16.00-17.00 อ.เนาวนิตย์ Handout_Neurologic Complication in ESRD

Neurologic Complication in ESKD Asst. Prof. Naowanit Nata, MD Nephrology Division, Department of Medicine Phramongkutklao Hospital & College of Medicine

Outlines v Case-based discussion 1 v Case-based discussion 2 v Case-based discussion 3 v Case-based discussion 4

Case 1.

A 70-year-old man with DM, stroke HT, ESRD was admitted due to uremia and on first HD. After HD, he developed headache, confusion, and nausea. Physical examination: BP 160/90 mmHg, RR 16/min, PR 80/min, BT 37 C, Neurology exam: Confusion, no localizing sign. v Hct 30%, BUN 170, Cr 19.3 mg/dLF, PG 80 mg/dL v Na 134, K 4, Cl 105, HCO3 18 mEq/L, Ca 8.7, PO4 6.8 mg/dL, Dry weight Try Hemodialysis prescription Pre BW 70 kg Heparin 2500 unit BFR 300/min Na 140 mEq/L Meal/drink 0.5 kg Total UF 2.5 kg DFR 500/min K 2.0 mEq/L Temp 36.0 HCO3 35 mEq/L Dialyzer High flux Ca 2.5 mEq/L What is the most like cause of headache and confusion? A. Intradialytic hypertension B. Dialysis disequilibrium syndrome C. Acute hemorrhagic stroke due to heparin D. Hyponatremia

A 70-year-old man with DM, stroke HT, ESRD was admitted due to uremia and on first HD. After HD, he developed headache, confusion, and nausea. Physical examination: BP 160/90 mmHg, RR 16/min, PR 80/min, BT 37 C, Neurology exam: Confusion, no localizing sign. v Hct 30%, BUN 170, Cr 19.3 mg/dLF, PG 80 mg/dL v Na 134, K 4, Cl 105, HCO3 18 mEq/L, Ca 8.7, PO4 6.8 mg/dL, Dry weight Try Hemodialysis prescription Pre BW 70 kg Heparin 2500 unit BFR 300/min Na 140 mEq/L Meal/drink 0.5 kg Total UF 2.5 kg DFR 500/min K 2.0 mEq/L Temp 36.0 HCO3 35 mEq/L Dialyzer High flux Ca 2.5 mEq/L What is the most like cause of headache and confusion? A. Intradialytic hypertension B. Dialysis disequilibrium syndrome C. Acute hemorrhagic stroke due to heparin D. Hyponatremia

Acute complications commonly occur during routine HD Complication Percent of treatment Hypotension 25-55% Cramps 5-20% Nausea and vomiting 5-15 Headache 5% Itching 5% Chest pain 2-5% Back pain 2-5% Fever and chills <1% Bregman H, et al. Complications during hemodialysis. In: Handbook of Dialysis, Dauugirdas JT, Ing TS (Eds), Little, Brown, New York 1994. p.149.



Dialysis Headache v Definition: Headache with no specific characteristics occurring during and caused by HD. It resolves spontaneously within 72 hours after the HD session has ended Diagnostic criteria: A. At least three episodes of acute headache fulfilling criterion C B. The patient is on HD C. Evidence of causation demonstrated by at least two of the following: 1. Each headache has developed during a session of HD 2. Either or both of the following: 2a) Each headache has worsened during the dialysis session 2b) Each headache has resolved within 72 hours after the end of the dialysis session 3. Headache episodes cease altogether after successful KT and termination of HD D. Not better accounted for by another ICHD-3 diagnosis The International Classification of Headache Disorders 3 rd Edition (ICHD-3). International Headache Society 2017/18

Differential Diagnosis Cause of Headache during Dialysis 1. Intradialytic hypotension/Intradialytic hypertension 2. Dialysis disequilibrium syndrome (DDS) 3. High urea removal rates 4. Caffeine removal 5. Hypoglycemia/hyperglycemia/hypernatremia/hyponatremia 6. Uremia 7. Medication-induced headaches 8. Dialysis-associated somatic complaints 9. Dialysis-associated headache may be associated with increased intraocular pressure 10. Stroke, Subdural hematoma/ICH/intracranial lesion • Sav MY, et al . Hemodialysis-related headache. Hemodial Int 2014; 18:725. • Milinkovic M, et al. Hemodialysis headache. Clin Nephrol 2009; 71:158. • van Brussel MS, et al. Headache during hemodialysis - an uncommon cause for a common problem. Clin Nephrol 2008; 69:219. • Barrett BJ, et al. Clinical and psychological correlates of somatic symptoms in patients on dialysis. Nephron 1990; 55:10. • Sousa Melo E, Carrilho Aguiar F, Sampaio Rocha-Filho PA. Dialysis Headache: A Narrative Review. Headache 2017; 57:161

Differential Diagnosis Cause of Headache during Dialysis 1. Intradialytic hypotension/Intradialytic hypertension 2. Dialysis disequilibrium syndrome (DDS) 3. High urea removal rates 4. Caffeine removal 5. Hypoglycemia/hyperglycemia/hypernatremia/hyponatremia 6. Uremia 7. Medication-induced headaches 8. Dialysis-associated somatic complaints 9. Dialysis-associated headache may be associated with increased intraocular pressure 10. Stroke, Subdural hematoma/ICH/intracranial lesion • Sav MY, et al . Hemodialysis-related headache. Hemodial Int 2014; 18:725. • Milinkovic M, et al. Hemodialysis headache. Clin Nephrol 2009; 71:158. • van Brussel MS, et al. Headache during hemodialysis - an uncommon cause for a common problem. Clin Nephrol 2008; 69:219. • Barrett BJ, et al. Clinical and psychological correlates of somatic symptoms in patients on dialysis. Nephron 1990; 55:10. • Sousa Melo E, Carrilho Aguiar F, Sampaio Rocha-Filho PA. Dialysis Headache: A Narrative Review. Headache 2017; 57:161

Mistry K. International Journal of Nephrology and Renovascular Disease 2019:12 69–77

Signs and Symptoms of Dialysis Disequilibrium Syndrome (DDS) Symptoms v Nausea Emesis Headache Dizziness v Muscle cramps vAgitation Disorientation v Confusion v Tremors v Visual disturbances Signs: v Changes in mental status v Asterixis v Seizures v Coma v Death Mistry K. International Journal of Nephrology and Renovascular Disease 2019:12 69–77

Risk Factors for Developing Dialysis Disequilibrium Syndrome (DDS) 1. First dialysis treatment 2. Children/Elderly 3. High BUN prior to a dialysis session (eg, BUN >175 mg/dL) 4. Hypernatremia 5. Hyperglycemia 6. Metabolic acidosis 7. Preexisting neurologic abnormalities (head trauma, stroke, seizure disorder) 8. Preexisting cerebral edema 9. Conditions associated with an increased permeability of the blood brain barrier, eg, meningitis, vasculitis, CNS tumors, hemolytic uremic syndrome or thrombotic thrombocytopenic purpura • Mistry K. International Journal of Nephrology and Renovascular Disease 2019:12 69–77 • UpToDate ; 2020

Figure: Changes in brain urea transporter B (UT-B) and AQP4 and AQP) expression. (A) Normal, non-uremic milieu. (B) During chronic uremia, UT-B expression decreases by approximately 50%, while that of AQP4 and AQP9 increases by 50% or more. Cell volume remains unchanged compared with normal. (C) During rapid urea removal, as occurs during HD, the reduced number of brain UT-B results in slower movement of urea from the intracellular to extracellular compartment than is removed from the extracellular compartment by dialysis. The resulting osmotic gradient, coupled with increased brain AQP expression, results in water movement into cells, and subsequent cerebral edema. Mistry K. International Journal of Nephrology and Renovascular Disease 2019:12 69–77

A 70-year-old man with DM, stroke HT, ESRD was admitted due to uremia and on first HD. After HD, he developed headache, confusion, and nausea. Physical examination: BP 160/90 mmHg, RR 16/min, PR 80/min, BT 37 C, Neurology exam: Confusion, no localizing sign. v Hct 30%, BUN 170, Cr 19.3 mg/dLF, PG 80 mg/dL v Na 134, K 4, Cl 105, HCO3 18 mEq/L, Ca 8.7, PO4 6.8 mg/dL, Dry weight Try Hemodialysis prescription Pre BW 70 kg Heparin 2500 unit BFR 300/min Na 140 mEq/L Meal/drink 0.5 kg Total UF 2.5 kg DFR 500/min K 2.0 mEq/L Temp 36.0 HCO3 35 mEq/L Dialyzer High flux Ca 2.5 mEq/L What is the most like cause of headache and confusion? A. Intradialytic hypertension B. Dialysis disequilibrium syndrome C. Acute hemorrhagic stroke due to heparin D. Hyponatremia

Prevention of Dialysis Disequilibrium Syndrome (DDS) This can be achieved using three strategies: 1. Decreased clearance so as to lessen the reduction of plasma osmolality, and thus osmotic gradient post dialysis 2. Increased time over which clearance is performed and 3. Adding another osmotically active agent like sodium or mannitol as urea is removed by hemodialysis, so that plasma osmolality does not change significantly • Mistry K. International Journal of Nephrology and Renovascular Disease 2019:12 69–77 • UpToDate; 2022

Prevention of Developing Dialysis Disequilibrium Syndrome (DDS) Patients being newly initiated on HD - 1st HD: Set 2 hour, BFR 150-250 mL/min, DFR = 2 x BFR Target reducing urea by 40-50% - 2nd HD: (consecutive days) ↑ BFR 50 mL/min and ↑ dialysis time by 30 minutes - 3rd HD: Standard prescription; BRF, DFR, duration • Mistry K. International Journal of Nephrology and Renovascular Disease 2019:12 69–77 • UpToDate; 2022

Prevention of DDS Patients with recurrent nonadherence to HD - No Na modeling capability; linear or exponential modeling profiles. - if 50% urea clearance is expected, we set initial dialysate Na to be 10-15 mEq/L> predialysis serum Na and the final dialysate Na 5 mEq/L > predialysis serum Na (an average >10 mEq/L higher) - Not have Na modeling capability, then (if 50% urea clearance is expected) we dialyze using a dialysate sodium that is 10 mEq/L higher than baseline Na • Mistry K. International Journal of Nephrology and Renovascular Disease 2019:12 69–77 • UpToDate; 2022

Case 2.

A 30-year-old man with HT, dyslipidemia, ESRD due to IgA nephropathy on HD 2 times/week for 3 year ago. Medication: - Amlodipine 10 mg/day - Simvastatin 20 mg/day - Calcium carbonate 1.5 gm/day v Hct 30%, Hb 10.1 g/dL v Na 130, K 3.4, Cl 105, HCO3 28 mEq/L v Ca 8.0, PO4 4.6 mg/dL v BUN 98, Cr 9.6 mg/dL v FPG 105 mg/dL v sp Kt/V 1.9

Dry weight 62 kg BFR 350/min Hemodialysis prescription Pre BW 67 kg DFR 500/min Na 135 mEq/L Weight gain 5.0 kg Temp 36.0 K 2.0 mEq/L Meal/drink 0.5 kg Dialyzer High flux HCO3 34 mEq/L Total UF 5 kg Ca 2.5 mEq/L Time BFR PR BP UFR Total UF (/min) (/min) (mmHg) (mL/h) (mL) 8.00 130/80 0 8.30 350 70 120/80 1250 500 9.00 350 70 130/70 1250 1000 9.30 350 75 140/60 1250 1500 10.00 350 70 120/80 1250 2000 10.30 350 72 110/70 1250 2200 11.00 350 62 120/70 1250 2500 11.30 350 70 120/70 1250 3200 12.00 350 65 110/60 1000 4000 350 70 1000 Muscle clamp Next Step Approach and Management/prevention?

Acute complications commonly occur during routine HD Complication Percent of treatment Hypotension 25-55% Cramps 5-20% Nausea and vomiting 5-15 Headache 5% Itching 5% Chest pain 2-5% Back pain 2-5% Fever and chills <1% 15% of premature discontinuations of dialysis Bregman H, et al. Complications during hemodialysis. In: Handbook of Dialysis, Dauugirdas JT, Ing TS (Eds), Little, Brown, New York 1994.

Clinical of HD-associated Cramps v Most common: Lower extremity (but the muscles of the hands, arms, and abdomen may also be affected) v Often in older, nondiabetic, anxious patients v ↓ PTH with ↑serum CPK v Solute concentrations: Low concentrations of Na v ↑ Ultrafiltration required to remove excessive fluid ingested in the interdialytic period v Hemodiafiltration compared with high-flux hemodialysis in older adults • Canzanello VJ, Burkart JM. Semin Dial 1992; 5:299. • McGee SR. Arch Intern Med 1990; 150:511. • Morena M, Jaussent A, Chalabi L, et al. Kidney Int 2017; 91:1495. Reduction in muscle perfusion in response to hypovolemia with compensatory vasoconstriction Canzanello, VJ, Burkart, JM. Semin Dial 1992; 5:299.

Identify HD-associated Cramps Prevention Cause Acute management

HD-associated Cramps Identify Acute Prevention Cause management Assess: Etiology of cramps: Medications associated with cramps: v Structural foot/leg v ↓Plasma volume v Hypotension v IV iron sucrose (up to 23%) disorders v Hyponatremia v Oral contraceptive (3.5-14%) v Peripheral vascular v Hypocalcemia v Statins (4-5%) v Hypomagnesemia v Pyrazinamide (1-10%) disease v Hypokalemia v long-acting ß-agonists (2-3%) v Poor BS control v ↓Carnitine v Thiazide-like diuretics v Iron deficiency v Tissue hypoxia v ↑serum leptin • Canzanello VJ, Burkart JM. Semin Dial 1992; 5:299. • McGee SR. Arch Intern Med 1990; 150:511. • Hung CY, Chen YL, Chen CS, et al. Blood Purif 2009; 27:159.

HD-associated Cramps Identify Acute Prevention Cause management Forced stretching of the if severe Increase plasma muscle Reduce/stop UF osmolality - Nifedipine (10 mg) oral DM patient: (option; if ↑BP) - Hypertonic NaCl (Dose; 23.5% NaCl 15-20 mL, 3% NaCl 50- 100 mL, 7.05%NaCl 25-50 mL • Canzanello VJ, Burkart JM. Hemodialysis-associated muscle cramps. Semin Dial 1992; 5:299. - Mannitol infusion: Dose ;12.5-37.5 g/dialysis • UpToDate, December 2022 -Non DM: - 50% D/W (25-50 mL) or hypertonic solution as above

Effects of Different Therapies in 100 Episodes of Hemodialysis-related Muscle Cramps Relief Obtained 5%Dextrose N 7.05%NaCl 50%DextroseN (%) (%) N (%) N=33 Complete N=35 N=32 Patial 18 (55%)* None 8 (23%) 19 (59%)* 8 (24%) 14 (40%) 7 (22%) 7 (21%) 13 (37%) 6 (19%) *p < 0.02 versus 5% Dextrose group (complete versus partial + none). p < 0.05 versus 5% Dextrose group (complete versus none). Adapted from Sherman RA, Goodling KA, Eisinger RP. Acute therapy of hemodialysis-related muscle cramps. Am J Kidney Dis 1982; 2:287.

Effects of Different Therapies in 100 Episodes of Hemodialysis-related Muscle Cramps Relief Obtained 5%Dextrose N 7.05%NaCl 50%DextroseN (%) (%) N (%) N=33 Complete N=35 N=32 Patial 18 (55%)* None 8 (23%) 19 (59%)* 8 (24%) 14 (40%) 7 (22%) 7 (21%) 13 (37%) 6 (19%) *p < 0.02 versus 5% Dextrose group (complete versus partial + none). p < 0.05 versus 5% Dextrose group (complete versus none). Adapted from Sherman RA, Goodling KA, Eisinger RP. Acute therapy of hemodialysis-related muscle cramps. Am J Kidney Dis 1982; 2:287.

HD-associated Cramps Identify Acute management Prevention Cause First step: Correct cause Forced stretching of the if severe Increase plasma muscle Reduce/stop UF osmolality Hypertonic saline may result in DM patient: post-dialysis thirst, interdialytic - Hypertonic NaCl (Dose; 23.5% NaCl 15-20 mL, 3% NaCl 50- weight gain and fluid overload 100 mL, 7.05%NaCl 25-50 mL - Mannitol infusion: Dose ;12.5-37.5 g/dialysis • Canzanello VJ, Burkart JM. Hemodialysis-associated muscle cramps. Semin Dial 1992; 5:299. -Non DM: - 50% D/W (25-50 mL) or hypertonic solution as above • UpToDate, December 2022

Dry weight 62 kg BFR 350/min Hemodialysis prescription Pre BW 67 kg DFR 500/min Na 135 mEq/L Weight gain 5.0 kg Temp 36.0 K 2.0 mEq/L Meal/drink 0.5 kg Dialyzer High flux HCO3 34 mEq/L Total UF 5 kg Ca 2.5 mEq/L Time BFR PR BP UFR Total UF (/min) (/min) (mmHg) (mL/h) (mL) 8.00 0 8.30 350 70 130/80 1250 500 9.00 -350 Forced 7s0 tretchin12g0/ 8o0 f the m12u50scle 1000 9.30 1500 10.00 -350 Reduce7d5 UF 130/70 1250 2000 10.30 1250 2200 11.00 350 70 140/60 1250 2500 11.30 3200 12.00 -350 50% D/72W (50 m12L0/)80 4000 350 62 110/70 1250 120/70 1250 35M0 uscle cla7m0 p 350 65 120/70 1000 350 70 110/60 1000

Identify HD-associated Cramps Prevention Cause Acute management

Prevention of Muscle Clamps in Hemodialysis Patients by Quinine Sulphate v Frequency of muscle cramps during HD after Prevention Quinine Placebo (Total dialysis = 162) (Total dialysis = 162) Dialysis with cramps 10 28 Dialysis without cramps 152 134 X2=13.99, p<0.001 v9 patients on HD with frequent muscle cramps were given 320 mg quinine sulphate or placebo at the beginning of each dialysis for a period of 12 weeks. Adapted from KAJI DM, et al. PREVENTION OF MUSCLE CRAMPS IN HEMODIALYSIS PATIENTS BY QUININE SULPHATE. The lancet, July 10, 1976.

• El-Tawil S, et all. Quinine for muscle cramps. Cochrane Database of Systematic Reviews 2015, Issue 4. Art. No.: CD005044. DOI: 10.1002/14651858.CD005044.pub3.

Quinine versus placebo: Difference in number of cramps over 2 weeks • El-Tawil S, et all. Quinine for muscle cramps. Cochrane Database of Systematic Reviews 2015, Issue 4. Art. No.: CD005044. DOI: 10.1002/14651858.CD005044.pub3.

Quinine versus vitamin E: Difference in number of cramps in 2 weeks • El-Tawil S, et all. Quinine for muscle cramps. Cochrane Database of Systematic Reviews 2015, Issue 4. Art. No.: CD005044. DOI: 10.1002/14651858.CD005044.pub3.

HD-associated Cramps Acute management Prevention Identify Cause Nonpharmacologic Pharmacologic: v Quinine sulfate (250-300 mg) given 2 hours before HD v Adjusted dry weight (↑0.5 kg if no edema/adjust BIA) v Dietary counseling on minimal interdialytic weight gain (optional) v Dialysis prescription, Stretching exercises v Oxazepam (5-10 mg) given 2 hours before HD v Biofeedback program (blood volume monitoring) (optional) (optional) v Vitamin E (400 mg) and vitamin C (250 mg) daily v BT monitoring (BTM) (optional) v Dialysate Na profile (optional), UF profile (optional) (optional) v Isolated UF or sequential UF followed by dialysis (optional) v Gabapentin 300 mg given before each HD session v Hemodiafitration (optional) v More frequent (short daily/nocturnal) HD (optional) (optional) v L-carnitine (20 mg/kg) given IV after HD or orally (330 mg 2-3 times/day) (optional) UpToDate 2022

Case 3.

Dry weight 72 kg Hemodialysis prescription Pre BW 20 kg Weight gain 2.0 kg BFR 350/min Na 135 mEq/L Meal/drink 0 kg Total UF 2 kg DFR 500/min K 2.0 mEq/L Temp 36.0 HCO3 34 mEq/L Dialyzer High flux Ca 2.5 mEq/L Time BFR PR BP Total UF At 2-4 hours: He developed (/min) (/min) (mmHg) (mL) bilateral headache and/or 8.00 140/80 0 pulsating 8.30 350 70 130/70 250 9.00 350 70 130/70 500 9.30 350 75 128/60 750 10.00 350 70 128/80 1000 10.30 350 72 130/70 1100 11.00 350 62 130/70 1250 11.30 350 70 130/70 1600 12.00 350 65 130/70 2000 350 70

Dry weight 72 kg Hemodialysis prescription Pre BW 20 kg Weight gain 2.0 kg BFR 350/min Na 135 mEq/L Meal/drink 0 kg Total UF 2 kg DFR 500/min K 2.0 mEq/L Temp 36.0 HCO3 34 mEq/L Dialyzer High flux Ca 2.5 mEq/L v The elTiimmei nation BoFfR caffeine PfRrom the bBoP dy is faTsotta al UnF d dose- dependent with( /am itny) pical p(/lmaisn)ma hal(mf-mliHfge) of 2.5(–m4L) hours 8.00 350 70 140/80 0 v HD: Re8m.30ove fast 350 70 130/70 250 9.00 350 75 130/70 500 9.30 350 70 128/60 750 Coffee Lover Man 10.00 350 72 128/80 1000 350 10.30 62 130/70 1100 11.00 350 70 130/70 1250 11.30 350 65 130/70 1600 12.00 350 70 130/70 2000

Caffeine-Withdrawa Headache (CWH) Criteria for caffeine-withdrawa headache (CWH) by International Classification of Headache Disorders: 1. Headache is bilateral and/or pulsating, occurs when intake is interrupted or delayed in person with caffeine consumption of ≥200 mg/day for 2 weeks 2. Develops within 24 h after last caffeine intake 3. Relieved within 1 hour by 100 mg of caffeine UpToDate 2022

Case 4.

A 65-year-old woman with DM, ESRD on HD v อาการระหวา่ ง HD: ใจสน/ั เหนอื/ ย แนน่ หนา้ อก ซมึ ลง v BT 37ºC, HR 120/min, RR 24/min, BP 90/50 mmHg v Eye ground: Bubbles within the retinal arteries v Drowsiness, no localizing sign v Stat EKG: Non-specific ST-segment and T-wave changes What is the most likely diagnosis?

Air Embolism UpToDate 2022 v 0.5-1 ml/kg air may be fatal v 3 vulnerable areas - Arterial needle - Pre-pump arterial tubing segment - Opened end of central venous catheter v High BFR >> may allow rapid entry of large volume of air despite small leaks Comprehensive Clinical Nephrology 6th ed.

Massive Cerebral Air Embolism v Gas is present throughout both hemispheres, and there is evidence of diffuse cerebral edema. Valentino R, et al. Lancet 2003; 361:1848.

Clinical Findings in Air Embolism Symptoms Physical findings Pulmonary: Dyspnea (100 percent incidence) v Tachypnea \"Gasp reflex\"* v Wheeze \"Sucking sound\"¶ v Rales v Respiratory failure Cardiac: Substernal chest pain v Hypotension v Tachycardia Neurologic: Sense of doom v Mill wheel murmur Dizziness/lightheadedness v Signs of right heart failure (eg, elevated JVP) Skin v Shock Ocular v Change in mental status v Focal neurological deficits v Crepitus over superficial vessels (seen rarely in setting of massive air embolus) v Livedo reticularis v Bubbles within the retinal arteries UpToDate 2022

Clinical and Management of Air Embolism v In the sitting position - Air entry through a peripheral vein bypasses the heart and causes venous emboli in the cerebral circulation v In the supine position - Air introduced through a central venous line will be trapped in the right ventricle, interferes with cardiac output, and, if it is large enough, leads to obstructive shock Comprehensive Clinical Nephrology 6th ed.

Outlines v Case-based discussion 1 v Case-based discussion 2 v Case-based discussion 3 v Case-based discussion 4

Thank You for Your Attention Col. Naowanit Nata, MD Nephrology Division, Department of Medicine Phramongkutklao Hospital & College of Medicine