STATE OF THE ART SCHÄDELHINRTRAUMA...12.01.16 Schädelhirntrauma – State of the Art 6 L.-O. D....

STATE OF THE ART SCHÄDELHINRTRAUMA

12.01.16 Thomas Brunner, Stv. Leiter Anästhesie/Intensivmedizin 1

STATE OF THE ART SCHWERES SCHÄDELHIRNTRAUMA •  Aktuelle Guidelines •  Evidenz zu aktuellen Therapieoptionen •  Praktische Aspekte

12.01.16 Schädelhirntrauma – State of the Art 2


REVIEW

SEVERE TRAUMATIC BRAIN INJURY MANAGEMENT AND CLINICALOUTCOME USING THE LUND CONCEPT

L.-O. D. KOSKINEN, a* M. OLIVECRONA a,b ANDP. O. GRANDE c

aDepartment of Pharmacology and Clinical Neuroscience,Neurosurgery, Umea University, SwedenbDepartment of Anaesthesia and Intensive Care, University ofOrebro, SwedencDepartment of Clinical Science in Lund, Anaesthesia andIntensive Care, Lund University, Sweden

Abstract—This review covers the main principles of theLund concept for treatment of severe traumatic brain injury.This is followed by a description of results of clinical studiesin which this therapy or a modified version of the therapyhas been used. Unlike other guidelines, which are basedon meta-analytical approaches, important components ofthe Lund concept are based on physiological mechanismsfor regulation of brain volume and brain perfusion and toreduce transcapillary plasma leakage and the need forplasma volume expanders. There have been nine non-randomized and two randomized outcome studies withthe Lund concept or modified versions of the concept. Thenon-randomized studies indicated that the Lund concept isbeneficial for outcome. The two randomized studies weresmall but showed better outcome in the groups of patientstreated according to the modified principles of the Lundconcept than in the groups given a more conventional treat-ment.This article is part of a Special Issue entitled: Brain com-

pensation. For good?. ! 2014 IBRO. Published by ElsevierLtd. All rights reserved.

Key words: severe traumatic brain injury, Lund concept,management, outcome.

ContentsIntroduction 245Measurement of ICP and CPP 246Treatment of sTBI 247Treatment of ICP 247Blood volume expanders 247

Principles of transcapillary exchange in tissues outside thebrain 248Blood transfusion 249Treatment to improve perfusion 249Osmotherapy 250Lung function 250Anti-stress therapy 251Temperature 251Nutrition 251Drainage of CSF and decompressive surgery 251

Clinical outcome studies 251The Lund concept 251Modified Lund concept 251The Lund concept and meningitis 252

Discussion 252Summary 253References 253

INTRODUCTION

Originally, the Lund concept (LC) for treatment of severetraumatic brain injury (sTBI) was a theoretical approachmainly based on the physiological andpathophysiological principles of brain volume and brainperfusion regulation (Asgeirsson et al., 1994; Grandeet al., 1997; Grande, 2006). The concept aimed at coun-teracting an increase in intracranial pressure (ICP) or toreduce an already raised ICP after sTBI, while improvingcompromised perfusion in and around the contusionareas at the same time. It can be described as an ICP-and perfusion-guided approach. The main componentsof the LC have found support in experimental and clinicalstudies, as described later in this review.

So far, no TBI guidelines have been tested in a largerandomized clinical trial and from that point of view thereis limited high-level clinical evidence for all TBI guidelinespresented today (Muzevic and Splavski, 2013). A specifictherapy therefore must be based on other types of inputsuch as smaller clinical outcome studies including meta-analysis, experimental studies and basal physiologicalprinciples.

Even though different guidelines differ in essentialaspects, the Brain Trauma Foundation’s guidelines havemoved closer to the LC during the past 10 years, e.g.concerning cerebral perfusion pressure (CPP) and theuse of vasopressors (Bullock et al., 1996, 2000; BrainTrauma Foundation, 2007). In contrast to Brain Trauma

http://dx.doi.org/10.1016/j.neuroscience.2014.06.0390306-4522/! 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

*Corresponding author. Tel: +46-706259701.E-mail address: [email protected] (L.-O. D.Koskinen).Abbreviations: ARDS, acute respiratory distress syndrome; CPP,cerebral perfusion pressure; Hb, hemoglobin; ICP, intracranialpressure; LC, Lund concept; MAP, mean arterial pressure; PEEP,positive endexpiratory pressure; sTBI, severe traumatic brain injury;SAH, subarachnoid hemorrhage; TER, transcapillary exchange rate.

Neuroscience 283 (2014) 245–255

245

L.-O. D. Koskinen et al. / Neuroscience 283 (2014) 245–255


L.-O. D. Koskinen et al. / Neuroscience 283 (2014) 245–255

Foundation guidelines—in which the ICP-reducing ther-apy should start when ICP is above 20 mmHg (BrainTrauma Foundation, 2007)—the LC recommends thatthe therapy should start as early as possible after arrivalat the hospital, in an attempt to counteract the develop-ment of brain edema and to ensure that there is early opti-mization of the perfusion. To our knowledge, no clear sideeffects have appeared with the LC, which means that itcan be given early and to all patients independent ofseverity of the injury and independent of the degree ofautoregulation. The LC has not changed since its intro-duction, except that dihydroergotamin is no longer used.Dihydroergotamin, which reduces ICP via cerebralvenous constriction, was used in the initial version of theconcept in patients with uncontrolled increase in ICP(Asgeirsson et al., 1994). It was withdrawn because ofpossible side effects related to peripheral vasoconstrictionin high doses. For details of the LC guidelines, see;Asgeirsson et al. (1994), Grande (2006, 2011) and

Olivecrona et al. (2007, 2009a,b). A simplified schematicalgorithm of the LC used in the clinical setting is shown inFig. 1.

MEASUREMENT OF ICP AND CPP

Like in other guidelines, monitoring of ICP is an essentialpart of the LC, and the monitoring should be started assoon as possible after the arrival at the hospital. Themethod of ICP monitoring can either be by externalventricular drainage or by an intraparenchymal device. Itis also crucial to monitor the arterial pressure and themean arterial pressure (MAP).

The reference points for MAP and ICP must beidentical when calculating CPP. For example, a headelevation of 15 degrees with the zero-reference point forthe ICP at the external meatus and the zero-referencepoint for the MAP at the heart level gives a difference ofaround 10 mmHg compared to treatment of the patient

Fig. 1. A simplified schematic algorithm of the LC used in the clinical setting. For doses of the pharmacological substances used and otherparameters, see Grande (2006).

246 L.-O. D. Koskinen et al. / Neuroscience 283 (2014) 245–255

THERAPIEOPTIONEN

•  BLS, BICS, MMM •  Oxygenation/Ventilation, Kreislaufsupport, Gerinnung,

Thromboseprophylaxe, Ernährung, Monitoring, ... •  Sedation •  Entfernung von Raumforderungen, Liquordrainage •  Osmotherapie •  Hypothermie •  Kraniektomie



T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 370;22 nejm.org may 29, 2014 2121

review article

Critical Care MedicineSimon R. Finfer, M.D., and Jean-Louis Vincent, M.D., Ph.D., Editors

Traumatic Intracranial HypertensionNino Stocchetti, M.D., and Andrew I.R. Maas, M.D., Ph.D.

From the Department of Pathophysiology and Transplantation, Milan University, and Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Cà Granda–Ospedale Maggiore Policlinico — both in Milan (N.S.); and the Department of Neu-rosurgery, Antwerp University Hospital–University of Antwerp, Edegem, Belgium (A.I.R.M.). Address reprint requests to Dr. Stocchetti at Fondazione IRCCS Cà Granda–Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milan, Italy, or at [email protected]; or to Dr. Maas at the Department of Neurosurgery, Antwerp University Hospital–University of Antwerp, Wilrijkstraat 10, 2650 Edegem, Belgium, or at [email protected].

N Engl J Med 2014;370:2121-30.DOI: 10.1056/NEJMra1208708Copyright © 2014 Massachusetts Medical Society.

A n elevation in intracranial pressure can be a medical or surgical emergency. There are many possible conditions that can lead to elevated intracranial pressure on either an acute or a chronic basis (Table 1).

In this article, we focus on the increased intracranial pressure that occurs in pa-tients after traumatic brain injury, since this is an area in which there are both physiological and clinical data.

Traumatic brain injury is a medical and social problem worldwide, with an estimated 10 million cases leading to hospitalization or death each year.1 In low- and medium-income countries, in which the use of motor-powered transportation is increasing, the incidence of this condition is rising2 and involves predominantly young men. In contrast, in richer countries, the epidemiology of traumatic brain in-jury is changing because of two main factors: the rate of traffic incidents is decreas-ing owing to successful enforcement of safety laws and preventive measures, whereas the aging of the population makes such injury in the elderly more frequent.2-4

Falls are a frequent cause of injury in older patients, often resulting in contusive brain injury. Elderly patients often have multiple coexisting illnesses and are fre-quently taking a number of medications, including anticoagulants and platelet aggregation inhibitors.4 These medications may contribute to the development of hematomas and hemorrhagic expansion of contusions. In the past, it was gener-ally thought that traumatic brain injury in elderly persons was associated with a uniformly bad outcome, and as a consequence more aggressive treatment was often withheld.5 Although increasing age is unequivocally an independent predic-tor of a poor outcome,6 recent data suggest that favorable outcomes, at least in the short term, are no longer uncommon among elderly patients7; however, these pa-tients require sustained, high-level medical care and rehabilitation.

Pathoph ysiol o gy

Normal intracranial pressure in adults is below 15 mm Hg, with transient increases due to coughing or sneezing. Intracranial-pressure values that are sustained above 20 mm Hg are considered to be pathologic in adults and an indication for intensifying treatment in patients with traumatic brain injury. Under normal conditions, the total volume within the skull remains constant and is determined by the sum of the cerebrospinal fluid, blood, and brain-tissue compartments. The volume of these compartments is tightly regulated, and cerebral blood flow is kept constant by autoregulation. When additional volume is added to the system, compensatory mechanisms (e.g., displace-ment of cerebrospinal fluid to the spinal subarachnoid space and compression of the cerebral venous bed) operate to keep intracranial pressure constant.

The relationship between intracranial volume and intracranial pressure is expo-nential. Initially, pressure increases only slightly with increasing volume, but when the buffering capabilities of the system are exceeded, intracranial pressure rises

The New England Journal of Medicine Downloaded from nejm.org at KANTONSBIBLIOTHEK VADIANA on December 19, 2015. For personal use only. No other uses without permission.

Copyright © 2014 Massachusetts Medical Society. All rights reserved.

N Engl J Med 2014;370:2121-30


N Engl J Med 2014;370:2121-30


n engl j med 370;22 nejm.org may 29, 20142126

and intracranial pressure through multiple mech-anisms. In the first minutes of infusion, mannitol and hypertonic saline expand the plasma volume, decrease blood viscosity, and reduce the cerebral blood volume.29 Once plasma osmolarity in-creases, a gradient across the blood–brain bar-rier is established, and water is extracted from the brain. This effect may last for up to several hours, until the osmotic equilibrium is reestab-lished. The integrity of the blood–brain barrier is a prerequisite for the efficacy of hyperosmolar agents. Mannitol is an osmotic diuretic and may cause dehydration and hypovolemia. Hypertonic saline may cause abrupt increases in the sodium

plasma concentration. Comparisons between mannitol and hypertonic saline for the treatment of increased intracranial pressure have not shown a clear superiority of one option over the other.29

Induced arterial blood hypocarbia (hyperventi-lation) reduces intracranial pressure at the expense of decreasing cerebral blood flow as a result of vasoconstriction.30 Hyperventilation carries a seri-ous risk of cerebral ischemia. For this reason, cur-rent guidelines recommend additional monitor-ing for cerebral ischemia (e.g., by the monitoring of oxygen saturation in the jugular bulb and of brain-tissue oxygenation) when hyperventilation is used.31

TherapySteps

Levels ofEvidence Treatment Risk

1Intubation

Normocarbicventilation

2 Level III Increased sedation

3 Not reported

Not reported

Ventricular CSF drainage

4 Level IIHyperosmolar therapy

Mannitol or hypertonic saline

5 Level III Induced hypocapnia

6 Level III Hypothermia

7 Level II Metabolic suppression (barbiturates)

8 Not reported Decompressive craniectomy

Infection or delayed hematomaSubdural effusionHydrocephalus and syndrome

of the trephined

Hypotension and increased numberof infections

Coughing, ventilator asynchrony,ventilator-associated pneumonia

Fluid and electrolyte disturbances and infection

Excessive vasoconstriction and ischemia

Negative fluid balanceHypernatremiaKidney failure

Infection

Hypotension

Figure 3. Staircase Approach to the Treatment of Increased Intracranial Pressure.

The level of therapy in patients with raised intracranial pressure is increased step by step, with more aggressive interventions when there is no response. The sequence of interventions may vary among different institutions; every intervention is associated with adverse effects. Shown are the levels of evidence that underpin various approaches to treatment. Levels of evidence are based on the criteria for classifi-cation of evidence, as used in international guidelines.24 The revised guidelines for the management of severe traumatic brain injury and the surgical guidelines for the management of such injury do not contain any evidence on ventricular drainage of cerebrospinal fluid (CSF) or the use of decompressive craniectomy. Level I evidence25 shows that decompressive craniectomy is effective in reducing intracranial pressure but may worsen the long-term outcome and is associated with several complications. Among them is the syndrome of the tre-phined, in which a sunken skull flap develops with a (poorly understood) neurologic deterioration.



GUIDELINES ZUM MONITORING EVIDENZ ZU THERAPIEOPTIONEN •  Multimodales Monitoring

•  ICP •  PtiO2 •  PRx, CPPopt

•  Osmotherapie •  Therapeutischen Hypothermie •  Adjuvante Therapien

•  EPO, Progesteron, Steroide



Peter Le RouxDavid K. MenonGiuseppe CiterioPaul VespaMary Kay BaderGretchen M. BrophyMichael N. DiringerNino StocchettiWalter VidettaRocco ArmondaNeeraj BadjatiaJulian BoeselRandall ChesnutSherry ChouJan ClaassenMarek CzosnykaMichael De GeorgiaAnthony FigajiJennifer FugateRaimund HelbokDavid HorowitzPeter HutchinsonMonisha KumarMolly McNettChad MillerAndrew NaidechMauro OddoDaiWai OlsonKristine O’PhelanJ. Javier ProvencioCorinna PuppoRichard RikerClaudia RobertsonMichael SchmidtFabio Taccone

Consensus summary statementof the International MultidisciplinaryConsensus Conference on MultimodalityMonitoring in Neurocritical CareA statement for healthcare professionals from theNeurocritical Care Society and the European Societyof Intensive Care Medicine

Received: 26 May 2014Accepted: 7 June 2014Published online: 20 August 2014! Springer-Verlag Berlin Heidelberg andESICM 2014

The Neurocritical Care Society affirms thevalue of this consensus statement as aneducational tool for clinicians.

This article is being simultaneouslypublished in Neurocritical Care andIntensive Care Medicine.

This article is being simultaneouslypublished in Neurocritical Care andIntensive Care Medicine.This article isendorsed by the Neurocritical Care Society(NCS), the European Society of Intensive

Care Medicine (ESICM), the Society forCritical Care Medicine (SCCM) and theLatin America Brain Injury Consortium andis being simultaneously published inNeurocritical Care and Intensive CareMedicine. It will be published in IntensiveCare Medicine in an abridged version.

Electronic supplementary materialThe online version of this article(doi:10.1007/s00134-014-3369-6) containssupplementary material, which is availableto authorized users.

P. Le Roux ())Brain and Spine Center, Suite 370,Medical Science Building,Lankenau Medical Center,100 East Lancaster Avenue,Wynnewood, PA 19096, USAe-mail: [email protected].: ?1 610 642 3005

D. K. MenonNeurosciences Critical Care Unit,Division of Anaesthesia,University of Cambridge Consultant,Addenbrooke’s Hospital, Box 93,Cambridge CB2 2QQ, UKe-mail: [email protected]

Intensive Care Med (2014) 40:1189–1209DOI 10.1007/s00134-014-3369-6 CONFERENCE REPORTS AND EXPERT PANEL

Peter Le RouxDavid K. MenonGiuseppe CiterioPaul VespaMary Kay BaderGretchen M. BrophyMichael N. DiringerNino StocchettiWalter VidettaRocco ArmondaNeeraj BadjatiaJulian BoeselRandall ChesnutSherry ChouJan ClaassenMarek CzosnykaMichael De GeorgiaAnthony FigajiJennifer FugateRaimund HelbokDavid HorowitzPeter HutchinsonMonisha KumarMolly McNettChad MillerAndrew NaidechMauro OddoDaiWai OlsonKristine O’PhelanJ. Javier ProvencioCorinna PuppoRichard RikerClaudia RobertsonMichael SchmidtFabio Taccone

Consensus summary statementof the International MultidisciplinaryConsensus Conference on MultimodalityMonitoring in Neurocritical CareA statement for healthcare professionals from theNeurocritical Care Society and the European Societyof Intensive Care Medicine

Received: 26 May 2014Accepted: 7 June 2014Published online: 20 August 2014! Springer-Verlag Berlin Heidelberg andESICM 2014

The Neurocritical Care Society affirms thevalue of this consensus statement as aneducational tool for clinicians.

This article is being simultaneouslypublished in Neurocritical Care andIntensive Care Medicine.

This article is being simultaneouslypublished in Neurocritical Care andIntensive Care Medicine.This article isendorsed by the Neurocritical Care Society(NCS), the European Society of Intensive

Care Medicine (ESICM), the Society forCritical Care Medicine (SCCM) and theLatin America Brain Injury Consortium andis being simultaneously published inNeurocritical Care and Intensive CareMedicine. It will be published in IntensiveCare Medicine in an abridged version.

Electronic supplementary materialThe online version of this article(doi:10.1007/s00134-014-3369-6) containssupplementary material, which is availableto authorized users.

P. Le Roux ())Brain and Spine Center, Suite 370,Medical Science Building,Lankenau Medical Center,100 East Lancaster Avenue,Wynnewood, PA 19096, USAe-mail: [email protected].: ?1 610 642 3005

D. K. MenonNeurosciences Critical Care Unit,Division of Anaesthesia,University of Cambridge Consultant,Addenbrooke’s Hospital, Box 93,Cambridge CB2 2QQ, UKe-mail: [email protected]

Intensive Care Med (2014) 40:1189–1209DOI 10.1007/s00134-014-3369-6 CONFERENCE REPORTS AND EXPERT PANEL

Intensive Care Med (2014) 40:1189–1209

MULTIMODALES MONITORING

•  Multimodales Monitoring versucht das Zielorgan Hirn und dessen Zustand mit unterschiedlichen Techniken abzubilden

•  „It must be recognized that no monitor in the end will change outcome. Instead it is how that information is interpreted and integrated into clinical decision-making and then how the patient is treated. That will influence outcome“



MULTIMODALES MONITORING ICP •  „ICP and CPP monitoring are recommended as a part of protocol-

driven care in patients who are at risk of elevated intracranial pressure“ •  „We recommend that ICP and CPP monitoring be used to guide

medical and surgical interventions and to detect life-threatening imminent herniation; however, the threshold value of ICP is uncertain on the basis of the literature“

•  „ICP per se does not provide a useful prognostic marker of functional outcome“




n engl j med 367;26 nejm.org december 27, 2012 2471

The new england journal of medicineestablished in 1812 december 27, 2012 vol. 367 no. 26

A Trial of Intracranial-Pressure Monitoring in Traumatic Brain Injury

Randall M. Chesnut, M.D., Nancy Temkin, Ph.D., Nancy Carney, Ph.D., Sureyya Dikmen, Ph.D., Carlos Rondina, M.D., Walter Videtta, M.D., Gustavo Petroni, M.D., Silvia Lujan, M.D., Jim Pridgeon, M.H.A., Jason Barber, M.S.,

Joan Machamer, M.A., Kelley Chaddock, B.A., Juanita M. Celix, M.D., Marianna Cherner, Ph.D., and Terence Hendrix, B.A., for the Global Neurotrauma Research Group*

A BS TR AC T

From the Departments of Neurological Surgery (R.M.C., N.T., S.D., J.P., J.B., K.C., J.M.C.), Orthopaedics and Sports Medi-cine (R.M.C.), Biostatistics (N.T.), and Rehabilitation Medicine (S.D., J.M.), Uni-versity of Washington, Harborview Medi-cal Center, Seattle; the Department of Medical Informatics and Clinical Epide-miology, Oregon Health and Science Uni-versity, Portland (N.C.); Hospital de Emer-gencias Dr. Clemente Alvarez, Santa Fe (C.R., G.P., S.L.), and Hospital Nacional Professor Alejandro Posadas, Buenos Aires (W.V.) — both in Argentina; and the De-partments of Psychiatry (M.C.) and HIV Neurobehavioral Research Programs (T.H.), University of California, San Diego, La Jolla. Address reprint requests to Dr. Chesnut at the University of Washington, Harbor-view Medical Center, Department of Neurological Surgery, 325 Ninth Ave., Box 359766, Seattle, WA 98104, or at [email protected].

*Members of the Global Neurotrauma Research Group are listed in the Sup-plementary Appendix, available at NEJM.org.

This article was published on December 12, 2012, and last updated on December 5, 2013, at NEJM.org.

N Engl J Med 2012;367:2471-81.DOI: 10.1056/NEJMoa1207363Copyright © 2012 Massachusetts Medical Society.

BackgroundIntracranial-pressure monitoring is considered the standard of care for severe trau-matic brain injury and is used frequently, but the efficacy of treatment based on monitoring in improving the outcome has not been rigorously assessed.MethodsWe conducted a multicenter, controlled trial in which 324 patients 13 years of age or older who had severe traumatic brain injury and were being treated in intensive care units (ICUs) in Bolivia or Ecuador were randomly assigned to one of two specific protocols: guidelines-based management in which a protocol for monitoring intra-parenchymal intracranial pressure was used (pressure-monitoring group) or a proto-col in which treatment was based on imaging and clinical examination (imaging–clinical examination group). The primary outcome was a composite of survival time, impaired consciousness, and functional status at 3 months and 6 months and neuro-psychological status at 6 months; neuropsychological status was assessed by an exam-iner who was unaware of protocol assignment. This composite measure was based on performance across 21 measures of functional and cognitive status and calculated as a percentile (with 0 indicating the worst performance, and 100 the best performance).ResultsThere was no significant between-group difference in the primary outcome, a com-posite measure based on percentile performance across 21 measures of functional and cognitive status (score, 56 in the pressure-monitoring group vs. 53 in the imag-ing–clinical examination group; P = 0.49). Six-month mortality was 39% in the pressure-monitoring group and 41% in the imaging–clinical examination group (P = 0.60). The median length of stay in the ICU was similar in the two groups (12 days in the pressure-monitoring group and 9 days in the imaging–clinical examination group; P = 0.25), although the number of days of brain-specific treatments (e.g., administration of hyperosmolar fluids and the use of hyperventilation) in the ICU was higher in the imaging–clinical examination group than in the pressure-monitor-ing group (4.8 vs. 3.4, P = 0.002). The distribution of serious adverse events was similar in the two groups.ConclusionsFor patients with severe traumatic brain injury, care focused on maintaining mon-itored intracranial pressure at 20 mm Hg or less was not shown to be superior to care based on imaging and clinical examination. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01068522.)

The New England Journal of Medicine Downloaded from nejm.org on November 26, 2015. For personal use only. No other uses without permission.


N Engl J Med 2012;367:2471-81

BEST-TRIP •  Benchmark Evidence from South American Trials: Treatment of

Intracranial Pressure (BEST TRIP) •  Multizenter •  324 Patienten in Bolivien und Ecuador •  Pressure-monitoring group vs. Imaging–clinical examination group) •  „For patients with severe traumatic brain injury, care focused on

maintaining intracranial pressure at 20mmHg or less was not shown to be superior to care based on imaging and clinical examination“


N Engl J Med 2012;367:2471-81


Original Articles

A Consensus-Based Interpretation of the BenchmarkEvidence from South American Trials:

Treatment of Intracranial Pressure Trial

Randall M. Chesnut,1 Thomas P. Bleck,2 Giuseppe Citerio,3 Jan Classen,4 D. James Cooper,5

William M. Coplin,6 Michael N. Diringer,7 Per-Olof Grande,8 J. Claude Hemphill III,9 Peter J. Hutchinson,10

Peter Le Roux,11 Stephan A. Mayer,12 David K. Menon,13 John A. Myburgh,14 David O. Okonkwo,15

Claudia S. Robertson,16 Juan Sahuquillo,17 Nino Stocchetti,18 Gene Sung,19 Nancy Temkin,1,20

Paul M. Vespa,21 Walter Videtta,22 and Howard Yonas23

Abstract

Widely-varying published and presented analyses of the Benchmark Evidence From South American Trials: Treatment ofIntracranial Pressure (BEST TRIP) randomized controlled trial of intracranial pressure (ICP) monitoring have suggesteddenying trial generalizability, questioning the need for ICP monitoring in severe traumatic brain injury (sTBI), re-assessingcurrent clinical approaches to monitored ICP, and initiating a general ICP-monitoring moratorium. In response to this disso-nance, 23 clinically-active, international opinion leaders in acute-care sTBI management met to draft a consensus statement tointerpret this study. A Delphi method–based approach employed iterative pre-meeting polling to codify the group’s generalopinions, followed by an in-person meeting wherein individual statements were refined. Statements required an agreementthreshold of more than 70% by blinded voting for approval. Seven precisely-worded statements resulted, with agreement levelsof 83% to 100%. These statements, which should be read in toto to properly reflect the group’s consensus positions, conclude thatthe BEST TRIP trial: 1) studied protocols, not ICP-monitoring per se; 2) applies only to those protocols and specific study groupsand should not be generalized to other treatment approaches or patient groups; 3) strongly calls for further research on ICPinterpretation and use; 4) should be applied cautiously to regions with much different treatment milieu; 5) did not investigate theutility of treating monitored ICP in the specific patient group with established intracranial hypertension; 6) should not change thepractice of those currently monitoring ICP; and 7) provided a protocol, used in non-monitored study patients, that should beconsidered when treating without ICP monitoring. Consideration of these statements can clarify study interpretation.

Key words: BEST TRIP trial; Consensus Development Conference; intracranial pressure; neurocritical care; traumaticbrain injury

1Department of Neurological Surgery, 20Department of Biostatistics, University of Washington, Seattle, Washington.2Department of Neurology, Rush University Medical Center, Chicago Illinois.3Department of Health Sciences, University of Milano-Bicocca, Milano, Italy.4Division of Critical Care Neurology and Comprehensive Epilepsy Center, Columbia University, New York, New York.5Department of Intensive Care, Alfred Hospital, Melbourne, VIC, Australia.6Neurosurgery Intensive Care, St. Anthony Hospital, Lakewood, Colorado.7Department of Neurology, Washington University School of Medicine, St. Louis, Missouri.8Anesthesiology and Intensive Care, University Hospital of Lund, Lund, Sweden.9Departments of Neurology and Neurological Surgery, University of California, San Francisco, San Francisco, California.

10Division of Neurosurgery, Addenbrooke’s Hospital and University of Cambridge, Cambridge, United Kingdom.11Neurosurgery, Lankenau Medical Center, Wynnewood, Pennsylvania.12Institute for Critical Care Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.13Division of Anaesthesia, University of Cambridge, Cambridge, United Kingdom.14Department of Intensive Care Medicine, University of New South Wales and the George Institute for Global Health, Sydney, Australia.15Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.16Department of Neurological Surgery, Baylor College of Medicine, Houston, Texas.17Department of Neurological Surgery, Vall d’Hebron University Hospital, Barcelona, Spain.18Department of Physiopathology and Transplant, Milan University and Neuro ICU Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico, Milan, Italy.19Department of Neurology, University of Southern California, Los Angeles, California.21Department of Neurology, University of California Los Angeles, Los Angeles, California.22Intensive Care Medicine, Hospital Nacional Professor Alejandro Posadas, Buenos Aires, Argentina.23Department of Neurological Surgery, University of New Mexico, Albuquerque, New Mexico.

JOURNAL OF NEUROTRAUMA 32:1722–1724 (November 15, 2015)ª Mary Ann Liebert, Inc.DOI: 10.1089/neu.2015.3976

1722

JOURNAL OF NEUROTRAUMA 32 (2015):1722–1724

CONSENSUS STATEMENTS BEST TRIP •  Statement 1 (100% Consensus)

•  The BEST-TRIP trial compared two management protocols for treatment of severe TBI: one involving ICP monitoring and the other involving serial CT imaging and neurologic examination

•  Statement 2 (100% Consensus) •  The BEST TRIP trial found no difference in outcome between

patients treated according to BTF guidelines and patients treated according to a novel standardized protocol of sequential CT imaging and clinical examination



•  The previously unstudied Imaging and Clinical Examination (ICE) protocol may lead to non-inferior clinical outcomes, compared with the BTF guidelines

•  Statement 4 (94% Consensus) •  The external validity of the BEST TRIP trial is low, primarily due to

unquantified uncertainties surrounding the influence of the prehospital environment and rehabilitation



•  Further investigation is necessary in the areas of selection of patients for ICP monitoring, determination of patient-specific ICP thresholds and development of treatment methods and paradigms

•  Statement 6 (94% Consensus) •  For those currently monitoring ICP, the results of the BEST TRIP

trial should not change their practice


MULTIMODALES MONITORING PbtO2, SjvO2, NIRS •  „We suggest the use of brain oxygen monitoring to assist titration of

medical and surgical therapies to guide ICP/CPP therapy“ •  „Observational studies suggest a potential benefit when PbtO2-guided

therapy is added to a severe TBI management protocol“ •  „We recommend that brain oxygen monitors be used with clinical

indicators and other monitoring modalities for accurate prognostication“



MULTIMODALES MONITORING AUTOREGULATION •  „Continuous bedside monitoring of autoregulation is now feasible, and

we suggest that should be considered as a part of MMM“ •  „We suggest that monitoring and assessment of autoregulation may be

useful in broad targeting of cerebral perfusion management goals and prognostication in ABI“



PRx CPPopt •  CPP vs PRx •  CPPopt = CPP mit dem tiefsten PRx


2456 Crit Care Med 2012 Vol. 40, No. 8

Survival after traumatic brain injury (TBI) is dependent on the control of intracranial hy-pertension and the provision

of hemodynamic support to achieve an “adequate” cerebral perfusion pressure (CPP). However, the idea of a single val-ue (or even a single range) of CPP being

adequate for the diverse group of TBI patients is an oversimplification (1–3). Age and premorbid arterial blood pres-sure (ABP) are examples of factors likely to influence individual CPP targets, with elderly, hypertensive patients requiring a higher CPP compared with young, nor-motensive patients. Although multimodal brain monitoring, including continuous brain-tissue oxygenation, near infrared spectroscopy, transcranial Doppler ul-trasonography, and microdialysis pro-vide valuable information at the bedside regarding the adequacy of CPP, these technologies are costly and restricted to a relatively small number of specialized neurocritical care units. The 2007 Brain Trauma Foundation guidelines advocated randomized controlled trials to verify the feasibility and the impact on outcome of strategies based on individualized CPP management following severe TBI (4). A method for individualization of CPP-oriented management based on deter-mination of cerebrovascular reactivity

Objectives: We have sought to develop an automated methodol-ogy for the continuous updating of optimal cerebral perfusion pres-sure (CPPopt) for patients after severe traumatic head injury, using continuous monitoring of cerebrovascular pressure reactivity. We then validated the CPPopt algorithm by determining the association between outcome and the deviation of actual CPP from CPPopt.

Design: Retrospective analysis of prospectively collected data.Setting: Neurosciences critical care unit of a university

hospital.Patients: A total of 327 traumatic head-injury patients admit-

ted between 2003 and 2009 with continuous monitoring of arterial blood pressure and intracranial pressure.

Measurements and Main Results: Arterial blood pressure, intra-cranial pressure, and CPP were continuously recorded, and pressure reactivity index was calculated online. Outcome was assessed at 6 months. An automated curve fitting method was applied to de-termine CPP at the minimum value for pressure reactivity index (CPPopt). A time trend of CPPopt was created using a moving 4-hr win-dow, updated every minute. Identification of CPPopt was, on average, feasible during 55% of the whole recording period. Patient outcome

correlated with the continuously updated difference between medi-an CPP and CPPopt (chi-square = 45, p < .001; outcome dichotomized into fatal and nonfatal). Mortality was associated with relative “hy-poperfusion” (CPP < CPPopt), severe disability with “hyperperfusion” (CPP > CPPopt), and favorable outcome was associated with smaller deviations of CPP from the individualized CPPopt. While deviations from global target CPP values of 60 mm Hg and 70 mm Hg were also related to outcome, these relationships were less robust.

Conclusions: Real-time CPPopt could be identified during the re-cording time of majority of the patients. Patients with a median CPP close to CPPopt were more likely to have a favorable outcome than those in whom median CPP was widely different from CPPopt. Deviations from individualized CPPopt were more predictive of out-come than deviations from a common target CPP. CPP manage-ment to optimize cerebrovascular pressure reactivity should be the subject of future clinical trial in severe traumatic head-injury patients. (Crit Care Med 2012; 40: 2456–2463)

KEY WORDS: cerebral perfusion pressure; cerebrovascular pres-sure reactivity; intracranial pressure; longitudinal recording clini-cal outcome; traumatic brain injury

Neurologic Critical Care

Continuous determination of optimal cerebral perfusion pressure in traumatic brain injury*

Marcel J. H. Aries, MD; Marek Czosnyka, PhD; Karol P. Budohoski, MD; Luzius A. Steiner, MD, PhD; Andrea Lavinio, MD; Angelos G. Kolias, MSc, MRCS; Peter J. Hutchinson, PhD, FRCS (SN); Ken M. Brady, MD; David K. Menon, PhD; John D. Pickard, FRCS (SN), FMedSci; Peter Smielewski, PhD

*See also p. 2526.From the Division of Neurosurgery (MJHA, MC,

KPB, AL, AGK, PJH, JDP, PS), Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK; Department of Neurology (MJHA), University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands; Department of Anaesthesia (LAS), Lausanne University Hospital, Lausanne, Switzerland; Neurosciences Critical Care Unit (AL, DKM), Addenbrooke’s Hospital, Cambridge, UK; and Department of Anesthesiology and Critical Care Medicine (KMB), Texas Children’s Hospital, Houston, TX.

The software for brain monitoring ICM+ (http://www.neurosurg.cam.ac.uk/icmplus) is licensed by the University of Cambridge (Cambridge Enterprise). Mr. Czosnyka and Mr. Smielewski have a finan-cial interest in a part of the licensing fee. Dr. Aries received a travel grant from the European Federation of Neurological Societies (EFNS), and is supported by the Netherlands Organisation for Health Research and Development. Dr. Steiner is supported by a grant from the Swiss National Science Foundation. Dr. Kolias is supported by an National Institute for Health Research

(NIHR) Academic Clinical Fellowship and a Raymond and Beverly Sackler Studentship. Mr. Hutchinson is supported by an Academy of Medical Sciences/Health Foundation Senior Scientist Fellowship and grants from the Medical Research Council/NIHR. Mr. Menon is sup-ported by funding from the Medical Research Council, the NIHR Cambridge Biomedical Centre, and an NIHR Senior Investigator award. Mr. Pickard is a NIHR senior inves-tigator awardee and a principal investigator within the NIHR Biomedical Research Centre (Cambridge University Hospital Foundation Trust) and lead principal investiga-tor for the Medical Research Council “Acute Brain Injury Programme” grant. The authors acknowledge great support from Addenbrooke’s Hospital Neurocritical Care Unit staff and Academic Neurosurgical Unit registrars, without whose help the collection of computerized data never would have succeeded. The remaining authors have not disclosed any potential conflict of interest.

For information regarding this article, E-mail: [email protected]

Copyright © 2012 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins

DOI: 10.1097/CCM.0b013e3182514eb6

Crit Care Med 2012; 40: 2456–2463

AUTOREGULATION

•  Retrospective analysis of prospectively collected data •  Single Center (Addenbrookes NCCU, Cambridge) •  327 traumatic head-injury patients with continuous monitoring of

arterial blood pressure and intracranial pressure •  PRx •  CPPopt •  Outcome vs. CPPopt




the need to raise the CPP, with the con-verse being true for ascending curves. Therefore, the one-sided curve gives ap-propriate clinical guidance of CPP to some extent. Interestingly, the overall dis-tribution of curve types was not different using the calculation window of 4, 12 hrs or total monitoring period, which might indicate that the current TBI CPP treat-ment regime at our center does not allow for studying the full range of CPP values. Only when the data from all patients were

pooled together the full autoregulatory range of CPP was revealed (Fig. 2).

Optimal CPP As a Threshold for Autoregulation-Oriented Therapy

The need to define optimal CPP for in-dividual TBI patients has been stressed by several authors (1–4, 13, 14). The Brain Trauma Foundation guidelines (2007) for management of severe TBI recommended that CPP should be managed within the

range of 50–70 mm Hg (level-III evi-dence). The Foundation concluded that a critical threshold for ischemia gener-ally lies in the realm of 50–60 mm Hg, and breaching such a threshold should be avoided (4). Furthermore, maintain-ing the CPP at levels that are too high (>70 mm Hg) might also have a negative influence on the outcome. A previous study by our group, including patients from the period 1992 to 2001, suggested that higher CPP levels were associated

Figure. 3. Graphs of the relationship between mortality rate (Glasgow Outcome Scale score 1), unfavorable outcome (Glasgow Outcome Scale score 1–3), se-vere disability rate (Glasgow Outcome Scale score 3), and difference between continuous calculation of median cerebral perfusion pressure (CPP) and optimal CPP using the moving window of 4 hrs (n = 299); A, The mortality increases steadily when median CPP is increasingly below the threshold of optimal CPP, and decreases slightly with increasing values above optimal CPP; B, This graph shows the asymmetrical inversed U-shaped curve between favorable outcome and the difference between the median CPP – optimal CPP; C, A nearly linear relationship between median CPP values above the optimal CPP threshold and severe disability rate can be seen; D, A U-shaped curve demonstrating that the smallest incidence of unfavorable outcome was associated with median CPP around optimal CPP.








MULTIMODALES MONITORING CEREBRALE MIKRODIALYSE •  „We suggest the use of cerebral microdialysis to assist titration of

medical therapies such as systemic glucose control, transfusion, therapeutic hypothermia, hypocapnia and hyperoxia“

•  „We recommend that cerebral microdialysis only be used in combina- tion with clinical indicators and other monitoring modalities for prognostication“




Copyright 2014 American Medical Association. All rights reserved.

Effect of Erythropoietin and Transfusion Thresholdon Neurological Recovery After Traumatic Brain InjuryA Randomized Clinical TrialClaudia S. Robertson, MD; H. Julia Hannay, PhD; José-Miguel Yamal, PhD; Shankar Gopinath, MD;J. Clay Goodman, MD; Barbara C. Tilley, PhD; and the Epo Severe TBI Trial Investigators

IMPORTANCE There is limited information about the effect of erythropoietin or a highhemoglobin transfusion threshold after a traumatic brain injury.

OBJECTIVE To compare the effects of erythropoietin and 2 hemoglobin transfusionthresholds (7 and 10 g/dL) on neurological recovery after traumatic brain injury.

DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial of 200 patients(erythropoietin, n = 102; placebo, n = 98) with closed head injury who were unable to followcommands and were enrolled within 6 hours of injury at neurosurgical intensive care units in2 US level I trauma centers between May 2006 and August 2012. The study used a factorialdesign to test whether erythropoietin would fail to improve favorable outcomes by 20% andwhether a hemoglobin transfusion threshold of greater than 10 g/dL would increase favorableoutcomes without increasing complications. Erythropoietin or placebo was initially doseddaily for 3 days and then weekly for 2 more weeks (n = 74) and then the 24- and 48-hourdoses were stopped for the remainder of the patients (n = 126). There were 99 patientsassigned to a hemoglobin transfusion threshold of 7 g/dL and 101 patients assignedto 10 g/dL.

INTERVENTIONS Intravenous erythropoietin (500 IU/kg per dose) or saline. Transfusionthreshold maintained with packed red blood cells.

MAIN OUTCOMES AND MEASURES Glasgow Outcome Scale score dichotomized as favorable(good recovery and moderate disability) or unfavorable (severe disability, vegetative, ordead) at 6 months postinjury.

RESULTS There was no interaction between erythropoietin and hemoglobin transfusionthreshold. Compared with placebo (favorable outcome rate: 34/89 [38.2%; 95% CI, 28.1% to49.1%]), both erythropoietin groups were futile (first dosing regimen: 17/35 [48.6%; 95% CI,31.4% to 66.0%], P = .13; second dosing regimen: 17/57 [29.8%; 95% CI, 18.4% to 43.4%],P < .001). Favorable outcome rates were 37/87 (42.5%) for the hemoglobin transfusionthreshold of 7 g/dL and 31/94 (33.0%) for 10 g/dL (95% CI for the difference, −0.06 to 0.25,P = .28). There was a higher incidence of thromboembolic events for the transfusionthreshold of 10 g/dL (22/101 [21.8%] vs 8/99 [8.1%] for the threshold of 7 g/dL, odds ratio,0.32 [95% CI, 0.12 to 0.79], P = .009).

CONCLUSIONS AND RELEVANCE In patients with closed head injury, neither the administrationof erythropoietin nor maintaining hemoglobin concentration of greater than 10 g/dL resultedin improved neurological outcome at 6 months. The transfusion threshold of 10 g/dL wasassociated with a higher incidence of adverse events. These findings do not support eitherapproach in this setting.

TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00313716

JAMA. 2014;312(1):36-47. doi:10.1001/jama.2014.6490

Author Audio Interview atjama.com

Related article page 85

Supplemental content atjama.com

Author Affiliations: Department ofNeurosurgery, Baylor College ofMedicine, Houston, Texas(Robertson, Gopinath); Departmentof Psychology, University of Houston,Houston, Texas (Hannay); Division ofBiostatistics, University of TexasHealth Science Center at HoustonSchool of Public Health, Houston(Yamal, Tilley); Department ofPathology and Immunology, BaylorCollege of Medicine, Houston, Texas(Goodman).

Group Information: The Epo SevereTBI Trial Investigators are listed at theend of the article.

Corresponding Author: Claudia S.Robertson, MD, Department ofNeurosurgery, Baylor College ofMedicine, One Baylor Plaza, Houston,TX 77030 ([email protected]).

Section Editor: Derek C. Angus, MD,MPH, Associate Editor, JAMA([email protected]).

Research

Original Investigation | CARING FOR THE CRITICALLY ILL PATIENT

36 jama.com

Copyright 2014 American Medical Association. All rights reserved.

JAMA. 2014;312(1):36-47

ERYTROPOIETIN AND TRANSFUSION THRESHOLD •  Randomized clinical trial of 200 patients •  To compare the effects of erythropoietin and 2 hemoglobin transfusion

thresholds (7 and 10 g/dL) on neurological recovery after traumatic brain injury

•  „Neither the administration of erythropoietin nor maintaining hemoglobin concentration of greater than 10 g/dL resulted in improved neurological outcome at 6 months“

•  „The transfusion threshold of 10 g/dL was associated with a higher incidence of adverse events“



Articles

www.thelancet.com Vol 386 December 19/26, 2015 2499

Erythropoietin in traumatic brain injury (EPO-TBI): a double-blind randomised controlled trialAlistair Nichol, Craig French, Lorraine Little, Samir Haddad, Jeff rey Presneill, Yaseen Arabi, Michael Bailey, D James Cooper, Jacques Duranteau, Olivier Huet, Anne Mak, Colin McArthur, Ville Pettilä, Markus Skrifvars, Shirley Vallance, Dinesh Varma, Judy Wills, Rinaldo Bellomo, for the EPO-TBI Investigators and the ANZICS Clinical Trials Group*

SummaryBackground Erythropoietin might have neurocytoprotective eff ects. In this trial, we studied its eff ect on neurological recovery, mortality, and venous thrombotic events in patients with traumatic brain injury.

Methods Erythropoietin in Traumatic Brain Injury (EPO-TBI) was a double-blind, placebo-controlled trial undertaken in 29 centres (all university-affi liated teaching hospitals) in seven countries (Australia, New Zealand, France, Germany, Finland, Ireland, and Saudi Arabia). Within 24 h of brain injury, 606 patients were randomly assigned by a concealed web-based computer-generated randomisation schedule to erythropoietin (40 000 units subcutaneously) or placebo (0·9% sodium chloride subcutaneously) once per week for a maximum of three doses. Randomisation was stratifi ed by severity of traumatic brain injury (moderate vs severe) and participating site. With the exception of designated site pharmacists, the site dosing nurses at all sites, and the pharmacists at the central pharmacy in France, all study personnel, patients, and patients’ relatives were masked to treatment assignment. The primary outcome, assessed at 6 months by modifi ed intention-to-treat analysis, was improvement in the patients’ neurological status, summarised as a reduction in the proportion of patients with an Extended Glasgow Outcome Scale (GOS-E) of 1–4 (death, vegetative state, and severe disability). Two equally spaced preplanned interim analyses were done (after 202 and 404 participants were enrolled). This study is registered with ClinicalTrials.gov, number NCT00987454.

Findings Between May 3, 2010, and Nov 1, 2014, 606 patients were enrolled and randomly assigned to erythropoietin (n=308) or placebo (n=298). Ten of these patients (six in the erythropoietin group and four in the placebo group) were lost to follow up at 6 months; therefore, data for the primary outcome analysis was available for 596 patients (302 in the erythropoietin group and 294 in the placebo group). Compared with placebo, erythropoietin did not reduce the proportion of patients with a GOS-E level of 1–4 (134 [44%] of 302 patients in the erythropoietin group vs 132 [45%] of 294 in the placebo group; relative risk [RR] 0·99 [95% CI 0·83–1·18], p=0·90). In terms of safety, erythropoietin did not signifi cantly aff ect 6-month mortality versus placebo (32 [11%] of 305 patients had died at 6 months in the erythropoietin group vs 46 [16%] of 297 [16%] in the placebo group; RR 0·68 [95% CI 0·44–1·03], p=0·07) or increase the occurrence of deep venous thrombosis of the lower limbs (48 [16%] of 305 vs 54 [18%] of 298; RR 0·87 [95% CI 0·61–1·24], p=0·44).

Interpretation Following moderate or severe traumatic brain injury, erythropoietin did not reduce the number of patients with severe neurological dysfunction (GOS-E level 1–4) or increase the incidence of deep venous thrombosis of the lower limbs. The eff ect of erythropoietin on mortality remains uncertain.

Funding The National Health and Medical Research Council and the Transport Accident Commission.

IntroductionTraumatic brain injury is a devastating condition associated with substantial mortality and lifelong disability.1 No multicentre, phase 3 randomised controlled trial of a neuroprotective agent in patients with traumatic brain injury has shown an improvement in a patient-centred outcome.2 However, potential exists to attenuate secondary brain injury and improve outcomes after traumatic brain injury.3,4 Erythropoietin is a glycoprotein hormone with pleiotropic cytokine-like neuro cytoprotective eff ects,5 independent of ery thropoiesis, which could aff ect the outcomes of patients with moderate or severe traumatic brain injury.5,6 Erythropoietin is neuroprotective and improves functional outcome in animal models with traumatic brain injury.7 In critically ill trauma patients, a

large multicentre randomised controlled trial showed, on post-hoc analysis, that erythropoietin reduced 29-day mortality8 but increased rates of venous thromboembolism. A recent multicentre phase 2 study of patients with traumatic brain injury reported no improvement in functional outcomes with erythropoietin.9 This factorial study of 200 patients compared two regimens of erythropoietin and had low statistical power. Thus, substantial uncertainty remains regarding the true potential for erythropoietin to favourably aff ect patient outcomes after traumatic brain injury.10

Therefore, we undertook an international, multicentre, placebo-controlled, randomised trial to assess the eff ect of erythropoietin on neurological outcomes11 following traumatic brain injury. We also actively monitored patients

Lancet 2015; 386: 2499–506

Published OnlineOctober 7, 2015http://dx.doi.org/10.1016/S0140-6736(15)00386-4

See Comment page 2452

*The Erythropoietin in Traumatic Brain Injury (EPO-TBI) trial is a collaboration of the Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group and the Australian and New Zealand Intensive Care Research Centre. A complete list of investigators in the EPO-TBI trial is provided in the appendix.

Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (Prof A Nichol PhD, L Little MBioethics, J Presneill PhD, Y Arabi MD, M Bailey PhD, Prof D J Cooper MD, Prof O Huet PhD, A Mak BScPharm, C McArthur MBChB, Prof V Pettilä PhD, S Vallance MPH, J Wills DMU, Prof R Bellomo MD); University of Melbourne, Melbourne, VIC, Australia (C French MBBS, Prof R Bellomo); The Alfred, Melbourne, VIC, Australia (Prof A Nichol, Prof D J Cooper, A Mak, S Vallance, D Varma MBBS, J Wills); School of Medicine and Medical Sciences, University College Dublin, Dublin Ireland (Prof A Nichol); St Vincent’s University Hospital, Dublin, Ireland (Prof A Nichol); Western Health, Melbourne, VIC, Australia (C French); King Abdulaziz Medical City, National Guard Health Aff airs, Riyadh, Saudi Arabia (S Haddad MD); University of Queensland, Brisbane, QLD, Australia (J Presneill); Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia (J Presneill); King Saud Bin Abdulaziz University for Health Sciences and

Lancet 2015; 386: 2499–506

EPO-TBI •  Doppelblind, placebokontrolliert, Multicenter •  606 Patienten, 40‘000E sc Erythropoietin max. 3x •  „Following moderate or severe traumatic brain injury, erythropoietin did

not reduce the number of patients with severe neurological dysfunction (GOS-E level 1–4) or increase the incidence of deep venous thrombosis of the lower limbs. The effect of erythropoietin on mortality remains uncertain“


Lancet 2015; 386: 2499–506


n engl j med 371;26 nejm.org december 25, 2014 2457

The new england journal of medicineestablished in 1812 december 25, 2014 vol. 371 no. 26

Very Early Administration of Progesterone for Acute Traumatic Brain Injury

David W. Wright, M.D., Sharon D. Yeatts, Ph.D., Robert Silbergleit, M.D., Yuko Y. Palesch, Ph.D., Vicki S. Hertzberg, Ph.D., Michael Frankel, M.D., Felicia C. Goldstein, Ph.D., Angela F. Caveney, Ph.D.,

Harriet Howlett-Smith, R.N., Erin M. Bengelink, M.A., Geoffrey T. Manley, M.D., Ph.D., Lisa H. Merck, M.D., M.P.H., L. Scott Janis, Ph.D., and William G. Barsan, M.D., for the NETT Investigators*

A BS TR AC T

From the Departments of Emergency Medicine (D.W.W., H.H.-S.) and Neurology (M.F., F.C.G.), Emory University School of Medicine and Grady Memorial Hospital, and the Department of Biostatistics, Rollins School of Public Health, Emory University (V.S.H.) — all in Atlanta; the Department of Public Health Sciences, Medical University of South Carolina, Charleston (S.D.Y., Y.Y.P.); the Depart-ments of Emergency Medicine (R.S., E.M.B., W.G.B.) and Psychiatry (A.F.C.), University of Michigan, Ann Arbor; the Department of Neurosurgery, University of California, San Francisco, San Francisco (G.T.M.); the Department of Emergency Medicine, Warren Alpert Medical School of Brown University, Providence, RI (L.H.M.); and the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (L.S.J.). Address reprint requests to Dr. Wright at 49 Jesse Hill Jr. Dr., Atlanta, GA 30303, or at [email protected].

*A complete list of the Neurological Emer-gencies Treatment Trials (NETT) inves-tigators is provided in the Supplemen-tary Appendix, available at NEJM.org.

This article was published on December 10, 2014, at NEJM.org.

N Engl J Med 2014;371:2457-66.DOI: 10.1056/NEJMoa1404304Copyright © 2014 Massachusetts Medical Society.

BACKGROUNDTraumatic brain injury (TBI) is a major cause of death and disability worldwide. Progesterone has been shown to improve neurologic outcome in multiple experimen-tal models and two early-phase trials involving patients with TBI.

METHODSWe conducted a double-blind, multicenter clinical trial in which patients with severe, moderate-to-severe, or moderate acute TBI (Glasgow Coma Scale score of 4 to 12, on a scale from 3 to 15, with lower scores indicating a lower level of consciousness) were randomly assigned to intravenous progesterone or placebo, with the study treatment initiated within 4 hours after injury and administered for a total of 96 hours. Efficacy was defined as an increase of 10 percentage points in the proportion of patients with a favorable outcome, as determined with the use of the stratified dichotomy of the Extended Glasgow Outcome Scale score at 6 months after injury. Secondary outcomes included mortality and the Disability Rating Scale score.

RESULTSA total of 882 of the planned sample of 1140 patients underwent randomization before the trial was stopped for futility with respect to the primary outcome. The study groups were similar with regard to baseline characteristics; the median age of the patients was 35 years, 73.7% were men, 15.2% were black, and the mean Injury Severity Score was 24.4 (on a scale from 0 to 75, with higher scores indicating greater severity). The most frequent mechanism of injury was a motor vehicle acci-dent. There was no significant difference between the progesterone group and the placebo group in the proportion of patients with a favorable outcome (relative ben-efit of progesterone, 0.95; 95% confidence interval [CI], 0.85 to 1.06; P = 0.35). Phlebitis or thrombophlebitis was more frequent in the progesterone group than in the placebo group (relative risk, 3.03; CI, 1.96 to 4.66). There were no significant differences in the other prespecified safety outcomes.

CONCLUSIONSThis clinical trial did not show a benefit of progesterone over placebo in the im-provement of outcomes in patients with acute TBI. (Funded by the National Institute of Neurological Disorders and Stroke and others; PROTECT III ClinicalTrials.gov number, NCT00822900.)



N Engl J Med 2014;371:2457-66

PROTECT III TRIAL

•  Doppelblind, placebokontrolliert, Multizenter •  882 Patienten (vorzeitig abgebrochen 1140 geplant) •  „This clinical trial did not show a benefit of progesterone over placebo

in the improvement of outcomes in patients with acute TBI“


N Engl J Med 2014;371:2457-66


Surgical Neurology International Editor:James I. Ausman, MD, PhD University of California, Los Angeles, CA, USA

OPEN ACCESSFor entire Editorial Board visit : http://www.surgicalneurologyint.com

© 2015 Surgical Neurology International | Published by Wolters Kluwer - Medknow

AbstractBackground: Intracranial hypertension, defined as an intracranial pressure (ICP) >20 mmHg for a period of more than 5 min, worsens neurologic outcome in traumatic brain injury (TBI). While several mechanisms contribute to poor outcome, impaired cerebral perfusion appears to be a highly significant common denominator. Management guidelines from the Brain Trauma Foundation recommend measuring ICP to guide therapy. In particular, hyperosmolar therapy, which includes mannitol or hypertonic saline (HTS), is frequently administered to reduce ICP. Currently, mannitol (20%) is considered the gold standard hyperosmolar agent. However, HTS is increasingly used in this setting. This review sought to compare the efficacy of mannitol to HTS in severe TBI.Methods: The PubMed database was used to systematically search for articles comparing mannitol to HTS in severe TBI. The following medical subject headings were used: HTS, sodium lactate, mannitol, ICP, intracranial hypertension, and TBI. We included both prospective and retrospective randomized controlled studies of adult patients with intracranial hypertension as a result of severe TBI who received hyperosmolar therapy.Results: Out of 45 articles, seven articles were included in our review: 5 were prospective, randomized trials; one was a prospective, nonrandomized trial; and one was a retrospective, cohort study.Conclusions: While all seven studies found that both mannitol and HTS were effective in reducing ICP, there was heterogeneity with regard to which agent was most efficacious.

Key Words: Hypertonic saline, intracranial pressure, mannitol, traumatic brain injury

INTRODUCTION AND BACKGROUND

Sustained intracranial hypertension, defined as an intracranial pressure (ICP) >20 mmHg for a period of more than 5 min, has been demonstrated to worsen neurologic outcome for patients with traumatic brain injury (TBI). While several mechanisms contribute to poor outcome, impaired cerebral perfusion appears

Review Article

Mannitol or hypertonic saline in the setting of traumatic brain injury: What have we learned?Myles Dustin Boone, Achikam Oren-Grinberg, Timothy Matthew Robinson1, Clark C. Chen2, Ekkehard M. Kasper1

Department of Anesthesiology, Beth Israel Deaconess Medical Center, 1Department of Surgery, Division of Neurosurgery, Beth Israel Deaconess Medical Center, Boston, MA, 2Division of Neurosurgery, UCSD Medical Center, San Diego, CA, USA

E-mail: *Myles Dustin Boone - [email protected]; Achikam Oren-Grinberg - [email protected]; Timothy Matthew Robinson - [email protected]; Clark C. Chen - [email protected]; Ekkehard M. Kasper - [email protected] *Corresponding author

Received: 04 June 15 Accepted: 18 September 15 Published: 23 November 15

Access this article onlineWebsite:www.surgicalneurologyint.comDOI: 10.4103/2152-7806.170248 Quick Response Code:

How to cite this article: Boone MD, Oren-Grinberg A, Robinson TM, Chen CC, Kasper EM. Mannitol or hypertonic saline in the setting of traumatic brain injury: What have we learned?. Surg Neurol Int 2015;6:177.http://surgicalneurologyint.com/Mannitol-or-hypertonic-saline-in-the-setting-of-traumatic-brain-injury:-What-have-we-learned?/

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

For reprints contact: [email protected]

Surg Neurol Int. 2015; 6: 177

HTS VS. MANNITOL

•  Hämodynamik •  Plasmaexpansion und zentrale Stimulation Cardiac Output

•  Immunmodulation, Anti-Inflammation •  TNFalpha vs. IL-ra, IL-10

•  Neurochemie •  Na+/Glutamat-Co-Transport reduziert Glutamat extrazellulär

•  Mikrozirkulation •  Verbesserung Mikrozirkulation und DO2


Surg Neurol Int. 2015; 6: 177

HTS VS. MANNITOL

•  Einfacheres Monitoring •  hyperosmolares Nierenversagen? •  Bisher keine pontine Myelinolyse beschrieben

•  Mannitol ist altbewährt •  Chlorid-Belastung?




n engl j med nejm.org 1

From the Centre for Clinical Brain Sci-ences (P.J.D.A.), Department of Anaes-thesia, Critical Care, and Pain Medicine (H.L.S., B.A.H., C.G.B., J.K.J.R.), and Centre for Population Health Sciences (A.R., G.D.M.), University of Edinburgh, and Critical Care, Western General Hos-pital, NHS Lothian (B.A.H., J.K.J.R.) — all in Edinburgh. Address reprint requests to Dr. Andrews at Ward 20, Intensive Care Unit, Western General Hospital, Crewe Rd., Edinburgh EH4 2XU, United King-dom, or at p . andrews@ ed . ac . uk.

* A complete list of investigators in the European Study of Therapeutic Hypo-thermia (32–35°C) for Intracranial Pres-sure Reduction after Traumatic Brain Injury (the Eurotherm3235 Trial) is pro-vided in the Supplementary Appendix, available at NEJM.org.

This article was published on October 7, 2015, at NEJM.org.

DOI: 10.1056/NEJMoa1507581Copyright © 2015 Massachusetts Medical Society.

BACKGROUNDIn patients with traumatic brain injury, hypothermia can reduce intracranial hyper-tension. The benefit of hypothermia on functional outcome is unclear.

METHODSWe randomly assigned adults with an intracranial pressure of more than 20 mm Hg despite stage 1 treatments (including mechanical ventilation and sedation manage-ment) to standard care (control group) or hypothermia (32 to 35°C) plus standard care. In the control group, stage 2 treatments (e.g., osmotherapy) were added as needed to control intracranial pressure. In the hypothermia group, stage 2 treatments were added only if hypothermia failed to control intracranial pressure. In both groups, stage 3 treatments (barbiturates and decompressive craniectomy) were used if all stage 2 treatments failed to control intracranial pressure. The primary outcome was the score on the Extended Glasgow Outcome Scale (GOS-E; range, 1 to 8, with lower scores indicating a worse functional outcome) at 6 months. The treatment effect was estimated with ordinal logistic regression adjusted for pre-specified prognostic factors and expressed as a common odds ratio (with an odds ratio <1.0 favoring hypothermia).

RESULTSWe enrolled 387 patients at 47 centers in 18 countries from November 2009 through October 2014, at which time recruitment was suspended owing to safety concerns. Stage 3 treatments were required to control intracranial pressure in 54% of the patients in the control group and in 44% of the patients in the hypothermia group. The adjusted common odds ratio for the GOS-E score was 1.53 (95% confi-dence interval, 1.02 to 2.30; P = 0.04), indicating a worse outcome in the hypother-mia group than in the control group. A favorable outcome (GOS-E score of 5 to 8, indicating moderate disability or good recovery) occurred in 26% of the patients in the hypothermia group and in 37% of the patients in the control group (P = 0.03).

CONCLUSIONSIn 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. (Funded by the National Institute for Health Research Health Technology Assess-ment program; Current Controlled Trials number, ISRCTN34555414.)

A BS TR AC T

Hypothermia for Intracranial Hypertension after Traumatic Brain Injury

Peter J.D. Andrews, M.D., M.B., Ch.B., H. Louise Sinclair, R.G.N., M.Sc., Aryelly Rodriguez, M.Sc., Bridget A. Harris, R.G.N., Ph.D.,

Claire G. Battison, R.G.N., B.A., Jonathan K.J. Rhodes, Ph.D., M.B., Ch.B., and Gordon D. Murray, Ph.D., for the Eurotherm3235 Trial Collaborators*

Original Article



N Engl J Med 2015; 373:2403-2412



Hypothermia for Intr acr anial Hypertension

The inclusion criteria were changed in Janu-ary 2012, on the basis of the pilot-phase find-ings,23 to remove an upper age limit (previously 65 years) and to increase the time from injury from 72 hours to 10 days. These changes allowed the enrollment of older patients and those with evolving brain swelling.

ICUs in hospitals that provide specialist neu-rologic treatment for traumatic brain injury were

recruited (25 centers in the United Kingdom and 39 elsewhere). Evidence of expertise with intra-cranial-pressure monitoring and therapeutic cooling were necessary.

Data CollectionAn online case-report form (Lincoln, Paris) was used for collection of data (Fig. S8 in the Supple-mentary Appendix), including baseline demo-

Figure 1. Stages of Therapeutic Management and Trial Follow-up.

CSF denotes cerebrospinal fluid, EEG electroencephalographic, GOS-E Extended Glasgow Outcome Scale, ICU inten-sive care unit, and MOHS modified Oxford Handicap Scale.

Intracranial pressure >20 mm Hg within 10 days after injury

Stage 3 Options (if required)

Day 28, Hospital Discharge, or DeathMOHS grade, length of stay in ICU and hospital

6-Mo Follow-upGOS-E score

Stage 1

Stage 2

Stage 3

Trial Follow-up

Traumatic Brain InjuryStage 1 treatment:

Admission to ICUMechanical ventilationSedationAnalgesia with or without paralysisHead of bed elevated to 30 degrees Intravenous fluids with or without inotropes to maintain

mean arterial pressure ≥80 mm HgStage 1 options:

Ventriculostomy with or without CSF drainageSurgical removal of space-occupying lesions

Control GroupContinue stage 1 treatments and add stage 2

treatments without therapeutic hypothermiaStage 2 treatment:

Mannitol (maintain serum osmolarity<315 mOsm per kilogram of water)

Hypertonic saline (avoid in hyponatremia,caution with cardiac or pulmonary problems)

Inotropes to maintain cerebral perfusionpressure ≥60 mm Hg

Barbiturates not permitted

Hypothermia GroupContinue stage 1 treatments and initiate

hypothermiaAdd stage 2 treatments only if neededBarbiturates not permitted

Continued medical careBarbiturate therapy with processed EEG monitoringDecompressive craniectomyFurther surgical intervention if required



EUROTHERM3235 TRIAL

•  Multizenter •  347 Patienten (600 geplant, abgebrochen for safety reasons) •  Standard care + Osmotherapie vs. Standard care + Hypothermie

•  „In patients with an intracranial pressure of more than 20mmHg 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“


EUROTHERM3235 TRIAL

•  Hypothermie senkt ICP, ändert nichts am Outcome •  Nicht als frühe Therapieoption •  Rescue Therapie vor Kraniektomie •  Ziel 35°C, kein Überschiessen beim Aufwärmen •  Aufwärmen? Wie? •  Fieberkontrolle ist wichtig!


ZUSAMMENFASSEND PRAKTISCHE ASPEKTE •  BLS, BICS •  SHT-Protokoll mit festgelegten Therapiemodalitäten

•  Sedation •  Liquordrainage, Entfernung Raumforderungen •  Osmotherapie •  Hypothermie •  Kraniektomie


ZUSAMMENFASSEND PRAKTISCHE ASPEKTE •  Multimodales Monitoring

•  Sondenlage? Läsion? Penumbra? •  Messwerte plausibel? Fehlmessungen?

•  Individualisierte Vital- und Zielparameter mit Hilfe des MMM •  ICP, PbtO2, Mikrodialyse, PRx/CPPopt



Glucose ⇓

ptiO2⇓

Ischämie (DO2 ⇓) - CBF/CI - CPP/ICP - caO2

DO2 ⇑ ⇑ CPP/CBF/CI ⇓ ICP ⇑ caO2 (SpO2, Hb)

ptiO2 N

VO2 ⇑ ± Hypoglycämie - Fieber - Krampf

VO2 ⇓ Sedation Temp. Kontrolle Anticonvulsiva Ernährung/Glucose

LPR ⇑

Pyruvat ⇓ (+ ptiO2⇓)

ischäme Hyperglycolyse DO2 ⇓ - CBF/CI - CPP/ICP - caO2

DO2 ⇑ ⇑ CPP/CBF/CI ⇓ ICP ⇑ caO2 (SpO2, Hb)

Pyruvat N / ⇑ (+ ptiO2 N)

non-ischäme Hyperglycolyse VO2 ⇑ - mitoch. Dysfunktion - Fieber - Krampf

VO2 ⇓ Sedation Temp. Kontrolle Anticonvulsiva Ernährung/Glucose

KLINIK STEPHANSHORN BRAUERSTRASSE 95 CH-9016 ST. GALLEN

HERZLICHEN DANK MED. PRACT. THOMAS BRUNNER STV. LEITER ANÄSTHESIE/INTENSIVMEDIZIN


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