BJA
Editorial IV
24 Goodnough LT, Spain DA, Maggio P. Logistics of transfusion support for patients with massive hemorrhage. Curr Opin Anaesthesiol 2013; 26: 208–14 25 Goodnough LT, Shander A. How I treat warfarin-associated coagulopathy in patients with intracerebral hemorrhage. Blood 2011; 117: 6091–9 26 Octapharma. Octaplas summary of product characteristics. Available from http://www.octapharma.co.uk/index.php?eID=tx_ nawsecuredl&u=0&file=uploads/media/octaplasLG_SmPC_01.pdf& t=1393419280&hash=ddc2b6fbb6e096a0a733896dc09c0f220a7e e262 (accessed 25 February 2014) 27 Cote CJ, Drop LJ, Hoaglin DC, Daniels AL, Young ET. Ionized hypocalcemia after fresh frozen plasma administration to thermally injured children: effects of infusion rate, duration, and treatment with calcium chloride. Anesth Analg 1988; 67: 152– 60 28 Theusinger OM, Baulig W, Seifert B, et al. Relative concentrations of haemostatic factors and cytokines in solvent/detergenttreated and fresh-frozen plasma. Br J Anaesth 2011; 106: 505 – 11 29 Solomon C, Pichlmaier U, Schoechl H, et al. Recovery of fibrinogen after administration of fibrinogen concentrate to patients with severe bleeding after cardiopulmonary bypass surgery. Br J Anaesth 2010; 104: 555–62 30 Danish Medicine Agency. Medicine prices in Denmark. Available from http://www.medicinpriser.dk/ (accessed 29 October 2013) 31 Shander A, Hofmann A, Ozawa S, et al. Activity-based costs of blood transfusions in surgical patients at four hospitals. Transfusion 2010; 50: 753– 65 32 Glenngard AH, Persson U, Soderman C. Costs associated with blood transfusions in Sweden—the societal cost of autologous, allogeneic and perioperative RBC transfusion. Transfus Med 2005; 15: 295–306
British Journal of Anaesthesia 112 (5): 787–90 (2014) Advance Access publication 24 February 2014 . doi:10.1093/bja/aeu006
EDITORIAL IV
Surrogate measures, do they really describe anaesthetic state? F. S. Servin 1* and V. Billard 2 1 2
Service d’anesthe´sie, APHP-Hoˆpital Bichat, 46, rue Henri Huchard, 75018 Paris, France Service d’anesthe´sie, Institut Gustave Roussy, 114, rue E´douard-Vaillant, 94805 Villejuif Cedex, France
* Corresponding author. E-mail: [email protected]
Characterization of anaesthesia is tricky, in particular, to go beyond the usual definition of a ‘state of non-responsiveness to various types of stimulations’, and to find indicators useful for titrating drug administration. General anaesthesia is usually split into two main domains: unconsciousness (nonresponse to verbal stimulation and amnesia) and analgesia (non-response to noxious stimulations).1 2 Unconsciousness may be directly assessed at induction of anaesthesia (loss of verbal contact) and after recovery (absence of recall), but usually not during maintenance. The adequacy of the
balance between analgesia and stimulation can be clinically estimated through movement, haemodynamic changes, and autonomic nervous system responses (sweat and lacrimation, modification in pupil diameter); these clinical endpoints have limitations when used for titrating anaesthetic drugs in clinical practice, specifically in paralysed patients. Furthermore, as adequate anaesthesia is defined as non-responsiveness, clinical assessment cannot distinguish between adequate drug delivery and overdosing if overdosing does not induce adverse effects.
787
Downloaded from http://bja.oxfordjournals.org/ at Universidade Federal do Amazonas on April 27, 2014
14 Inaba K, Branco BC, Rhee P, et al. Impact of plasma transfusion in trauma patients who do not require massive transfusion. J Am Coll Surg 2010; 210: 957– 65 15 Sorensen B, Bevan D. A critical evaluation of cryoprecipitate for replacement of fibrinogen. Br J Haematol 2010; 149: 834–43 16 Bevan DH. Cardiac bypass haemostasis: putting blood through the mill. Br J Haematol 1999; 104: 208– 19 17 Ahmed S, Harrity C, Johnson S, et al. The efficacy of fibrinogen concentrate compared with cryoprecipitate in major obstetric haemorrhage—an observational study. Transfus Med 2012; 22: 344– 9 18 World Health Organization (WHO). 63rd World Health Assembly. Availability, safety and quality of blood products. 2010. Available from http://apps.who.int/gb/ebwha/pdf_files/WHA63/A63_R12-en .pdf (accessed 22 October 2013) 19 Ranucci M, Solomon C. Supplementation of fibrinogen in acquired bleeding disorders: experience, evidence, guidelines, and licences. Br J Anaesth 2012; 109: 135– 7 20 Ranucci M. Fibrinogen supplementation in cardiac surgery: where are we now and where are we going? J Cardiothorac Vasc Anesth 2013; 27: 1–4 21 Weber CF, Gorlinger K, Meininger D, et al. Point-of-care testing: a prospective, randomized clinical trial of efficacy in coagulopathic cardiac surgery patients. Anesthesiology 2012; 117: 531– 47 22 Schochl H, Nienaber U, Hofer G, et al. Goal-directed coagulation management of major trauma patients using thromboelastometry (ROTEM)-guided administration of fibrinogen concentrate and prothrombin complex concentrate. Crit Care 2010; 14: R55 23 Hiippala ST, Myllyla GJ, Vahtera EM. Hemostatic factors and replacement of major blood loss with plasma-poor red cell concentrates. Anesth Analg 1995; 81: 360–5
BJA
788
(delta) and 10 Hz (spindle).14 Thereafter, fast frequency activity decreases unmasking low frequencies activity.15 For intermediate duration administration or concentrations, both effects may neutralize and EEG-derived parameters may show no change. Moreover, nitrous oxide also acts at the spinal level, where it stimulates superficial neurones and depresses deep neurones,16 and at the midbrain level to modulate ascendant nociceptive inputs17 and stimulate reticular neurones. As all single EEG-derived parameters, BISTM is unable to describe all these complex phenomena. It is recorded through a single frontal sensor, and therefore will catch accurately frontal changes but neither alterations in other territories such as the parietal area which is deeply depressed by nitrous oxide nor changes in the parietal/frontal equilibrium.18 To limit EMG and environment artifacts, BISTM signal processing is filtered at 32 Hz (as State Entropy and PSI). It may therefore miss fast frequency peaks, and appear ‘blind’ to nitrous oxide effect if predominant in fast frequencies. Laboratory (volunteers) studies were able to describe accurately nitrous oxide effects because they could record EEG in a quiet noise-free environment which is certainly not the case in an operating theatre. Lastly, spinal and midbrain effects of nitrous oxide, particularly relevant to the analgesic component of anaesthesia are not directly displayed on cortical EEG whatever the analysis technique used. Clinical results illustrate these limitations. Quite a few clinical works have studied the influence of nitrous oxide on BISTM values before and during surgery and their results are deeply confusing. When nitrous oxide 70% was used as the sole hypnotic administered to healthy volunteers, it induced loss of consciousness without modifying the BISTM , in contrast with what was observed with sevoflurane.19 In another study including 48 patients with epidural analgesia, inhalation of increasing nitrous oxide concentrations resulted in a progressive reduction in the OAA/S without corresponding decrease in BISTM values.20 Similar results were observed with cerebral state index (CSI)21 and Entropy.22 During sevoflurane anaesthesia titrated on BISTM (40–60), adding nitrous oxide consistently decreased BISTM and Entropy23 24 with the deepening of anaesthesia. This decrease was not observed with propofol,24 possibly because propofol inhibited reticular neurones, whereas sevoflurane did not. During gynaecological surgery with very low dose of alfentanil given at induction, adding nitrous oxide allowed decreasing the amount of sevoflurane necessary to maintain a chosen MPF (2–3 Hz) linearly with nitrous oxide fraction.25 During a deeper sevoflurane anaesthesia (BISTM 35), adding nitrous oxide slightly decreased BISTM , markedly decreased State Entropy but left PSI unchanged.26 During an isoflurane anaesthesia deep enough to achieve burst suppression, adding nitrous oxide decreased the burst suppression ratio and seemed to lighten anaesthesia.27 Several mechanisms have been proposed, such as an increase in cerebral blood flow or an activation of reticular neurones counteracting the effect on cortical neurones.27 After a noxious stimulation such as intubation, paradoxical BISTM and SEF decreases have been observed in the presence of nitrous oxide, but this effect disappeared
Downloaded from http://bja.oxfordjournals.org/ at Universidade Federal do Amazonas on April 27, 2014
Monitoring systems have been developed to compensate for these limitations. These are based on indirect (surrogate) measures, including the observation and analysis of cortical EEG. Several parameters have thus been proposed, such as the bispectral index (BISTM )3 which still plays a predominant role, mainly due to the fact that it was the first commercially available device with a clearly defined range supposed to correspond to an adequate ‘depth of anaesthesia’. As adrenergic stimuli induce arousal reactions which can be reflected on cortical EEG, the BISTM has also been used to assess the adequacy of analgesia.4 The BISTM is a complex and not completely accessible parameter established to statistically quantify the hypnotic effect of propofol.3 It was further found able to discriminate hypnotic levels induced by isoflurane and midazolam, albeit with less precision.5 However, ‘depth of anaesthesia’ monitors based on the EEG have demonstrated their usefulness in allowing adjustments of drug delivery to individual needs in clinical practice, decreasing both the risks of overdosing and of awareness, and slightly decreasing the recovery time.6 Liu and colleagues7 consider the sparing effect of nitrous oxide (N2O) on propofol and remifentanil consumptions when those drugs are administered through a closed-loop system using the BISTM as the control parameter. They do not find any clinically significant difference in propofol or remifentanil consumption whether or not nitrous oxide is added to the inhaled mixture. Liu and colleagues’ system uses the BISTM to control both propofol and remifentanil administrations, the hypnotic being driven by progressive changes in the parameter, and the opioid by rapid changes seemingly corresponding to arousal reactions. They claim that their system, being independent from the clinician, is more reliable to detect any difference induced by nitrous oxide administration than all the other studies published so far which were based on haemodynamic and clinical observation. However, no other descriptors of ‘adequacy of anaesthesia’ are considered in their system. Nitrous oxide has actually initiated the era of modern anaesthesia more than 150 yr ago, when it was used in dental surgery. It has a weak sedative action, with a minimum alveolar concentration (MAC) around 1.04 (0.10) (SE) atm absolute, measured in hyperbaric conditions,8 and may provoke loss of consciousness through a mechanism called dissociative anaesthesia, similar to that obtained with ketamine, both agents acting through the N-methyl-D-aspartate (NMDA) receptor.9 However, nitrous oxide is nowadays mainly considered as an analgesic. As such, it reduces the amount of both volatile and propofol required to blunt motor responses to skin incision (MAC, EC50) by about 30%.10 11 The influence of nitrous oxide on the central nervous system is very complex. Conversely to GABA-ergic hypnotics which induce mainly cortical EEG depression (i.e. slowing and synchronization preceding burst suppression), nitrous oxide, antagonist of the NMDA receptor, also stimulates the EEG and increases fast frequencies activity (.30 Hz), specially in the frontal area.12 13 This activation occurs early after introducing nitrous oxide and is associated with phase coupling peaks around 4 Hz
Editorial IV
BJA
Editorial IV
Abbreviations and definitions31 BISTM SEF
MPF
Entropy
Bispectral index of EEG including bispectrum, quasi burst, and b ratio. Spectral edge frequency. Frequency of the spectrum below which are gathered 95% of the frequency components of an EEG epoch. Median power frequency is the frequency of the spectrum below which are gathered 50% of the frequency components of an EEG epoch. This returns two indexes both expressing the irregularity, complexity, or unpredictability characteristics of EEG signal: state entropy (including frequencies from 0.5 to 32 Hz) and response entropy.
Patient state index
Q EEG-derived parameter including EEG power, frequency, and phase information from anterior –posterior relationships of the brain and coherence between bilateral brain regions.
Declaration of interest None declared.
References 1 Prys-Roberts C. Anaesthesia: a practical or impractical construct? Br J Anaesth 1987; 59: 1341–5 2 Shafer SL, Stanski DR. Defining depth of anesthesia. Handb Exp Pharmacol 2008; 409– 23 3 Kearse LA Jr, Manberg P, Chamoun N, deBros F, Zaslavsky A. Bispectral analysis of the electroencephalogram correlates with patient movement to skin incision during propofol/nitrous oxide anesthesia. Anesthesiology 1994; 81: 1365– 70 4 Guignard B, Menigaux C, Dupont X, Fletcher D, Chauvin M. The effect of remifentanil on the bispectral index change and hemodynamic responses after orotracheal intubation. Anesth Analg 2000; 90: 161– 7 5 Glass PS, Bloom M, Kearse L, Rosow C, Sebel P, Manberg P. Bispectral analysis measures sedation and memory effects of propofol, midazolam, isoflurane, and alfentanil in healthy volunteers. Anesthesiology 1997; 86: 836–47 6 Punjasawadwong Y, Boonjeungmonkol N, Phongchiewboon A. Bispectral index for improving anaesthetic delivery and postoperative recovery. Cochrane Database Syst Rev 2007; CD003843 7 Liu N, Le Guen M, Boichut N, et al. Nitrous oxide does not produce a clinically important sparing effect during close-loop delivered propofol–remifentanil anaesthesia guided by the bispectral index: a randomized multicentre study. Br J Anaesth 2014; 112: 842– 51 8 Hornbein TF, Eger EI II, Winter PM, Smith G, Wetstone D, Smith KH. The minimum alveolar concentration of nitrous oxide in man. Anesth Analg 1982; 61: 553–6 9 Sleigh JW, Barnard JP. Entropy is blind to nitrous oxide. Can we see why? Br J Anaesth 2004; 92: 159– 61 10 Davidson JA, Macleod AD, Howie JC, White M, Kenny GN. Effective concentration 50 for propofol with and without 67% nitrous oxide. Acta Anaesthesiol Scand 1993; 37: 458– 64 11 Torri G, Damia G, Fabiani ML. Effect on nitrous oxide on the anaesthetic requirement of enflurane. Br J Anaesth 1974; 46: 468– 72 12 Foster BL, Liley DT. Nitrous oxide paradoxically modulates slow electroencephalogram oscillations: implications for anesthesia monitoring. Anesth Analg 2011; 113: 758–65 13 Yamamura T, Fukuda M, Takeya H, Goto Y, Furukawa K. Fast oscillatory EEG activity induced by analgesic concentrations of nitrous oxide in man. Anesth Analg 1981; 60: 283–8 14 Hagihira S, Takashina M, Mori T, Mashimo T. The impact of nitrous oxide on electroencephalographic bicoherence during isoflurane anesthesia. Anesth Analg 2012; 115: 572– 7 15 Rampil IJ, Kim JS, Lenhardt R, Negishi C, Sessler DI. Bispectral EEG index during nitrous oxide administration. Anesthesiology 1998; 89: 671– 7 16 Antognini JF, Atherley RJ, Laster MJ, Carstens E, Dutton RC, Eger EI II. A method for recording single unit activity in lumbar spinal cord
789
Downloaded from http://bja.oxfordjournals.org/ at Universidade Federal do Amazonas on April 27, 2014
when an opioid bolus was added.28 In another study, nitrous oxide inhibited both BISTM changes during intubation and clinical response (isolated forearm) suggesting that an adequate level of analgesia had been achieved.29 In summary, the effect of nitrous oxide on EEG and EEGderived parameters during anaesthesia is only one of all nitrous oxide pharmacodynamic effects, along with sedation, immobility, or haemodynamic control. It depends on both excitation/depression and cortical/subcortical balances. These balances vary with the associated drugs (volatile vs propofol), on the degree of EEG depression, and on the nociception/antinociception equilibrium. The results achieved by Liu and colleagues,7 titrating anaesthesia entirely on a single EEG parameter, confirm a small influence of nitrous oxide to maintain a chosen value of this surrogate parameter through dosing of GABA-ergic drugs. These authors were unable to demonstrate any influence on the level of sedation in the absence of stimulation, because nitrous oxide was introduced after intubation, at a time when the doses required for surgery were far above those required for loss of consciousness. Moreover, considering control over adrenergic stimuli, one may even suspect that both groups were not at the same depth of analgesia (despite similar BISTM ), since the incidence of movement was divided by three in the nitrous oxide group, and the incidence of antihypertensive medication by two. At a time when instrumental monitoring is more and more prominent in our anaesthesia practice, this work is a useful reminder of the fact that a mathematical construction based on cortical EEG may not (yet?) include all the complexity surrounding pharmacological loss of consciousness and control over adrenergic stimuli, and thus be unable to completely describe anaesthesia. The future of drug adjustments might well include more complex algorithms combining surrogate measures of sedation (EEG), surrogate measures of analgesia (i.e. pupil dilatation reflex),30 and clinical signs considered in their surgical context.
BJA 17
18
19
20
22
23
24 Ozcan MS, Ozcan MD, Khan QS, Thompson DM, Chetty PK. Does nitrous oxide affect bispectral index and state entropy when added to a propofol versus sevoflurane anesthetic? J Neurosurg Anesthesiol 2010; 22: 309–15 25 Ropcke H, Schwilden H. Interaction of isoflurane and nitrous oxide combinations similar for median electroencephalographic frequency and clinical anesthesia. Anesthesiology 1996; 84: 782– 8 26 Soto RG, Smith RA, Zaccaria AL, Miguel RV. The effect of addition of nitrous oxide to a sevoflurane anesthetic on BIS, PSI, and entropy. J Clin Monit Comput 2006; 20: 145–50 27 Yli-Hankala A, Lindgren L, Porkkala T, Jantti V. Nitrous oxidemediated activation of the EEG during isoflurane anaesthesia in patients. Br J Anaesth 1993; 70: 54 –7 28 Oda Y, Tanaka K, Matsuura T, Hase I, Nishikawa K, Asada A. Nitrous oxide induces paradoxical electroencephalographic changes after tracheal intubation during isoflurane and sevoflurane anesthesia. Anesth Analg 2006; 102: 1094–102 29 Coste C, Guignard B, Menigaux C, Chauvin M. Nitrous oxide prevents movement during orotracheal intubation without affecting BIS value. Anesth Analg 2000; 91: 130– 5 30 Oka S, Chapman CR, Kim B, Nakajima I, Shimizu O, Oi Y. Pupil dilation response to noxious stimulation: effect of varying nitrous oxide concentration. Clin Neurophysiol 2007; 118: 2016– 24 31 Rampil IJ. A primer for EEG signal processing in anesthesia. Anesthesiology 1998; 89: 980– 1002
British Journal of Anaesthesia 112 (5): 790–3 (2014) doi:10.1093/bja/aeu009
EDITORIAL V
‘For now we see through a glass, darkly’: the anaesthesia syndrome R. D. Sanders 1,2*, A. Absalom 3, J. W. Sleigh 4 and on behalf of the ConsCIOUS Group† 1
Department of Anaesthesia, Royal Brompton Hospital; Surgical Outcomes Centre, University College London Hospital, London, UK Wellcome Department of Imaging Neuroscience, Institute of Cognitive Neuroscience, University College London, 17 – 19 Queen Square, London WC1N 3AR, UK 3 Department of Anesthesiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands 4 Department of Anaesthesia, University of Auckland, Hamilton, New Zealand 2
* Corresponding author: Wellcome Department of Imaging Neuroscience, Institute of Cognitive Neuroscience, University College London, 17-19 Queen Square, London WC1N 3AR, UK. E-mail: [email protected]
In this issue of the British Journal of Anaesthesia, Zand and colleagues1 revisit the isolated forearm technique (IFT) pioneered in obstetric anaesthesia by Tunstall.2 Their data are consistent with Tunstall’s early studies during anaesthesia for Caesarean section showing that 33–42% of patients may respond intra-operatively.2 3 Zand and colleagues1 made similar observations after rapid sequence induction with thiopental: 41, 46, and †
23% of the subjects responded at laryngoscopy, intubation, and skin incision, respectively. Prima facie, these are potentially alarming statistics, raising questions over the ‘adequacy of anaesthesia’ provided during and after rapid sequence induction, and hence a thorough critique of their methodology is warranted. Strengths of this paper include the standardized and clinically relevant approach (including drug dosing), relatively large
CONSciousness, Connectedness, IntraOperative Unresponsiveness Study (ConsCIOUS) Group: Anthony Absalom, Ram Adapa, Vincent Bonhomme, Mark Coburn, Robert D. Sanders, Gerhard Schneider, Jamie Sleigh, Rob Stephens.
790
Downloaded from http://bja.oxfordjournals.org/ at Universidade Federal do Amazonas on April 27, 2014
21
in rats anesthetized with nitrous oxide in a hyperbaric chamber. J Neurosci Methods 2007; 160: 215–22 Shafer SL, Hendrickx JF, Flood P, Sonner J, Eger EI II. Additivity versus synergy: a theoretical analysis of implications for anesthetic mechanisms. Anesth Analg 2008; 107: 507– 24 Kuhlmann L, Foster BL, Liley DT. Modulation of functional EEG networks by the NMDA antagonist nitrous oxide. PLoS One 2013; 8: e56434 Barr G, Jakobsson JG, Owall A, Anderson RE. Nitrous oxide does not alter bispectral index: study with nitrous oxide as sole agent and as an adjunct to i.v. anaesthesia. Br J Anaesth 1999; 82: 827–30 Park KS, Hur EJ, Han KW, Kil HY, Han TH. Bispectral index does not correlate with observer assessment of alertness and sedation scores during 0.5% bupivacaine epidural anesthesia with nitrous oxide sedation. Anesth Analg 2006; 103: 385–9, table of contents Anderson RE, Barr G, Jakobsson JG. Cerebral state index during anaesthetic induction: a comparative study with propofol or nitrous oxide. Acta Anaesthesiol Scand 2005; 49: 750– 3 Anderson RE, Jakobsson JG. Entropy of EEG during anaesthetic induction: a comparative study with propofol or nitrous oxide as sole agent. Br J Anaesth 2004; 92: 167– 70 Hans P, Bonhomme V, Benmansour H, Dewandre PY, Brichant JF, Lamy M. Effect of nitrous oxide on the bispectral index and the 95% spectral edge frequency of the electroencephalogram during surgery. Anaesthesia 2001; 56: 999–1002
Editorial V
Editorial IV
24 Goodnough LT, Spain DA, Maggio P. Logistics of transfusion support for patients with massive hemorrhage. Curr Opin Anaesthesiol 2013; 26: 208–14 25 Goodnough LT, Shander A. How I treat warfarin-associated coagulopathy in patients with intracerebral hemorrhage. Blood 2011; 117: 6091–9 26 Octapharma. Octaplas summary of product characteristics. Available from http://www.octapharma.co.uk/index.php?eID=tx_ nawsecuredl&u=0&file=uploads/media/octaplasLG_SmPC_01.pdf& t=1393419280&hash=ddc2b6fbb6e096a0a733896dc09c0f220a7e e262 (accessed 25 February 2014) 27 Cote CJ, Drop LJ, Hoaglin DC, Daniels AL, Young ET. Ionized hypocalcemia after fresh frozen plasma administration to thermally injured children: effects of infusion rate, duration, and treatment with calcium chloride. Anesth Analg 1988; 67: 152– 60 28 Theusinger OM, Baulig W, Seifert B, et al. Relative concentrations of haemostatic factors and cytokines in solvent/detergenttreated and fresh-frozen plasma. Br J Anaesth 2011; 106: 505 – 11 29 Solomon C, Pichlmaier U, Schoechl H, et al. Recovery of fibrinogen after administration of fibrinogen concentrate to patients with severe bleeding after cardiopulmonary bypass surgery. Br J Anaesth 2010; 104: 555–62 30 Danish Medicine Agency. Medicine prices in Denmark. Available from http://www.medicinpriser.dk/ (accessed 29 October 2013) 31 Shander A, Hofmann A, Ozawa S, et al. Activity-based costs of blood transfusions in surgical patients at four hospitals. Transfusion 2010; 50: 753– 65 32 Glenngard AH, Persson U, Soderman C. Costs associated with blood transfusions in Sweden—the societal cost of autologous, allogeneic and perioperative RBC transfusion. Transfus Med 2005; 15: 295–306
British Journal of Anaesthesia 112 (5): 787–90 (2014) Advance Access publication 24 February 2014 . doi:10.1093/bja/aeu006
EDITORIAL IV
Surrogate measures, do they really describe anaesthetic state? F. S. Servin 1* and V. Billard 2 1 2
Service d’anesthe´sie, APHP-Hoˆpital Bichat, 46, rue Henri Huchard, 75018 Paris, France Service d’anesthe´sie, Institut Gustave Roussy, 114, rue E´douard-Vaillant, 94805 Villejuif Cedex, France
* Corresponding author. E-mail: [email protected]
Characterization of anaesthesia is tricky, in particular, to go beyond the usual definition of a ‘state of non-responsiveness to various types of stimulations’, and to find indicators useful for titrating drug administration. General anaesthesia is usually split into two main domains: unconsciousness (nonresponse to verbal stimulation and amnesia) and analgesia (non-response to noxious stimulations).1 2 Unconsciousness may be directly assessed at induction of anaesthesia (loss of verbal contact) and after recovery (absence of recall), but usually not during maintenance. The adequacy of the
balance between analgesia and stimulation can be clinically estimated through movement, haemodynamic changes, and autonomic nervous system responses (sweat and lacrimation, modification in pupil diameter); these clinical endpoints have limitations when used for titrating anaesthetic drugs in clinical practice, specifically in paralysed patients. Furthermore, as adequate anaesthesia is defined as non-responsiveness, clinical assessment cannot distinguish between adequate drug delivery and overdosing if overdosing does not induce adverse effects.
787
Downloaded from http://bja.oxfordjournals.org/ at Universidade Federal do Amazonas on April 27, 2014
14 Inaba K, Branco BC, Rhee P, et al. Impact of plasma transfusion in trauma patients who do not require massive transfusion. J Am Coll Surg 2010; 210: 957– 65 15 Sorensen B, Bevan D. A critical evaluation of cryoprecipitate for replacement of fibrinogen. Br J Haematol 2010; 149: 834–43 16 Bevan DH. Cardiac bypass haemostasis: putting blood through the mill. Br J Haematol 1999; 104: 208– 19 17 Ahmed S, Harrity C, Johnson S, et al. The efficacy of fibrinogen concentrate compared with cryoprecipitate in major obstetric haemorrhage—an observational study. Transfus Med 2012; 22: 344– 9 18 World Health Organization (WHO). 63rd World Health Assembly. Availability, safety and quality of blood products. 2010. Available from http://apps.who.int/gb/ebwha/pdf_files/WHA63/A63_R12-en .pdf (accessed 22 October 2013) 19 Ranucci M, Solomon C. Supplementation of fibrinogen in acquired bleeding disorders: experience, evidence, guidelines, and licences. Br J Anaesth 2012; 109: 135– 7 20 Ranucci M. Fibrinogen supplementation in cardiac surgery: where are we now and where are we going? J Cardiothorac Vasc Anesth 2013; 27: 1–4 21 Weber CF, Gorlinger K, Meininger D, et al. Point-of-care testing: a prospective, randomized clinical trial of efficacy in coagulopathic cardiac surgery patients. Anesthesiology 2012; 117: 531– 47 22 Schochl H, Nienaber U, Hofer G, et al. Goal-directed coagulation management of major trauma patients using thromboelastometry (ROTEM)-guided administration of fibrinogen concentrate and prothrombin complex concentrate. Crit Care 2010; 14: R55 23 Hiippala ST, Myllyla GJ, Vahtera EM. Hemostatic factors and replacement of major blood loss with plasma-poor red cell concentrates. Anesth Analg 1995; 81: 360–5
BJA
788
(delta) and 10 Hz (spindle).14 Thereafter, fast frequency activity decreases unmasking low frequencies activity.15 For intermediate duration administration or concentrations, both effects may neutralize and EEG-derived parameters may show no change. Moreover, nitrous oxide also acts at the spinal level, where it stimulates superficial neurones and depresses deep neurones,16 and at the midbrain level to modulate ascendant nociceptive inputs17 and stimulate reticular neurones. As all single EEG-derived parameters, BISTM is unable to describe all these complex phenomena. It is recorded through a single frontal sensor, and therefore will catch accurately frontal changes but neither alterations in other territories such as the parietal area which is deeply depressed by nitrous oxide nor changes in the parietal/frontal equilibrium.18 To limit EMG and environment artifacts, BISTM signal processing is filtered at 32 Hz (as State Entropy and PSI). It may therefore miss fast frequency peaks, and appear ‘blind’ to nitrous oxide effect if predominant in fast frequencies. Laboratory (volunteers) studies were able to describe accurately nitrous oxide effects because they could record EEG in a quiet noise-free environment which is certainly not the case in an operating theatre. Lastly, spinal and midbrain effects of nitrous oxide, particularly relevant to the analgesic component of anaesthesia are not directly displayed on cortical EEG whatever the analysis technique used. Clinical results illustrate these limitations. Quite a few clinical works have studied the influence of nitrous oxide on BISTM values before and during surgery and their results are deeply confusing. When nitrous oxide 70% was used as the sole hypnotic administered to healthy volunteers, it induced loss of consciousness without modifying the BISTM , in contrast with what was observed with sevoflurane.19 In another study including 48 patients with epidural analgesia, inhalation of increasing nitrous oxide concentrations resulted in a progressive reduction in the OAA/S without corresponding decrease in BISTM values.20 Similar results were observed with cerebral state index (CSI)21 and Entropy.22 During sevoflurane anaesthesia titrated on BISTM (40–60), adding nitrous oxide consistently decreased BISTM and Entropy23 24 with the deepening of anaesthesia. This decrease was not observed with propofol,24 possibly because propofol inhibited reticular neurones, whereas sevoflurane did not. During gynaecological surgery with very low dose of alfentanil given at induction, adding nitrous oxide allowed decreasing the amount of sevoflurane necessary to maintain a chosen MPF (2–3 Hz) linearly with nitrous oxide fraction.25 During a deeper sevoflurane anaesthesia (BISTM 35), adding nitrous oxide slightly decreased BISTM , markedly decreased State Entropy but left PSI unchanged.26 During an isoflurane anaesthesia deep enough to achieve burst suppression, adding nitrous oxide decreased the burst suppression ratio and seemed to lighten anaesthesia.27 Several mechanisms have been proposed, such as an increase in cerebral blood flow or an activation of reticular neurones counteracting the effect on cortical neurones.27 After a noxious stimulation such as intubation, paradoxical BISTM and SEF decreases have been observed in the presence of nitrous oxide, but this effect disappeared
Downloaded from http://bja.oxfordjournals.org/ at Universidade Federal do Amazonas on April 27, 2014
Monitoring systems have been developed to compensate for these limitations. These are based on indirect (surrogate) measures, including the observation and analysis of cortical EEG. Several parameters have thus been proposed, such as the bispectral index (BISTM )3 which still plays a predominant role, mainly due to the fact that it was the first commercially available device with a clearly defined range supposed to correspond to an adequate ‘depth of anaesthesia’. As adrenergic stimuli induce arousal reactions which can be reflected on cortical EEG, the BISTM has also been used to assess the adequacy of analgesia.4 The BISTM is a complex and not completely accessible parameter established to statistically quantify the hypnotic effect of propofol.3 It was further found able to discriminate hypnotic levels induced by isoflurane and midazolam, albeit with less precision.5 However, ‘depth of anaesthesia’ monitors based on the EEG have demonstrated their usefulness in allowing adjustments of drug delivery to individual needs in clinical practice, decreasing both the risks of overdosing and of awareness, and slightly decreasing the recovery time.6 Liu and colleagues7 consider the sparing effect of nitrous oxide (N2O) on propofol and remifentanil consumptions when those drugs are administered through a closed-loop system using the BISTM as the control parameter. They do not find any clinically significant difference in propofol or remifentanil consumption whether or not nitrous oxide is added to the inhaled mixture. Liu and colleagues’ system uses the BISTM to control both propofol and remifentanil administrations, the hypnotic being driven by progressive changes in the parameter, and the opioid by rapid changes seemingly corresponding to arousal reactions. They claim that their system, being independent from the clinician, is more reliable to detect any difference induced by nitrous oxide administration than all the other studies published so far which were based on haemodynamic and clinical observation. However, no other descriptors of ‘adequacy of anaesthesia’ are considered in their system. Nitrous oxide has actually initiated the era of modern anaesthesia more than 150 yr ago, when it was used in dental surgery. It has a weak sedative action, with a minimum alveolar concentration (MAC) around 1.04 (0.10) (SE) atm absolute, measured in hyperbaric conditions,8 and may provoke loss of consciousness through a mechanism called dissociative anaesthesia, similar to that obtained with ketamine, both agents acting through the N-methyl-D-aspartate (NMDA) receptor.9 However, nitrous oxide is nowadays mainly considered as an analgesic. As such, it reduces the amount of both volatile and propofol required to blunt motor responses to skin incision (MAC, EC50) by about 30%.10 11 The influence of nitrous oxide on the central nervous system is very complex. Conversely to GABA-ergic hypnotics which induce mainly cortical EEG depression (i.e. slowing and synchronization preceding burst suppression), nitrous oxide, antagonist of the NMDA receptor, also stimulates the EEG and increases fast frequencies activity (.30 Hz), specially in the frontal area.12 13 This activation occurs early after introducing nitrous oxide and is associated with phase coupling peaks around 4 Hz
Editorial IV
BJA
Editorial IV
Abbreviations and definitions31 BISTM SEF
MPF
Entropy
Bispectral index of EEG including bispectrum, quasi burst, and b ratio. Spectral edge frequency. Frequency of the spectrum below which are gathered 95% of the frequency components of an EEG epoch. Median power frequency is the frequency of the spectrum below which are gathered 50% of the frequency components of an EEG epoch. This returns two indexes both expressing the irregularity, complexity, or unpredictability characteristics of EEG signal: state entropy (including frequencies from 0.5 to 32 Hz) and response entropy.
Patient state index
Q EEG-derived parameter including EEG power, frequency, and phase information from anterior –posterior relationships of the brain and coherence between bilateral brain regions.
Declaration of interest None declared.
References 1 Prys-Roberts C. Anaesthesia: a practical or impractical construct? Br J Anaesth 1987; 59: 1341–5 2 Shafer SL, Stanski DR. Defining depth of anesthesia. Handb Exp Pharmacol 2008; 409– 23 3 Kearse LA Jr, Manberg P, Chamoun N, deBros F, Zaslavsky A. Bispectral analysis of the electroencephalogram correlates with patient movement to skin incision during propofol/nitrous oxide anesthesia. Anesthesiology 1994; 81: 1365– 70 4 Guignard B, Menigaux C, Dupont X, Fletcher D, Chauvin M. The effect of remifentanil on the bispectral index change and hemodynamic responses after orotracheal intubation. Anesth Analg 2000; 90: 161– 7 5 Glass PS, Bloom M, Kearse L, Rosow C, Sebel P, Manberg P. Bispectral analysis measures sedation and memory effects of propofol, midazolam, isoflurane, and alfentanil in healthy volunteers. Anesthesiology 1997; 86: 836–47 6 Punjasawadwong Y, Boonjeungmonkol N, Phongchiewboon A. Bispectral index for improving anaesthetic delivery and postoperative recovery. Cochrane Database Syst Rev 2007; CD003843 7 Liu N, Le Guen M, Boichut N, et al. Nitrous oxide does not produce a clinically important sparing effect during close-loop delivered propofol–remifentanil anaesthesia guided by the bispectral index: a randomized multicentre study. Br J Anaesth 2014; 112: 842– 51 8 Hornbein TF, Eger EI II, Winter PM, Smith G, Wetstone D, Smith KH. The minimum alveolar concentration of nitrous oxide in man. Anesth Analg 1982; 61: 553–6 9 Sleigh JW, Barnard JP. Entropy is blind to nitrous oxide. Can we see why? Br J Anaesth 2004; 92: 159– 61 10 Davidson JA, Macleod AD, Howie JC, White M, Kenny GN. Effective concentration 50 for propofol with and without 67% nitrous oxide. Acta Anaesthesiol Scand 1993; 37: 458– 64 11 Torri G, Damia G, Fabiani ML. Effect on nitrous oxide on the anaesthetic requirement of enflurane. Br J Anaesth 1974; 46: 468– 72 12 Foster BL, Liley DT. Nitrous oxide paradoxically modulates slow electroencephalogram oscillations: implications for anesthesia monitoring. Anesth Analg 2011; 113: 758–65 13 Yamamura T, Fukuda M, Takeya H, Goto Y, Furukawa K. Fast oscillatory EEG activity induced by analgesic concentrations of nitrous oxide in man. Anesth Analg 1981; 60: 283–8 14 Hagihira S, Takashina M, Mori T, Mashimo T. The impact of nitrous oxide on electroencephalographic bicoherence during isoflurane anesthesia. Anesth Analg 2012; 115: 572– 7 15 Rampil IJ, Kim JS, Lenhardt R, Negishi C, Sessler DI. Bispectral EEG index during nitrous oxide administration. Anesthesiology 1998; 89: 671– 7 16 Antognini JF, Atherley RJ, Laster MJ, Carstens E, Dutton RC, Eger EI II. A method for recording single unit activity in lumbar spinal cord
789
Downloaded from http://bja.oxfordjournals.org/ at Universidade Federal do Amazonas on April 27, 2014
when an opioid bolus was added.28 In another study, nitrous oxide inhibited both BISTM changes during intubation and clinical response (isolated forearm) suggesting that an adequate level of analgesia had been achieved.29 In summary, the effect of nitrous oxide on EEG and EEGderived parameters during anaesthesia is only one of all nitrous oxide pharmacodynamic effects, along with sedation, immobility, or haemodynamic control. It depends on both excitation/depression and cortical/subcortical balances. These balances vary with the associated drugs (volatile vs propofol), on the degree of EEG depression, and on the nociception/antinociception equilibrium. The results achieved by Liu and colleagues,7 titrating anaesthesia entirely on a single EEG parameter, confirm a small influence of nitrous oxide to maintain a chosen value of this surrogate parameter through dosing of GABA-ergic drugs. These authors were unable to demonstrate any influence on the level of sedation in the absence of stimulation, because nitrous oxide was introduced after intubation, at a time when the doses required for surgery were far above those required for loss of consciousness. Moreover, considering control over adrenergic stimuli, one may even suspect that both groups were not at the same depth of analgesia (despite similar BISTM ), since the incidence of movement was divided by three in the nitrous oxide group, and the incidence of antihypertensive medication by two. At a time when instrumental monitoring is more and more prominent in our anaesthesia practice, this work is a useful reminder of the fact that a mathematical construction based on cortical EEG may not (yet?) include all the complexity surrounding pharmacological loss of consciousness and control over adrenergic stimuli, and thus be unable to completely describe anaesthesia. The future of drug adjustments might well include more complex algorithms combining surrogate measures of sedation (EEG), surrogate measures of analgesia (i.e. pupil dilatation reflex),30 and clinical signs considered in their surgical context.
BJA 17
18
19
20
22
23
24 Ozcan MS, Ozcan MD, Khan QS, Thompson DM, Chetty PK. Does nitrous oxide affect bispectral index and state entropy when added to a propofol versus sevoflurane anesthetic? J Neurosurg Anesthesiol 2010; 22: 309–15 25 Ropcke H, Schwilden H. Interaction of isoflurane and nitrous oxide combinations similar for median electroencephalographic frequency and clinical anesthesia. Anesthesiology 1996; 84: 782– 8 26 Soto RG, Smith RA, Zaccaria AL, Miguel RV. The effect of addition of nitrous oxide to a sevoflurane anesthetic on BIS, PSI, and entropy. J Clin Monit Comput 2006; 20: 145–50 27 Yli-Hankala A, Lindgren L, Porkkala T, Jantti V. Nitrous oxidemediated activation of the EEG during isoflurane anaesthesia in patients. Br J Anaesth 1993; 70: 54 –7 28 Oda Y, Tanaka K, Matsuura T, Hase I, Nishikawa K, Asada A. Nitrous oxide induces paradoxical electroencephalographic changes after tracheal intubation during isoflurane and sevoflurane anesthesia. Anesth Analg 2006; 102: 1094–102 29 Coste C, Guignard B, Menigaux C, Chauvin M. Nitrous oxide prevents movement during orotracheal intubation without affecting BIS value. Anesth Analg 2000; 91: 130– 5 30 Oka S, Chapman CR, Kim B, Nakajima I, Shimizu O, Oi Y. Pupil dilation response to noxious stimulation: effect of varying nitrous oxide concentration. Clin Neurophysiol 2007; 118: 2016– 24 31 Rampil IJ. A primer for EEG signal processing in anesthesia. Anesthesiology 1998; 89: 980– 1002
British Journal of Anaesthesia 112 (5): 790–3 (2014) doi:10.1093/bja/aeu009
EDITORIAL V
‘For now we see through a glass, darkly’: the anaesthesia syndrome R. D. Sanders 1,2*, A. Absalom 3, J. W. Sleigh 4 and on behalf of the ConsCIOUS Group† 1
Department of Anaesthesia, Royal Brompton Hospital; Surgical Outcomes Centre, University College London Hospital, London, UK Wellcome Department of Imaging Neuroscience, Institute of Cognitive Neuroscience, University College London, 17 – 19 Queen Square, London WC1N 3AR, UK 3 Department of Anesthesiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands 4 Department of Anaesthesia, University of Auckland, Hamilton, New Zealand 2
* Corresponding author: Wellcome Department of Imaging Neuroscience, Institute of Cognitive Neuroscience, University College London, 17-19 Queen Square, London WC1N 3AR, UK. E-mail: [email protected]
In this issue of the British Journal of Anaesthesia, Zand and colleagues1 revisit the isolated forearm technique (IFT) pioneered in obstetric anaesthesia by Tunstall.2 Their data are consistent with Tunstall’s early studies during anaesthesia for Caesarean section showing that 33–42% of patients may respond intra-operatively.2 3 Zand and colleagues1 made similar observations after rapid sequence induction with thiopental: 41, 46, and †
23% of the subjects responded at laryngoscopy, intubation, and skin incision, respectively. Prima facie, these are potentially alarming statistics, raising questions over the ‘adequacy of anaesthesia’ provided during and after rapid sequence induction, and hence a thorough critique of their methodology is warranted. Strengths of this paper include the standardized and clinically relevant approach (including drug dosing), relatively large
CONSciousness, Connectedness, IntraOperative Unresponsiveness Study (ConsCIOUS) Group: Anthony Absalom, Ram Adapa, Vincent Bonhomme, Mark Coburn, Robert D. Sanders, Gerhard Schneider, Jamie Sleigh, Rob Stephens.
790
Downloaded from http://bja.oxfordjournals.org/ at Universidade Federal do Amazonas on April 27, 2014
21
in rats anesthetized with nitrous oxide in a hyperbaric chamber. J Neurosci Methods 2007; 160: 215–22 Shafer SL, Hendrickx JF, Flood P, Sonner J, Eger EI II. Additivity versus synergy: a theoretical analysis of implications for anesthetic mechanisms. Anesth Analg 2008; 107: 507– 24 Kuhlmann L, Foster BL, Liley DT. Modulation of functional EEG networks by the NMDA antagonist nitrous oxide. PLoS One 2013; 8: e56434 Barr G, Jakobsson JG, Owall A, Anderson RE. Nitrous oxide does not alter bispectral index: study with nitrous oxide as sole agent and as an adjunct to i.v. anaesthesia. Br J Anaesth 1999; 82: 827–30 Park KS, Hur EJ, Han KW, Kil HY, Han TH. Bispectral index does not correlate with observer assessment of alertness and sedation scores during 0.5% bupivacaine epidural anesthesia with nitrous oxide sedation. Anesth Analg 2006; 103: 385–9, table of contents Anderson RE, Barr G, Jakobsson JG. Cerebral state index during anaesthetic induction: a comparative study with propofol or nitrous oxide. Acta Anaesthesiol Scand 2005; 49: 750– 3 Anderson RE, Jakobsson JG. Entropy of EEG during anaesthetic induction: a comparative study with propofol or nitrous oxide as sole agent. Br J Anaesth 2004; 92: 167– 70 Hans P, Bonhomme V, Benmansour H, Dewandre PY, Brichant JF, Lamy M. Effect of nitrous oxide on the bispectral index and the 95% spectral edge frequency of the electroencephalogram during surgery. Anaesthesia 2001; 56: 999–1002
Editorial V
