2012 applied physiology in intensive care medicine 1

M R Pinsky · L Brochard · G Hedenstierna · M Antonelli (Eds.) Applied Physiology in Intensive Care Medicine M R Pinsky · L Brochard · G Hedenstierna M Antonelli (Eds.) Applied Physiology in Intensive Care Medicine Physiological Notes – Technical Notes – Seminal Studies in Intensive Care Third Edition Editors MichaeL R. Pinsky, MD Dept. of critical care Medicine University of Pittsburgh Medical center  scaife hall 606 3550 Terrace street Pittsburgh, Pa 15261 Usa GÖRAN HEDENSTIERNA, MD Dept. clinical Physiology Uppsala University Hospital 751 85 Uppsala sweden LaURenT BRochaRD, MD Dept. intensive care Medicine hôpital henri Mondor 51 av. Maréchal Lattre de Tassigny 94010 créteil cX France MassiMo anToneLLi General intensive care Unit Università cattolica des sacro cuore Largo a. Gemelli 8 00168 Rome italy „ The articles in this book appeared in the journal “ intensive care Medicine   between 2002 and 2011 ISBN 978-3-642-28269-0 e-ISBN 978-3-642-28270-6 DOI 10.1007/978-3-642-28270-6 Springer Heidelberg New York Dordrecht London Library of Congress Control Number: 2012933785 © Springer-Verlag Berlin Heidelberg 2006, 2009, 2012 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 Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher’s location, in its current version, and permission for use must always be obtained from Springer Permissions for use may be obtained through RightsLink at the Copyright Clearance Center Violations are liable to prosecution under the respective Copyright Law 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 While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made The publisher makes no warranty, express or implied, with respect to the material contained herein Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com) Preface The practice of intensive care medicine is at the very forefront of treatment and monitoring response The substrate of this care is the critically ill patient who, by definition, is at the limits of his or her physiologic reserve Such patients need immediate, aggressive but balanced life-altering interventions to minimize the detrimental aspects of acute illness and hasten recovery Treatment decisions and response to therapy are usually assessed by measures of physiologic function, such as cardiorespiratory monitoring By necessity, the treatments and monitoring are constantly evolving and require intimate knowledge of the operation of complex instruments, like echocardiography, mechanical ventilation, and hemodialysis Furthermore, they need to be applied quickly and correctly at the bedside by the primary care intensivists However, how one uses such information from the monitoring and guides treatment is often unclear and rarely supported by prospective clinical trials In reality, the bedside clinician is forced to rely primarily on physiologic principals in determining the best treatments and response to therapy However, the physiologic foundation present in practicing physicians is uneven and occasionally supported more by habit or prior training than science A series of short papers published in Intensive Care Medicine from 2002 until July 2011 with the rubrics Physiologic Notes and Technical Notes attempt to capture the essence of the physiologic perspectives and technical challenges that underpin both our understanding of disease and response to therapy and treatments The present volume combines these papers with associated seminal articles addressing these central issues and published in the same time interval This volume was created to address this fundamental unevenness in our understanding of applied physiology, to underscore what is currently known, and to illustrate how measures and monitoring interact with organ system function and response to therapy This collection of physiologic perspectives written by some of the most respected experts in the field represent an up-to-date and invaluable compendium of practical bedside knowledge essential to the effective delivery of acute care medicine Although this text could be read from cover to cover, the reader is encouraged to use this text as a reference source, referring to individual physiologic notes and reviews that pertain to specific clinical issues In that way the relevant information will have immediate practical meaning and hopefully become incorporated into routine practice We hope that the reader finds these papers and reviews useful in their practice and enjoys reading them as much as we enjoyed editing the original articles Michael R Pinsky, MD, Dr hc Laurent Brochard, MD, PhD Gö ran Hedenstierna, MD, PhD Massimo Antonelli, MD, PhD Contents Physiological Notes Alveolar ventilation and pulmonary blood flow: the VA /Q concept 43 ENRICO CALZIA, PETER RADERMACHER 1.1 Pulmonary Mechanisms of hypoxemia 47 1.1.1 Respiratory Mechanics Intrinsic (or auto-) PEEP during controlled mechanical ventilation ROBERT RODRÍGUEZ-ROISIN, JOSEP ROCA Pulse oximetry 51 AMAL JUBRAN LAURENT BROCHARD Effects of body temperature on blood gases 55 Intrinsic (or auto-) positive end-expiratory pressure during spontaneous or assisted ventilation ANDREAS BACHER LAURENT BROCHARD FRANK BLOOS, KONRAD REINHART Work of breathing 11 BELEN CABELLO, JORDI MANCEBO Relation between PaO2/FIO2 ratio and FIO2: a mathematical description 63 Interpretation of airway pressure waveforms 15 JÉRƠME ABOAB, BRUNO LOUIS, BJƯRN JONSON, LAURENT BROCHARD Venous oximetry , 59 EVANS R FERNÁNDEZ-PÉREZ, ROLF D HUBMAYR Measurement of respiratory system resistance during mechanical ventilation 17 Hypoxemia due to increased venous admixture: influence of cardiac output on oxygenation 67 JUKKA TAKALA CLAUDE GUERIN, JEAN-CHRISTOPHE RICHARD Understanding wasted/ineffective efforts in mechanically ventilated COPD patients using the Campbell diagram 21 A critique of Stewart’s approach: the chemical mechanism of dilutional acidosis 71 DANIEL DOBERER, GEORG-CHRISTIAN FUNK, KARL KIRCHNER, BRUNO SCHNEEWEISS THEODOROS VASSILAKOPOULOS Is there an optimal breath pattern to minimize stress and strain during mechanical ventilation? 25 JOSEF X BRUNNER, MARC WYSOCKI 1.1.2 Gas Exchange Dead space 31 UMBERTO LUCANGELO, LLUIS BLANCH The multiple inert gas elimination technique (MIGET) 35 PETER D WAGNER 1.2 Cardiovascular Pulmonary vascular resistance: A meaningless variable? 79 ROBERT NAEIJE Pulmonary artery occlusion pressure 83 MICHAEL R PINSKY Clinical significance of pulmonary artery occlusion pressure 87 MICHAEL R PINSKY Pulmonary capillary pressure 91 JUKKA TAKALA VIII Contents Ventricular interdependence: how does it impact on hemodynamic evaluation in clinical practice? 95 FRANÇOIS JARDIN 2.1 Cyclic changes in arterial pressure during mechanical ventilation 99 A new automated method versus continuous positive airway pressure method for measuring pressure–volume curves in patients with acute lung injury 159 FRANÇOIS JARDIN Left ventricular rotation: a neglected aspect of the cardiac cycle 103 STEFAN BLOECHLINGER, WILHELM GRANDER, JUERG BRYNER, MARTIN W DÜNSER 1.3 Metabolism and Renal Function Lactic acidosis 111 DANIEL DE BACKER Defining acute renal failure: physiological principles 115 RINALDO BELLOMO, JOHN A KELLUM, CLAUDIO RONCO Hypotension during intermittent hemodialysis: new insights into an old problem 121 FRÉDÉRIQUE SCHORTGEN 1.4 Cerebral Function Intracranial pressure Part one: Historical overview and basic concepts 127 PETER J D ANDREWS, GIUSEPPE CITERIO Intracranial pressure Part two: Clinical applications and technology 131 GIUSEPPE CITERIO, PETER J D ANDREWS Neuromonitoring in the intensive care unit Part I Intracranial pressure and cerebral blood flow monitoring 135 ANUJ BHATIA, ARUN KUMAR GUPTA Neuromonitoring in the intensive care unit Part II Cerebral oxygenation monitoring and microdialysis 145 Technical Notes Sub-section Respiratory ENRIQUE PIACENTINI, MARC WYSOCKI, LLUIS BLANCH Bedside estimation of recruitable alveolar collapse and hyperdistension by electrical impedance tomography 165 EDUARDO L V COSTA, JOÃO BATISTA BORGES, ALEXANDRE MELO, FERNANDO SUAREZ-SIPMANN, CARLOS TOUFEN JR, STEPHAN H BOHM, MARCELO B P AMATO Cuff-leak test for the diagnosis of upper airway obstruction in adults: a systematic review and meta-analysis 171 MARIA ELENA OCHOA, MARIA DEL CARMEN MARÍN, FERNANDO FRUTOS-VIVAR, FEDERICO GORDO, JAIME LATOUR-PÉREZ, ENRIQUE CALVO, ANDRES ESTEBA N Reproduction of inert gas and oxygenation data: a comparison of the MIGET and a simple model of pulmonary gas exchange 181 STEPHEN E REES, S KJỈRGAARD, S ANDREASSEN, G HEDENSTIERNA Performance of different continuous positive airway pressure helmets equipped with safety valves during failure of fresh gas supply 189 MANUELA MILAN, ALBERTO ZANELLA, STEFANO ISGRÒ, SALUA ABD EL AZIZ EL SAYED DEAB, FEDERICO MAGNI, ANTONIO PESENTI, NICOLÒ PATRONITI Validation of Bohr dead space measured by volumetric capnography 195 GERARDO TUSMAN, FERNANDO SUAREZ-SIPMANN, Joà o B. BoRGes, GÖ Ran heDensTieRna ,  STEPHAN H BOHM ANUJ BHATIA, ARUN KUMAR GUPTA 2.2 The relationship between the intracranial pressure–volume index and cerebral autoregulation 153 Lithium dilution cardiac output measurement in the critically ill patient: determination of precision of the technique 201 A LAVINIO, F A RASULO, E DE PERI, M CZOSNYKA, N LATRONICO M CECCONI, D DAWSON, R M GROUNDS, A RHODES Sub-section Hemodynamic Contents Tracking changes in cardiac output: methodological considerations for the validation of monitoring devices 209 PIERRE SQUARA, MAURIZIO CECCONI, ANDREW RHODES, MERVYN SINGER, JEAN-DANIEL CHICHE The influence of the airway driving pressure on pulsed pressure variation as a predictor of fluid responsiveness 217 LAURENT MULLER, GUILLAUME LOUART, PHILIPPE-JEAN BOUSQUET, DAMIEN CANDELA, LANA ZORIC, JEAN-EMMANUEL DE LA COUSSAYE, SAMIR JABER, JEAN-YVES LEFRANT Diagnostic accuracy of passive leg raising for prediction of fluid responsiveness in adults: systematic review and meta-analysis of clinical studies 225 FABIO CAVALLARO, CLAUDIO SANDRONI, CRISTINA MARANO, GIUSEPPE LA TORRE, ALICE MANNOCCI, CHIARA DE WAURE, GIUSEPPE BELLO, RICCARDO MAVIGLIA, MASSIMO ANTONELLI Fluid responsiveness predicted by noninvasive Bioreactance-based passive leg raise test 235 BRAHIM BENOMAR, ALEXANDRE OUATTARA, PHILIPPE ESTAGNASIE, ALAIN BRUSSET, PIERRE SQUARA Comparison of cardiac output and blood volumes in intrathoracic compartments measured by ultrasound dilution and transpulmonary thermodilution methods 243 GENNADY GALSTYAN, MYCHAYLO BYCHININ, MIKAEL ALEXANYAN, VLADIMIR GORODETSKY In vivo accuracy of two intraparenchymal intracranial pressure monitors 249 THOMAS LESCOT, VINCENT REINA, YANNICK LE MANACH, FILIPPO BOROLI, DORIAN CHAUVET, ANNE-LAURE BOCH, LOUIS PUYBASSET Effect of tidal volume, intrathoracic pressure, and cardiac contractility on variations in pulse pressure, stroke volume, and intrathoracic blood volume 255 JAUME MESQUIDA, HYUNG KOOK KIM, MICHAEL R PINSKY IX Seminal Studies in Intensive Care Manipulating afterload for the treatment of acute heart failure A historical summary 265 CLAUDE PERRET , JEAN-FRANÇOIS ENRICO Nosocomial pneumonia 269 WALDEMAR G JOHANSON, LISA L DEVER The introduction of positive endexpiratory pressure into mechanical ventilation: a retrospective 277 KONRAD J FALKE Elastic pressure-volume curves in acute lung injury and acute respiratory distress syndrome 281 BJÖRN JONSON The concept of “baby lung” 289 LUCIANO GATTINONI, ANTONIO PESENTI The effects of anesthesia and muscle paralysis on the respiratory system 299 GÖRAN HEDENSTIERNA, LENNART EDMARK Diaphragmatic fatigue during sepsis and septic shock 309 SOPHIE LANONE, CAMILLE TAILLÉ, JORGE BOCZKOWSKI, MICHEL AUBIER The use of severity scores in the intensive care unit 317 JEAN-ROGER LE GALL Oxygen transport—the oxygen delivery controversy 323 JEAN-LOUIS VINCENT, DANIEL DE BACKER Organ dysfunction during sepsis  331  SUVEER SINGH, TIMOTHY W EVANS Ventilator-induced lung injury: from the bench to the bedside 343 LORRAINE N TREMBLAY, ARTHUR S SLUTSKY Remembrance of weaning past: the seminal papers 353 MARTIN J TOBIN Interactions between respiration and systemic hemodynamics Part I: basic concepts 363 FRANÇOIS FEIHL, ALAIN F BROCCARD Goal-directed therapy in high-risk surgical patients: a 15-year follow-up study Discussion This long-term follow-up study of a randomized controlled clinical trial into deliberate perioperative elevation of oxygen delivery demonstrates an improvement in longterm survival for those patients who underwent goaldirected therapy This could have implications when assessing the economic benefits of short-term interventions such as this, as the upfront resource costs can be countered by the impact on longevity This may have implications for the assessment of future trials and of critical care use for surgical patients The results suggest that there is a long-term survival benefit for patients who underwent goal-directed resuscitation of their cardiovascular system, with this group having more than twice as many survivors 15 years after the initial surgery This difference was apparent at all times during that period Our results suggest that this survival benefit was mainly due to the ability of the initial therapy to reduce the number of postoperative complications in the goal-directed therapy group In particular, those patients who did not develop a postoperative cardiac complication seemed to derive the greatest benefit The survival curves following randomization were significantly different, suggesting that the effect of the intervention may be longer-reaching than was previously thought In order to test this, we repeated the analysis, resetting the baseline at 28 days This has obvious implications, as the two groups are not now equivalent and other confounding factors may interact with our model The survival curves after this point were not significantly different The important point to consider is that, if the intervention used in the trial was simply delaying deaths, the analysis post 28 days would be expected to show increased mortality for the protocol group subsequent to this time point—or in other words patients who did not die early would die later It is of course not possible to identify which patients have their death simply delayed; however, this is not what we found In this study the survival curves, although not significantly different, demonstrated the opposite effect, with the goal-directed therapy group continuing to show a benefit, suggesting that, if anything, the short-term benefit was maintained for the entire 15-year follow-up period Our analysis found three factors to be associated with increased long-term survival benefit: age, randomization to protocol, and avoidance of a significant postoperative complication These three factors are independent of one another, although they may not be mutually exclusive For instance, the patients randomized to the protocol group developed fewer complications, and thus will have done even better The avoidance of a complication has a significant impact on longevity, even if the patients were randomized to an accepted standard of care Importantly, in the group of patients who did develop at least one 421 complication, randomization to the goal-directed group was still associated with a positive effect on survival post 28 days This is a very important finding Indeed, while it is not possible to predict with 100% accuracy which patients will develop a complication, goal-directed therapy appears to have an effect on long-term survival even if it cannot completely avoid the development of a complication Our results are in keeping with many larger datasets that have followed up postoperative patients beyond the traditional 30-day follow-up period, albeit not following a goal-directed hemodynamic protocol [13, 14] The definition of mortality from major surgery is absolutely clear, but the definition and collection of data that relate to perioperative complications are far less so, making comparisons across surgical technique and institutions difficult [15] Current estimates of postoperative complication rates in the developed world suggest that rates between 3% and 17% may be reflective of current practice [16, 17] In 2004 the cost of treating surgical complications alone was an additional US $25 billion to the US healthcare system [17] Of note in the last few years is the recognition of the long-term health consequences/associations that result from perioperative complications, with alarming reductions in life expectancy In 2005, Khuri et al [14] reported a series of over 105,000 patients from the Veterans Affairs as part of the National Surgical Quality Improvement Program (NSQIP), showing a reduction in median life expectancy of 69% for any of 22 perioperative complications experienced The occurrence of a 30-day postoperative complication was more important than any pre- or intraoperative factors, even after excluding deaths at 30 days, in predicating long-term survival after major surgery Although the largest study to date, similar effects are being reported for various operations and complications, suggesting a consistently negative impact on long-term survival of perioperative complications [18, 19] The nature of the complication and the type of procedure has generally been reflected in the degree to which life expectancy has been affected However, a recent report of over 10,500 patients suggests that, even if perioperative organ dysfunction completely resolves, there is still a negative effect on/association with long-term survival [20] It is not illogical to assume that trying to reduce perioperative complications would lead to significant improvements in surgical outcome and possibly life expectancy Our study has a number of significant limitations that need to be borne in mind when interpreting the results Firstly, the original study was stopped early because of excess mortality in the control group and only contained 107 patients, which limits the statistical power of our results Secondly the original study was not powered beyond 30-day mortality and was not designed for 422 A Rhodes et al long-term follow-up Thirdly the cause of death was not established for each patient (due to the potential inaccuracy of death certification), only their survival status In conclusion, we have shown that short-term intervention such as perioperative goal-directed augmentation of global oxygen delivery may have longer-lasting effects on survival than was previously considered We believe that it is possible that these effects are at least in part due to their ability to reduce major complications in the perioperative period These techniques deserve greater study, in particular to confirm this suggestion of a longer-term impact on quality of life and longevity Our study also shows that critical care treatment can have much longer beneficial health implications than those related to the immediate physiological changes This has important implications for other treatment trials in critical care, and must be borne in mind when critical care follow-up studies, which tend to focus on various negative physiological and psychological outcomes, are placed in a wider health context References Boyd O, Jackson N (2005) How is risk defined in high-risk surgical patient management? Crit Care 9:390–396 Pearse R, Harrison D, James P, Watson D, Hinds C, Rhodes A, Grounds RM, Bennett E (2006) Identification and characterisation of the high-risk surgical population in the United Kingdom Crit Care (London, England) 10:R81 Shoemaker WC, Appel PL, Kram HB, Waxman K, Lee TS (1988) Prospective trial of supranormal values of survivors as therapeutic goals in high-risk surgical patients Chest 94:1176–1186 Boyd O, Grounds RM, Bennett ED (1993) A randomized clinical trial of the effect of deliberate perioperative increase of oxygen delivery on mortality in high-risk surgical patients JAMA 270:2699–2707 Sinclair S, James S, Singer M (1997) Intraoperative intravascular volume optimisation and length of hospital stay after repair of proximal femoral fracture: randomised controlled trial BMJ 315:909–912 Wilson J, Woods I, Fawcett J, Whall R, Dibb W, Morris C, McManus E (1999) Reducing the risk of major elective surgery: randomised controlled trial of preoperative optimisation of oxygen delivery BMJ 318:1099–1103 Polonen P, Ruokonen E, Hippelainen M, Poyhonen M, Takala J (2000) A prospective, randomized study of goaloriented hemodynamic therapy in cardiac surgical patients Anesth Analg 90:1052–1059 Venn R, Steele A, Richardson P, Poloniecki J, Grounds M, Newman P (2002) Randomized controlled trial to investigate influence of the fluid challenge on duration of hospital stay and perioperative morbidity in patients with hip fractures Br J Anaesth 88:65–71 Gan TJ, Soppitt A, Maroof M, el-Moalem H, Robertson KM, Moretti E, Dwane P, Glass PS (2002) Goal-directed intraoperative fluid administration reduces length of hospital stay after major surgery Anesthesiology 97:820–826 10 Kern JW, Shoemaker WC (2002) Metaanalysis of hemodynamic optimization in high-risk patients Crit Care Med 30:1686–1692 11 Pearse R, Dawson D, Fawcett J, Rhodes A, Grounds RM, Bennett E (2005) Early goal-directed therapy after major surgery reduces complications and duration of hospital stay A randomised, controlled trial [ISRCTN38797445] Crit Care (London, England) 9:R687–R693 12 Poeze M, Greve J, Ramsay G (2005) Meta-analysis of hemodynamic optimization: relationship to methodological quality Crit Care (London, England) 9:R771–R779 13 Silber JH, Rosenbaum PR, Trudeau ME, Chen W, Zhang X, Kelz RR, Mosher RE, Even-Shoshan O (2005) Changes in prognosis after the first postoperative complication Med Care 43:122–131 14 Khuri SF, Henderson WG, DePalma RG, Mosca C, Healey NA, Kumbhani DJ (2005) Determinants of long-term survival after major surgery and the adverse effect of postoperative complications Ann Surg 242:326–341 discussion 341–323 15 Hutter MM, Rowell KS, Devaney LA, Sokal SM, Warshaw AL, Abbott WM, Hodin RA (2006) Identification of surgical complications and deaths: an assessment of the traditional surgical morbidity and mortality conference compared with the American College of Surgeons-National Surgical Quality Improvement Program J Am Coll Surg 203:618–624 16 Weiser TG, Regenbogen SE, Thompson KD, Haynes AB, Lipsitz SR, Berry WR, Gawande AA (2008) An estimation of the global volume of surgery: a modelling strategy based on available data Lancet 372:139–144 17 Mangano DT (2004) Perioperative medicine: NHLBI working group deliberations and recommendations J Cardiothorac Vasc Anesth 18:1–6 18 Gawande AA, Thomas EJ, Zinner MJ, Brennan TA (1999) The incidence and nature of surgical adverse events in Colorado and Utah in 1992 Surgery 126:66–75 19 Kable A, Gibberd R, Spigelman A (2008) Predictors of adverse events in surgical admissions in Australia Int J Qual Health Care 20:406–411 20 Bihorac A, Yavas S, Subbiah S, Hobson CE, Schold JD, Gabrielli A, Layon AJ, Segal MS (2009) Long-term risk of mortality and acute kidney injury during hospitalization after major surgery Ann Surg 249:851–858 R Moreno C L Sprung D Annane S Chevret J Briegel D Keh M Singer Y G Weiss D Payen B H Cuthbertson J.-L Vincent Time course of organ failure in patients with septic shock treated with hydrocortisone: results of the Corticus study was quantified by the use of the sequential organ failure assessment (SOFA) score Results: From March 2002 to November 2005, 499 patients were enrolled (hydrocortisone 251, placebo 248) Both groups presented a similar SOFA score at baseline (hydrocortisone 10.8 ± 3.2 vs placebo 10.7 ± 3.1 points) There was no difference in 28-day mortality between the two treatment groups (hydrocortisone 34.3% vs placebo 31.5%) There was a decrease in the SOFA score of hydrocortisone-treated patients from day to day compared to the placebo-treated patients (p = 0.0027), driven by an improvement in cardiovascular organ dysfunction/failure (p = 0.0005) and in liver failure (p \ 0.0001) in the hydrocortisone-treated patients Conclusion: Patients randomized to treatment with hydrocortisone demAbstract Introduction: Corticoonstrated a faster decrease in total steroids have been proposed to organ dysfunction/failure determined decrease morbidity and mortality in by the SOFA score, primarily driven patients with septic shock An impact by a faster improvement in cardioon morbidity should be anticipated to vascular organ dysfunction/failure be earlier and more easily detected This organ dysfunction/failure than the impact on mortality Meth- improvement was not accompanied ods: Prospective, randomized, by a decreased mortality double-blind, placebo-controlled study of 28-day mortality in patients Keywords Corticosteroids Á Steroids Á with septic shock for \72 h who Hydrocortisone Á Septic shock Á underwent a short high-dose ACTH Mortality Á Organ dysfunction Á test in 52 centers in European Organ failure Á Sequential Organ countries Patients received 11-day Failure Assessment score SOFA treatment with hydrocortisone or placebo Organ dysfunction/failure M.R Pinsky et al (eds.), Applied Physiology in Intensive Care Medicine 1: Physiological Notes – Technical Notes – Seminal Studies in Intensive Care, DOI 10.1007/978-3-642-28270-6_66, © Springer-Verlag Berlin Heidelberg 2012 423 424 R Moreno et al Introduction Study population The use of 28-day mortality has constituted the most commonly chosen endpoint in sepsis studies Mortality is easy to define and measure, and represents a clinically very relevant endpoint Some authors, such as Petros, have questioned the adequacy of all-cause mortality as an endpoint [1] In the case of sepsis and multiple organ failure, studies require large numbers of patients with their associated costs Patients in intensive care, even with strict inclusion criteria for sepsis or septic shock, not constitute a homogeneous population Patients are heterogeneous with different diagnoses, time courses, ages, co-morbidities, sites of infection and invading microorganisms In addition, patients have different degrees of physiological dysfunction resulting in diverse mortality risks that are difficult to adjust for post-hoc by general severity scores such as the APACHE II [2] or the SAPS II [3] Only one multicenter randomized clinical trial in patients with severe sepsis and septic shock demonstrated a decreased 28-day all-cause mortality [4] The study also showed an improved morbidity evidenced by decreases in Sequential Organ Failure (SOFA) scores [5] Despite this fact the controversy over the appropriate endpoint for clinical trials continues [6] Morbidity and organ failure-free days in addition to mortality have recently been proposed as endpoints [7] The resolution of organ failure may represent a reasonable outcome because it results in a reduction in morbidity with less need for life support [8] and perhaps even costs [9] The Corticosteroid Therapy of Septic Shock (CORTICUS) study’s primary endpoint was 28-day all-cause mortality in corticotropin non-responders The analysis of the presence, amount and evolution of organ failure was a pre-planned secondary outcome The hypothesis was that patients treated with hydrocortisone when compared to placebo would have a faster resolution of organ dysfunction/failure The objective of this paper is to present the results of this analysis and to discuss their implications Patients were enrolled from March 2002 until 30 November 2005 All patients 18 years of age or above were prospectively enrolled in the study if they met all eligibility criteria including: (1) clinical evidence of infection, (2) evidence of a systemic response to infection, (3) evidence of shock within the previous 72 h defined by a systolic blood pressure (SBP) \90 mmHg despite adequate fluid replacement OR need for vasopressors for at least h, (4) hypoperfusion or organ dysfunction attributable to sepsis and (5) informed consent according to local regulations Main exclusion criteria included underlying disease with a poor prognosis, immunosuppression and prior administration of corticosteroids [7] Study treatment The study drug was administered as a 50-mg intravenous bolus every h for days, then tapered to 50 mg intravenously every 12 h for days 6–8, 50 mg every 24 h for days 9–11 and then stopped In the control group, a matching placebo was used at similar times Data collection Patient data included: (1) general characteristics including demographics, diagnoses and recent surgery, (2) severity of illness assessed by vital signs, Simplified Acute Physiology Score (SAPS) II [11], and (3) interventions including type and doses of vasopressors Laboratory variables included hematological, chemistry and blood gas determinations Cultures of blood and other potential sites of infection were recorded A short corticotrophin (ACTH) test was performed using blood samples taken immediately before and 60 after an intravenous bolus of 0.25 mg tetracosactrin (Novartis, Nuremberg, Germany or Alliance, Chippenham, UK) During the 28-day period post-randomization, data were collected for vital signs, laboratory results, cultures and any major intervention Mortality at 28 days was recorded Materials and methods Study design The CORTICUS study was a multicenter, randomized, double-blind, placebo-controlled study of hydrocortisone therapy in patients with septic shock in 52 intensive care units (ICUs) [10] This article reports a preplanned analysis of the presence, amount and evolution of organ dysfunction Definitions Organ system dysfunction/failure was assessed by the Sequential Organ Failure Assessment (SOFA) score [12], and computed at study baseline (day 0) and at days 1–7, 14 and 28 A score of or points in each of the six organ/systems was considered as evidence of organ dysfunction, and a score of or points was considered as evidence of organ failure Organ failure reversal was Time course of organ failure in patients with septic shock treated with hydrocortisone: results of the Corticus study The main outcome of this trial was all-cause mortality at day 28 This specific study targeted the secondary endpoint of organ system failure reversal for each organ, especially shock Statistical analysis All analyses were performed according to a pre-established plan The population was analyzed by an ‘‘intention to treat’’ principle All results of organ dysfunction/failure are presented as mean ± standard deviation with minimum and maximum values indicated by brackets Since data were gathered over time on the same patient, mixed effects models that are appropriate for clustered and dependent data were used to study the relationship between the treatment arms and the course of SOFA scores [14] SOFA analyses were restricted to day 0–7 measurements since no consecutive daily data were available thereafter Normal distributions and a linear relationship with time were assumed To test for time by treatment interaction on the SOFA components (measured on categorical scales ranging from to 4), multinomial regression models were used [15] To assess the underlying assumption of randomly missing data, differences in available data were checked over time across randomized groups by generalized linear models with binomial link Finally, to account for the potential competing risks of death in the ICU, the effect of treatment was assessed on the cumulative incidence of organ failure reversal, taking into account death prior to resolution as a competing event; cumulative incidence curves were then compared by the Gray test All tests and p-values presented were two-sided All statistical analyses and model fits were based on standard statistical packages (R and SAS) 25 90th percentile Q3 Total Study outcomes group) At baseline, the two groups were well balanced for demographics, clinical characteristics, the type and site of infection, and infecting microorganisms as previously reported [10] There were 233 (46.7%) corticotropin nonresponders (hydrocortisone 125; placebo 108) and 254 (50.9%) responders (hydrocortisone 118; placebo 136) As reported previously, there was no difference in 28-day mortality between patients assigned to hydrocortisone or placebo, respectively, in the overall population (34.3 vs 31.5%) or in patients responding (28.8 vs 28.7%) or not responding to corticotropin (39.2 vs 36.1%) [7] The course of the total SOFA score over the first week in the two treatment groups is displayed in Fig No evidence of any difference between available data across randomized groups was observed (data not shown) The total SOFA score was similar at baseline in both groups [hydrocortisone: 10.8 ± 3.2 (4–21); placebo: 10.7 ± 3.1 (3–21); p = 0.55; Table 1] Thereafter, a significant time effect was observed (p \ 0.0001) together with a time by treatment interaction (p = 0.0025) The rate of decrease in SOFA score from day to day in the placebo group was approximately 75% of that observed in the hydrocortisone group The hydrocortisone patients had a greater and faster decrease in the cardiovascular component (p \ 0.0001) as well as the liver component (p \ 0.0001) (Fig 2) Hydrocortisone-treated patients were more likely to become vasopressor-free (having a SOFA sub-score of or 1) (p = 0.0024) with a higher mean number of vasopressor-free days in the first days (2.5 ± 2.4) compared to the placebo group (1.4 ± 2.4) (p \ 0.0001) In addition, hydrocortisone-treated patients more rapidly reached bilirubin levels below mg/dl as compared to those in the placebo group (p = 0.0006) There were no 20 SOFA defined as a score or sub-score below in patients with an initial score of C3 Maximum and delta SOFA scores were calculated as described previously [13] Reversal of shock was defined as the maintenance of a SBP C90 mmHg without vasopressor support for C24 h A new septic shock episode was defined as a new episode of septic shock after reversal of the initial septic shock Nonresponders to the corticotropin test were defined by a cortisol increase B9 lg/dl 425 median HydroC Placebo Q1 10th percentile 15 10 Results D0 hydroC 251 placebo 248 D1 245 240 D7 210 207 D14 166 160 D28 84 97 During the study period, 499 patients were analyzed (251 Fig Comparison of the SOFA score course in the two randomin the hydrocortisone group and 248 in the placebo ized groups 426 R Moreno et al Table Comparison of baseline SOFA scores according to ran- for renal failure, with 60.5% of organ failure reversal by domization group day 28 in the hydrocortisone-treated patients as compared Hydrocortisone 251 SOFA: mean (SD) 10.85 (3.2) Cardiovascular component 2 47 200 Liver component 107 47 47 Coagulation component 141 39 38 22 Renal Component 77 48 46 35 40 CNS component 103 26 16 25 48 Pulmonary component 0 66 84 88 Placebo 248 10.68 (3.1) p-value 0.55 1 45 198 0.97 110 40 45 0.93 131 51 39 12 0.096 70 56 54 37 28 0.44 116 25 16 17 50 0.69 70 15 89 73 0.37 differences over time between the two treatment groups for the coagulation (p = 0.95), renal (p = 0.76), or central nervous system components (p = 0.34) There were no differences in the pulmonary component between the treatment groups in the evolution over time of PaO2/FiO2 (p = 0.74) or the numbers of ventilator-free days during the first days (0.5 ± 2.1 days in the hydrocortisone group vs 0.5 ± 2.5 days in the placebo group, p = 0.27) The subsets of patients with initial organ failures were evaluated taking into account those deaths priors to organ failure resolution within the 28 days as competing events As shown in Table 2, the cumulative incidence of resolution of cardiovascular failure was shortened in the hydrocortisone-treated patients, with 67.1% with organ failure reversal at day 28 versus 58.2% in the placebotreated patients (p = 0.041 by the Gray test; Fig 3a), with no evidence of an increased mortality prior to the resolution (p = 0.48) This was similarly observed to 44.3% in the placebo-treated patients (p = 0.039; Fig 3b) Although the proportion of shock reversals was similar in non-responders [96/125 (76.8%) hydrocortisone, 76/108 (70.4%) placebo, p = 0.34]; responders [100/118 (84.7%) hydrocortisone, 105/136 (77.2%) placebo, p = 0.17] or all patients [202/251 (80.5%) hydrocortisone, 185/248 (74.6%) placebo, p = 0.14], the time for the cardiovascular component of the SOFA score was significantly shorter in patients receiving hydrocortisone, for the overall group (p = 0.003), responders (p = 0.003) and nonresponders (p \ 0.05) No consistent pattern was seen regarding other components of the SOFA score (ESM, Tables E1–E6) There were no differences in the 234 hydrocortisone-treated patients compared to the 232 patients receiving placebo for adverse events including stroke (3 vs 1), acute myocardial infarction (14 vs 13) and peripheral limb ischemia (0 vs 1), nor in the 28-day mortality from multiple system organ failure [41 of 86 (48%) vs 38 of 78 (49%)], respectively No patient had a severe adverse event with bowel infarction Discussion Hydrocortisone treatment failed to improve 28-day mortality in the CORTICUS study for all patients or for non-responders and responders to ACTH, but did improve organ function as reflected by a faster decrease in SOFA scores The cardiovascular and liver effects made the greatest contributions to decreasing the total SOFA score This is in line with earlier reports [16] Although there was no difference in overall shock reversal, patients receiving hydrocortisone reversed their shock faster than patients receiving placebo because of faster weaning of vasopressor support This more rapid shock reversal with steroid therapy is consistent with previous reports [16–19] This may be related to the fact that hydrocortisone can improve the hemodynamic response to noradrenaline, an effect independent of adrenal insufficiency [20], which seems dependent on the severity of illness as recently demonstrated by Minneci et al [21] The improvement in liver function with a decrease in bilirubin in the hydrocortisone-treated patients was probably related to the improved hemodynamics, but is also consistent with previous reports of improvement in bilirubin clearance with hydrocortisone after liver resection [22] Of note, in patients with acute renal failure at baseline, hydrocortisone accelerated the recovery of renal function Although resolution of organ failure might be a more appropriate outcome for ICU studies, it should occur only when there is a consistent reversal of several organ Time course of organ failure in patients with septic shock treated with hydrocortisone: results of the Corticus study hydrocortisone 200 150 50 0 days days hydrocortisone placebo 7 150 100 50 50 100 150 Number of patients 200 200 250 250 Number of patients 100 Number of patients 150 100 Number of patients 200 250 250 placebo 50 Fig Comparison of the SOFA sub-scores course in the two randomized groups, namely cardiovascular (upper plots) and liver (lower plots) components; the darker the gray boxes, the lower the SOFA sub-score values (ranging from to 4) 427 days systems with a concomitant trend (even if nonsignificant) towards an improved mortality Unfortunately, this was not the case in this study There was no consistent reversal of several organ systems, and if anything the mortality did not decrease but increased, albeit nonsignificantly Strengths of this study include the use of data from a prospective, randomized, controlled, multicenter study with analysis of a pre-specified secondary outcome Limitations include the fact that the study was underpowered and had slow recruitment; organ system data collection did not occur during all 28 study days, and this is a substudy of the original study [10] Thus, time was modeled by treatment interaction in SOFA scores and sub-scores by using mixed effects models that allow the analysis of such incomplete longitudinal data This required the assumption of data missing at random, which was checked by testing for time by treatment interaction in the available data There was no evidence of any difference in the frequency with which data were missing days over time between randomized groups However, deaths during study days 0–7 were first considered as noninformative dropouts in the analysis of SOFA course over time This could be an issue when dealing with the whole longitudinal process, and thus, the analysis of a competing risks model of resolution of organ failure and prior death within the first 28 days is also reported This analysis showed a delayed resolution of cardiovascular failure in the placebo arm as compared to the hydrocortisone arm (p = 0.04), with no evidence of increased mortality prior to the resolution (p = 0.48) There are also limitations in the use of the SOFA score in evaluating clinical trials For each organ the parameters used may not be indicative of all of that organ’s function For respiratory function positive end-expiratory pressure is not included, and for the cardiovascular system treatment-related adrenergic support is included Despite these limitations, the SOFA score is the most commonly used organ dysfunction/ failure score in practice [5] 0.42 0.80 0.8 0.6 0.0 0.77 0.67 0.4 0.043 0.49 0.039 0.13 The question arises as to whether hydrocortisone should be used to reverse septic shock earlier to replace vasopressor therapy despite the fact that the steroids not improve overall survival Although physicians will evaluate the risks and benefits of vasopressor versus steroid therapy for each individual patient, the present guidelines [23] recommend giving hydrocortisone only to the patients ‘‘in septic shock after blood pressure is identified to be poorly responsive to fluid and vasopressor therapy’’ as steroids reversed shock and improved survival only in refractory septic shock patients [17], but not in the Corticus study Although there are doctors who will continue to use steroids for patients with vasopressor responsive (not refractory) septic shock to hasten shock reversal, this practice is not consistent with the current guidelines [23] The faster reversal of shock in patients receiving hydrocortisone did not improve survival and was associated with more superinfections and the occurrence of new sepsis and septic shock episodes [10] Although continued therapy with vasopressors can lead to complications, the present study did not demonstrate any evidence of increased bowel infarction or a greater mortality from multiple organ failure in the placebo group who received vasopressor therapy for longer periods of time Therefore, the danger of superinfections and new sepsis appears to outweigh that of continued vasopressor therapy On the basis of these findings, hydrocortisone cannot be recommended as a general adjuvant therapy for 15 20 25 1.0 0.6 0.8 Hydrocortisone Placebo 0.4 0.29 0.54 10 Days B 0.65 0.75 0.2 67 39 21 10 4 21 15 65 12 28 25 67 44 18 162 15 113 34 Cumulative incidence of renal failure resolution Cardiovascular initial failure 73 No resolution Resolution 49 Death prior to resolution 19 Liver initial failure No resolution Resolution Death prior to resolution Coagulation initial failure 25 No resolution Resolution 18 Death prior to resolution Renal initial failure 75 No resolution 10 Resolution 45 Death prior to resolution 20 CNS initial failure 73 No resolution Resolution 48 Death prior to resolution 22 Pulmonary initial failure 172 No resolution 12 Resolution 129 Death prior to resolution 31 Hydrocortisone Placebo 0.2 Hydrocortisone Placebo p-value 251 248 Gray test A Cumulative incidence of cardiovascular resolution Table Comparison of organ failure reversal over 28 days following organ failures observed at baseline according to randomization group 1.0 R Moreno et al 0.0 428 10 15 20 25 Days Fig Cumulative incidence of organ failure resolution (i.e., score value \3) according to treatment arm: cardiovascular failure (a), renal failure (b) vasopressor responsive septic shock, even though they hasten shock reversal Acknowledgments The CORTICUS study was supported by the European Commission contract QLK2-CT-2000-00589, the European Society of Intensive Care Medicine (ESICM), the International Sepsis Forum (ISF) and the Gorham Foundation Roche Diagnostics GmbH, Mannheim/Penzberg, Germany, provided the ElecsysÒ Cortisol immunoassay The EU Commission and other sponsors had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; or in the preparation, review or approval of the manuscript Thanks also to Prof Dr Wolfgang Hartl for suggestions that greatly improved the quality of the manuscript Time course of organ failure in patients with septic shock treated with hydrocortisone: results of the Corticus study Appendix Steering Committee: C Sprung (Chairman); D Annane; J Briegel; D Keh; R Moreno; D Pittet; M Singer; Y Weiss Safety and Efficacy Monitoring Committee: J Cohen (Chairman); C Dore; T Evans; N Soni, F Sorenson (Analytica International) Study Coordinating Center: C Sprung (Physician Coordinator); J Benbenishty (Nurse Coordinator); A Avidan, E Ludmir; J Kabiri; K Furmanov; B Hain; O Kalugin; I Zack Clinical Evaluation Committee: Y Weiss (Chairman); D Annane; J Briegel; S Goodman; D Keh; R Moreno; M Singer; C Sprung Berlin Coordinating Center: D Keh (Chairman); A Goessinger French Coordinating Center: D Annane (Chairman); N Zinsou, D Friedman Munich Central Laboratory Harmonization: J Briegel (Chairman); M Vogeser Statistical Analyses: Analytica International- F Sorenson, K Freivogel CORTICUS Investigators: Austria: LKH Feldkirch, Feldkirch (P Fae); Krankenhaus Barmherzige Schwestern, Linz (J Reisinger); Universitaetsklinik fuer Innere Medizin II, Wien (G Heinz); Belgium: Hopital St Joseph, Arlon (M Simon); Department of Critical Care Medicine, St Luc University Hospital, UCL, Brussels (P–F Laterre, X Wittebole, MN France); University Hospital Erasme, Universite´ de Bruxelles, Brussels (J.L Vincent, D DeBacker); CHU Charleroi, Charleroi (P Biston) France: Hopital de Caen, Caen (C Daubin); Hopital Raymond Poincare, Garches (D Annane, D Lipiner, V Maxime); Hopital Huriez, Lille (PA Rodie Talbere, B Vallet); Hopital Caremeau, Nimes (J.Y Lefrant); Hopital SaintAntoine, Paris (G Offenstadt); Hopital Lariboisiere, Paris (D Payen, A.C Lukaszewicz) Germany: Zentralklinikum Augsburg, Augsburg (H Forst, G Neeser, Y Barth); Charite Universitaetsmedizin Berlin, Campus Virchow- 429 Klinikum (D Keh, J.Langrehr, M.Oppert, C.Spies), Campus Mitte (C Spies, S.Rosseau), Campus Benjamin Franklin (J Weimann); Evangelisches Waldkrankenhaus Spandau, Berlin (M Reyle Hahn); St Joseph-Krankenhaus, Berlin (M Schmutzler); Vivantes Klinikum Spandau, Berlin (K.J Slama), Vivantes Klinikum Neukoelln, Berlin (H.Gerlach), Vivantes Klinikum im Friedrichshain,Berlin (S Veit); Inst For Anaesthesia & Operative Intensive Care Medicine, Darmstadt (M Welte, L Von Beck); University Hospital Carl Gustav Carus, Dresden (C Marx); Krankenhaus Hennigsdorf, Hennigsdorf (A Lange); Friedrich-Schiller Universitaet, Jena (K Reinhart, F Bloos, F Brunkhorst); Klinikum KemptenOberallgaeu, Kempten (M Haller); Klinikum of Landshut, Landshut (U Helms); Klinikum Mannheim, Mannheim (A Kalenka, F Fiedler); Universitaetsklinikum Marburg, Marburg (M Max); Klinik fuer Anaesthesiologie, Klinikum der Universitaet, LudwigMaximilians-Universitaet, Munich (J Briegel); Department of Surgery, Klinikum der Universitaet-Grosshadern, Munich (W Hartl); Staedtisches Krankenhaus MuenchenHarlaching, Munich (M Klimmer, T Helmer); Universitaet Erlangen-Namberg, Nuernberg (M Baumgaertel); Klinikum Ernst von Bergman, Potsdam (D Pappert) Israel: Haemek Hospital, Afula (A Lev); Hadassah Medical Organization, Jerusalem (Y Weiss, C Sprung, J Benbenishty, O Shatz); Belinson Medical Centre, Petach Tikva (P Singer); Ichilov Hospital, Tel Aviv (A Nimrod) Italy: Policlinico di Tor Vergata, Rome (S Natoli); Centro di Rianimazione, Ospedale S Eugenio, Rome (F Turani) Netherlands: Erasmus University Medical Center, Rotterdam (B Van der Hoven) Portugal: Hospital de St Antonio Capuchos, Lisbon (R Moreno, R Matos) United Kingdom: Aberdeen Royal Infirmary, Aberdeen (B.H Cuthbertson, S Roughton); The Ipswich Hospital NHS, Ipswich (M Garfield); The General Infirmary at Leeds, Leeds (A Mallick); University College London Hospitals NHS Foundation Trust, London (M Singer, M McKendry); Southampton General Hospital, Southampton (T Woodcock) References Petros AJ, Marshall JC, van-Saene HK (1995) Should morbidity replace mortality as an endpoint for clinical trials in intensive care? 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Intensive Care Med 26:3–5 19 Keh D, Boehnke T, Weber-Cartens S, Schulz C, Ahlers O, Bercker S, Volk H-D, Doecke W-D, Falke KJ, Gerlach H (2003) Immunologic and hemodynamic effects of ‘‘Low-Dose’’ hydrocortisone in septic shock A double-blind, randomized, placebocontrolled, crossover study Am J Respir Crit Care Med 167:512–520 20 Saito T, Takanashi M, Gallagher E, Fuse A, Suzaki S, Inagaki O, Yamada K, Ogawa R (1995) Corticosteroid effect on early beta-adrenergic downregulation during circulatory shock: hemodynamic study and betaadrenergic receptor assay Intensive Care Med 21:204–210 21 Minneci PC, Deans KJ, Banks SM, Eichacker PQ, Natanson C (2004) Meta-Analysis: the effect of steroids on survival and shock during sepsis depends on the dose Ann Intern Med 141:47–56 22 Hayashi Y, Takayama T, Yamazaki S, Moriguchi M, Ohkubo T, Nakayama H, Higaki T (2011) Validation of perioperative steroids administration in liver resection: a randomized controlled trial Ann Surg 253:50–55 23 Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut J-F, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent J-L (2008) Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2008 Intensive Care Med 34:17–60 Index A Acid-base disorders, 71, 72, 76–77 Acidosis, 71–77, 111–113, 256, 266, 327, 334, 349, 388, 408, 410–413 Acute lung injury (ALI), 33, 47–49, 67, 70, 88, 93, 112, 159–163, 169, 222, 223, 235, 281–286, 332, 335, 337–350, 413 Acute respiratory distress syndrome (ARDS), 19, 25, 27, 33, 40, 47–49, 53, 63, 65, 66, 69, 81, 85, 88, 93, 95, 96, 99, 101, 122, 159, 160, 218, 221–223, 273, 278–286, 289–295, 303, 304, 324, 326, 332, 335, 337, 343–345, 348–350, 378, 407–413 Acute respiratory failure (ARF), 47, 102, 273, 278, 283, 303 Airway closure, 290, 301–303 Airway pressure (Paw), 4, 7, 8, 11–13, 15–18, 24, 25, 70, 85, 87, 99, 159–163, 165, 166, 169, 189–193, 221, 223, 256, 260, 261, 277, 282, 284, 293, 294, 304, 343, 345, 346, 356, 364, 368, 377, 408–411 ALI See Acute lung injury (ALI) Alveolar–capillary, 43, 68, 345–347, 378 Alveolar dead space, 181, 183, 184, 197, 410, 411 Alveolar partial pressure of CO2 (PACO2), 25, 31–33, 44, 48, 49, 55–57, 63–65, 131, 148, 154, 184, 187, 195–198, 343, 348, 350, 355, 356, 409, 410 Alveolar recruitment, 33, 49, 169, 408, 410–413 Anesthesia, 58, 182, 205, 245, 269, 278, 279, 299–305, 393, 395, 396 ARDS See Acute respiratory distress syndrome (ARDS) Arterial lactate, 111, 112, 381–384 Aspiration, 146, 270, 272, 346, 347, 410 Atelectasis, 39, 41, 47, 48, 63, 65, 70, 187, 197, 289, 299–305, 346 B Baby lung, 278, 280, 289–295, 348 Baro-/volutrauma, 291, 294, 295, 345 Bedside measurements, 13, 87–89 Bicarbonate, 23, 71–75, 77, 124, 349 Bioenergetic failure, 331 Blood flow, 31, 33, 36–39, 43–45, 48, 49, 60, 68, 79–81, 84, 88, 91, 93, 94, 96, 105, 111, 121, 129, 135–142, 146, 148, 183, 218, 228, 244, 303, 304, 311, 313, 324–326, 332, 334, 364, 365, 369, 370, 376, 382, 383, 387, 388 Blood gas monitoring, 55–57, 244 Blood pressure, 53, 59, 79, 80, 115, 121, 127, 133, 136, 137, 139, 154, 160, 196, 202, 218, 265–267, 309, 310, 332, 336, 363, 374, 375, 378, 382, 383, 385, 392–395, 424, 428 Blood volume, 45, 86, 91, 96, 100, 121–124, 128, 131, 136, 155, 156, 239, 243–246, 255–261, 266, 364, 365 Bohr’s dead space (VDBohr), 195–198 Brain injury, 132–137, 139, 140, 142, 145–149, 154, 155 Breath pattern, 25–28 Buffering, 72, 75, 76, 154–156, 367 C Canine model, 106, 256 Capillary density, 382, 385–387 Carbon dioxide, 32, 55, 57, 73, 131, 136, 140, 183, 184, 191, 355, 408 Carbon dioxide rebreathing, 189 Cardiac index (CI), 89, 228, 265, 267, 323, 325, 327, 332, 408–410, 413 Cardiac output (CO), 33, 35, 37–41, 43, 45, 47–49, 52, 59, 60, 65, 67–70, 81, 82, 85, 87, 88, 96, 100, 101, 124, 183, 201–206, 209–214, 217, 218, 225–228, 230–232, 235, 236, 238, 243–246, 256, 265–268, 277–280, 290, 300, 302, 304, 310, 323–326, 332, 334, 364–369, 373–378, 381–383, 385, 386, 388, 391–393 Cardiac preload, 221, 256, 365, 366, 374, 392 Cardiovascular issues in the ICU, 363 methodology, 201, 209, 244, 356, 357, 403 monitoring, 201, 209–214, 235 statistics, 201, 236–237 Cecal ligation and puncture (CLP), 391–394 Central venous pressure (CVP), 59, 96, 201, 203, 204, 217–219, 221, 222, 236, 266, 334, 337, 342, 382, 383, 385 Cerebral autoregulation, 128, 140, 153–156 Cerebral perfusion pressure (CPP), 128, 129, 133, 135, 136, 139–141, 147, 148, 153–156 Cerebrospinal fluid (CSF) pressure, 127, 129, 155, 249, 252 CI See Cardiac index (CI) CLP See Cecal ligation and puncture (CLP) CO See Cardiac output (CO) Competing risks, 399, 400, 403, 425, 427 M.R Pinsky et al (eds.), Applied Physiology in Intensive Care Medicine 1: Physiological Notes – Technical Notes – Seminal Studies in Intensive Care, DOI 10.1007/978-3-642-28270-6, © Springer-Verlag Berlin Heidelberg 2012 431 432 Index Compliance, 3, 4, 12, 13, 17, 63, 80, 86, 89, 95, 96, 129, 131, 132, 137, 155, 161–162, 166–169, 174, 202, 218, 221, 230, 239, 256–261, 278–281, 283–285, 289–291, 301, 303, 343, 346–348, 354, 357, 365–367, 378, 404, 409, 410 Complications, 51, 53, 132–134, 137, 140, 147, 171, 189, 192, 201, 235, 249, 269, 299, 301, 305, 326, 334, 344, 363, 418–422, 428 Computed tomography (CT), 154, 155, 165, 167–169, 250, 284, 290–293, 301–304, 348 Continuous positive airway pressure (CPAP), 45, 159–163, 189–193, 277, 376, 377 Control of breathing, 353, 359 Corticosteroids, 134, 336, 424, 432 CPAP See Continuous positive airway pressure (CPAP) CPP See Cerebral perfusion pressure (CPP) Critical care, 139, 146, 148, 217, 245, 338, 373–378, 421, 422 Critical illness, 72, 108, 118, 121, 335, 336 Critically ill patients, 17, 33, 42, 51–53, 59–61, 68, 83, 87, 95, 103, 106–109, 112, 113, 116, 121, 122, 124, 201–206, 222, 238, 243, 274, 280, 309, 321, 326, 327, 333, 334, 336, 338, 344, 382 Cross-fertilization, 353, 359 CSF pressure See Cerebrospinal fluid (CSF) pressure CT See Computed tomography (CT) Cuff-leak test, 171–178 CVP See Central venous pressure (CVP) Cytopathic hypoxia, 331, 332 D Dead space, 25, 26, 28, 31–33, 35, 36, 39, 40, 43–45, 48, 49, 63, 181–184, 186, 187, 195–198, 343, 354, 407–411 Diagnostic testing, 173, 178, 353, 354, 357, 359 Diaphragm, 8, 19, 45, 301–305, 309–313, 354–358, 368, 373–375 Diastolic function, 103, 106, 108, 109, 365, 368–369 Diffusion limitation, 35, 36, 40 Dilutional effects, 76 Distress syndrome, 19, 25, 27, 33, 40, 47–49, 53, 63, 65, 66, 69, 81, 85, 88, 93, 95, 96, 99, 101, 122, 159, 160, 218, 221–223, 273, 278–286, 289–295, 303, 304, 324, 326, 332, 335, 337, 343–345, 348–350, 378, 407–413 Doppler, transcranial, 135, 139–140, 145, 148, 153, 154 E Echocardiography, 96, 101, 106, 230, 334, 375, 378, 391–396, 408, 409, 412 Electrical impedance tomography (EIT), 165–169 End expiratory lung volume (EELV), 3, 22, 23, 25–28, 160, 161, 294, 295, 301, 345, 346, 409 End-expired carbon dioxide (FECO2), 31, 183 End-tidal carbon dioxide (PetCO 2), 32, 136, 190, 191, 196, 198 Erythrocyte, 58, 75 Event-specific hazard, 399, 401, 403, 404 External ventricular drainage (EVD), 249–252 F Flowmetry, laser Doppler, 135, 141 Fluid challenge, 89, 96, 205, 210, 217–219, 223, 226, 261, 374, 375 Fluid responsiveness (FR), 100, 217–223, 225–232, 235–240, 255, 260, 261, 376 Fluid resuscitation, 88, 89, 260, 261, 334, 335, 388, 391–396 Fluid therapy, 109, 225, 392 FR See Fluid responsiveness (FR) Fractional shortening (FS), 392–395 Fraction of inspired oxygen (FiO2), 67, 184, 190–192, 196, 219, 325, 336, 408, 410, 413, 426 G Gas exchange, 11, 17, 31, 35, 36, 38, 40, 41, 43–45, 47, 48, 53, 57, 181–187, 192, 195, 256, 280, 282, 290, 291, 293, 295, 299–300, 346, 349, 357 Gastric tonometry, 327, 334 Glucose, 111–113, 131, 149, 336 H Haemorrhage, 132, 137, 140, 147, 149, 154 Heart failure, 45, 60, 89, 100, 106, 108, 109, 122, 235, 260, 261, 265–268, 368, 369, 373 Heart–lung interactions, 255, 363 Hemodynamics, 7, 8, 45, 48, 87, 101, 117, 128, 139, 140, 148, 154, 156, 205, 209, 226, 255, 267, 290, 333–336, 350, 363–370, 373–378, 385, 391, 393–395, 408, 410, 426 Hemorrhage, 88, 93, 250, 289, 324, 345, 346, 368, 381–388, 410 Hydrocortisone, 336, 423–429 Hypercapnia, 33, 43, 45, 49, 223, 293, 335, 348, 349, 355, 357, 407–413 Hyperthermia, 55, 58 Hypotension, 33, 121–124, 146, 154, 220, 309, 310, 313, 327, 335, 338, 347, 348, 368, 378, 392 Hypothermia, 52, 55–58, 94, 133 Hypoxemia, 35, 40, 45, 47–49, 51, 52, 63–70, 87, 111, 113, 122, 182, 266, 278, 290, 303, 324, 408 Index I IAP See Intra-abdominal pressure (IAP) ICP See Intracranial pressure (ICP) Ileal mucosal capillary velocity, 387 Ileal serosal capillary velocity, 387 Inert gases, 35–42, 44, 47, 181–187, 196, 197, 300, 302, 357 Infusion solutions, 71 Inotropic agents, 108, 265, 327 Inspiratory carbon dioxide (PiCO2), 190–192 Inspired oxygen fraction (FIO2), 35, 36, 40, 41, 43, 47–49, 53, 56, 57, 63–67, 182–187, 190–192, 196, 219, 290, 300, 305, 325, 336, 408, 410, 413, 426 Insulin, 336 Intensive care unit mortality, 339–404 Intermittent positive-pressure ventilation (IPPV), 256–258, 260, 344 Intermittent thermodilution (ITD), 201, 202, 204, 205, 211 Intra-abdominal, 60, 375 Intra-abdominal pressure (IAP), 19, 259 Intracranial pressure (ICP), 127–142, 146, 153–156, 249–252, 334, 349 Intramucosal acidosis, 381, 388 Intrathoracic blood volume (ITBV), 45, 100, 243, 244, 255–261 IPPV See Intermittent positive-pressure ventilation (IPPV) ITD See Intermittent thermodilution (ITD) K Kaplan–Meier survival analysis, 394, 418, 419 L Lactate, 60, 61, 76, 111–113, 146, 149, 266, 267, 324, 325, 327, 334, 381–384, 388, 418 Lactic acidosis, 111–113 Laser Doppler flowmetry (LDF), 135, 141 Left ventricular (LV) performance, 83, 87, 89, 102 Left ventricular twist, 103 LiDCOTMplus, 202 Likelihood ratio, 171–174, 177, 178 Lithium dilution cardiac output measurement, 201–206 Long term outcome, 350, 417 Lung injury, 19, 25–28, 33, 40, 47, 49, 63, 67, 70, 88, 93, 112, 113, 159–163, 165, 169, 182, 184, 235, 280–286, 289, 293, 332, 335, 343–350, 407, 408 Lung recruitment, 165, 167, 169, 184, 348, 350, 408 Lungs, 3, 4, 7, 12, 15, 16, 18, 25–28, 33, 36, 39, 45, 49, 56, 67, 68, 80, 86, 112, 113, 181–183, 196, 198, 221, 223, 244, 266, 433 270–273, 279, 280, 284, 285, 289–291, 293, 294, 301, 303–305, 343–349, 354, 366–368, 374, 377 LV stroke volume (SVLV), 88, 89, 99, 104, 256, 259, 260, 373, 374 M Mathematical fitting of respiratory data, 159 Mathematical models, 63, 75, 104, 129, 153, 154, 161, 181, 184, 186, 245, 357 Mechanical ventilation (MV), 3–4, 7, 8, 11, 13, 15, 17–19, 23–28, 31, 32, 45, 53, 65–67, 92, 95, 99–102, 121, 165, 177, 183, 202, 210, 218, 223, 226, 230, 255, 270, 272, 273, 277–280, 289–291, 293, 294, 299, 301–303, 313, 318, 338, 343–348, 350, 353, 354, 356, 363, 366, 370, 375–378, 408, 413 complication, 363 weaning, 353, 363 Mechanics, 25, 27, 45, 104–106, 163, 167, 169, 273, 281, 282, 290, 301–302, 357, 358, 377 Meta-analysis, 171–178, 225–232 Metascience, 353, 358 MFI See Microvascular flow index (MFI) Microcirculation, 33, 113, 140, 141, 323, 381–388 Microdialysis, 145–149 Microvascular blood flow, 141, 324, 387 Microvascular dysfunction, 322 Microvascular flow index (MFI), 382, 385, 387 MIGET See Multiple inert gas elimination technique (MIGET) MODS See Multiple organ dysfunction syndrome (MODS) Mortality, 42, 53, 66, 108, 113, 117, 118, 133, 134, 139, 146, 154, 235, 249, 267, 290, 309, 317–321, 327, 332–336, 338, 343, 348–350, 378, 391–396, 399–404, 413, 418, 421, 423–428 Moses’ method, 172, 173, 228 Multiple inert gas elimination technique (MIGET), 35–42, 47, 181–187, 196–198, 300, 302 Multiple organ dysfunction syndrome (MODS), 317, 318, 331–334, 337 Multiple organ failure, 121, 332, 333, 336, 392, 424, 428 Muscles atrophy, 311 MV See Mechanical ventilation (MV) N Near-infrared spectroscopy (NIRS), 145, 147–148 Nitric oxide, 45, 88, 94, 310–313, 333, 335, 338, 350 Noninvasive cardiac output monitoring device (NICOM), 236, 237, 240 Nosocomial infections, 399–401, 403, 404 Nosocomial pneumonia (NP), 269–274, 400–404 434 Index O Organ dysfunction, 59, 218, 317, 323, 331–338, 421, 423–425 Organ failure, 113, 124, 312, 317, 318, 323, 326, 332–334, 336, 349, 350, 392, 413, 423–429 Outcome, 28, 33, 53, 60, 66, 106, 113, 118, 132–134, 136–138, 142, 146–149, 154, 173, 174, 177, 201, 218, 226, 286, 312, 317, 319–321, 326, 332–336, 348–350, 354, 358, 359, 381, 382, 392, 395, 400, 401, 417, 419–422, 424–427 Oximetry, jugular venous, 145–147 Oxygen transport, 290, 323–327, 333, 357, 381–383 Oxyhemoglobin saturation, 55, 57, 58 P PACO2 See Alveolar partial pressure of CO2 (PACO2) Passive leg raising (PLR), 213, 214, 225–232, 235–240, 374 Passive leg raising-induced changes in arterial pulse pressure (PLR-cPP), 227, 228, 230 Passive leg raising-induced changes in cardiac output (PLR-cCO), 227, 228, 230 Pathophysiology, 13, 21, 24, 27, 59–61, 76, 149, 270–271, 274, 285, 286, 310, 332–333, 353–359, 391 PEEP See Positive end-expiratory pressure (PEEP) Peripheral tissue perfusion, 141, 265, 325, 327, 334, 386 Pharmacology, 108, 259, 266, 268, 311, 313, 338 pH neutral solution, 72 PiCCO-technology, 243, 244 Population attributable fraction, 402, 404 Positive end-expiratory pressure (PEEP), 3–4, 7–9, 12, 17, 23, 24, 28, 33, 48, 86, 159, 165, 168, 169, 182, 192, 196, 212–214, 277, 280, 283–286, 289–292, 294, 304, 343–350, 358, 364, 366–370, 373, 376, 377, 407–413, 427 Positive pressure, 80, 85, 93, 159, 190, 258, 277, 345, 364, 369, 373–376 Positive pressure ventilation, 8, 11, 99, 256, 259, 343, 354 Pressure, 3–4, 7–9, 11–13, 15–19, 21–26, 28, 31–33, 35–37, 40, 43–45, 48, 53, 55–57, 59, 64, 67, 68, 70, 73–77, 79–89, 91–96, 99–102, 104–109, 115, 121, 127–142, 146, 147, 153–156, 159–163, 165, 166, 169, 183, 189–193, 196, 202–206, 217–223, 226–232, 236, 238, 239, 243, 246, 249–252, 255–261, 265–268, 277–286, 289–295, 304, 335, 343–349, 354, 356–358, 364–370, 373–378, 382, 392, 394, 395, 407–413, 424, 427, 428 Pressure monitor, 136, 154, 249–252, 334 Pressure–volume curves, 11, 21–23, 129, 159–163, 167, 168, 281–286, 290, 293, 346, 348, 350, 408–411 Pressure–volume index (PVI), 129, 153–156 Protected specimen brush (PSB), 269, 273 Pulmonary artery catheter (PAC), 59, 61, 67, 87, 93, 201, 212, 218, 219, 334, 382 Pulmonary artery occlusion pressure (PAOP), 83–89, 91, 93, 96, 218, 219, 368, 374, 383, 385 Pulmonary gas exchange, 35, 43–44, 48, 53, 57, 181–187, 357 Pulmonary hemodynamics, 48, 87 Pulse pressure (PP), 99, 100, 201, 219, 223, 226–228, 231, 232, 236, 238, 255–261, 375 Pulse pressure analysis algorithm (PulseCO), 201, 202 Pulse pressure variation (PPV), 99–102, 217–223, 226, 236, 238, 257, 258 PVI See Pressure–volume index (PVI) R Randomized clinical trials, 353, 413, 424 Receiver-operating characteristic (ROC) curves, 217, 219, 221, 222, 226, 230–232, 238, 239, 319, 320, 357 Recoil, 3, 15, 18, 21, 103–109, 281, 301 Recovery, 41, 124, 132, 154, 155, 284, 394, 417, 418, 426 Red blood cell velocity (RBCV), 383–387 Reintubation, 171–178, 354 Respiratory mechanics, 25, 27, 163, 301, 357, 358 Respiratory muscles, 8, 11, 12, 21, 23, 24, 301, 304, 305, 309–313, 353, 354, 356, 357, 359 Respiratory physiology, 281, 354 Respiratory system compliance, 3, 4, 17, 63, 161, 282, 289, 290, 301, 409, 410 resistance, 3, 4, 17, 18, 282, 301 Respiratory variables, 410, 411, 413 Right heart, 45, 67, 407 ROC curves See Receiver-operating characteristic (ROC) curves S Safety valves, 189–193 Scoring system, 317, 318, 320, 321, 331, 333 Sepsis, 60, 70, 112, 113, 115, 121, 122, 146, 161, 204, 309–313, 318, 321, 323, 326, 327, 331–338, 346, 385, 387, 388, 391, 392, 395, 396, 424, 428 Sepsis syndrome, 331, 332 Septic shock, 60, 61, 100, 104, 122, 161, 218, 219, 309–313, 326, 327, 331, 333–337, 375, 387, 391, 392, 423–428 Sequential Organ Failure Assessment score (SOFA), 317, 318, 333, 336, 423–427 Serendipity, 353, 359 Shock, 33, 59–61, 70, 83, 111, 161, 218–220, 309–313, 323–327, 331–337, 345, 374, 381, 382, 423–428 Shunt, 33, 35, 37–41, 43–45, 47–49, 61, 63–70, 181–184, 186, 187, 198, 219, 245, 277, 290, 299, 300, 302, 304, 382, 388 Index Sleep, 88, 369 SOFA See Sequential Organ Failure Assessment score (SOFA) Spectroscopy, near-infrared, 145, 147–148 Static pressure–volume curves of the respiratory system, 159 Statistical analysis, 159, 160 Steroids, 174, 335–337, 423, 426, 428 Stewart’s approach, 71–77 Stress–strain index (SSI), 26–28 Stroke volume (SV), 88, 89, 96, 99, 104, 106, 109, 201, 211, 214, 218, 222, 223, 228–231, 236, 238, 255–261, 265–268, 373–375, 377, 392–396 Stroke volume variation (SVV), 218, 223, 230, 238, 256–261 Strong ion difference, 71, 73, 77 Subarachnoid, 127, 132, 140, 147, 148, 154 Subarachnoid hemorrhage, 249, 251 Subdistribution hazard, 399–404 Sublingual capillary velocity, 387 Summary receiver-operator characteristic (SROC) curves, 172, 173, 177, 226, 228, 232 Surgery, 41, 52, 106, 108, 148, 149, 174, 205, 235, 236, 240, 245, 271, 277, 278, 299, 301, 304, 327, 334, 336, 412, 417–421, 424 Survival analysis, 394, 401, 418–420 SV See Stroke volume (SV) SVV See Stroke volume variation (SVV) Systolic function, 96, 100, 103, 106–108, 408, 410, 412 T Thermal diffusion flowmetry, 135, 141–142 THRT See Transient hyperaemic response test (THRT) Tidal volume (Vt), 3, 4, 12, 17, 19, 23, 25–28, 31–33, 39, 45, 48, 49, 160, 161, 163, 165, 166, 174–176, 192, 195, 196, 218–223, 255–261, 277, 280, 283, 285, 286, 290, 291, 293–295, 304, 335, 337, 343–350, 356, 357, 375, 378, 408–411, 413 Tissue PCO2, 35 435 Torsion, 103–109 Total end-diastolic blood volume (TEDV), 244, 245 Transcranial Doppler (TCD), 135, 139–142, 145, 147, 148, 153, 154 Transcutaneous oximetry, 196 Transducers, 83, 84, 127, 129, 133, 136, 137, 139, 154, 160, 229, 249–252, 282, 382, 409 Transient hyperaemic response test (THRT), 140, 154, 155 Transpulmonary thermodilution, 219, 243–246 Traumatic brain injury (TBI), 127, 132–137, 139, 140, 145, 147–149, 154, 155, 249, 251 Treatment, 47, 51, 70, 75, 83, 109, 137, 140, 184, 205, 220, 240, 252, 265–268, 277, 286, 289, 290, 293, 295, 303, 304, 312, 321, 326, 331, 334, 336, 337, 347, 378, 381, 391, 394, 409, 418, 422, 424–428 U Ultrasonography, 135, 139, 142 Ultrasound dilution (UD) technology, 243–246 Upper airway obstruction, 88, 171–178 V Ventilation, 33, 85, 229, 232, 256, 300, 305 Ventilation/perfusion inequality, 35, 36 Ventilator-induced lung injury (VILI), 293–295, 343–348, 350 Ventricular stroke volume (SVRV), 256–261 Volume expansion (VE), 71, 96, 100–102, 116, 217, 236, 265, 366, 375–377 Volumetric capnography, 31, 33, 495–498 W Weaning, 11, 13, 172, 313, 338, 353–359, 363, 370, 377, 378, 426 ... M.R Pinsky et al (eds.), Applied Physiology in Intensive Care Medicine 1: Physiological Notes – Technical Notes – Seminal Studies in Intensive Care, DOI 10 .10 07/978-3-642-28270-6_3, © Springer-Verlag... M.R Pinsky et al (eds.), Applied Physiology in Intensive Care Medicine 1: Physiological Notes – Technical Notes – Seminal Studies in Intensive Care, DOI 10 .10 07/978-3-642-28270-6_4, © Springer-Verlag... (eds.), Applied Physiology in Intensive Care Medicine 1: Physiological Notes – Technical Notes – Seminal Studies in Intensive Care, DOI 10 .10 07/978-3-642-28270-6_5, © Springer-Verlag Berlin Heidelberg