ENDOUROLOGY AND STONE DISEASE Effect of Irrigation Solution Temperature on Complications of Percutaneous Nephrolithotomy: A Randomized Clinical Trial Seyed Reza Hosseini1*,Mohammad Ghasem Mohseni2,Seyed Mohammad Kazem Aghamir3, Hamed Rezaei4 Purpose: Many factors affecthypothermia and shivering during percutaneous nephrolithotomy and in recovery. Hence this study was carried out to determine the effect of irrigation solution temperature on complications of percutaneous nephrolithotomy. Materials and Methods: In this randomized clinical trial, 60 patients undergoing PCNL in Sina University Hos- pital were enrolled. The patients were randomly assigned in three groups according to simple random manner. The groups included three groups of room temperature fluid (24 degree), warm solution (37 degree), and cold fluid (20 degree) during nephroscopy. Results: Although the initial core temperature was alike across the groups (P > .05); the hypothermia rate oc- cured in all 20 patients in the cold fluid group (P = .012). There was significant difference between the groups in terms of final temperature and alteration amount (P = .001). The mean VAS scores were significantly lower in the warm fluid group compared with the others groups at recovery, and 8hrs post-operatively (P = .03). Assessment of shivering rates revealed that 3(15%) patients in warm solution group shivered compared to8 (40%) patients in cold fluid group (P = .018). Conclusion: Warm irrigation solution during PCNL results in significantly decreased hypothermia, mean postop- erative pain score and shivering. Hence use of warm irrigation fluid for this matter is recommended. Keywords: hypothermia; irrigation fluid; percutaneous nephrolithotomy INTRODUCTION Percutaneous nephrolithotomy (PCNL) is a routine treatment for stones larger than two centimeters, staghorn calculi, and resistant to extracorporeal shock- wave lithotripsy (ESWL). It is usually done by fluoros- copy or ultrasonography via the calyceal system. Even for the most experienced urologist, major complications can still occur in up to 7% of patients undergoing PNL and minor complications may be encountered in up to 25% of patients. Hemorrhage is the most significant complication of PCNL, with transfusion rates reported to be from less than 1% to 10%. (1,17) During nephroscopy, continuous irrigation of pyeloc- alyceal system with fluids is required to develop good visual field. The irrigation fluid temperature is studied in different endoscopic procedures showing controver- sial results. Postoperative hypothermia may result in hazardous complications such as myocardial ischemia, coagulopathy, surgical wound infection, decreased drug metabolism, and shivering(2).To our knowledge, only one study about hypothermia in PCNL has evaluated the anesthetic complications of hypothermia.(3) The optimal temperature of irrigation solution is not clear and not evidence based. Use of warm intra-oper- ative solution may be effective for reduction of postop- erative hypothermia risk. On the other hand use of cold 1Associate Professor, Department of Urology, Tehran University of Medical Sciences ,Tehran, Iran. 2Professor, Department of Urology, Tehran University of Medical Sciences ,Tehran, Iran. 3Associate Professor, Department of Urology, Tehran University of Medical Sciences, Tehran, Iran. 4Resident of Urology, Tehran University of Medical Sciences ,Tehran, Iran. *Correspondence: Department of Urology, Sina Hospital, Imam Khomeini Ave., Tehran, Iran. E mail: rhosseinim@yahoo.com. Received January 2018 & Accepted January 2019 fluid may result in better intra-operative homeostasis due to peripheral blood vessel vasoconstriction. Finding the appropriate temperature for irrigation fluid would result in better surgical outcomes and decreased intra-operative complications such as bleeding and would prepare better visual appearance during nephros- copy, and may result in less hypothermia and related complications. Accordingly, in this study, intra-oper- ative and post-operative complications in PCNL were compared across three groups including those receiving solution with room temperature, warm fluid, and cold solution. MATERIALS AND METHODS Study population In this randomized clinical trial, 60 patients undergoing PCNL in Sina University Hospital were enrolled. The subjects had an age range of 18 to 60 years old. In our department, PCNL is performed in patients with kidney stones more than 2 cm in diameter, stones refractory to extracorporeal shock wave lithotripsy, proximal ure- teral stones larger than 1.5 cm in diameter, diverticular stones, and stones producing distal obstruction. The ex- clusion criteria wasmedium to high cardiovascular risk, coagulation disorder, renal failure, hepatic failure, dia- betes mellitus, and hypothyroidism. The Helsinki Dec- Urology Journal/Vol 16 No. 6/ November-December2019/ pp. 525-529. [DOI: 10.22037/uj.v0i0.4399] laration was respected during the study and informed consent form was signed by all patients. Also, the study was approved by the Ethical Committee of Tehran Uni- versity of Medical Sciences. Patients’ enrollment algorithm is illustrated in Figure 1. Routine laboratory exams (FBS,CBC,BUN.Creati- nine,urine culture) were perfomed before surgery. Study design A randomized multi-arm parallel-group clinical trial with balanced randomization (1:1:1) was conducted at the De¬partment of Urology of Tehran University of Medical Sciences in Tehran, Iran. The study group al- location was by a sequentially running computer-gener- ated block randomization list as blocks of three unique numbers/block, ranging from 1 to 3 unsorted. Sample size was calculated considering a 5 percent expected difference between core temperature in three groups as the primary outcome of interest. We conducted a test with a significance level of 0.05 and power of 0.80 and an¬ticipated that groups of equal size were required. We concluded that at least 20 pateints were needed in each group. The groups included three groups of room temperature fluid (24°C), warm solution (37°C), and cold fluid (20°C) during nephroscopy. Demographic data, previous medical history, stone-related data, and operation data were recorded in three groups. Surgical technique The patients were not warmed before operation. All pa- tients were transferred to operation room and anesthe- tized with general method during 20-minute period. The core temperature was assessed and recorded just before initiation of anesthesia. Esophageal temperature probes were planted to measure core temperature. The probe was connected to the monitoring system continuously, during the operations, and monitored the patients’ tem- perature constantly. However, core temperature record- ed its average every 10 minutes. Temperature of the op- erating room was constantly set at 23 ± 1°C, by a central thermostat. Six patients were excluded before operation due to preoperative hypothermia (core temperature less than 36°C). The operations were carried out by single practiced surgeon endourologist. The irrigation fluid volume and duration of operation (just prone PCNL time) were also recorded. After general anesthesia, a 5F urethral catheter was placed cystoscopically and percutaneous access was obtained while the patient was placed in a prone posi- tion. Then the access to calyceal system was developed by Shiba needle under fluoroscopy guide and it was dilatated with plastic dilatator up to 30F. Then amplatz sheath was inserted and stones were removed using ne- phroscope 26F and pneumatic lithoclast. Distilled water was used as irrigation fluid in pressure of 60 mmHg. To ensure patient safety, core temperature was measured during the procedure; if patients suffered severe hypo- thermia, the surgeon stopped the irrigation and patient warming using blanket and warmer was performed. Outcome assessment The core temperature as the primary outcome of inter- est was recorded again just after operation. The rest of data were secondary outcome. Then, the patients were transferred to the recovery room and underwent routine monitoring for at least one hour. The shivering at recov- ery room was recorded. Post-operative pain scores were evaluated using a 10-cm self assessed visual analog scale (VAS) with 0 indicating no pain and 10 represent- ing the worst pain experienced by the patient in the re- covery room and 8 hours after PCNL. The reader(fourth author; urology resident) was blinded to both patient groups. After operation, routine labex- amination and plain abdominal radiography were per- formed. Also, the abdominal CT-scan was done as in- dicated. Stone-free was defined as stone diameter less than 4 mm. The complications were categorized to five levels by modified Clavien system.(4) Data analysis was performed by SPSS (version 24.0) software [Statistical Procedures for Social Sciences; Chicago, Illinois, USA]. Fisher exact and Kruskal wal- lis tests were used and were considered statistically sig- nificant at p values less than .05. RESULTS Three groups of patients consisting of 20 patients in each were compared . The age, body mass index (BMI), hemoglobin decrease, irrigation volume, stone size, sur- gical duration, and hospital stay were similar in terms of a number of background variables (Table 1). Although the initial core temperature was alike across the groups (P > .05); there was significant difference between groups for final temperature and alteration amount (Table 2). Males comprised 80%, 65%, and 70% of pa- tients in the room temperature fluid, warm solution, and cold fluid group, respectively (P = .563). Seventy percent, 80%, and 80% were stone-free in Irrigation solution temperature and complications of PCNL-Hosseini et al. Table 1. Background data across the groups. Variable Room temperature fluid Body temperature fluid Cold fluid P Value Age 45.9 ± 11.9 44.9 ± 12.2 39.9 ± 16.6 0.345 BMI (kg/m²) 26.5 ± 3.4 25.6 ± 2.1 24.8 ± 3.6 0.241 hemoglobin decrease (g/dl) 1.6 ±1.1 1.5 ± 0.9 2.1 ± 1.0 0.132 irrigation volume (liter) 12.1 ± 2.8 12.6 ± 3.3 12.8 ± 3.2 0.768 stone size (cm) 3.1 ± 0.9 3.2 ± 1.1 3.6 ± 1.3 0.331 Operation duration (min) 85.0 ± 31.2 85.7 ± 38.7 86.5 ± 30.1 0.988 Hospital stay (day) 5.2 ± 2.5 4.8 ± 1.4 5.1 ± 2.3 0.778 Creatinine increase(mg/dl) 0.5 ± 0.2 0.4 ± 0.1 0.6 ± 0.4 0. 11 Variable Room temperature fluid Body temperature fluid Cold fluid P Value Initial temperature 36.8 ± 0.4 36.7 ± 0.4 36.6 ± .4 0.259 Final temperature 35.7 ± 0.9 36.1 ± 0.6 35.0 ± 1.1 0.001 Temperature alteration 1.1 ± 0.8 0.6 ± 0.4 1.6 ± 0.9 0.001 Table 2. Core temperature across the groups. Endourology and Stone Diseases 526 groups of room temperature fluid, warm solution, and cold fluid, respectively (P = .700). Assessment of shiv- ering rates revealed that patients in the warm solution group shivered less compared with other groups al- though it was not statistically significant (Table 3) (P = .198). The mean VAS scores were significantly lower in warm fluid group compared with the others groups at recovery, and 8hrs post-operatively (Table 3) (P = .03). Clavein complications grading was same across the groups (Table 4). The hypothermia significantly occurred in cold fluid group (Table 5) (P = .021). DISCUSSION The main finding of the present study is that warm ir- rigation solution could significantly decrease hypother- mia, the mean postoperative pain score and shivering. Previous studies showed that cardiovascular, hemor- rhagic and infectious complications are significantly more frequent in hypothermic than in normothermic patients(2). Lots of studies have proved that cold stress could influence the immune responses by elevating the levels of inflammatory cytokines, including pro- and anti-inflammatory cytokines. It has been reported that many proinflammatory cytokines, such as TNF-a, IL-1, IL-6, significantly increased under cold stress. For min- imally invasive procedures like PCNL, this response is concerned with regional pain.(5) The effects of fluid temperature on core temperature in patients under endoscopic surgeries has been assessed in different studies. The effects on bleeding volume and homeostasis of cold solution are established in some investigations. The effects of experimental lowering of temperature on decreased blood flow are reported by some animal studies(6). Also, it has been demonstrated in human studies such as prostatectomy procedures, re- sulting in appropriate hemostasis.(7) The bleeding time more than two times after superficial lowering of the temperature is reported in human volunteers (8). Use of warm irrigation fluid has also been studied in some reports. In the study by Parodi et al.(9), use of warm fluid for irrigation during arthroscopy had no ef- fect on reduction of hypothermia in shoulder joint but it had an significant effect in the hip joint. This differ- ence in a single study may also explain variations in different studies. As in our study, Jin and colleagues(10) recommended the use of warm irrigation solution to re- duce hypothermia and shivering and also intra-opera- tive blood loss after endoscopics surgeries.Althoughin our study, hemoglobin level differences were not sig- nificant. The isothermal solution led to further fluid overload after operation due to decreased viscosity(11). There are few studies discussing this issue in endo- scopic urological procedures. Mirza et al. reported that hypothermia is common after endoscopic urological procedures which isrelated to duration of operation, weight, irrigation fluid volume, and type of procedure. (12) Rezaei et al. showed that using warm saline irri- gation in ureteral endoscope results in better surgical outcomes including a lower ureteral spasm rate, greater ureteral muscle relaxation and better access to the upper ureteral zone, and a lower rate of complications, such as ureteroscope impaction, ureteral dislodge and stone retropulsion.(13) Regarding these confounding factors, we matched all of these variables across the groups of the current study. Also, warm and isothermal irrigation fluids were effective to reduce the hypothermia rate af- ter TURP (14). Use of isothermal fluid was also effective on hypothermia reduction in another study.(15) Similar results were also reported by Tekgul and colleagues(3) compared to the irrigation fluid with room temperature and warm solution in PCNL and reported that lower hy- pothermia and shivering were seen in the warm fluid group. Compared to this study, longer follow-up was made in our study during hospitalization to discharge. In line with the mentioned study,, using warm irrigation fluid resulted in lower hypothermia after procedure, but the complications that could be related to hypothermia, as surgical site infection or coagulopathy were not seen more frequently in patients suffering from hypothermia. This may be due to shortness of surgical time or limit- ed number of patients studied in this survey. Actually, longer operation time may exaggerate the impact of irrigation fluid temperature on core body temperature and subsequently such complications. Also in the pres- ent study, the mean VAS score was significantly lower in the warm fluid group compared tothe other groups in the recovery and 8hrs post-operatively. In our re- cently published article, we showed that pain score af- ter PCNL has an important role in needing analgesic drugs. (16) Therefore, warm fluid group may be received low dose analgesic drugs compare other groups. Some of limitation of our study were small sample size and limited temperature range of irrigation solutions to compare because of there was no distinct evidence that support to use extreme temperatures in practice . Fu- Table 3. Complications across the groups. Variable Room temperature fluid Body temperature fluid Cold fluid p-value test Shivering* 5 (25%) 3 (15%) 8 (40%) 0.198 Fever 1 (5%) 3 (15%) 3 (15%) 0.68 Fisher exact DVT --- --- 1 (5%) 1.000 Fisher exact Angioembolization 1 (5%) --- --- 1.000 Fisher exact Transfusion 1 (5%) 1 (5%) 1 (5%) 1.000 --- Grade Room temperature fluid Body temperature fluid Cold fluid p-value of kruskal wallis 1 2 (10%) 1 (5%) 1 (5%) 0.910 2 2 (10%) 3 (15%) 4 (20%) 3 1 (5%) ---- ---- Negative 15 (75%) 16 (80%) 15 (75%) Table 4.Clavein complications grading across the groups. Irrigation solution temperature and complications of PCNL-Hosseini et al. Vol 16 No 06 November-December2019 527 ther studies recommended more patients to attain more reliable results. CONCLUSIONS Overall, according to our study, it was concluded that use of warm irrigation solution during PCNL results in significantly less hypothermia, mean postoperative pain score and shivering. Hence, use of warm irrigation fluid for this matter is recommended. However, further stud- ies with larger sample size and multi-center sampling are required to attain more definite results with higher reliability and potency for generalization. REFERENCES 1. Preminger GM, Assimos DG, Lingeman JE, et al. Chapter 1: AUA guideline on management of staghorn calculi: diagnosis and treatment recommendations. J Urol. 2005;173:1991– 2000. 2. Torossian A, Brauer A, Hocker J, Bein B, Wulf H, Horn EP. Preventing inadvertent perioperative hypothermia. Deutsches Arzteblatt international. 2015; 112:166-72. 3. Tekgul ZT, Pektas S, Yildirim U, et al. A prospective randomized double-blind study on the effects of the temperature of irrigation solutions on thermoregulation and postoperative complications in percutaneous nephrolithotomy. J Anesth. 2015; 29:165-9. 4. Tefekli A, Ali Karadag M, Tepeler K, et al. Classification of percutaneous nephrolithotomy complications using the modified claviengrading system: looking for a standard. Eur Urol. 2008; 53:184-90. 5. Guo JR, Li SZ, Fang HG. Different duration of cold stress enhances pro-inflammatory cytokines profile and alterations of Th1 and Th2 type cytokines secretion in serum of wistar rats. J Anim Vet Adv. 2012; 11:1538– 1545 6. Venjakob AJ, Vogt S, Stockl K, Tischer T, Jost PJ, Thein E. Local cooling reduces regional bone blood flow. Journal of orthopaedic research: official publication of the Orthopaedic Research Society.2013; 31:1820-7. 7. Zorn KC, Bhojani N, Gautam G, Shikanov S, Gofrit ON, Jayram G. Application of ice cold irrigation during vascular pedicle control of robot-assisted radical prostatectomy: EnSeal instrument cooling to reduce collateral thermal tissue damage. J Endourol.2010 24:1991-6. 8. Romlin B, Petruson K, Nilsson K.Moderate superficial hypothermia prolongs bleeding time in humans. Acta Anaesthesiol Scand.2007;51:198-201. 9. Parodi D, Valderrama J, Tobar C, Besomi J, Lopez J, Lara J. Effect of warmed irrigation solution on core body temperature during hip arthroscopy for femoroacetabular impingement. Arthroscopy: the journal of arthroscopic & related surgery: official publication of the Arthroscopy Association of North America and the International Arthroscopy Association. 2014; 30: 36-41. 10. Jin Y, Tian J, Sun M, Yang KA. systematic Table 5. Hypothermia across the groups. Grade Mild (34-36 degree) Moderate (32-33.9 degree) Negative True p-value of kruskal wallis Room temperature fluid 11 (55%) 1 (5%) 8 (40%) 0.021 Body temperature fluid 6 (30%) --- 14 (70%) Cold fluid 13 (65%) 3 (15%) 4 (20%) Figure 1. Patient flowchart Irrigation solution temperature and complications of PCNL-Hosseini et al. Endourology and Stone Diseases 528 Vol 16 No 06 November-December2019 529 review of randomised controlled trials of the effects of warmed irrigation fluid on core body temperature during endoscopic surgeries. J Clin Nurs. 2011; 20:305-16. 11. Kim YS, Lee JY, Yang SC, Song JH, Koh HS, Park WK. Comparative study of the influence of room-temperature and warmed fluid irrigation on body temperature in arthroscopic shoulder surgery. Arthroscopy: the journal of arthroscopic & related surgery : official publication of the Arthroscopy Association of North America and the International Arthroscopy Association. 2009; 25:24-9. 12. Mirza S, Panesar S, AuYong KJ, French J, Jones D, Akmal S.The effects of irrigation fluid on core temperature in endoscopic urological surgery. J Perioper Pract 2007; 17:49-51. 13. Mohammadzadeh Rezaei MA, Akhavan Rezayat A, Tavakoli M, Jarahi L. Evaluation the result of warm normal saline irrigation in ureteral endoscopic surgeries. Urol J. 2018; 15:83-86. 14. Okeke LI. Effect of warm intravenous and irrigating fluids on body temperature during transurethral resection of the prostate gland. BMC urol. 2007; 7:15. 15. Pit MJ, Tegelaar RJ, Venema PL. Isothermic irrigation during transurethral resection of the prostate: effects on peri-operative hypothermia, blood loss, resection time and patient satisfaction. Br J Urol. 1996; 78:99- 103. 16. Hosseini SR, Imani F, Shayanpour G, Khajavi MR. The effect of nephrostomy tract infiltration of ketamine on postoperative pain and peak expiratory flow rate in patients undergoing tubeless percutaneous nephrolithotomy: a prospective randomized clinical trial. Urolithiasis. 2017 ;45:591-595. 17. Maghsoudi R, Etemadian M, Kashi ,AH, Ranjbaran A. The Association of Stone Opacity in Plain Radiography with Percutaneous Nephrolithotomy Outcomes and Complications. Urol J. 2016 8;13:2899-2902. Irrigation solution temperature and complications of PCNL-Hosseini et al.