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`MYLAN PHARMS. INC. EXHIBIT 1119 PAGE 1
`
`

`

`TTilUilIfl
`
`Critical Care
`
`VoLUME 2
`
`edited [y
`William G. lililson, lUlll, M[
`Directororo,",t/llf E',!;3'3if,n';,tcareproqram
`. . Depa.rtment of Anestneii'otogy ana Criticit;;;
`5 in o oi or' nii di" i, e
`u n i v e r s i ty of c a t i f o r n i +,8:
`t ?,li! n
`Director of Trauma Anesthesia
`Associate Director Surgical tntensive Care lJnit
`UC San Diego-Medical Center
`San Diego,-California, U.S.A.
`
`Christo[hff M. G]ande, Mlf, Mpll
`r n t e r n a t ilJZi f:: : i :E ::g' (, ro c, s )
`Ba lti more, Ma ryl a nd, u.S.A.
`llauid B. lfout, lUlD, mCS
`John E. Connolly professor and Chairman
`De-partment of Surgery
`University of Catifornia, Schdot 6f Medicine
`,, I #i : 3',,f :! {f: i:",,
`",
`O ra nge, Ca lifo rn i a, U.S.A.
`
`informa
`
`healthcare
`
`New York London
`
`tf
`
`.
`
`II tIrI I
`
`I)
`
`III I Itt t,
`
`MYLAN PHARMS. INC. EXHIBIT 1119 PAGE 2
`
`

`

`lnforma Healthcare USA, Inc'
`52 Vanderbilt Avenue
`New York, NY 10017
`o 2007 by Informa Healthcare USA, lnc'
`lnforma Healthcare is an Informa business
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`No claim to original U.S Government works
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`ro98765432
`International Standard Book Number-1 O: 0 -8247 -2920 -X (Hardcover)
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`Library of Congress Cataloging-in-Publication Data
`Trauma / edited by William C. Wilson, Christopher M Grande, David B Holt'
`P'; cm'
`Includes bibliographical references and index,
`(hardcover : v' 1 : alk' paper)
`ISBN-l3: 978-0-8247-2919-6 (hardcover : v. I : alk. pape$, lsBN-I0:0-8217-2979-6
`ISBN-13: 97g-0-8247-2920-2 (hardcover: r'.2: alk. paper), ISBN-10:0-8247-2920-X (hardcover: v.2; alk paper) l"Wounds and iniuries
`--Treatment. 2. Surgical emergencies. 3. Critical care medicine . l. Wilson, William C. II. Grande, Christopher M III' Hoyt' David B'
`IDNLM: l. wounds and Injurls.2. critical care.3. Emergencies. vo 700T773520071
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`\/isit the Informa Web site at
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`MYLAN PHARMS. INC. EXHIBIT 1119 PAGE 3
`
`

`

`11
`
`1'l
`
`Effect of Carbon Dioxide Tension . . . . 10
`Effect of Oxygen Tension. . . . 10
`NeurogenicControl.... 10
`i
`Measurement of Cerebral Blood Flow . . .
`Statcs of Brnin Actiztity . . . . LL
`Consciousness and Unconscrousness . . .
`Sleep....11
`Seizures....11
`Anesthesia....1l
`BrainstemDeath....ll
`Pathophysiology . . . . 17
`Gross Patlnlogy ....11
`Contusion....ll
`Hemorrhage....11
`Diffuse Axonal lnjury . ... 1.2
`CellDeath....12
`Necrosis....12
`Apoptosis....12
`Hybrid Necrosis-Apoptosis/
`Necrosis-Apoptosis Spectrum . . . . 12
`Mecharisnts of CelI Death . . . .12
`Excitotoxicity. . .. 12
`Oxidative Stress. . . . 13
`Calcium-Sensitive Enzyme Activation. ... 13
`The Role of Mitochondria . . . . 13
`Inflammation....13
`GeneExpression....13
`Raised lntrnqanial Pressure . . . . 13
`Changes in Cerebrnl Circulatiott Following
`Trnunotic Brain In jury . . . .14
`Cerebral Blood Flow... . 14
`Autoregulation and Vasoreactivity . . . . 1.4
`Mechanisms....14
`Physiological Basis of Treatment Models . . . . 14
`Metabolic and Neuroendocrine Contplications of
`Trnunrntic Brnin Injury . . . . 14
`Cerebral Metabolism. . . . 14
`Basal Metabolic Rate. . . . 14
`Sync-lrome of Inappropriate ADH
`Secretion....15
`Diabetes lnsipidus. . . . 15
`Disturbed Glucose Metabolism.. . . 15
`Hypothalamic and Pituitary Injury. . . . 15
`Spinal Cord Pathophysiology . . . . 15
`Drugs, Anesthesia, Intensiae Care, and
`Neuroprotection. . .. L5
`Anesthesia and Intensive Care. . . . 15
`Neuroprotection. . . .16
`Eye to the Future ....L7
`Summary ....18
`KeyPoints. ..18
`References....79
`
`IIf T
`
`2.
`
`Pulmonary Physiology Review. . . . 23
`Slmmsuddin Akhtar
`
`I
`Introduction....23
`r Mechanics of Respiration . . . .23
`Luttg Volwnes and Capacities . . . .23
`Minut e Ventilatiort ( Alaeol ar Ventilat ion gnd
`Spncc)...,23
`
`Dend
`
`xilt
`
`Forrutord Richard Henry Carmona. . . .7)
`Formtord Peter J. F. Baskett . . . . ui
`Foreword Paul E. Pepe....uii
`Forsword Kenneth L. Manox .... uiii
`Preface....ix
`Ackrtozuledgnrents. . . . xi
`Contributors . .. . xhtii
`
`SECIION A: BillSlG SGIENCE PRE4EW
`Sec'tion Edilon Rahul landial
`
`1. Neurophysiology Review.... 1
`Paul Picton and Charles D. Denkin
`I Introduction....l
`r Applied Anatomy....1
`Brnitr....7
`Four Major Lobes (Frontal. parietal,
`Temporal, and Occipital). . . . 1
`CerebralCortex....l
`Thalamus, Hypothalamus, and the Basal Ganglia . .
`Cerebellum and Cerebellar Cortex. . . . 2
`Brnittstem....3
`SpinalCord....3
`Arterinl Supply nnd Venous Drainnge of the
`Cuttral Nen-totts System . .. . 3
`Brain ancl Brninstem.... J
`SpinalCord....3
`Cerebrospitnl Fluid System . . . . 4
`Blood-Brnin Barrier . ... S
`Ccllular Elements .... S
`Autortomic Nen",ous Sastetn .. . . 5
`Sympathetic (Thoraco-Lumbar) . . . . 5
`Parasympathetic (Cranio-sacral) . . .. 5
`Neurotransmission (Cholinergic vs.
`Adrenergic) and Receptor Subtypes . . . .6
`AutonomicTone....T
`Location of Higher hftellectual Brnin Functiorrs . . . .7
`Speech and Language.. . . 7
`Memory. . . .7
`Physiology.. . . 7
`Inrpulse Generntion . . . . 7
`Membrane Structure. . . . Z
`Transport Across Membranes. . . . 7
`Resting Membrane Potential.. . . 8
`ActionPotential ....8
`Metabolism....8
`Aerobic and Anaerobic Metapolism. . .
`SiO2, AVDOT, and CMRO2. . . .9
`Brain Parenchymal Gas Tensions . . . . 9
`Intrncranial Pressure . . . . 9
`The Monro-Kellie Doctrine. . . . 9
`Measurement of Intracranial Pressure .
`Cerebral Perfusion Pressure and
`Intracranial Presstrre. . . . l0
`Cerebral Blood Flotu . . . . 10
`Autoregulation....l0
`
`MYLAN PHARMS. INC. EXHIBIT 1119 PAGE 4
`
`

`

`xtv
`
`Contents
`
`Lung Ctntpliance . . . . 25
`Airutay Resistance . . . . 26
`Work of Brenthing . . . . 27
`Pulmonary Circulation . . . . 27
`Fnctors Affecting Regionnl Pulntotmnl Blood
`Floro....27
`ZonesofWest....28
`F actors Affectittg P ulmotnry Vasc rlnr
`Resistance....28
`Cardiac Output/Perfusion Pressure.., . 28
`LungVolume.-..28
`Hypoxia....28
`Metabolic and Humoral Control . . . .29
`NeuralControl ....29
`Gas Exchange in the Lung . . . .29
`Ventilation-Perfusion Relntiottship in the Luttg . . . .29
`Shunt, Dead Space, and Efcct of V lQ lnequalifi on
`Ot,erall Gas Exclrarrge . . . . 30
`Diffttsion of Gases: The Blood-Gas Barricr . . . .30
`Aluettlar Gas Composition . . . . 31
`Gas Transport Between Lungs and Tissues . . . .32
`Oxygen Deliaery Conceytts . . .. 32
`Deterninants of 02 Deliuery . . . . 32
`Structural Biology of Hemoglobin. . . . 32
`O2-Hemoglobin Disassociation Curve. . . .32
`Carbon Dioxide Transport . . . . 34
`Pathn'ays of CO2 Transport . . . .34
`CO2 Dissociation Curve. . . .34
`Regulation of Breathing. .. . 35
`Ncural Control of Breathing . . . .35
`Chemicnl Control of Breathing .. . . J6
`Effect of CO2 on Ventilatory Response . . . .36
`Influence of 02 on Respiratory Control . . . .37
`Integrated Effects of pCO2, pH, and pC)2 on
`Respiratory Control. . . . 37
`Nonchemical Puhnonary ReJlexes . . . . 37
`Heart-Lung Interactions . . . . 37
`Effect of Pleural Pressure on preload and
`Afterload . .. .37
`Eft'ct of Alaettlar Presswe on preload and
`Afterload. . . .38
`Effect of Positioe End Expirntory pressure on
`Cnrdiac Function . .. . 38
`Re.flex Effects of Lung lnflntion on
`Henrcdynanics....38
`Respiratory Physiology at Extremes of Age
`andPregnancy....38
`Respiratory Changes in tlrc Elderly. . . . 3g
`Structural Alterations in the Upter and
`Lor,r'er Airwa1,s. . . . J8
`Changes in Respiratory Mechanics and Lunq
`Volume. . . .38
`Impaired Efficiency of Gas Exchange . . . .3g
`Alterations in Ventilatorl. Drive. . . .39
`Clinical Implications. . . . 39
`Respiratory Changes in the Neonate . . . .39
`Structural Alterations in the Upper ancl
`LowerAirways....39
`Changes in Respiratory Mecl.ranics and Lurrq
`Volume. . . .39
`Impaired Efficiency of Gas Exchange . . . .39
`Alterations in Ventilatory Drive . . I. +0
`Clinical Implications. . . . 40
`.C.h.anges Durirrg prcgnntrctl . . . .40
`Resp.irat.ory
`Structural Alterations in the Upper and
`Lower Airrvays....40
`Changes in Respiratory Mechanics and Lung
`Volume. . . .40
`Impaired Eff. iciency of Gas Exchan ge . . . . 40
`Alterations in Ventilatory Dr.ive . . ].40
`
`Clinical Implications. . . . 40
`I Nonpulmonar), Fullction of the Lur-rg . . . . 40
`r Respiratory Adjustment in Healtl-r and
`Disease ....41
`r Eye to the Future . . . .47
`I Summary....42
`o- Ke1'Points....42
`I References....43
`
`3. Cardiovascular Physiology Review. . . .45
`Cerard R. Mnnccke, lr. and Daz,id M. Roth
`r Introduction....45
`r The Pumping Mechanism of the Heart and
`Mechanics of the Vascular System . . . .45
`The Flotu of Blood in the Cardiouascular
`System....45
`Local Cttntrol of Cardiac FtLttctiort . . . .45
`TIrc Cnrdiac Work Loop: " PrcsstLre WLtrk"
`and "Voltnne Work" .. . . 47
`The Effect of Respirntion on Ciruilatory
`Mechnnics....48
`Neural Cotttrol of Cnrdiouasuilar
`Ftutction....48
`Hunornl Cortrol of
`Cardioaasnilar Furctiort . . . . 49
`r Cardiac Cellular Physiology . . . .49
`CelIuIar Homeostasis and Excitfttion-Contractiort
`Coupling....49
`Myocnrdial Orygen Balance . . . . 49
`r Cardiac Electrophysiologlt .... 51
`Celhtlnr Electroplrysiology and tlrc Cardinc
`Action Potentinl . . . . 51
`Tlte Nornnl Cnrdiac Conduction SystenL . . . . 52
`Tlre PatlrcTlrysiology of Connnon
`Dysrhythnins....52
`r The Cardiac Cycle and the Central
`Venous Waveforms ... . 53
`r The Pathophysiology of Conditions
`Commonly Associated with Trauma . . . . 54
`Hypooolentia....54
`Cardiac Tamltonode . . . . 54
`Tensiort Pneumothorax. . . . 55
`Cardinc Contusion . . . . 56
`HeadTraumn....56
`r Eye to the Future . . . .56
`I Summary....56
`r Key Points. . ..56
`I References....57
`
`4. Clinical Pharmacology Review. . . .59
`Doug Hunfuu. nnd Fariuar lahansouz
`I Introduction....59
`Pharnmcokinetics . .. . 59
`Bioavailability. . . . 59
`Volume of Distribution. . . . 59
`Proteir.r Binding. . . . 60
`Clearance. . . .60
`Half-Life....61
`Plnrmacodynamics . . . . 6L
`r Alteratiorr of Pharmacokinetic and
`Pharmacod;'namic parameters in the
`CriticallyIll....6l
`OrganFailure....61
`Renal....62
`Hepatic. . . .63
`
`.,J
`
`MYLAN PHARMS. INC. EXHIBIT 1119 PAGE 5
`
`

`

`Contents
`
`Local Anesthetics (Sodium Chnnnel Blockers) . . . . g0
`Opittids....81
`General Considerations. . . . 81
`Specific Opioids. . . . 8t
`Relative Potencies of Opioids. . . . 8J
`Adverse Side Effects of Opioid Therapy . . . . 83
`Sedatiue, Hypnotic, and Anxiolytic DrLgs . . . .94
`Benzodiazbpines. . . . 84
`Propofol....85
`Dexmedetomidine. . . .85
`Ketamine....86
`Neuroleptic Drugs .. . . 86
`Skeletal MtLscle Antispasticity Dntgs . . . .86
`()tlrcr Analgesic Agents .. . . 86
`Routes ttf Adrtinistratiort . . . . 87
`Intravenous Route. . . . 87
`Intramuscular Injections. . . . 88
`Enteral Administration. . . . 88
`Clinical Assessment of Pain and Sedation . . . . BB
`Pain Assessment Scores . . . . 88
`Sedatiotr Scoring Tools nnd Electric Brain
`Actiaity Monitoring . . . . 89
`SedationScores....8g
`Electric Brain Activity Monitoring. . . .89
`Assesstnettt of Delirium . . . . 90
`Analgesia and Sedation for Acute Trauma . . . . g0
`Prchospitnl Consitleratiorrs . . . . 91
`Ceneral Approach and Recommendations. . . . 91
`Specific Prehospital Scenarios. . . . 92
`Trnuma Resuscitation Suite Considerntions . ... 92
`Ceneral Approach and Recommendations . . . .92
`Specific Trauma Resuscitation Suite
`Scenarios. . . .92
`Anafgesia and Sectation for Critical Care . . . . g4
`Arnlgesia....94
`Sedation for Treatment of Anxiety and
`Agitntion....94
`Trea"hnent of Delirium . . . . g6nl
`Special Conditions in Trauma and Critical
`Care....96
`ThoracicTraumn....96
`Burns....95
`Organ Dysfunction. . . . 96
`Drug Addiction, Dependence, ond Tolerance . . . .97
`Age-Related Considerations . . . . 97
`Pediatric Patients.. . . 92
`Elderly Patients. . . . 98
`I Eye to the Future . . . .98
`I Summary ....98
`v" Key Points... .99
`I References. .. .99
`
`Neuromuscular Blockade for Trauma and
`CriticalCare....103
`Nitin Shah
`r Introduction....103
`r History of Neuromuscular Blocking
`Drugs....103
`r Physiology of the Neuromuscular
`function ....704
`NeuronttLsctLlar lunction Anatonry .. . . 104
`TIre Motor Nerue Terrnitnl . .. . i04
`Postjunctional Acetylcholine Receptor . . . . 1.04
`r Clinical Pharmacology of Neuromuscular
`BlockadeDrugs....105
`Depolorizittg Drugs (Succinylcholhd . . . . 106
`
`Cardiovascular....65
`Endothelial (Burn). . .. 65
`Central Nervous System. . . . 66
`Gastrointestinal., . . 66
`Respiratory....66
`Muscle Disorders. . . . 66
`Hyperdynnmic Stntc . . . . 67
`Acid-Base Disorders . . . . 67
`Drug Internctiorts . .. . 67
`Absorption. . . .67
`Distribution....67
`Metabolism (Cytochrome P450
`EnzymeSystem) ....68
`Therapeutic Drug Monitoring. . . . 68
`Antimicrobinl Agents .. . . 69
`Aminoglycosides. . . . 69
`Vancomycin....69
`Cotrimoxazole....69
`Miscell nneous An t i- i nfe c t iae
`Agents....69
`Fluconazole and
`Itraconazole....69
`Ganciclovir....69
`Cardiovasnlar DnLgs . . . . 69
`Digoxin....69
`Lidocaine....70
`Procainamide....70
`Anticonoulsants . .. . 70
`Phenytoin....70
`Carbamazepine....70
`ValproicAcid....71
`Barbiturates....71
`Imnumosuppressants . ., . 7'L
`Cyclosporine....71
`Tacrolimus....71
`Sirolimus....71
`Miscellaneous (Mycophenolate and
`Azathioprine)....72
`Drug-Induced Fever .. ..72
`Drug-Induced Rash (Toxic Epidermal
`Necrolysis/Stevens -|ohnson
`Syndrome) ....72
`Eye to the Future . . . .73
`Summary ....73
`Key Points ....74
`References ....74
`
`IIt
`
`I
`
`'
`
`SECTl0til B: ANAIGESIA, SEDATION, AND NEUR0MUSCUI-AR BTOCKADE
`Section Editor: Todd Dorman
`
`5. Analgesia and Sedation for Trauma and
`Critical Care...,77
`Benjamin I. Atwnter, Lintla Pelinko, Srdjttn Nerleljkoz,ic, antl
`Agnes Ricartl-Hibon
`
`6.
`
`t
`Introduction....77
`I Adverse Effects of Uncontroiled pain . . . .77
`t General Approach: Analgesia and Sedation
`Pvramicl ....79
`I Nlechanisms of Pain . . . .78
`Neurnl Pstlriotttls . . .. 78
`Progressiort fron ,\ctrtc to Ptrsistert pnin . . . .7g
`Preenptiue Annlgcsin antl prtin Rctillctiorr . . . .79
`I Pharmacology Review ....79
`N onst aroitlal Anti-i ttJlanmtttory D ntgs f
`Cyclooxyganse Enzynte Inhibitttrs . . . . g0
`
`ll
`
`MYLAN PHARMS. INC. EXHIBIT 1119 PAGE 6
`
`

`

`xvi
`
`Contents
`
`Nondepolarizing Drrtgs . .. . 707
`Rocuronium . '..708
`Vecuronium ....L08
`Pancuronium . ..108
`Atracurium ....109
`Cisatracurium ....109
`Other Neuromuscular Blockade Drugs Seldom Used
`in Critical Care .. .. 709
`Plmrmacokhrctics and Plnrnncodtlnarnics . . . . 709
`r Neuromuscular Blockade Antagonists.... 110
`l Disease State and Drug Interactions . . . . 110
`r Dosing Strategies ....711
`I
`Indications for Neuromuscular Blockade Drugs in
`the Critically 111 . . . . 1L2
`Relatizte Requirenrcnts . . . . 712
`Informed Anecdote ....113
`Subjective Impressions . .. 113
`Obiective Assessment . . . . 1L3
`Gonl-Directed lndications . . . . 113
`r Monitoring of Neuromuscular Blockade . . . .1L4
`Technical Aspects of Periltlrcrnl Nerce Stitrrulator
`Mortitoring....174
`Single Stimulus. .. . 114
`Train-of-Four Stimulation . . . . 114
`Tetanic Stimulation .... 114
`Post-tetanic Facilitation or
`Potentiation ....115
`Double-Burst Stimulation . . . . 115
`Ozterestimntittn and Underest imat ion of
`Neuronruscular Blocknde Using a
`Peripheral Nertte Stimulntor . . . . 776
`P r ecatLt io ns Whi I c Usi ng P eriyther nl
`Nerae Monitorins . . . . 1L7
`r Prolonged Motor Weakness Following
`Neuromuscular Blockade (aka Posfparalytic
`Syndrome) ....777
`I Critical Illness Polyneuropathy . . . .718
`r Critical Illness-Related Myopathy . . . .718
`Steroid-Rclated Mrlopothy . . . . I18
`Sepsis-Relotetl Myopnth:y . . . . 119
`r Eye to the Future . . . .119
`r Summary ....7L9
`v' KeyPoints....720
`I References....L20
`
`SECflON G: MONITORING C0i{SIDERAII0NS FOR TRAUMA AND
`GRMCAL CARE
`Section Editor: los6 A. Acosta
`
`7. Neurological Monitoring. . . .125
`Ahnrcd Fikry Attnallnh and W. Antlreu Kofte
`r Introduction....L25
`I Intracranial Pressure Mouitoring . . . .125
`Anntorny antl Physiologtl .,..125
`lntracrnniol Pressw.e Mouiktring
`Techniques.... L27 . "':
`Verrtriculostony . . . . L27
`Ricl'rmond Bolt. . .:. 128
`Epidural Intracranial Pressure Monit<trs . . . .129
`Intraparenchl mal InlracrarriaI Pr.essure
`Monitors ....129
`Intracrartinl Pressurt, Wnoet'onns . . . . 129
`r Brain Electrical Activity . . . .131
`Electroencaphnlogram .. . . 731
`
`Effect of Anesthetic Agents, Analgesics, and
`Sedati'r'es on Electroencephalogram
`. . . . 1-3L
`Electroencephalogram Chalrges Resulting
`from Critical Care Events . . . .133
`Brain Death ...,733
`Processed Electroencepthnlogrant Mottitoring . . . . 133
`B is1tect r al El e c tr oencephal o gr am S igr nI Pr o cess i n g
`and Monitoring....733
`Eaoked Potentials . . . . 134
`Brainstem Auditory Evoked
`Potentials ....134
`Visual Evoked Potentials . . . . 134
`Somatosensory Evoked Potentials . . . . 134
`Motor Evoked Potentials ....134
`Clinical Interpretation of Evoked Potential
`Changes in Context of Critical Care Events . . . . 135
`r Cerebral Blood Flow.. . . .735
`Transcranittl Doppler Ultrasonography . . . .735
`Laser Doppler Velochnetry f Flownretry . . . . L36
`Cerebral Angiograplty . . . . 736
`P erfusi on Co n ryttt ed Tomo gr nphy
`(Helical Cornputer Tomograplry with Contrnst
`Injectiort)....736
`Magnetic Resonance Angiography . . . . 136
`Xenon-Enhanced Computed Tonrography . . . . 1-37
`Xenon-1.33 Clearance . . . . 137
`Positron Emission Tomograltlty . . . . L37
`Single Phototr Emission Contputed
`Tomograplry ....L37
`I Intracranial Oxygen Saturation . . . .737
`lugular Bulb Venous Oxygen Snturation . . . .137
`Nenr Infrared SpectroscoTty . . . . 738
`Brnin Tissue PO2 Probes . . . .1.38
`r Eye to the Future . . . .739
`I Summary ....739
`t' KeyPoints....140
`I References....140
`
`8.
`
`Respiratory Monitoring .. . . 1.45
`lonnthan B. Cohen, Enrico M. Camporesi, and
`Hans. W. Schweiger
`I Introduction....L45
`I Carbon Dioxide Monitoring . . . .745
`Mctabolic Status of tlrc Patient . . . .745
`Correct Placement of the Endotracheal Tube . . . . L45
`Cardiac Output ....146
`Vetrtilntiort Status . . . . 146
`Waoefonn Annlysis . . . . 746
`Prcdictiort of Outconre in Trauma Patients . . . . L47
`r Oxygen Monitorirrg ....L47
`IrrsTtircd Gas and Alzreolar Gas Monitoring . . . .747
`Arterinl Blood Gas Monitoring . . . .148
`Calculntion of Right-to-Left Transp ulmonarq
`Shunt ....149
`Conrylications with Arterial Blood
`Gas Mcnsurement . . . . 150
`Conrylicatiorts with Pulse O xinrctry
`Measurenrcnt....150
`Mixed Venous Oximetry . . . . L51
`Tissue Oxygcn Monitoring . .. . 751
`Near Infrared Spectroscopy .... L5L
`Monitoring the Splanchnic System:
`Gastric Tonometry . . . . 151
`r Eye to the Future . . . .152
`r Summary....752
`
`MYLAN PHARMS. INC. EXHIBIT 1119 PAGE 7
`
`

`

`Contents
`
`xvtt
`
`r KeyPoints....152
`r References....752
`
`9. Cardiovascular Monitoring.... 1S5
`William C. Chiu
`I Introduction....155
`r Electrocardiography ....75s
`Heart Rate and Pulse Monitorilry . . . .lis
`Iscltcnrin Monitoring . . . . 156
`ST Segment Depr6ssion .... 156
`ST Segment Elevation . . .. 156
`Dysrhythmia Monitoring . . .. 757
`r Arterial Pressure Monitoiing . . . .1Sg
`Physiology of Systenic Artirial pressurc . . .. tSB
`Arterial Pressure Wnoeform Chnracteristics . . . .7Sg
`Noninaasizte Monitoring oJ' Arterial pressure . . . .1Sg
`Manual lntermittent Techniques . . . . 1Sg
`Automated Intermittent Devices . . . . 1Sg
`Continuous Automated Technology . . . . L60
`Inaasiae Monitoring of Arterial priisure . . . .160
`History....160
`lndications ... .160
`Site Selection ....160
`Complications ....161
`Systolic pressure Variation,... 162
`r Central Venous pressure Monitoring . . . .162
`htdications . . . . 762
`SiteSelection....162
`Interyretation . . . . 1.62
`Effect of Mechanical Ventilation and pEEp . . . . t6J
`Pathologic Central Venous pressure
`Waveforms....16J
`r Pulm.onary Artery Catheter Monitoring . . . .16J
`lndications....L64
`MeastLrement of Cardiac Outpttt . . . .164
`Thermomodification Techniqu e . . . . -164
`Fick Principle (Conservation of Mass) . . . . 165
`Insution Tecltnique . . . . 165
`SiteSelection....165
`Pulmonary Artery Catheter Aclvancement
`Considerations ... . 166
`Interpretation of pAC Wnoelbrrns nnd
`Pressure....166
`Effect of Mechanical Ventilation . . . .166
`Eft-ectofpEEp....166
`Hemodynamic profiles .... L66
`I Continuous Cardiac Output Monitoring . . . .167
`Modified pulmonary Ariery Catbtcr, .l . . rcz
`Noninuasiae Cardiac Orttput Monitorins
`Deuices....16g
`r Eye to the Future . . . .169
`I Summary....L6g
`o^ KeyPoints....168
`I References....768
`
`10.
`
`Splanchnic and Renal Monitoring . . . .177
`Eanrcn O'Reillrl nnd ELtgenio Lttjnn
`r Introduction....L77
`r Splanchnic Monitoring ....171
`Anntomy nnd pnthopltysiology . . . . 177
`Splanchnic Circulation ....iZl
`Pathological Consequences of Splanchnic
`Hypoperfusion....172
`Ctstric pH MonitorittC. . . . . 172
`
`Physiological Tenets of Gastric pH
`Monitoring....172
`Techniques of Gastric Tonometry . . . .I74
`Outcome Studies . .. . 174
`Srblingual Capnography .. . . 775
`Physiological Tenets of Sublingual
`Capnography....175
`Technique of Sublingual Capnography .. ..L75
`Outcomes Sttrdies. ... L75
`Su.rognte Mensures of Splnncluric
`Well-Being....17S
`Lactic Acidosis . ... 175
`Tolerance of Enteral Nutrition . . . .175
`Stress Gastritis ... . 126
`r Renal lVlonitoring ....176
`Itftroduction....176
`Arntotny and plrysiology . . . . 176
`Renal Circulation. . . . 776
`Pathology of Renal Hypoperfusion .. . . L7g
`UrineOutput....17g
`Monitoring Urine Output .. . . L7g
`24,Hour Urine Oupu[ and Outcomes . . . .17g
`Tubular Function . . . . 77g
`Creatinine and Creatinine Clearance . . . .17g
`Fractional Excretion of Sodium .. ..L79
`Fractional Excretion of Urea . . . .1,7g
`Urine-Concentrating Ability . . . . L79
`hnaging in Genitourinan/ Corulitiotts . . . . t7g
`Renal Ultrasound. . . ..179
`_ Computed Tomography .... 1g0
`r Eye to the Future . . . .1g0
`I Summary....180
`ry' KeyPoints....180
`I References....1g1
`
`11. Temperature Monitoring. . . . Lg5
`Abdallah Ktbbara ttnd Chiles E. Sntitlt
`I
`Introdurction.... 1g5
`r History of Thermometrv....1g5
`r Establishment of Normal Temperature....1g6
`I Thermoregulation ....79g
`Hypotlnlnmus....1g9
`Mcchanisms of Thennoregttlntion ... .1gg
`Heot production . ... 1gg
`Heat Loss....1gg
`Cowftercurrent Hent Exchange (Vasoconstrtction f
`Vasodilation)....I99
`Pathopthrlsiology of Temperahtre Chnnge . . . . 1gg
`Heat Bnlnnce....lgg
`I Temperature Monitoring Rationale .... Lg9
`Irtcidence and Risk Fnciors for Hypotherntia in
`Trntuna....1gg
`H y po ther m in- A6soc i ated I nc r easetl Mo r tol it v
`nnd Morbidity....190
`Cardiac Effects. . . . 191
`Vascular....1.91
`Coagulopathy ....191
`Respiratory ....1.91
`Cellular Immune Response and
`Irrfection ....19L
`Glucose and Electrolvtes . . . . 192
`Splanchnic and Renai Etfects.... I92
`Gcnernl Anesthesia . . . . 192
`Regiorrnl Anesthesin. . . . 192
`Deliblnte LIse of Hypothermia: l,.t CLtrtjiac rtntl
`Neuro-anesthesia .. . . 192
`
`MYLAN PHARMS. INC. EXHIBIT 1119 PAGE 8
`
`

`

`Unifying the Effects of Secondarv
`(and Son-re Primary) Insults . . . .207
`Cerebral Metnbolic Rate for Oxygut . . . .207
`Cercbrnl Blood Flow, Cerehrnl Petfusion PresstLre
`arfi Atttoregulation . . . . 207
`Irtracrarinl Pressure . . . . 208
`The Role of Monitoring in the Management of
`Traumatic Brain Injury . . . . 208
`Management of TBI in the Intensive Care
`Unit. .. .208
`Tlrc Evolution of lntensiue Care Llnit Managemcnt for
`Ti'aumatic Brain Inju'y ....208
`Sptecific Therapies of In4tortnrrce in tlrc Management
`of Traunmtic Brain Injury . . . .208
`Oxygen ....208
`Intravascular Repletion for Hypotension . . . .208
`Ventilation, PaCO2, and Effects of
`Intratl'roracic Pressure ... . 209
`Sedation, Analgesia, Neuromuscular
`Blockade ....209
`Head Elevation and Extracerebral
`Venous Drainage . . . . 270
`Surgery for Evacuation of Hematomas . . . .210
`Ventriculosioml' for External Ventricular
`Drainage .. . .210
`Osmotic Diuretics for Control of Cytotoxic and
`Vasogerric Edema. .. . 210
`Loop Diuretics ... .2L0
`Steroids ....2L0
`Vasopressors to Increase Cerebral
`Perfusion Pressure .... 211
`Barbiturates....2I1
`Temperature Control Inciuding
`Hypotherrnia . . .211
`Seizure Control. . . . 271
`Decompressive Craniectomy . . . . 211
`Chest Physiotherapy and Endotracheal
`Suctioning ....271.
`Nirnodipine to Control Vasospasm . . . .211
`Managernent of Hyperglycenr;u . . . . Zlt
`Manngement by Standnrdized protocol . . . .217
`The Lmd Protocol .. ..212
`Associated*Organ System Complications Following
`taunratic Brain Iniun' . . .. 212
`Nertroganic Pulnnniry Edenn . . . . 272
`HyTternntronin . . . . 212
`HyTtonntrenria: SIADH os. Cerebral Salt Wnsting
`Syndronrc....213
`Other Aspects of Critical Care for Traumirtic
`Brain Injury Patients ....215
`Ertternl Nutrition . . . . 213
`Acutc Respiratory Distress Sqndrorne
`ntd Scpsis....213
`Weaning md Extubntiotl . . . . 21J
`Irrdicatiorts .for Ti'acheosf ttntV . . . .2L3
`Tht Dingrcsis nnd Trcatrncirt of Auitolion
`"
`Followirtg Ettubntion . . . . 214
`Rehabilitation Begins in the Intensive
`CareUnit....214
`Approln'intc Sensory Stinudntiort . .. . 214
`Spasticity nnd Contractltres . . . . 214
`Heterotopic Ossificntion of loirtts . . . .214
`Mnnngemant of Long Bone Fracttres . . . .214
`D;'ing in the Intensi.r'e Care Unit From a Head
`Injury. ...274
`Braht Deatlr ard Btainstcm Deatlt . . . .214
`Orgnn Dotntiotr After Ttau.nntic Brnin Iniury . . . .214
`Conrntrtrticotiort witlt Fantily Merrfucrs . . . .-215
`l\'/itlilnld or llithdrnwnl of Trcotttrcnt . . . .215
`
`XVII'
`
`Contents
`
`Exteunl Factors AJJecting Tentperature
`Meastu'enrcnt....193
`Thermometer Instrumentation Available . . . . 1.93
`Temperature Monitoring Sites . . . . 193
`Core Sites....L93
`Esophagus ....793
`Nasopharyngeal . . . . L93
`Pulmonary Artery .... 194
`Tympanic Membrane (Ear) . ... 194
`Intermediate Sites . . . . 795
`Mouth....195
`Rectum.. .195
`Bladder ....196
`Axilla and Groin.... 196
`Peripheral Skin Sites . . . . 197
`Eye to the Future . . . .798
`Summary....1.98
`KeyPoints....198
`References ....1.99
`
`ll
`I
`
`IIfI
`
`sECIl0N D: l{EUROt0GlGAt INJUR|ES AitD O0NS|DERAT|ONS
`Section Editor Lawrence F. Marchall
`
`12. Traumatic Brain Injury: Critical Care
`Management....201
`Anrte J. Stttclife
`I Introduction....201
`r The Goal: To Facilitate a Good Outcome . . . .201
`Defining a Good Neurological Orftcortte . . . . 201
`Duratiott Endpoints atd Otlter Corrr]tlsyiliss sy
`Outcome Mensurements . . .. 207
`Glasgow Outcome Scale . .. . 201
`Disability Rating Scale . . . . 202
`htrplications for Intensioists . . . . 202
`Assessing the Evidence Base . . . .202
`Participating in a Multidisciplinary
`Approach to Cate . . . . 202
`Discussions with Relatives . ... 202
`Mortality and Morbiditrl After Disclnr.qe
`FollowirtgTBl ....202
`I Primary Brain Injury . . . .202
`Parenchrlnml Tissue Damage . . . . 203
`White and Grey Matter lnjuries . . . .20J
`Anatonrical Locations of lniurv and
`Implications....203
`Epidural Hematoma . . . . 208
`Subdural Hematona ... . 203
`lntracerebrsl Hentorrhnge . . . . 204
`Subnrnclnnid Hcmorrhigc . . .. 205
`Vasculor Injury .. . . 20i
`r Secondary Brain lnjury. . . .205
`Cytotoxic Cellular Edenn . . . . 205
`Interstitinl Edemn: Vasogenic and
`Hydrostntic....205
`Hyperemin ....206
`Hypotensiott.,..206
`Hyytoxia....206
`Herniation....206
`Hy1:erglyceruia . . . . 206
`Feper....207
`Seizures....207
`Hydroceythalus . . . . 207
`Vasospasm....207
`Cerebral lnfectiorr., . . 207
`Repefusion hlury ., .. 207
`
`re
`
`n
`
`-.?
`
`L
`
`MYLAN PHARMS. INC. EXHIBIT 1119 PAGE 9
`
`

`

`Contents
`
`xtx
`
`Initial Management . . . . 242
`Neurological Consequences of Subarachnoid
`Hemorrhage....24J
`Medical Consequences of Subarachnoid
`Hemorrhage....244
`Arteriovenous Malformation. . . . 244
`Patlrogenesis....244
`Presentntion....245
`Dingnostic Eualuation . . . . 245
`Thernpt1....245
`Medicnl Intensiae Cnre Unit Managenrcnt . . . .246
`Intracerebral Hemorrhage . . . . 216
`Pathogenesis....246
`Prescntation....246
`Dittgnostic Eztaluntiorr . . . . 247
`Tlrcrapy....248
`Medicnl Interrciae Care Llnit
`Managetnent....24g
`Ischemic Cerebrovascular Disease . . . . 24g
`Pathophysiology . ... 249
`Laboratory and Ratliological Eanluation . . . .250
`Marngement....25L
`Strpportive Care. . . . 252
`Thrombolytics, Anticoagulations, and
`Antiplatelet Drugs. . . . 252
`Miscellaneous Cerebrovascular Lesions .... 253
`Trattnrntic Aneurysms . . . . 253
`Cerebral Venous Thrombosis . . . . 253
`Carotid Capernous Sinus Fistulae . . . .253
`Eye to the Future . . . .2SB
`Summary ....254
`KeyPoints....254
`References ....255
`
`IIft
`
`1.5.
`
`Pediatric Neurological Trauma and Other
`Emergencies ....259
`lr,9r!: K...Hsmid., Phitippa Nezofiettt, Mictroel L. Leuy,
`RalrrLI lnndial, nntl PeIer I. Daztis
`
`Introduction ....259
`Pediatric-Specific Intracranial pressure
`Consiclerations. . . . 259
`Closed Head tauma ... . 261
`Epidemiology....261
`Meclutnisms of Iniunt . . . . 261
`Injtrries from Fills. . . . zOt
`Injuries Resulting from Vehicular Crash. . . .261
`Shaken Baby Syndrome and Other Forms of
`ChildAbuse....261
`Imaging Following Mild Altertttions itt
`Cttnsciottsness .. . . 262
`Specific Patl.tologic Lcsions . . . . 262
`Intracerebral Hematoma .. . . 262
`Epidural Hematoma .... 262
`Strbdtrral Hematoma ... . 262
`Complex Depressed Skull Fractures . . . .263
`Cranial Burst Fractures in Infants . . . .26J
`Penetrating Tiauma . . . . 253
`Prognostic Fnctors for penetrating Hentl
`[njury....263
`Strrgicnl ApTtroach to penetrnting Hend
`Irrjury . . .261
`Tratrmatic Birth Injuries . . . . 264
`Traumatic Vascular Lesions . . . . 265
`Cert,icnl Cnrotid Injury . . .. 265
`Vcrtebrnl Artery [njuries . . . . 266
`Intracraittl Vnsalnr Iniurv . . . . 266
`Trnuttntic Anetrrysms .'. . .-267
`
`I T
`
`rt
`
`I Uncertainties in the lvlanagement of Tranmatic
`Brain Injury ....215
`r Eye to the Future . . . .275
`I Summary....21-s
`t' KeyPoints....216
`I References....276
`
`13. Spinal Cord Injtrry: Critical Care Management. .. .221
`Cfuistopher lunker and Lucis Pnlladino
`r Introduction....221
`I Anaiomical Considerations.. .. 221
`Skeletal Structure ... . 221
`VasctLlar Anatomy .. .. 227
`r Pathophysiology of Spinal Cord Injury and
`the Basis of Pharmacological Interveition. . . .221
`Pathoplrysiology . . . . 227
`Bnsis of Pharmncological Interoention . . . .222
`Phnrmacology for Specific Treatnrcnt of
`Spinnl Cord Injury .. ..225
`r Initial Assessment and Management . . . .223
`r Radiologic Diagnosis ....223
`r Nonsurgical Stabilization.... 226
`I Specific Spinal Cord fnjury Syndromes . . . .226
`r Systemic Manifestations of Spinal Cord Injury and
`Related Management . ...227
`Cardiou.tscular . . . . 227
`Spinal Shock ....227
`Early Cardiovascular Resuscitation Foilowrng
`Spinal Cord Injury .. .. 227
`Puhnonnry....228
`Early Pulmonary Complications of
`Spinal Cord lnjury . . .. 228
`Thromboembolic Complicatit-rns . . . . 229
`Chronic pulmonary Complications of Spinal
`Cord Injury (Ventilator Weaning,
`Diaphragmatic pacing, Chronic Ventilator
`Dependence) ....229
`Tracheostomy Decision Making in Spinal
`Cord Injury patients . . .. 230
`Castrointestinal Sqstem . . .. 2J7
`Enteral Nutrition. . . .231
`Ulcer Prophylaxis. . .. 231
`Genitourinary System . . . . 251
`Cutnneous tlnd Muscltloskeletttl Stlsterns . . . .232
`PressureSores....2J2
`Contractures and Spasticitv . ... 2A2
`r Eye to the Future . . . .232
`I Summary....233
`o' KeyPoints....233
`t References....234
`
`14. Management of Intracerebral Vascular
`Catastrophes....23g
`Raluil-lmulial, Henry E. Aryan, Sarnrtel A. Httglrcs,
`and Hoi Smtg LI
`
`TI
`
`MYLAN PHARMS. INC. EXHIBIT 1119 PAGE 10
`
`

`

`Contents
`
`I Congenital Vascular Anomalies . . . .267
`Vein o.f Galert Arrcmtlsrtr . . . .267
`Arteriovenc-rtts Malfolmatious . . . . 268
`Auewtlsnrs....268
`Cnt,ertnus Artgiomas nnd Vcnttus At