Objectives Approach to patients with suspected muscle disease • Provide an overview of clinical approach to muscle disease based on patterns of weakness Ba kr i Elsh eikh , MBBS Assistant Professor Department of Neurology Ohio State University Medical Center • Discuss the role of different diagnostic tests in muscle disease

Objectives Goals of evaluation • What is the site of the lesion? – Is it muscle? • Provide an overview of clinical approach – Where in the muscle? to muscle disease based on patterns of • What is the cause of the ? weakness – HditHereditary: MD; Myotonias; Metabolic; Mitochondrial – Acquired: • Discuss the role of different diagnostic Inflammatory; Endocrine; Toxic; Systemic tests in muscle disease illness • What is the treatment ?

1 Shot gun approach History of present illness • Age at symptom onset • Time constrains “Reality of the practice of – Birth vs. childhood vs. adulthood medicine”! – Mild childhood sx. are usually missed • Evolution of symptoms • Focused & systematic approach is the most – Acute/sub-acute vs. Chronic vs. Static efficient approach • Weakness

• “ Good history and examination ..can not be – Proximal vs. Distal vs. Cranial replaced” • & exercise intolerance – Metabolic and mitochondrial • Search for clues in the H &P – Cardiopulmonary; depression; systemic illness • Myoglobinuria

Chief complaint More History

• Negative sx. • Positive sx. • PMH ― Weakness ― – Thyroid, parathyroid, adrenal, GH, cancer, HIV ― Fatigue – Cardiac, pulmonary, musculoskeletal ― Cramp • FH ― Atrophy ― CtContrac ture – X-linked, AD, AR, maternal transmission ― Exercise ― Myotonia • SH intolerance – Smoking >>paraneoplastic ― Periodic • Meds paralysis – Statins, amiodarone, chloroquine, Colchicine,

2 Examination Vignette 1

• Pattern of weakness (6 major patterns) • 45 y/o WF – Symmetry – Weakness – Location (proximal/distal) – Cranial (ocular, facial, pharyngeal) – Difficulty going up steps • Calf hypertro phy – Facial and knuckles rash – True vs. pseudo – Swelling around the eyes • Other features – Frontal balding, cataract, face muscle – Difficulty swallowing wasting – Recent h/o ovarian cancer – Dysmorphic features – Rash – CK normal – Liver enlargement

“ Limb-Girdle” Proximal Weakness Pattern • Most common • Idiopathic (IIM) • Symmetric – PM, IBM, NM • Proximal; Proximal >> Distal • Adults and children • muscle involvement • F > M • Remember to examine muscles against gravity • Onset: Wks- Months • Examples • Weakness: Symmetric; Proximal & Distal – Acquired: PM, DM, endocrine and toxic • Myalgia myopathies • Facial weakness – Hereditary: DMD, BMD, LGMD, Pompe disease • Dysphagia ~30% • Mimickers • Rash – SMA, LEMS, CIDP

3 Dermatomyositis rash Muscle Enzymes Wong et al. Am J Clin Path. 83 • Amato et al. Ann Neurol 96

• 1537 subjects ― DM (9 pts) 758 (± 6929) ― PM (22 pts) 5097 (± 7706) • High CK group (52-520 U/L) ― sIBM (15 pts) 698 (± 430) – Black men Diffuse erythematous • CK in normal in 10% Erythematous macular rash rash on face & scalp Dermatomyositis pts neck & anterior chest (V-sign) • Intermediate CK group (25- 345 U/L) • Should be elevated in all PM – Black women and NM pts – Non-black men Heliotrope rash refer to • CK level doesn’t correlate with purplish (brown) • Low CK group (25-145 U/L) weakness eyelids discoloration – Non-black women often with periorbital • AST,ALT, LDH elevation edema Gottron’s sign scaly – GGT to follow liver lesions over knuckles disease and elbows Erythematous rash – post. Upper back & (shawl sign) Normal CK in slowly progressive myopathies

Calcification • Calcifications in subcutaneous tissues • 12 pts • Muscle discomfort 92% • P & D weakness 50% • Pressure points (buttocks, • Joint pain 75% knees, and elbows) • Pulmonary involvement 50% • Negative Jo-1 in five tested • Tend to occur in inadequately • EMG: Normal 36%; irritable treated patients IMACS myopathy 18%; non-irritable 45% • Bx. • More in children (30-70%) – Perimysial pathology (92%) – Acid phosphatase positive • Difficult to treat cellularity (83%)

4 EMG Other Laboratory work up

• ANA positive – DM 24-60% • ESR normal • AtAuto-antibodi es • Jo-1 20% IIM • Anti-SRP Myocarditis and NM • Mi-2 15-20% DM Fibs & PSW Myopathic MUPs

Muscle MRI DM-Muscle Biopsy • Abnormal signal • Multifocal – Edema • Severity vary within muscle – Inflammation specimen – Fatty replacement • Characteristic feature is perifascicular atrophy • Chronic disease – Seen in 50%-75% • Per ivascul ar i nfl ammati on • Muscle atrophy – Macrophages – B-cells • Current use – CD4+ >>PDCS – Identify biopsy side • Gene microarray studies – Increase expression of – Known & type 1 interferon & normal CK proteins they regulate • Flare vs. steroid Mammen A. Ann. N. Y. Acad. Sci. 2009 Amato AA, Russel JA 2008

5 Malignancy Treatment Summary

• Increased incidence of malignancy • RCT are rare • Usually after age 40 • Highest near time of diagnosis (1-3year) • is considered 1st line Rx • Still some risk after 3 year • Presence of malignancy doesn ’ t correlate with • IVIG i s a costl y R x of DM disease severity • Types of associated cancer • There is a role for steroid and IVIG sparing agents – Breast, ovary, lung, pancreas, non-Hodgkin’s, – Methotrexate, cyclosporine, mycophenolate mofetil stomach, colorectal, melanoma – Nasopharyngeal (Asia) • Patients should be encouraged to participate in • Treatment of malignancy may improve myositis research trials

Evaluation Distal weakness Pattern

• Muscle Biopsy • Suspected inflammatory • Make sure neuropathy (sensory) & MND • Baseline Dexa scan myopathy (asymmetry) are excluded • √ ck √ TSH • Malignancy screen • √ Autoimmune screen (> 40) • Examples • √ Jo-1 √ CBC √INR – Examination • EMG • General /skin – Myotonic dystrophy – √ myopathy √ mm – Ct chest – Distal myopathies irritability √ exclude • Lung fibrosis mimickers ex. – Ct abdomen/pelvis – Myofibrillar myopathy myotonia – Mammogram – Multiple proximal and – Colonoscopy distal muscles – Prostate – Thoracic paraspinal • Swallow evaluation

6 Vignette Myotonic Dystrophy 2 • 42 y/o female (DM2) • Share many DM1 features • Stiffness of the hands • x 5 years – >>> hip flexor weakness – <<< facial weakness • Swallowing difficulty • AD inheritance • Single locus at chromosome 3q 21.3 • Cataract surgery age 20 • Zinc finger protein 9 gene (ZNF9) • CCTG repeat expansion in intron 1 • Pacemaker • Disease severity independent of number of repeats • Excess daytime sleepiness • Screening for cardiac and pulmonary abnormalities similar to DM1

Myotonic Dystrophy 1 (DM1) Molecular genetic studies

• Most common adult muscular dystrophy • AD inheritance • Single locus in chromosome 19q13.3 • dystrophia myotonica protein kinase (DMPK) http://www.ncbi.nlm.nih.gov/sites/ • 3' untranslated region with increase in GeneTests/ trinucleotide CTG repeats • Multisystem disease – Cardiac conduction defects …..Pacemaker – Cardiomyopathy – Hypersomnia – Cognitive Impairment – Gastrointestinal symptoms – Insulin insensitivity

7 Distal myopathies Vignette Disease Gene Age at Initial muscles CK Muscle Bx onset

Welander 2p 13 > 40 Finger and wrist 1-4 X Rimmed • 23 y/o man extensors vacuoles Udd TTN >35 Anterior leg 1-4X ± Rimmed – Difficulty running compartment vacuoles

and toe walking Markesbery- ZASP >40 Anterior leg 1-3X Vacuolar & since age 3 Griggs compartment myofibrillar Distal MYOT > 40 Posterior > anterior 1-3X Vacuolar & – No arm weakness or myotlinopathy leg myofibrillar sensory symptoms Laing (MPD1) MYH 7 < 20 Anterior leg & neck 1-3X Type 1 fiber flexors atrophy

– FH: Pos. with male to Vocal cord & MATR3 35-60 Asymmetric lower leg 1-8 X Rimmed pharyngeal and hand; dysphonia vacuoles male transmission (MPD2) New Finnish 8 p22-q11 12 >30 Hands or anterior leg 1-4 X Dystrophic; – Weak ankle (MPD3) q13-22 rimmed dorsiflexor and big vacuoles Nonaka GNE 15-20 Anterior leg < 10 times Rimmed toe extensor compartment vacuoles

– CK normal Miyoshi DYSF 15-30 Posterior leg > 10 times Myopathic – EMG myopathic compartment

Distal myopathies Proximal Arm Distal Leg Weakness Disease Gene Age at Initial muscles CK Muscle Bx onset Pattern (Scapuloperoneal)

Welander 2p 13 > 40 Finger and wrist 1-4 X Rimmed extensors vacuoles

Udd TTN >35 Anterior leg 1-4X ± Rimmed compartment vacuoles • Scapular winging

Markesbery- ZASP >40 Anterior leg 1-3X Vacuolar & Griggs compartment myofibrillar • Scapular stabilizer weakness

Distal MYOT > 40 Posterior > anterior 1-3X Vacuolar & myotlinopathy leg myofibrillar • Ankle stabilizer weakness

Laing (MPD1) MYH 7 < 20 Anterior leg & neck 1-3X Type 1 fiber flexors atrophy • Asymmetry

Vocal cord & MATR3 35-60 Asymmetric lower leg 1-8 X Rimmed pharyngeal and hand; dysphonia vacuoles • Examples (MPD2) New Finnish 8 p22-q11 12 >30 Hands or anterior leg 1-4 X Dystrophic; – FSHD (MPD3) q13-22 rimmed vacuoles – LGMD Nonaka GNE 15-20 Anterior leg < 10 times Rimmed – Acid maltase deficiency compartment vacuoles – Myofibrillar myopathy Miyoshi DYSF 15-30 Posterior leg > 10 times Myopathic compartment – Scapuloperoneal dystrophy

8 Vignette Distal arm/Proximal Leg Weakness Pattern

• 32 y/o female • Distal forearm (wrist and finger flexor) and • Facial weakness quad (Knee extensor) weakness • Sleep eyes open • Can’t whistle • Asymmetric • Difficulty raising arm • Facial weakness -mild above shoulder • Example • Shoulder pain • Pos. FH –

Facioscapulohumeral dystrophy Sporadic Inclusion Body Myositis • Commonest IIM after age 50 Forearm atrophy/ • 3rd most common MD • Refractory PM weakness • Autosomal dominant linked to 4q35 • = IBM or dystrophy • More common in men • Deletion of 3.3 kb repeated sequence (D4Z4) • Onset: Months-Years • Symptoms begin < age 20 in ~ 80% • Dysphagia ~30-60% QdQuads weak ness • Typically begins in face; subtle or absent~4% • CK Mild to moderate • Not responsive to Shoulder weakness, pain presenting c/o in 80% • immunosuppressive Rx • ~20% asymptomatic at dx • CK mildly elevated • 15% will require use of wheel chair

Facial weakness 1/3

9 Ptosis With or Without Neck Extensor Weakness Ophthalmoplegia Pattern • Dropped head syndrome • Ptosis alone • DD: ALS, MG, – Myotonic dystrophy Parkinson’s – Cong. Myopathy • Examples – Myofibrillar Myopathies – INEM • Ptosis and Opthalmoplegia – Inflammatory myopathy – OPMD – FSHD – Mitochondrial myopathy Ex. CPEO – MD – NMJ disorders Ex. MG – Congenital Myopathy

Vignette Isolated Neck Extensor Myopathy

th • 35 y/o • 7 decade or older • Droopy eyelids • Weakness over days to Wks. • Progressive • Dull or burning neck pain ophthalmoplegia • Some report deltoid • Proximal weakness weakness • EMG changes limited to • Short stature cervical (mid to lower) • Third degree AV and upper thoracic spine block • MRI fatty replacement and atrophy of the Kearns-Sayre Syndrome paraspinal muscles.

10 Take Home Message • Detailed history and exam are fundamental steps Muscle Pain to reaching a specific diagnosis Epidemiology • Muscle disease can be distinguished from other disorders causing weakness • Most common complaint in NM clinics • Pattern of weakness help guide the work up • Normal CK does not exclude muscle disease – ~50% of referrals for muscle biopsy • EMG and muscle biopsy are valuable diagnostic • Prevalence of diffuse myalgia ~10% tools – ~20% prevalence of focal myalgia • Molecular genetic testing is emerging as a useful noninvasive diagnostic tool ~ not for fishing • 2020--50%50% complain of muscle tiredness expedition • Symptomatic management and screening for – Up to 25% of primary care OP visits complications decrease morbidity and mortality in • 90% of myalgia patients have fatigue muscle disease pts • Multidisciplinary team approach for MD pts is – 95% of CFS patients have myalgia crucial

Muscle Pain The Patient with Myalgia:Myalgia: Problems for Clinician Myths, Muscle Diseases, and (A Little) Madness • Pain only symptom in many patients – No signs of disease (eg(egweakness) – Difficult to assess at bedside Miriam Freimer, MD Department of Neurology • Myalgia may arise from many sources Vice Chair for Clinical Affairs – Ortho, rheum, gen med, psych Associate Professor of Clinical Neurology – May not be related to muscle disease Ohio State University • Many patients are ““undiagnosableundiagnosable”” in the usual sense

11 Diagnoses in Myalgia Approach to Patient with Patients Myalgia Mills and Edwards, 1983 Objectives

Diagnosis # Pts. % • Basic approach myalgia patient Enzyme defects 16 15% – When to biopsy and when to not! Inflammatory myopathy 8 7% • Present overview of myalgia in general Neurogenic disorders 7 6% – Terminology & classification Endocrine & metabolic 6 6% – Highlight mistakes & myths seen in clinic No diagnosis 72 66% • Discuss 4 muscle diseases with isolated generalized myalgia (i.e. no weakness) Total 109 100% – Including the “F---“F---word” ()

Filosto et al, Neurology 2007 Patient with Myalgia Case Presentation

68 yo male, 6 mos hx • Severe , AM stiffness, ADL loss – “Walking in glue ” • Many myalgia patients DO have biopsy • “ I don’t feel good!” abnormalities, but they are usually nonnon--specificspecific • Lost 10 pounds – They usually do NOT lead to a diagnosis • CK, EMG normal • Routine biopsy NOT indicated in patients with isolated myalgia; careful patient selection is • Referred for muscle bx. needed for presumed PM • Important info for referring doctors AND patients!

12 Evaluation of Muscle Pain Muscle Pain Terminology Screening examination Labs. CBC, ESR, TFTs, lytes) Types of Pain

Neuro. eval - strength, endurance testing Serum CK , electrodiagnostic studies • “I don’t have any pain at all…it just hurts!” • “Pain” can mean numbness, stiffness , Normal CK elevated Weak, abn EMG, CK tingling, restlessness, burning, swelling • Useful to classify 4 types of muscle pain Tender Tender <5x nl FET, >5x normal, points points No other Genetic – -- Cramps other sx present? absent? abn testing – Stiffness -- Aching myalgia PMR, MAD FM Repeat Biopsy Biopsy Statins

The Patient with Muscle Pain Deep Aching - General Approach Localized Muscle • Careful history attending to type of pain – Consideration of localization/pathogenesis PostPost--exerciseexercise myalgia (“weekend warrior”) – Analysis of disease possibilities Infiltrating processes (e.g. tumor, sarcoidsarcoid)) • Exam. with att enti on t o st rength t esti ng! FlFocal pressure necrosi s – Most common source of error!! Trauma • Judicious lab tests Localized infections (bacterial, parasitic) – Routine (e.g. CK and EMG) Venous occlusion – Specialized (FET, biopsy, genetic testing) Arterial ischemia (thrombotic or embolic) Referred “muscle” pain

13 Examples of Focal Myalgia Deep Aching - Generalized Differential Diagnosis With weakness Without weakness • PM, DM (20(20--25%)25%) • Infectious • Hypothyroidism myalgia (esp. • Mitochondrial dx. viral) • Myotonic dystrophy • Toxic myopathies 2 ((egeglovastatin) • Infectious • MADD myopathies • PMR • Other rare myopathies • Fibromyalgia Sarcoid Myopathy Diabetic Thigh Infarct

Diffuse Muscle Pain Inflammatory Muscle Disease* Evaluation of Muscle Pain

Screening examination Labs. CBC, ESR, TFTs, lytes)

Neuro. eval - strength, endurance testing Serum CK , electrodiagnostic studies

Normal CK elevated Weak, abn EMG, CK

Tender Tender <5x nl FET, >5x normal, points points No other Genetic other sx present? absent? abn testing

PMR, MAD FM Repeat Biopsy Biopsy Statins *Only ~25% of PM/DM pts. have significant myalgias

14 Statin Myopathy Characteristics Statin Myopathy Franc et al, 2003 Terminology & Epidemiology ACC & AHA & NHLBI list 4 entities (2002) • Statin myopathy – ANY muscle complaint – Up to 15-25% (including isolated CK rise ?) • Statin myalgia – pain without CK rise – 2-2 9% ooverallverall (up to 20%20% in sosomeme seseries)ries) • Statin myositis – pain/weakness/CK rise – Rare with biopsy proven inflammation, < 0.2% cases • Statin rhabdomyolysis – CK > 10x normal – < 1 per million scripts for all but cerivastatin (Baycol) SO •Symptoms can occur at any time in course! • Since 105 million patients should be on statins •Symptoms do NOT always resolve with drug DC – 5-6 million new statin myopathy cases!! ? Underestimate!

Statin Myopathy Predisposing Factors Statin Myopathy Management Patient Factors Medication Factors • Increased age • High statin dose • Tricky, since the meds ARE helpful • Agent (eg lovastatin) • Female sex – Cannot just blindly stop in all patients • Small stature • Polypharmacy • Liver, kidney – Colchicine • Rechallenge with other drug may be option dysfunction – Erythromycin – Usually doesn ’twork! t work! • Hypothyroidism – Cyclosporine • Symptomatic treatment (gabapentin, PT, – Niacin • Post-operative NSAIDs, short course steroids) – Calcium channel • Diet (eg grapefruit blockers • Little evidence for aerobic exercise, CoQ10, juice) – Nefaxodone carnitine • Genetic predisposition – Anti-fungals • “Tincture of time” sometimes best option • Underlying myopathy – Fibric acids (gemfibrozil) – Some patients have persistent symptoms! Cause still unknown!

15 Grable-Esposito et al Patient with Myalgia Muscle & Nerve 2010 Case Presentation 68 yo male, 6 mos hx • Severe myalgias, AM stiffness, ADL loss • 25 pts. on chronic statins (only 4 with – “Walking in pain) glue” – WeaknessWeakness, high CK after statins DCd • “ I don’t feel good!” – Necrotizing myopathy on muscle bx. • Lost 10 pounds – Responded to immunosppressive drugs • CK, EMG normal – 24 required multiple agents • Referred for muscle bx. for – 15 relapsed on withdrawal of agents presumed PM

Statin Myopathy Management The Patient with Myalgia Symptoms Case Presentation (myalgia, CK, weaknessweakness)

SxSx.. Resolve Sx. Persist • Examination NORMAL, including strength DC Statin • Screening blood work normal

Observe Stable Progression – Including CK, aldolase • EMG - completely normal (but painful)

Manage with diet, Treat symptoms Weakness • Muscle biopsy deferred niacin, bile resins Higher CK • ESR = 80 mm/hour; diagnosis of PMR

Resolve Persist • Prednisone 40 mgs/day – Complete resolution in 2 days Muscle bx.

16 Polymyalgia Rheumatica Polymyalgia Rheumatica Epidemiology Laboratory

• Technically not muscle disease per se • CK and EMGs normal • One of most common causes of myalgia • ESR very high (>100) – 600600--1000/100,0001000/100,000 in patients >age 50 – 1515--20%20% - normal ESR – Incidence of ~50/100,000 per year • TltbTemporal artery bx. only in patients with GCA sxssxs.. • Mean age of onset 70 (90% > age 60) (not in isolated PMR) • Female predominance of 3:1 • Muscle bx. not indicated • 50% of (GCA) get PMR – NonNon--specificspecific changes – Pathogenesis ? – 1515--20%20% of PMR develop GCA • Synovial pain

Polymyalgia Rheumatica Polymyalgia Rheumatica Symptoms Treatment

• Myalgia, stiffness, aching, • Prednisone (10(10--4040 mg/day) causes – Neck, , hips immediate and dramatic improvement • Worse in AM, movement – Diagnostic as well as therapeutic – Stiffness, “gelling” • Systemic symptoms in 40% • GCA requ ires higher doses – Fevers, depression, wt. – 6060--100100 mg orally or 1.0 gm IV loss, poor sleep, • Treat symptoms and ESR anorexia, , arthritis – Taper slowly when sxs.sxs. under control – Similar to FM – Usually requires 11--22 years treatment • Tenderness rare ((ddxddx FM) • 10% require treatment for over 10 years!

17 Fibromyalgia – The Madness Fibromyalgia Epidemiology Clinical Features • >3000 Medline articles since 1990! • ~2% population in US • Diffuse myalgia, stiffness, aching, joint pain – (3.4% F; 0.5% M) • Proximal predominance; can be anywhere – 3-6 mil. people in U. S. • Insidious onset (? postpost--infectious,infectious, trauma) • 7575--90%90% cases in women • Fatigue, morning stiffness, nonnon--restorativerestorative • Any age (children); especially elderly (7% of sleep in 75% women > age 60) – Anxiety --Swelling --Swelling ----HeadachesHeadaches • 20% of rheum. ppatients;atients; – IBS ----ImbalanceImbalance--Dysuria --Dysuria – 3rd most common – Raynaud’s ----DysmenorrheaDysmenorrhea--Dysesthesias --Dysesthesias (after OA, RA)

Fibromyalgia New ACR Diagnostic Criteria Notable Quotes Arth Care Res 2010;62:6002010;62:600--1010

• “I don’t know what that term means.” • “It’s just a waste-waste-basketbasket term.” • “That’s just a grabgrab--bagbag diagnosis.” • “Doctor’s diagnose that when they really don’t know what’s wrong with someone.” • Widespread pain > 3 mos.; no other cause • “I don’t think it’s a ‘real’ disease at all.” • Widespread pain index (WPI) > 7 and symptom • “All these people are just depressed.” severity (SS) scale score > 5 OR • “They’re all trying to get disability.” – WPI 3-6 and SS score > 9 • NO tender point exam! 88% correlation

18 FM - Pathogenic Fibromyalgia Hypotheses Tentative Conclusions Summary 1. FM is clearly NOT a primary muscle dx. • FM is NOT a muscle dx. (40 neg. studies) 2. FM is a “real” syndrome, as valid as any • FM is NOT entirely psych (30(30--50%50% with dx.) other in which criteria are clinical only. • FM is NOT a single disease (multiple studies) 3. FM is valuable concept for patient care • May be central up regulation of pain pathways (decreased subs. P in CSF) – Avoids unnecessary testing – Sorensen (1995) - improved with IV ketamine – Provides frame of reference for (NMDA ant.) in blinded, cont. trial of 31 pts. patient – No imp. with IV lidocaineor morphine – Helps design therapeutic program • May be variation of small fiber neuropathy 4. Diagnosis not diagnosis of exclusion

Fibromyalgia Evaluation of Muscle Pain Treatment Screening examination Beneficial Possibly Beneficial Labs. CBC, ESR, TFTs, lytes) Imipramine Pregabalin Neuro. eval - strength, endurance testing Duloxetine Fenfluramine Serum CK , electrodiagnostic studies Milnaci pran Fluoxeti ne Normal CK elevated Weak, abn EMG, CK Exercise NSAIDs (used alone) Tender Tender <5x nl FET, BCT >5x normal, points points No other Genetic Zolpidem other sx Amitriptyline present? absent? abn testing Cyclobenzaprine Clomipramine PMR, MAD FM Repeat Biopsy Biopsy Alprazolam Statins

19 Muscle Pain Summary

• Consider carefully the type of pain • Concentrate exam on strength testing! – Presence of tenderness • Eval uat e f urth er w ith CK , EMG, ESR • Do NOT automatically biopsy – Unrewarding most of the time! – Only in selected cases • Consider statin myopathy, MADD, PMR, FM in patients with “normal everything”.

Forearm Exercise Test Method

• IV in dominant antecubital vein (23 gaga)) – Kept open with heparin/saline boluses

• Draw baseline lactate and NH3 (on ice!) • Do not do ischemmically • Squeeze ball MAXIMALLY for 1 minute – Cuff deflated

• Lactate, NH3 at 1, 2, 4, 6, & 10 min • Do NOT do ischemically ((contracture)!)!

20