysis in the tumour and in the healthy samples taken from human livers after boron phenylalanine (BPA) infusion are shown; boron imaging was performed using neutron autoradiography.

L'utilisation pendant la circulation extracorporelle (CEC) des agents anesthésiques halogénés (AAH), bien que commune dans de nombreux pays, n'est pas de pratique courante en France. Les effets cardioprotecteurs des AAH sont clairement démontrés sur le plan expérimental et semblent avoir un impact clinique positif au cours de la chirurgie cardiaque [1,2]. Une étude effectuée dans notre établissement n'a pourtant pas montré d'effet cardioprotecteur lorsque l'AAH est administré uniquement avant la CEC [3]. Nous avons alors souhaité administrer les AAH tout au long de l'intervention, notamment pendant la CEC, afin d'avoir une concentration efficace de l'agent anesthésique lors du déclampage aortique susceptible de réduire les effets délétères de la reperfusion du myocarde. Après avis favorable de la Commission du médicament et des dispositifs médicaux stériles des hospices civils de Lyon, le service des Techniques biomédicales de l'hôpital Louis-Pradel a procédé à la mise en place d'une cuve de sévoflurane sur le circuit d'alimentation en gaz de l'oxygénateur d'une console de CEC. L'analyseur du respirateur d'anesthésie, connecté à la sortie de l'évent de l'oxygénateur, permet un monitorage du gaz carbonique et de l'AAH expirés. Durant la CEC, les AAH sont évacués via une prise SEGA. L'observation du BIS permet de moduler la fraction inspirée d'AAH administrée durant la CEC. Les premiers résultats nous indiquent qu'une fraction expirée située entre 1 et 2 % (0,5 et 1 MAC respectivement) assure généralement une anesthésie suffisante durant la CEC. Cette technique permet une anesthésie homogène durant l'ensemble de l'intervention, c'est-à-dire avant, pendant et après la CEC. Elle est rapidement réversible et autorise ainsi le « fast-track ». Elle procure en outre un contrôle efficace des poussées hypertensives per-CEC. L'utilisation pendant la CEC des AAH, outre sa simplicité de mise en œuvre, permet d'administrer un agent cardioprotecteur au décours immédiat du déclampage aortique et de réduire possiblement les effets délétères de la reperfusion. Des travaux sont en cours afin d'évaluer précisément ce gain pour le patient.

BACKGROUND:Volatile agents can mimic ischaemic preconditioning leading to a decrease in myocardial infarct size. The present study investigated if a 15 min sevoflurane administration before cardiopulmonary bypass (CPB) has a cardioprotective effect in patients undergoing coronary surgery. METHODS:Seventy-two patients were randomized in two centres. The intervention group (S) received 1 MAC sevoflurane administrated via the ventilator for 15 min followed by a 15 min washout before CPB, the control group did not. The primary outcome was the postoperative troponin Ic peak. A biopsy of the atrium was taken during canulation for enzyme dosages. Results are expressed as mean (SD). RESULTS:Neither troponin Ic nor tissular enzyme measurement exhibited any difference between the groups: peak of troponin Ic was 4.4 (5.6) in S group vs 5.2 (6.6) ng ml(-1) in control group (ns). Intratissular ecto-5'-nucleotidase activity was 7.1 (4.3) vs 8.5 (11.9), protein kinase C activity was 27.1 (15.7) vs 29.2 (28.7), tyrosine kinase activity was 101 (54.1) vs 98.5 (63.3), and P38 MAPKinase activity was 131.1 (76.1) vs 127.1 (86.8) nmol mg protein(-1) min(-1) in S group and control group, respectively (ns). However there were fewer patients with low postoperative cardiac index in S group (11% in S vs 35% in control group, P < 0.05) when considering the per protocol population. In S group, 25% of patients required an inotropic support during the postoperative period, vs 36% of patients in control group (ns). CONCLUSIONS:This study did not show a significant preconditioning signal after 15 min of sevoflurane administration. The 15 min duration might be too short or the concentration of sevoflurane too low to induce cardioprotection detected by troponin I levels.

Given the encouraging results from our previous work on the clinical application of BNCT on non-resectable, chemotherapy resistant liver metastases, we explore the possibility to extend our technique to lung metastases. A fundamental requirement for BNCT is achieving higher 10B concentrations in the metastases compared to those in healthy tissue. For this reason we developed a rat model with lung metastases in order to study the temporal distribution of 10B concentration in tissues and tumoral cells. Rats with induced lung metastases from colon adenocarcinoma were sacrificed two hours after intraperitoneal Boronphenylalanine infusion. The lungs were harvested, frozen in liquid nitrogen and subsequently histological sections underwent neutron autoradiography in the nuclear reactor Triga Mark II, University of Pavia. Our findings demonstrate higher Boron uptake in tumoral nodules compared to healthy lung parenchyma 2 hours after Boronphenylalanine infusion.

After a long series of studies on the effects of neutron irradiation of 10B loaded neoplastic cells both in culture and in animal experiments, we started the clinical application of BNCT on humans affected by liver metastases of a radically resected colon adenocarcinoma. The procedure we adopted includes a first surgical phase, with hepatectomy; a radiotherapeutic phase, in which the isolated liver, washed and chilled, is extracorporeally irradiated with thermal neutrons; and then a second surgical phase for the reconnection of the liver to the patient. Until now two patients have been subjected to the BNCT treatment. The first one survived 44 months with a good quality of life, and died because of diffuse recurrences of his intestinal tumour. The second patient had the same early perioperative course, but after 33 days a worsening of a dilatative cardiomyopaty, from which he was suffering, determined a cardiac failure and eventually death. This clinical experience, although limited, has shown that extracorporeal neutron irradiation of the liver is a feasible procedure, able to ensure the complete destruction of liver metastases and a possible long lasting survival. In our patients neutron irradiation caused massive cellular necrosis highly specific to tumour cells, whereas normal cells were mostly spared. Nevertheless, the impact of such a traumatic operation on the patient's organism must be taken into account. Finally, we have to be aware that the fight against tumour rarely leads to a complete victory. We now have an innovative weapon which is both powerful and partly unsettled: it must be refined and above all used.

Piriou, V.1; Mantz, J.2; Paquin, S.2; Lecharny, J. B.2; Goldfarb, G.; Chiari, P.1; Kitakaze, M.; Lehot, J. J.1 Author Information

OBJECTIVE:Volatile halogenated anaesthetics offer a myocardial protection when they are administrated before a myocardial ischaemia. Cellular mechanisms involved in anaesthetic preconditioning are now better understood. The objectives of this review are to understand the anaesthetic-induced preconditioning underlying mechanisms and to know the clinical implications.DATA SOURCES:References were obtained from PubMed data bank (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi) using the following keywords: volatile anaesthetic, isoflurane, halothane, sevoflurane, desflurane, preconditioning, protection, myocardium.DATA SYNTHESIS:Ischaemic preconditioning (PC) is a myocardial endogenous protection against ischaemia. It has been described as one or several short ischaemia before a sustained ischemia. These short ischaemia trigger a protective signal against this longer ischaemia. An ischemic organ is able to precondition a remote organ. It is possible to replace the short ischaemia by a preadministration of halogenated volatile anaesthetic with the same protective effect, this is called anaesthetic PC (APC). APC and ischaemic PC share similar underlying biochemical mechanisms including protein kinase C, tyrosine kinase activation and mitochondrial and sarcolemnal K(ATP) channels opening. All halogenated anaesthetics can produce an anaesthetic PC effect. Myocardial protection during reperfusion, after the long ischaemia, has been shown by successive short ischaemia or volatile anaesthetic administration, this is called postconditioning. Ischaemic PC has been described in humans in 1993. Clinical studies in human cardiac surgery have shown the possibility of anaesthetic PC with volatile anaesthetics. These studies have shown a decrease of postoperative troponin in patient receiving halogenated anaesthetics.

ISCHEMIC PRECONDITIONING (IPC) is an endogenous protection against prolonged ischemia. It has been described as a short ischemia before a sustained ischemia. 1 Murry C.E. Jennings R.B. Reimer K.A. Preconditioning with ischemia a delay of lethal cell injury in ischemic myocardium. Circulation. 1986; 74: 1124-1136 Crossref PubMed Scopus (6961) Google Scholar This sublethal ischemia triggers underlying protective biochemical mechanisms involving adenosine, protein kinase C, tyrosine kinase, free oxygen radical production, and activation of mitochondrial and/or sarcolemmal adenosine triphosphate-sensitive potassium (KATP) channels opening. 2 Yellon D.M. Downey J.M. Preconditioning the myocardium from cellular physiology to clinical cardiology. Physiol Rev. 2003; 83: 1113-1151 Crossref PubMed Scopus (868) Google Scholar Several other triggers of preconditioning have been described, such as hypoxia, thermal stress, pacing, or stretch. Pharmacologic agents are also able to mimic IPC with similar results; these agents include adenosine, acetylcholine, bradykinin, angiotensin, alpha-receptor agonists, or KATP channel openers. In addition, currently available anesthetic agents are also able to mimic preconditioning. 3 Cope D.K. Impastato W.K. Cohen M.V. et al. Volatile anesthetics protect the ischemic rabbit myocardium from infarction. Anesthesiology. 1997; 86: 699-709 Crossref PubMed Scopus (309) Google Scholar , 4 Kersten J.R. Schmeling T.J. Pagel P.S. et al. Isoflurane mimics ischemic preconditioning via activation of K(ATP) channels Reduction of myocardial infarct size with an acute memory phase. Anesthesiology. 1997; 87: 361-370 Crossref PubMed Scopus (450) Google Scholar Opioids 5 Gross G.J. Role of opioids in acute and delayed preconditioning. J Mol Cell Cardiol. 2003; 35: 709-718 Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar and all volatile halogenated anesthetics 6 Piriou V. Chiari P. Lhuillier F. et al. Pharmacological preconditioning comparison of desflurane, sevoflurane, isoflurane and halothane in rabbit myocardium. Br J Anaesth. 2002; 89: 486-491 PubMed Scopus (103) Google Scholar can protect the heart against ischemia when administrated before ischemia. Both IPC and anesthetic preconditioning (APC) present 2 temporal windows of preconditioning: an early phase lasting for only 1 to 2 hours and a second late phase, occurring between 12 and 72 hours after a preconditioning stimulus, which involves new protein synthesis such as nitric oxide synthases, heat stress proteins, antioxidant enzyme systems, and cyclooxygenase-2. IPC and APC share similar mechanisms, with slight differences. 7 Sergeev P. da Silva R. Lucchinetti E. et al. Trigger-dependent gene expression profiles in cardiac preconditioning. Anesthesiology. 2004; 100: 474-488 Crossref PubMed Scopus (94) Google Scholar Reduction in infarct size occurs with a similar magnitude by ischemic or anesthetic preconditioning. 8 Piriou V. Chiari P. Knezynski S. et al. Prevention of isoflurane-induced preconditioning by 5-hydroxydecanoate and gadolinium Possible involvement of mitochondrial adenosine triphosphate-sensitive potassium and stretch-activated channels. Anesthesiology. 2000; 93: 756-764 Crossref PubMed Scopus (86) Google Scholar IPC was demonstrated in 1986 in an experimental animal model 1 Murry C.E. Jennings R.B. Reimer K.A. Preconditioning with ischemia a delay of lethal cell injury in ischemic myocardium. Circulation. 1986; 74: 1124-1136 Crossref PubMed Scopus (6961) Google Scholar and in humans during cardiopulmonary bypass in 1993. 9 Yellon D.M. Alkhulaifi A.M. Pugsley W.B. Preconditioning the human myocardium. Lancet. 1993; 342: 276-277 Abstract PubMed Scopus (633) Google Scholar

BACKGROUND:Recent investigations have focused on the pivotal role of the mitochondria in the underlying mechanisms volatile anesthetic-induced myocardial preconditioning. This study aimed at examining the effect of anesthetic preconditioning on mitochondrial permeability transition (MPT) pore opening.METHODS:Anesthetized open chest rabbits were randomized to one of four groups and underwent 10 min of ischemia, except for the sham 1 group (n = 12). Before this, they underwent a treatment period consisting of (1) no intervention (ischemic group; n = 12), (2) 30 min of desflurane inhalation (8.9% end-tidal concentration) followed by a 15-min washout period (desflurane group; n = 12), or (3) ischemic preconditioning (IPC group; n = 12). A second set of experiments was performed to evaluate the effect of a putative mitochondrial adenosine triphosphate-sensitive potassium channel antagonist, 5-hydroxydecanoate (5-HD). The animals underwent the same protocol as previously, plus pretreatment with 5 mg/kg 5-HD. They were randomized to one of five groups: the sham 2 group, receiving no 5-HD (n = 12); the sham 5-HD group (n = 12); the ischemic 5-HD group (n = 12), the desflurane 5-HD group (n = 12), and the IPC 5-HD group (n = 12). At the end of the protocol, the hearts were excised, and mitochondria were isolated. MPT pore opening was assessed by measuring the amount of calcium required to trigger a massive calcium release indicative of MPT pore opening.RESULTS:Desflurane and IPC group mitochondria needed a higher calcium load than ischemic group mitochondria (362 +/- 84, 372 +/- 74, and 268 +/- 110 microM calcium, respectively; P < 0.05) to induce MPT pore opening. The sham 1 and sham 2 groups needed a similar amount of calcium to trigger mitochondrial calcium release (472 +/- 70 and 458 +/- 90 microM calcium, respectively). 5-HD preadministration had no effect on sham animals (458 +/- 90 and 440 +/- 128 microM calcium without and with 5-HD, respectively) and ischemic group animals (268 +/- 110 and 292 +/- 102 microM calcium without and with 5-HD, respectively) but abolished the effects of desflurane on calcium-induced MPT pore opening (362 +/- 84 microM calcium without 5-HD vs. 238 +/- 96 microM calcium with 5-HD; P < 0.05) and IPC (372 +/- 74 microM calcium without 5-HD vs. 270 +/- 104 microM calcium with 5-HD; P < 0.05).CONCLUSION:Like ischemic preconditioning, desflurane improved the resistance of the transition pore to calcium-induced opening. This effect was inhibited by 5-HD, suggesting a link between mitochondrial adenosine triphosphate-sensitive potassium and MPT.

The effect of neutron boron capture therapy (BNCT) was studied in rat tumor liver cells after induction of the liver metastases by splenic inoculation of cells from DHA/K12/TRb line. Ten days following the treatment, the BPA was injected into rats and therefore the animals were sacrificed, the liver was exposed to neutron irradiation and processed. In some experiments the liver was reimplanted (after irradiation) in syngenic animals and studied 3 days later, following sacrifice. Samples of tissue obtained from metastasised and non-metastasised areas of the liver parenchyma, before and after the neutron irradiation, were examined in light microscopy and electron microscopy. The analysis pointed out damages induced by the neutron treatment in single tumor cells mostly localised in the synusoidal blood stream. Debris and apoptotic cells were sometimes observed in the neoplastic nodules before treatment, while the tumor cell death (apoptosis) increased in the tumor cells following BNCT treatment. An intense scavenger activity of Kupffer cells after irradiation was accompanied by a strong acid phosphatase reaction detectable in wide cytoplasmic areas. In the liver parenchyma of reimplanted animals, the presence of large collagen bundles spread among the hepatocytes was observed at electron microscopy.

The purpose of this study was to evaluate boron distribution for a safe and effective BNCT (Boron Neutron Capture Therapy) of liver metastases. Samples both from healthy and tumour liver parenchyma were analysed, after i.v. boron administration, by: alpha particles counting under neutron irradiation; morphological analysis by standard haematoxylin-eosin staining; neutron autoradiography. Our method was unaffected by the cytological heterogeneity inside tumour nodules; it demonstrated selective boron distribution in tumour tissue and predicted estimated mean therapeutic doses in tumour and safety doses in healthy tissue. The time interval for efficient BNCT was 2 to 4 hours after i.v. boron administration.

The instant centre frequency (ICF) of RR interval has been proposed as a global index to analyse the sympathovagal interaction in the heart. The aim of this study was to assess the ICF during anaesthesia to test if it can reliably capture the neural control of the cardiovascular system. Twenty-four ASA II or III patients scheduled for cardiac surgery were included in the study. They were allocated in two groups: control, no treatment (group 1, n = 12), and beta-adrenergic blockade by atenolol (group 2, n = 12). Spectra of pulse interval series were computed with a time-frequency method and they were divided into: very low frequency (VLF, 0.000-0.040 Hz), low frequency (LF, 0.050-0.150 Hz) and high frequency (HF, 0.160-0.500 Hz). Normalized power was obtained by dividing the cumulative power within each frequency band (LF or HF) by the sum of LF and HF; the ratio of LF/HF was also calculated. Instant centre frequency is a time-varying parameter that the evolution along time of the gravity centrum of a local spectrum. All spectral indexes were recorded at the following time points: before induction, after induction and before intubation, during intubation, and after intubation. The atenolol group had lower normalized LF and the LF/HF ratio (P < 0.05) higher HF before induction; and lower LF/HF ratio after induction and before intubation (P < 0.05). The ICF was higher in atenolol group at all times. The ICF shifted towards HF frequency after induction and before intubation and shifted towards LF during intubation in both groups. The autonomic nervous system control on the heart through the interaction of sympathetic and parasympathetic reflex mechanisms could be studied by the ICF. The ICF may assess the autonomic cardiac modulation and may provide useful information for anaesthetic management.

BACKGROUND Recent investigations showed that isoflurane can induce pharmacological preconditioning. The present study aimed to compare the potency of four different halogenated anaesthetics to induce preconditioning. METHODS Anaesthetized open-chest rabbits underwent 30 min of coronary artery occlusion followed by 3 h of reperfusion. Before this, rabbits were randomized into one of five groups and underwent a treatment period consisting of either no intervention for 45 min (control; n = 10), or 30 min of 1 MAC halogenated anaesthetic inhalation followed by 15 min of washout. End-tidal concentrations of halogenated agents were 3.7% for sevoflurane (n = 11), 1.4% for halothane (n = 9), 2.0% for isoflurane (n = 11), and 8.9% for desflurane (n = 11). Area at risk and infarct size were assessed by blue dye injection and tetrazolium chloride staining. RESULTS Mean (SD) infarct size was 54 (18)% of the risk area in untreated controls and 40 (18)% in the sevoflurane group (P > 0.05, ns). In contrast, mean infarct size was significantly smaller in the halothane, isoflurane, and desflurane groups: 26 (18)%, 32 (18)% and 16 (17)%, respectively (P < 0.05 vs control). CONCLUSIONS Halothane, isoflurane and desflurane induced pharmacological preconditioning, whereas sevoflurane had no significant effect. In this preparation, desflurane was the most effective agent at preconditioning the myocardium against ischaemia.

Diaspirin cross-linked haemoglobin (DCLHb) is a haemoglobin-based oxygen carrier which had been proposed as a resuscitative solution to replace red cell transfusion in many clinical situations. The present study was designed to evaluate the effect of different volumes of DCLHb 10% (1, 5 and 10 mL kg-1) on the cardiovascular system during cardiopulmonary bypass (CPB), and to determine the effect of DCLHb (18 mL kg-1) when added directly to the CPB prime in anaesthetized swine. DCLHb, when used as a priming solution, induced a significant increase (around 20%) in mean arterial pressure (MAP), which persisted during the entire period of CPB (P < 0.05) as compared with controls. Administration of increasing doses of DCLHb during the time course of CPB resulted in a progressive increase in MAP (P < 0.05), suggesting a linear dose-response relationship. Nicardipine, a calcium channel blocker, returned MAP to baseline. Finally, weaning of CPB was easier in animals that received DCLHb, thereby suggesting a potential protective effect of free haemoglobin in this particular clinical situation.