9 th CEAAC INTENSIVE MEDICINE DAYS TURP syndrome

9 th CEAAC, INTENSIVE MEDICINE DAYS TURP syndrome: a skeleton in the closet is still lurking! Assoc. Prof. TATJANA ŠIMURINA, MD Ph. D tsimurina@unizd. hr tatjana. simurina@mefos. hr

Conflicts of Interest declaration I have no conflict of interest.

TURP • ~60% of men > 60 years suffer from BHP/LUTS (voiding problems, decreased Qo. L) • TURP: ~30% of urologists’ workload • Transurethral resection techniques: • m TURP (monopolar) • b TURP (bipolar, TUR in saline) • Minimally invasive surgical therapies, MIST: • • Laser enucleation L TURP [Ho. LEP, Thu. LEP, (Holmium/Thulium) laser enucleation] TUVP (transurethral evaporization) Transurethral needle ablation Plasma vaporization (”button” procedure), photoselective vaporization (PVP) TUMT (transurethral microwave therapy) WAVE (water vapor energy ablation) PUL (prostatic urethral lift) TUIP (transurethral incision prostate) Sun F, Sun X, Shi Q, Zhai Y. Medicine; 2018: 97: 51(e 13360)

Day case TURP: is it feasible? • • • Careful selection of candidates Management of patients’ expectations Proper surgical technique selection Improvement of instruments Hemostasis control (CTD, catheter tensioning device; TXA) Early urinary catheter removal Normal vital signs and adequate urine output Anesthetic management during and after TURP More experience with outpatient transurethral surgery Khan A. Urol Ann 2014; 6(4): 334– 9. Subrata SA, Istani YP, Kesetyaningsih TW. Int J of Urol Nurs 2018; 12(1): 35 46.

Ideal irrigation fluid (IF) does not exist! • • • Isotonic Nonhemolytic Nontoxic when absorbed Not metabolised Translucent Electrically inert Does not alter osmolality Rapidly excreted Osmotic diuretic Simple, easy to sterilize Inexpensive • No solution meets all of the criteria !

IFs for m TURP, b TURP, L TURP v Hypotonic solutions (electrolyte free): • Glycine 1. 2 1. 5%, Mannitol 3%, Sorbitol, Cytal (2. 7% sorbitol and 0. 54% mannitol), Glucose 2. 5 4% , Urea 1% • m TURP Monopolar diathermy • active electrode at the end of resectoscope and external return electrode • Higher risk of rapid absorption, fluid overload, dilutional hyponatremia • Distilled water is rarely used (extreme hypotonicity: hemolysis, shock and renal failure) v Isotonic solutions (electrolyte containing): • Normal saline, lactated Ringer • b TURP Bipolar diathermy • active and return electrodes are located within the resectoscope • Risk of fluid overload and surrounding tissue edema • Decreased risk of electrolyte disturbances • TURis, L TURP (Laser TURP) = TURP with normal saline: • • • decreased risk of TURP syndrom (but higher incidence of urethral stricture) no risk for hemolysis, improved coagulation, blood loss reduction no cardiac toxicity hyperchloremic acidosis, fluid overload impairment in cardiac function better visibility

Pharmacology of common fluids for irrigation Solution for irrigation Pharmacokinetics Pharmacodynamics (adverse effects) (Tonicity, osmolality m. Osm /kg) Normal saline (Isotonic, 308) T ½ half–life 110 min Distribution: • 25% intravascular space • 75% interstitial space Rapid infusion of large amount lead to hyperchloremic acidosis Ringer‘s lactate (Isotonic, 273) T ½ 50 min Hepatic metabolism of lactate Relative excess of bicarbonate from lactate metabolism (alkalosis, hyperkalemia) Glycine 1. 2% or 1. 5% (Hypotonic, 175 / 220) T ½ distribution 6 min; T ½ elimination 40 min Renal excretion 5 10% Penetration into the CNS (limited) Hepatic metabolism to ammonia Glycine (nonessential amino acid) inhibitory neurotransmitter in the CNS and retina Potentiation of the NMDA receptor Glycine toxicity: headache, nausea, facial warmth, visual impairment (blindness), myocardial depression Hyperammonemia: neurological symptoms Mannitol 3% (Hypotonic, 179) Mannitol 5% (Isotonic, 298) T ½ distribution 10 min; T½ elimination 100 min Osmotic diuresis Rapid expansion of intravascular volume fluid overload, pulmonary oedema, cardiac failure Bradycardia, hypotension Sorbitol 3. 5% (Hypotonic, 165) T ½ distribution 6 min T ½ elimination 33 min (5 10% renal excretion) Hepatic metabolism to fructose and lactate Unabsorbed: diuresis, laxative Metabolite fructose: hyperglycemia, lactic acidosis Hypoglycemia (fructose 1, 6 diphosphatase deficiency) Death ( fructose intolerance)

Complications of TURP Intraoperative Postoperative Myocardial ischemia (25%) Myocardial ischemia/ AMI Acute myocardial infarction, AMI (1 3%) DVT Hypothermia Clot retention (vagal stimulation, pain) (4. 9%) Shivering Bladder spasm Perforation of the bladder Bladder neck/urethral stricture (3 8%) Perforation of prostatic capsule Acute urinary retention (4. 5%) Penile erection Retrograde ejaculation (65. 4%) Lithotomy position: pulmonary compliance/ lung volumes decreased Urinary tract infection /epididiymitis (4. 1%) Lithotomy position: cardiac preload increase Postoperative cognitive dysfunction TURP syndrome (1%) Bleeding requiring transfusion (2. 9%) Taylor BL, Jaffe WI. Can J Urol 2015; 22(Suppl 1): 24 9. Ahyai SA, Gilling. P, Kaplan SA, et al. Eur Urol 2010; 58(3): 384 97.

TURP syndrome: a sceleton in the closet is still lurking! • Severe TURP syndrome is a very rare complication but potentially fatal with mortality rate ~ 25% • Group of clinical symptoms that occur during and post endoscopic surgical procedures as result of the rapid, high volume absorption of the irrigation fluid into the circulation resulting in hypoosmolality, dilutional hyponatremia, and metabolic acidosis • Clinical manifestations can also occur with a serum sodium level of > 125 mmol/l • °Incidence of TURP syndome: 0. 78% 1. 4% • *A large scale multicenter study of 10, 654 men: • • • †A 30 day mortality rate of 0. 1% Immediate morbidity of 11. 1 % nation wide, long term analysis of 23, 123 men: • Mortality for TURP at 90 days 0. 7% , 1 year, 2. 8%, 5 year 12. 7%, 8 years 20% • 8 year incidence of MI 4. 8% Šimurina T, Mraović B, Župčić M, et al. Liječ Vjesn 2020; 142: 160– 9 °Zepnick H, Steinbach F, Schuster F. Aktuelle Urol. 2008; 39(5): 369– 72 *Reich O, Gratzke C, Bachmann A, et al. J Urol. 2008; 180(1): 246 9 †Madersbacher S, Lackner J, Brössner C at al. Eur Urol 2005; 47(4): 499 504

Early, intermediate and late signs and symptoms of TURP syndrome Neurologic Cardiovascular Respiratory Metabolic Renal and other Headache Dizziness Hypertension O 2 desaturation Hyponatremia Acute renal failure Nausea, vomiting Reflex bradycardia Tachypnea Hypo osmolality Hemolysis/anemia Restlessness Tachiarrhythmias Hypoxemia Hypergycinemia Disorientation Hypotension (spinal + epidural; ac. Pulmonary edema Hyperammonemia Respiratory arrest Metabolic acidosis hypo. Na; periop. bleeding; vasovagal reflex, vasoactive substance from the op. field) Apprehension Negative inotropy Confusion ECG: widened QRS, ST elevation, T wave inversion Visual disturbances, transient blideness VEBs, Ventricular arrhythmias Somnolence Congestive heart failure Convulsions Myocardial infarction Coma, Death Cardiovascular collapse

Risk factors for TURP syndrome • Large prostate (>75 g)˚ • Prolonged resection time (>90 min): • RI, DM/HT, (renal insufficiency, diabetes mellitus and hypertension) >40 min • HT >45 min • High inflow irrigation fluids pressure (infusion bag higher than 100 cm) • Large irrigation fluid volume (+comorbidities) • • CAD, Coronary artery disease, ≥ 20 L (low salt diet, digitalis, diuretics, reduced exercise) DM, >24 L (reduced total body water, electrolytes and blood volume) DM / HT ( + large gland size, prolonged resection time), > 20 L CKD, Chronic kidney disease, ( + large gland size, prolonged resection time), >15 L • Capsular perforation, open prostatic veins and sinuses • Irrigation fluid type: hypotonic fluids, high volume of plasma substitute (colloids ≥ 500 m. L) • Preoperative hyponatremia • Smoking (prostatic vascular damage) • Acute urinary retention, distended bladder (high intravesical pressure) • Continuous irrigation fluid drainage (leaking into the abdominal / extraperitoneal space) • Age >80 years (23/98 , 23. 5% 95% CI 14. 9 32. 0%)* ˚Fujiwara A et al. BMC Urology 2014: 67 Narayanan KJ, Kannab VP. Int JRes Med Sci 2017; 5(8): 3317 21 *Nakahira J et al. BMC Anesthesiology 2014; 14: 30

• Retrospective study, N=1, 502 TURPs over 15 years, spinal anesthesia, 1. 5% glycine • • Resection time (min): median 55 (range 40 75) Resection weight (g): median 44 (range 24 65) Volume of intraoperative IF (L): median 28 (range 24 48) Blood analysis: preoperative vs postoperative values (median) • Hct 42 vs 33 % • Hb 142 vs 101 g/L • Na 142 vs 121 mmol/L • TURP complications (9 pts. were admitted to HDU; all pts. recovered within 48 h): • TURP syndrome in 48 patients (3. 2%) EARLY signs of TURP syndrome: nausea 44/48, apprehension 37/48, visual disturbance 29/48, vomiting 28/48, bradycardia 19/48, disorientation 17/48, dyspnea 17/48) • Capsular perforation in 16/48 pts. • Blood transfusion in 1 patient

Regional or General Anesthesia, that is the question ! Anesthesia ADVANTAGES REGIONAL GENERAL Detection of early signs of TURP syndrome Pts. unable to lie supine Earliy detection of capsular tears /bladder perforation Pts. with consistent cough Reduced blood loss (lower blood pressure) Incidence of myocardial ischemia is similar as for RA Peripheral vasodilatation minimizes circula tory overload Pts. who need ventilatory and hemodynamic support Pts. with severe respiratory disease Pts. who have contraindications or refuse RA Lower incidence of deep vein thrombosis, DVT Better safety in anticoagulated patients Good postoperative analgesia (lower incidence of postop. hypertension or tahycardia) Caudal and sacral blockade = hemodynamic stability DISADVANTAGES Penile erection interferes with surgery Lithotomy VT and FRC reduced /higher the risk of aspiration Lower safety in anticoagulated patients Penile erection Postoperative analgesics Short term morbidity, long term outcomes and mortality are similar with both techniques. At the present time, less emphasis is placed on RA.

Intraoperative monitoring • Standard monitors according to the recommendations: • • • Standard ASA monitors: pulse oximeter Sp. O 2 ; ECG; noninvasive blood pressure NIBP; and a temperature monitor WHO-WFSA International Standards for a Safe Practice of Anesthesia: Sp. O 2 ; intermittent monitoring of BP; confirmation of correct placement of ETT by auscultation and Et. CO 2 ; WHO Safe Surgery Checklist; a system for transfer of care at the end of an anesthetic Non Invasive hemodynamic monitoring (finger cuff: R/R, HR, CO) Direct arterial blood pressure Frequent blood sampling for electrolytes, blood gas analysis ABG, RBCs Transthoracic echocardiography Monitoring of the amount of intravenous fluid administration (normal saline) Ethanol monitoring of IF absorption Gelb AW, Morriss WW, Johnson W, et al. Can J Anaesth 2018; 65: 698. Whitaker D, Brattebø G, Trenkler S, et al. Eur J Anaesthesiol. 2017; 34(1): 4 7. http: //www. eba uems. eu/resources/PDFS/safety guidelines/EBA Minimal monitor. pdf Checketts MR, Alladi R, Ferguson K, et al. Anaesthesia 2016; 71: 85.

A prospective observational study, N = 20, ASA 1, 2, TURP under spinal anesthesia Irrigating fluid (IF) 2. 7% sorbitol, 0. 54% mannitol solution, 1% ethanol (fluid absorption ~ ethanol in expired breath) Pre and postoperative blood analysis : Hb, Hct, platelet count, PT INR, a. PTT, electrolyte (Na, K, Cl, i. Ca), ROTEM INTEM CT clotting time was significantly lengthened by 14% (P=0. 001) INTEM a angle was significantly decreased by 3% (P=0. 011) EXTEM CFT clot formation time was significantly prolonged by 18% (P=0. 008) EXTEM MCF maximum clot firmness was significantly decreased by 4% (P=0. 010) FIBTEM MCF was significantly decreased by 13% (P=0. 015) Hb (P<0. 001), Hct (P<0. 001), platelet counts (P<0. 001), K (P=0. 024), i. Ca (P=0. 004) were significantly decreased and PT INR (P=0. 001) significantly increased after surgery The amount of absorbed IF significantly correlated with the weight of resected tissue (P=0. 001) and change of INTEM-CT (P<0. 001) IF absorbed during TURP impaired the blood coagulation cascade by: disruption in the coagulation factor activity and lowering the coagulation factor concentration via dilution ROTEM as a point of care is helpful tool in ambulatory setting in the assessment of clotting function and early detection of a coagulopathic state

Case scenario • 75 year old male, history of hypertension and stroke • b TURP in lithotomy position under general anesthesia with LMA (refused neuraxial block) with PCV 18 cm H 2 O , rate 16, Fi. O 2 40% , sevoflurane 1. 5 % • Intraop. monitoring: Sp. O 2, body temp. , ECG, non invasive hemodynamic monitoring NIBP (MABP), HR • The surgery time ~ 80 min, surgery was uneventful, minimal blood loss • Intraop. normal saline NS 1500 ml IV, warmed NS for continuous irrigation (infusion bag 70 cm above the op. table) • Calculated IF deficit (difference of IF administered and volume removed by suction) ~ 2. 5 L • Near the end of surgery BP raised transiently from preop. 140/85 to 195/100 mm. Hg and HR from 85 to 105 bpm, Sp. O 2 decreased to 88%, TV decreased, from 450 to 300 ml • Auscultation: bilateral lung crepitation and wheezing. • Treatment: Surgery was terminated immediately, IF and IV fluids were stopped, Fi. O 2 increased to 100%, furosemide 40 mg IV, aminophylline IV • LMA was replaced with ETT, continued mechanical ventilation with PCV with propofol sedation for 90 minutes in PACU • Laboratory results: 1. ABG: hyperchloremic metabolic acidosis (p. H 7. 15, Sa. O 2 88%, chloride 118 mmol/L), 2. ABG: improvement (p. H 7. 35, Sa. O 2 98%, chloride 110 mmol/L), serum sodium 127 mmol/L, potassium 3. 5 mmol/, Hb 89 g/L • Chest X ray: obscured bilateral lower lung fields (pulmonary edema); ECG: no abnormalities • Discontinuation of sedation – spontaneous breathing, extubation, PACU stay ~150 minutes • Patient transfer to the ward and discharged to home next morning

Take home points • It is important to identify predictive factors for TURP complications, to take risk minimization measures and to provide early treatment. • TURPis (L TURP, b. TURP) techniques reduce a risk of surgical bleeding, TURP syndrome, catheterization period and there is no risk of cardiac toxicity. • Vigilance for IF toxicity and meticulous monitoring for early signs of fluid overload reduces perioperative morbidity. • Non invasive hemodynamic monitoring, point of care monitoring including ABG, CBC, electrolyte and ROTEM may provide early and complete insight of patients’ physiologic well being. • Appropriate communication with urologist, patients and escort is crucial to avoid delayed discharge or hospital readmission.

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