Metabolic Disorders and Critically Ill Patients From Pathophysiology to Treatment Carole Ichai Hervé Quintard Jean-Christophe Orban Editors 123 Metabolic Disorders and Critically Ill Patients Carole Ichai  •  Hervé Quintard Jean-Christophe Orban Editors Metabolic Disorders and Critically Ill Patients From Pathophysiology to Treatment Editors Carole Ichai Intensive Care Unit Hôpital Pasteur Centre Hospitalier Universitaire de Nice Université Côte d’Azur Nice France Hervé Quintard Intensive Care Unit Hôpital Pasteur Centre Hospitalier Universitaire de Nice Université Côte d’Azur Nice France Jean-Christophe Orban Intensive Care Unit Hôpital Pasteur Centre Hospitalier Universitaire de Nice Université Côte d’Azur Nice France Original French edition published by Springer-Verlag France, Paris, 2012, ISBN 978-2-287-99026-7 ISBN 978-3-319-64008-2    ISBN 978-3-319-64010-5 (eBook) https://doi.org/10.1007/978-3-319-64010-5 Library of Congress Control Number: 2017959327 © Springer International Publishing AG 2018 This work is subject to copyright All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed The use of general descriptive names, registered names, trademarks, service marks, etc in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Printed on acid-free paper This Springer imprint is published by Springer Nature The registered company is Springer International Publishing AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Contents Part I  Fluid and Electrolytes Disorders 1 Water and Sodium Balance��������������������������������������������������������������������    3 Carole Ichai and Daniel G Bichet 2 Sodium Disorders������������������������������������������������������������������������������������   33 Carole Ichai and Jean-Christophe Orban 3 Potassium Disorders��������������������������������������������������������������������������������   71 Carole Ichai 4 Phosphate and Calcium Disorders ��������������������������������������������������������  101 Carole Ichai Part II  Acid-Base Disorders 5 Interpretation of Acid-Base Disorders��������������������������������������������������  147 Hervé Quintard, Jean-Christophe Orban, and Carole Ichai 6 Acidosis: Diagnosis and Treatment��������������������������������������������������������  169 Hervé Quintard and Carole Ichai 7 Alkalosis: Diagnosis and Treatment������������������������������������������������������  195 Jean-Christophe Orban and Carole Ichai 8 Lactate: Metabolism, Pathophysiology��������������������������������������������������  215 Carole Ichai and Jean-Christophe Orban Part III  Kidney and Metabolic Disorders 9 Metabolism and Renal Functions ����������������������������������������������������������  241 Aurélien Bataille and Laurent Jacob 10 Extrarenal Removal Therapies in Acute Kidney Injury����������������������  255 Olivier Joannes-Boyau and Laurent Muller 11 Strategies for Preventing Acute Renal Failure��������������������������������������  275 Malik Haddam, Carole Bechis, Valéry Blasco, and Marc Leone v vi Contents Part IV  Brain and Metabolic Disorders 12 Cerebral Metabolism and Function ������������������������������������������������������  285 Lionel Velly and Nicolas Bruder 13 Cerebral Ischemia: Pathophysiology, Diagnosis, and Management��������������������������������������������������������������������������������������  301 Lionel Velly, D Boumaza, and Pierre Simeone 14 Evaluation of Cerebral Blood Flow and Brain Metabolism in the Intensive Care Unit ����������������������������������������������������������������������  327 Pierre Bouzat, Emmanuel L Barbier, Gilles Francony, and Jean-Franỗois Payen Part V Endocrine Disorders in Intensive Care Unit 15 Acute Complications of Diabetes������������������������������������������������������������  341 Jean-Christophe Orban, Emmanuel Van Obberghen, and Carole Ichai 16 Neuroendocrine Dysfunction in the Critically Ill Patients ������������������  365 Antoine Roquilly and Karim Asehnoune 17 Hyperglycemia in ICU����������������������������������������������������������������������������  379 Carole Ichai and Jean-Charles Preiser Part VI  Energetic Metabolism, Nutrition 18 Nutritional Requirements in Intensive Care Unit��������������������������������  401 Marie-Pier Bachand, Xavier Hébuterne, and Stéphane M Schneider 19 Pharmaconutrition in the Critically Ill Patient������������������������������������  421 Jean-Charles Preiser, Christian Malherbe, and Carlos A Santacruz 20 Oxygen and Oxidative Stress������������������������������������������������������������������  431 Jean-Christophe Orban and Mervyn Singer 21 Energy Metabolism: From the Organ to the Cell ��������������������������������  441 Hervé Quintard, Eric Fontaine, and Carole Ichai 22 Ischemia-Reperfusion Concepts of Myocardial Preconditioning and Postconditioning�������������������������������������������������������������������������������  453 Pascal Chiari, Stanislas Ledochowski, and Vincent Piriou 23 Targeted Temperature Management in Severe Brain-Injured Patient������������������������������������������������������������������������������  469 Hervé Quintard and Alain Cariou Part I Fluid and Electrolytes Disorders Water and Sodium Balance Carole Ichai and Daniel G. Bichet 1.1 Introduction Water is the major constituent of the body It represents the unique solvant of v­ arious molecules (electrolytes) of our body Although sodium is largely extracellular and potassium is intracellular, body fluids can be considered as being in a single “tub” containing sodium, potassium and water, because osmotic gradients are quickly abolished by water movements across cell membranes [1] As such, the concentration of sodium in plasma water should equal the concentration of sodium plus potassium in total body water: ( ) éë Na + ùû in plasma H O = 1.11 ´ é Na + e + K + e ù / total boby H O - 25.6 ë û This theoretical relationship was validated empirically by Edelman et al [2] who used isotopes to measure exchangeable body cations and water This equation has an intercept (−25.6); the regression line relating plasma sodium to the ratio of exchangeable (Na+ + K+) to total body water does not pass through zero because not all exchangeable sodium is free in solution Exchangeable sodium is the major extracellular cation and sodium bound in polyanionic proteoglycans is also found in bone, cartilage and skin [1] C Ichai (*) Intensive Care Unit, Hôpital Pasteur 2, 30 Voie Romaine, 06001 Nice, Cédex 1, France IRCAN (INSERM U1081, CNRS UMR 7284), University of Nice, Nice, France e-mail: ichai@unice.fr D.G Bichet Medicine and Molecular and Integrative Physiology, University of Montreal, Montréal, QC, Canada Hôpital du Sacré-Cœur de Montréal, 5400 Boul Gouin O, Montréal, QC, Canada, H4J 1C5 © Springer International Publishing AG 2018 C Ichai et al (eds.), Metabolic Disorders and Critically Ill Patients, http://doi.org/10.1007/978-3-319-64010-5_1 C Ichai and D.G Bichet Both water and sodium balances are physiologically strictly regulated by numerous hormonal, neuronal, and mechanical complex mechanisms in order to maintain intracellular and extracellular volumes constant 1.2 Body Compartments and Water Shifts 1.2.1 Body Compartments and their Composition Total body water (TBW) accounts for 50–70% of the total body weight in healthy adults This proportion varies according to numerous parameters, such as age, sex and the lean mass/fat mass ratio (lean mass is very poor in water) TBW distributes for 2/3 in the intracellular volume (ICV), and the remaining 1/3 in the extracellular volume (ECV) [3–10] The ICV is about 40% of total body weight Potassium (K+) is the most abundant intracellular cation (120 mmol/L), but large amount of proteins contribute also substantially to generate the oncotic pressure The ECV is distributed into the plasma volume and the interstitial one In normal physiological conditions, that is, in the absence of heart failure, cirrhosis and nephrotic syndrome, the plasma volume is equivalent to the “effective arterial blood volume” (EABV) which represents 1/4 to 1/3 of ECV, and 5% of the total body weight In physiological situations, EABV is composed at 93% by water that contains various solutes Some of them are ionized (anionic and cationic electrolytes) while others are not dissociated (blood urea nitrogen [BUN], glucose) Sodium (Na+) is the most abundant plasma cation and, together with accompanying anions, are the major determinants of the osmotic force developed in the plasma Non dissociated solutes (albumin, globulins and lipids) contribute for 7% of the plasma volume The interstitial volume is 3/4 to 2/3 of the ECV, i.e 15% of the total body weight Contrary to the plasma volume which is anatomically limited by the capillary endothelium, the interstitial compartment is a less well defined space located around cells, lymph and conjunctive tissues In terms of composition, the interstitial fluid is an ultrafiltrate of the plasma Consequently, its composition is close compared to plasma, but due to its negligeable concentration in protein, sodium is quite lower and chloride higher in the interstitial compartment For the same reasons, and because proteinates are impermeant solutes in the cells, the intracellular concentration in diffusible cations and in total ions is higher in cells: this is the Gibbs-Donnan equilibrium which creates an electrical difference in the membrane potential (Table 1.1) 1.2.2 W  ater and Electrolytes Shifts between the Body Compartments [3–10] 1.2.2.1 Movements across Intracellular and Extracellular Fluids Water moves freely across the semi-permeable cell membranes according to the osmotic gradient leading to a shift from the low to the high osmotic volume until reaching a transmembrane osmotic equilibrium (Fig.  1.1) [4, 11–15] Therefore, 1  Water and Sodium Balance Table 1.1  Main solutes and water composition of the body compartments Solutes (mEq/L) Na+ K+ Mg++ Ca++ Cl− HCO3− HPO42−/H2PO4− SO42− Blood urea nitrogen Glucose Organic acids− Proteinates− ECF Extracellular volume Blood plasma Interstitial fluid 137 142 2 1 111 105 30 26 2.3 1.2 5 5 5 17 ICF CM Red blood cells Intracellular volume 10 155 10 – 10 11 105 – Variable – 74 19 9.5 – 10 15 110 – – Variable – 320 ICF ECF CM 1a 1b water ICF ECF ECF CM 1c ICF CM 1d water Extracellular sodium Intracellular potassium Effective osmole Ineffective osmole Fig 1.1  Water movements between the extracellular (ECV) and intracellular volume (ICV) through the cell membrane (CM) (a) Normal volume and distribution of water in the ECV and ICV. The osmotic forces produced by the extracellular effective osmoles (mainly sodium) and the intracellular ones (mainly potassium) are equal, so that there is no osmotic gradient and consequently no water shift across the cell membrane ECV and ICV are isoosmotic and isotonic (b) Decrease (dehydration) of ICV. The accumulation of effective solutes (sodium or glucose) in the ECF creates an transmembrane osmotic gradient which induces water to cross cell membrane from the ICV to the ECV until reaching the osmotic equilibrium between both compartments (c) Increase (hyperhydration) of ICV. The loss of effective solutes (sodium or glucose) in the ECV creates a transmembrane osmotic gradient which induces water to cross cell membrane from the ECV to the ICV until reaching the osmotic equilibrium between both compartments (d) Normal volume and distribution of water in the ECV and ICV.  Ineffective solutes such as urea distributes equally between the ECV and ICV. Thus, osmotic forces developped by the extracellular effective and ineffective osmoles and the intracellular ones are equal, so that there is no osmotic gradient and consequently no water shift across the cell membrane ECV and ICV are isotonic but hyperosmotic 462 P Chiari et al mPTP opening, while the use of a Ca++ chelator such as EGTA inhibits it Intracellular Ca++ shifts, particularly during ischemia-reperfusion, are closely related to the sarcoplasmic reticulum Numerous studies have examined the relationship between mitochondria and reticulum, particularly focusing on their contact zones, the mitochondria-­associated membranes (MAM), which could be one of the key points of cell protection [36, 37] The matrix pH is also an important element of this regulation since its acidification decreases the opening probability of the mPTP. ROS are also potent activators of the mitochondrial permeability transition Cyclosporin A, by binding to cyclophilin D, prevents its attachment to the ANT and thus delays the opening of the mPTP [19, 31, 38, 39] mPTP opening during ischemia-reperfusion: Ischemia is accompanied by a very significant acidosis which maintains mPTP closed It was really only during reperfusion that the conditions for the opening of the mPTP are met Na+/H+ and Na+/Ca++ exchangers quickly correct acidosis at the cost of a high Ca++ overload of the mitochondrial matrix There is an associated ROS “burst” due to the replenishment of oxygen in the respiratory chain Reperfusion, by combining the optimal conditions for the opening of mPTP, is a decisive step in the generation of cellular damage from ischemia-reperfusion injury 22.3 Perioperative Cardioprotection Cardiovascular complications of perioperative myocardial ischemia are a leading cause of morbidity and mortality, both in cardiac and noncardiac surgery Aortic clamping, necessary in cardiac surgery, induces a sequence of myocardial ischemia-­ reperfusion Several studies have shown that elevated postoperative troponin I is an independent prognostic factor of morbi-mortality up to 36 months after cardiac surgery [40, 41] Major noncardiac surgery, such as arterial vascular surgery, especially when performed on a coronary artery disease patient, may be complicated by a perioperative myocardial infarction whose prognosis remains poor (close to 40% mortality) [42] Extensive research has been done on the perioperative setting to try to stop this process Pharmacological protective strategies by beta-blockers and statins in particular have been developed However, this issue of perioperative cardioprotection was clearly marked by the discovery in 1997 of the PreC effect of halogenated anesthetic agents [6] 22.3.1 Halogenated Agents and Cardioprotection Experimental data On an in vivo animal model, administration of isoflurane prior to a sequence of ischemia reperfusion reduced the size of myocardial infarction by 50% [43] This effect is inhibited by glibenclamide, a sulfonylurea which blocks the opening of KATP channels, thereby confirming the role played by these channels These early works were confirmed by a multitude of animal model studies (in vivo, ex vivo, and in vitro) as well as tissue from human atria removed during cardiac 22  Ischemia-Reperfusion Concepts of Myocardial Preconditioning and Postconditioning 463 surgery [20, 21] All halogenated agents (from the oldest, enflurane, halothane, and isoflurane, to the most recent, sevoflurane and desflurane) are cardioprotective to varying degrees depending on experimental conditions It is considered that here is a class effect There is a dose of anesthetic PreC as there is one for ischemic PreC. However, it is not useful to administer a dose greater than one MAC (minimum alveolar concentration) to trigger a protective signal Furthermore, these anesthetics are also capable of inducing a late PreC, since their administration induces a myocardial resistance to ischemia for days [44] Finally, a protective effect was found when a halogenated agent was administered during the first moments of reperfusion, defining a PostC effect [45, 46] Clinical studies So far, the cardioprotective effect of a halogenated agent has been mainly studied in the context of cardiac surgery Despite promising early works in terms of reducing postoperative troponin I levels, more recent studies have since tempered the enthusiasm by revealing a positive effect only on secondary postoperative outcomes such as BNP or cardiac index [47–50] Despite this, three meta-analyses demonstrate the protective effects of halogenated agents [51–53] These studies, based only on small studies, are not consistent in their findings Some found a positive effect in terms of postoperative troponin I elevation, while others in terms of mortality For noncardiac surgery, two recent studies found no beneficial effect of halogenated compared to intravenous general anesthesia [54, 55] However, many confounding factors may explain this apparent lack of effectiveness [56] The discrepancy between the experimental studies, all clearly in favor of halogenated agents, and clinical studies may be disturbing However, this difference is probably due to the inherent complexity of clinical research Clinical studies necessarily mix population with varying ages, conditions, and operating settings (type of surgery, different operators, multicenter study, heterogeneous coronary anatomy, etc.) with various pathologies and associated treatments 22.3.2 Clinical Factors Modulating this Anesthetic Cardioprotection Age modulates PreC since it has been shown that the senescent myocardium becomes less sensitive to the protective effect of a halogenated agent [57] Estrogens have a protective effect (possibly via an effect on the KATP channels and NO production) [58] Diabetes and hyperglycemia abolish PreC, probably through an ROS overproduction [59] Sulfonylureas, inhibiting the opening of KATP channels, have a potentially negative effect on the tolerance to myocardial ischemia and should therefore be stopped 24–48 h before surgery [43] The perioperative phase involves many treatments whose effects are variable (e.g., anti-protective effects of theophylline or anti-COX-2, protective effects of nicorandil, insulin, nitrates, or sildenafil) General anesthesia also combines anti-protecting agents such as midazolam and proven protective agents such as morphine [60, 61] Ketamine, according to studies, could have a positive or a negative effect on PreC [62] Statins, by acting very early 464 P Chiari et al in the synthetic pathway of cholesterol, inhibit other proteins such as protein Rho, which interacts with signaling pathways of cell death Many studies have demonstrated that the beneficial effects of statins are well beyond their cholesterol-­lowering effects (pleiotropic effects) [63] In addition, the discontinuation of statin therapy may induce a rebound effect Indeed, it has been shown that a discontinuation of statins in the postoperative phase of an aortic vascular surgery may increase the risk of perioperative myocardial infarction by 2.9 [64] These examples only bear witness to the difficulties to prove a statistically significant cardioprotective effect Conclusion The actual trend is to apply a multifocal strategy to protect high-risk patients from perioperative myocardial ischemia Cardioprotective attitudes include the 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[2] Indeed hyperthermia can improve excitotoxicity, metabolic dysfunction, inflammation, etc Control of fever is so a basic principle in brain injury cares [3] and will not be discussed here However, several recent data described that decrease temperature to lower level (32–36 °C), even in case of normothermia, could be helpful to protect the brain from injuries Indeed this targeted temperature management (TTM) is an established tool used to protect the central nervous system during surgery for long years [4] Part of this protection is mainly due to a decrease in metabolism [5] and in oxygen consumption [6], but also to a decrease in cerebral blood flow [7] Lot of other neuroprotective effects have been described previously as on integrity of blood-brain barrier [8], excitotoxic [9], or inflammation mechanism control (Fig.  23.1) It has only recently achieved a mainstream role in clinical practice, especially in post-cardiac arrest syndrome Indeed the decrease in core temperature improved neurologic recovery after cardiac arrest syndrome as described, 10 years ago, by randomized control trials [10] These observations conducted to a real change in ICU management of patients after cardiac arrest and have opened an important way of search Use of TTM in other brain injuries is less conclusive Severe brain injury, secondary to traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), stroke, meningitis, or intracerebral hemorrhage (ICH), can be complicated by several mechanisms that induce brain edema and increase in intracranial pressure (ICP) [11] The question to induce hypothermic state in this context is quite discussed and can have conflicting aspect H Quintard, M.D., Ph.D (*) Intensive Care Unit, Pasteur Hospital (CHU Nice), 30 voie romaine, 06000 Nice, France e-mail: quintard.h@chu-nice.fr A Cariou, M.D., Ph.D Intensive Care Unit, Cochin Hospital (AP-HP), 75000 Paris, France © Springer International Publishing AG 2018 C Ichai et al (eds.), Metabolic Disorders and Critically Ill Patients, http://doi.org/10.1007/978-3-319-64010-5_23 469 470 H Quintard and A Cariou Energy failure ↓Metabolic Io n Ionic pump dysfunction Glutamate release ↑Phospholipase activity B BBB permeability Leukocyte infiltration ↑Protease activity Cytotoxic edema Vasogenic edema ↑ Free radical mitochondrial dysfunction Cellular death ↑ ICP Inflammation Fig 23.1  Mechanisms involved in secondary brain injuries and neuroprotective mechanisms of hypothermia (blue circles) 23.1 Cardiac Arrest Sudden cardiac death remains a major public health issue, as highlighted by epidemiological data, showing that nearly 40,000 people are supported for out-of-­hospital cardiac arrest (CA) in France each year Even more problematic, only a very low proportion of resuscitated patients will recover and will leave the hospital without major neurological impairments [12] The evidence of further cerebral damage occurring during the reperfusion phase encouraged intense research aiming to limit the worsening of the neurological lesions occurring during the post-CA period Post-resuscitation fever has been rapidly identified as having a major detrimental effect [13] This culminated 10 years ago with the demonstration that post-CA cooling was an effective treatment in these patients Many animal models of cardiac arrest (CA) demonstrated that mild hypothermia can provide neuroprotective effects through different mechanisms of action such as a decrease in cerebral oxygen consumption, a reduction in apoptosis activation and mitochondrial dysfunction, a decrease in cerebral excitatory cascade, a decrease in local inflammatory response, a reduction in the production of free oxygen radicals production, and a decrease in vascular and membrane permeability These convergent experimental effects translated into clinical effects as revealed in the two landmark studies published in 2002 [10, 14] In these two pivotal trials, the implementation of induced hypothermia (between 32 and 34 °C) permitted to achieve a significantly higher survival rate without major sequel as compared with no specific temperature management These studies were decisive and led to a rapid change in international guidelines regarding the management of comatose patients after CA.  Until recently, it has been strongly recommended to routinely induce a 23  Targeted Temperature Management in Severe Brain-Injured Patient 471 moderate hypothermia (32–34 °C) for 12–24 h in all adults still comatose after restoration of spontaneous circulation Over the last decade, several clinical findings challenged this recommendation in different ways The most important point that is debated is the level of temperature that should be targeted The targeted temperature management (TTM) trial randomized 950 comatose patients after CA who were randomly assigned to 33 °C or 36 °C over the first 24 h [14] This large multicenter study did not retrieve any significant difference in any outcome criteria, including survival rate and neurological outcome As a consequence, the most recent guidelines considered that a range of temperature between 32 and 36 °C can be used in this setting Another consequence was that the appellation “TTM” is now widely accepted as referring to all intervention aiming to obtain and maintain a targeted level of temperature in this situation The population that might benefit from induced hypothermia also became an important concern If numerous observational studies further confirmed the benefit of this treatment in highly selected patients (i.e., those resuscitated from an out-of-­ hospital ventricular fibrillation or a pulseless ventricular tachycardia), the level of evidence remains weaker in patients presenting an initial non-shockable rhythm (i.e., those resuscitated from pulseless electrical activity or asystole) and in patients resuscitated from an in-hospital CA [15, 16] In these patients, data are conflicting, and if present, the clinical benefit of TTM is highly suspected to be very minor Considering that the risk-benefit ratio is sufficiently favorable, 2015 guidelines still recommend discussing the use of TTM in these patients Ongoing randomized studies focusing on these non-shockable patients will probably provide more information The way to perform an adequate TTM is also a matter of debate Even if based on low quality of evidence, it is generally recommended to use servo-controlled devices (i.e., devices driven by a feedback on patient’s temperature) These systems are known to faster reach the targeted temperature and to provide a greater stability during the maintenance phase [17] Whether an external or internal device should be preferred, it is at that time unknown as no adequately designed studies compared these two options 23.2 Traumatic Brain Injury Experimental trauma studies described promising results of hypothermia in control of increase ICP [11] and neuroprotective properties [8] Several mechanisms seem to be involved Phillips et al described action on apoptosis with a decrease in calcium entry via the N-methyl-D-aspartate and ryanodine receptors in cultured hippocampal neurons of brain submitted to trauma [18] Control of inflammation seems to be also involved in protection mechanisms encountered with hypothermia [19] Clinical studies described hypothermia as a promising therapy in TBI patients [20, 21] In a cohort of 82 patients, Marion et al described that moderate hypothermia (33 °C) conducted for 24 h in patients with severe brain injury and Glasgow score between and improved the outcome [20] Unfortunately, these promising 472 H Quintard and A Cariou results were contrasted by several data Clifton et al [22] conducted a study on 392 patients randomized in a normothermic group and a 33 °C group for 48 h but didn’t find any effect of hypothermia on recovery; moreover the hypothermic group had much more hypotensive episodes The limit of this study could be the prolonged delay reported to hypothermic temperature target, 8 ± 3 h, but the NABISH II study, which reduced this time, didn’t find any benefits of hypothermia on recovery Two studies conducted in pediatric population didn’t find neither any interest in therapeutic hypothermia in a population of severe injured patients with moreover a trendy to a worth neurologic prognosis and an increase in mortality in the group hypothermia [23, 24] The main problem of these several studies is the non-selection of TBI population for hypothermia and the heterogeneity of hypothermic methods used Effect of hypothermia on intracranial hypertension (HTIC), which is an independent mortality risk factor, has been described in the different previous studies [25, 26] However beneficial effect on recovery is not confirmed In a multicenter randomized control study, Shiozaki et al confirmed the lack of interest of hypothermia in a subpopulation of patient with low ICP [21] In a large multicenter study of 347 patients, in patients with an intracranial pressure of more than 20 mm Hg after traumatic brain injury, therapeutic hypothermia plus standard care to reduce intracranial pressure did not result in outcomes better than those with standard care alone [27] 23.3 Subarachnoid Hemorrhage (SAH) Delayed ischemic events can occur after SAH, secondary in part to vasospasm episodes As the greatest neuroprotective effects of TTM are seen when treatment is initiated before the onset of ischemia, the use of hypothermia to prevent delayed cerebral ischemia after subarachnoid hemorrhage (SAH) has been proposed The risk of coagulopathy [28] induced by hypothermia could be a limit, but several data described no bleeding risk in this context Indeed Torok et al described in an experimental subarachnoid model conducted in rat that mild hypothermia realized up to 3 h after the event can be neuroprotective and improve functional outcome without reported bleeding complications [29] Moreover several surgical reports have also been conducted during aneurysm surgery (clipping surgery), with promising results, and no bleeding problem were also reported This improvement of neurologic outcome was not however confirmed in a study conducted in 1001 patients needing a craniotomy for aneurysm clipping randomized in a normothermic and hypothermic group during procedure [30] Few clinical studies have been conducted in clinical SAH. In a group of patient experiencing intracranial hypertension or vasospasm, Seule et al considered mild hypothermia as the last resort treatment, even an important rate of complications was reported [31] Indeed they reported important rate of electrolyte disorders (77%) particularly hypernatremia, pneumonia (52%), thrombocytopenia (47%), and septic shock syndrome (40%) Moreover a study realized in patient with sustained intracranial hypertension and treated with barbiturates and hypothermia >72 h or 12 h) is realized, MacLellan [43] described an improvement in tissue loss and in functional outcome This improvement is lost when hypothermia is induced less than 12 h after ICH. Coagulopathy induced by hypothermia is probably responsible of this difference; even no data on volume expansion have been reported Few data are available in clinical practice In an historical cohort of patient, Staykov described a better prognosis in patients with ICH treated with mild hypothermia for 8–10 days [44] An ongoing study would assess the tolerability and the adverse 23  Targeted Temperature Management in Severe Brain-Injured Patient 475 events occurring after cooling of 32–34 °C in patients with ICH (GSW  >  7) (NCT01607151) [45] TTM seems experimentally to be an interesting approach to improve prognosis in brain-injured animals Nevertheless few clinical data support its use at the bedside Beside a real place for a decrease temperature in cardiac arrest and in sustained intracranial hypertension secondary to traumatic brain injury, few studies support a systematic use at the bedside in SAH, stroke, 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J Infect 62:172–177 42 Mourvillier B et al (2013) Induced hypothermia in severe bacterial meningitis: a randomized clinical trial JAMA 310:2174–2183 43 MacLellan CL, Davies LM, Fingas MS, Colbourne F (2006) The influence of hypothermia on outcome after intracerebral hemorrhage in rats Stroke 37:1266–1270 44 Staykov D et  al (2013) Mild prolonged hypothermia for large intracerebral hemorrhage Neurocrit Care 18:178–183 45 Rincon F, Friedman DP, Bell R, Mayer SA, Bray PF (2014) Targeted temperature management after intracerebral hemorrhage (TTM-ICH): methodology of a prospective randomized clinical trial Int J Stroke 9:646–651 .. .Metabolic Disorders and Critically Ill Patients Carole Ichai  •  Hervé Quintard Jean-Christophe Orban Editors Metabolic Disorders and Critically Ill Patients From Pathophysiology... International Publishing AG 2018 C Ichai et al (eds.), Metabolic Disorders and Critically Ill Patients, http://doi.org/10.1007/978-3-319-64010-5_1 C Ichai and D.G Bichet Both water and sodium balances... Jean-Christophe Orban, Emmanuel Van Obberghen, and Carole Ichai 16 Neuroendocrine Dysfunction in the Critically Ill Patients ������������������  365 Antoine Roquilly and Karim Asehnoune 17 Hyperglycemia