The Prophylaxis Effect of Ephedrine on Hemodynamic Variation in Patients Undergoing Percutaneous Nephrolithotomy Surgery with Spinal Anesthesia

Background Performing spinal anesthesia with at least hemodynamic variation and complications is always challenging for anesthesiologists. In this study, we investigated the effect of ephedrine and placebo on hemodynamic changes in patients undergoing percutaneous nephrolithotomy with spinal anesthesia. Methods This randomized, double-blind prospective clinical trial was conducted on 120 patients aged 20‒60 years with ASA (American Society of Anesthesiologists) classes I and II. Patients who were candidates for percutaneous nephrolithotomy with spinal anesthesia were divided into intervention (received 1 cc = 5 mg ephedrine) and control groups (received 1 cc normal saline). All vital parameters, including HR (heart rate) and NIBP (noninvasive blood pressure), were recorded perioperatively T0–T25) and finally at the end of surgery time (Tf). The results were analyzed by SPSS software version 23, and a P value ≤0.05 was considered significant. Results The mean arterial pressure during surgery between T3 and T9 and the mean heart rate in times of T3–T8 in the intervention group were higher than in the control group, and this difference was statistically significant (P < 0.05). The incidence of hypotension, bradycardia, nausea, and vomiting and the amount of prescribed ephedrine, atropine, and ondansetron in the control group were higher than in the intervention group (P=0.001). Seven patients in the control group and four in the intervention group had shivering, but this difference was not statistically significant (P=0.43). Conclusion This study showed the effectiveness of the prescription of 5 mg ephedrine two minutes before changing from the lithotomy position to the supine in maintaining hemodynamic stability, reducing hypotension, bradycardia, nausea, and vomiting, and the amount of prescribed ephedrine, atropine, and ondansetron. Trial Registrations. This trial is registered with IRCT20160430027677N22.


Introduction
Te core issue that anesthesiologists consider in all operations is patient safety and hemodynamic stability in anesthesia [1][2][3]. Regional anesthesia is the preferred method of anesthesia for lower abdominal, lower limb, urology, gynecology, and anorectal surgery [4]. Tis method's advantages include reducing patient mortality and complications, better analgesia during and after the operation, and economic superiority over general anesthesia [5]. Percutaneous nephrolithotomy (PCNL) is a minimally invasive surgical procedure applied to kidney stone removal. It is an efective and safe method for kidney stone removal with diferent structures. It was frst proposed in urology in 1976 and replaced open surgical treatment for removing stones in the upper part of the urinary tract [6]. Because percutaneous stone surgery has less morbidity, a shorter recovery, and less cost, it is currently considered the preferred treatment for most stones [7]. It seems that in recent years, facing severe complications, urologists are attempting to develop further and improve the percutaneous nephrolithotomy (PCNL) method to use it as a safe and low-complication method for treating kidney stones [6,7].
During this surgery, patients are placed in two diferent positions. First, the patient is placed in the lithotomy position (after induction of general anesthesia or spinal anesthesia), and in the continuation of the surgery, they are placed in the prone or lateral position to perform percutaneous nephrolithotomy (PCNL). Both positions will bring about hemodynamic changes for patients, and patients with coexistent diseases such as cardiovascular disease or diabetes can cause severe complications [8]. Today, the preferred anesthesia method in these surgeries is intrathecal anesthesia, according to the observed results, compared to general anesthesia [5,8]. Ephedrine is a noncatecholamine sympathomimetic amine drug that is used intravenously. Ephedrine increases blood pressure and HR (heart rate). It is also used orally as a bronchodilator due to the direct stimulating efects of beta2-adrenergic receptors. Its dose is 2.5-25 mg intravenously or 25-50 mg intramuscularly [9,10].
Some studies illustrated that using 0.5-0.75 μg/kg dexmedetomidine reduced the incidence and severity of bradycardia in percutaneous nephrolithotomy [11]. Roodneshin et al.' [12] study showed that choosing the optimal position in the PCNL technique depends on the patient's condition. If hemodynamic control matters to the anesthesiologist, then lateral positions are more appropriate. However, if pain control and a long time of analgesia are essential, a prone position may be preferred. Prophylactic ephedrine versus prophylactic ondansetron was compared in percutaneous nephrolithotomy (PCNL) by Nada and Hegab. During percutaneous nephrolithotomy (PCNL) operation, ondansetron 6 mg administered 5 minutes before spinal anesthesia was comparable to 15 mg ephedrine administered immediately after block in attenuating hypotension and bradycardia, as well as declined the number of patients who required rescue vasoconstrictors during surgery [13]. A clinical trial in Egypt assessed the efect of ondansetron on spinal-induced hypotension during PCNL operation. According to the study, ondansetron 4 mg IV (intravenous) 5 minutes before spinal anesthesia had no impact on reducing the incidence of hypotension, and also, the amount of ephedrine needed during PCNL under spinal anesthesia was not declined [14].
Considering the diferent results obtained regarding the efect of ephedrine on hemodynamic changes during various surgeries in clinical studies and also the recommendation of the researchers in the same studies to perform more studies in this feld, in this study, we investigated the efect of ephedrine and placebo on hemodynamic changes in patients undergoing percutaneous (PCNL) nephrolithotomy with spinal anesthesia.  Iranian  Registry  of  Clinical  Trials  (IRCTID:  IRCT20160430027677N22). Tis study was conducted on 120 patients aged 20-60 years with ASA (American Society of Anesthesiologists) classes I and II. Patients who were candidates for percutaneous (PCNL) nephrolithotomy with spinal anesthesia were divided into two intervention and control groups (Figure 1). According to the random number table, patients were randomly assigned to two groups, and the anesthesiologist and staf were unaware of which patient belonged to which group.

Subjects and
Setting. All patients were visited by an anesthesiologist the day before the surgery. Patients were kept fasting for at least 8 hours before surgery. Syringes were identical in appearance, and all of them were encoded, and the surgeon, staf, and anesthesiologist were unaware of the contents of the syringes. A standard pulse oximetry monitor, a noninvasive blood pressure (NIBP) measurement device, and an ECG (electrocardiogram) were connected in the operating room. After an 18 cm venous catheter was inserted, 10 ml/kg of ringer lactate was infused. Baseline heart rate (HR), blood pressure, and oxygen saturation were recorded.

Inclusion Criteria.
Patients who were candidates for PCNL elective surgery with pilocalyx stones larger than 20 mm and 10-20 mm stones resistant to ESWL (extracorporeal shock wave lithotripsy), lower calyx stones larger than 10 mm, large impacted proximal ureter stones, body mass index <30 kg/ m 2 ·h, aged 20-60, American Society of Anesthesiologists (ASA) classes I and II, and patients who have signed the consent form to participate in the trial were included.

Exclusion Criteria.
Patients aged under 20 years old, coagulopathy, untreated active urinary tract infection, patients with skeletal deformities, body mass index ≥30 kg/m 2 , history of systemic disease, mental illness, history of allergy to any of the drugs used during the study, history of peptic ulcer disease and antacid therapy, and drug abuse were excluded. Also, patients were excluded from the study in case of high-volume bleeding, blood transfusion, and the need to convert the spinal anesthesia method to general anesthesia.

Intervention Design
2.5.1. Intervention Group. 60 people received 5 mg ephedrine (1 ml) two minutes before changing from lithotomy to a supine position.

Control
Group. 60 people received one cc of normal saline (1 ml) as a placebo two minutes before changing from lithotomy to supine position.
Each ephedrine syringe contained 50 mg of ephedrine diluted with 9 ml of distilled water in 10 cc syringes, each cc containing 5 mg of ephedrine. Te placebo syringes were in the form of 10 cc syringes containing distilled water, and two minutes before changing the lithotomy position to the supine position, one cc of each was randomly injected intravenously into the patients in the study groups. Te patients, surgeons, and anesthesiologists were blinded to the allocation of the patients to the studied groups. All aseptic precautions were conducted before performing the spinal anesthesia. Spinal anesthesia was performed with a #25 needle (SPINAL ANESTHESIA NEEDLE, Dr.J brand, made in Japan, Quincke type) in the sitting position from the third and fourth intervertebral space (midline approach) and by injecting 12.5 mg hyperbaric bupivacaine in the subarachnoid space. Ten, the patients were placed in the supine position and received 4 liters of oxygen per minute during the operation through a simple face oxygen mask. Sensory levels were determined by the pinprick test after block (every 15-20 seconds for 3 minutes), and the motor blockade was evaluated using Bromage's criteria until the level of spinal anesthesia was raised to the T8 level.
Cystoscopy was performed in lithotomy position, a ureteric catheter was entered into the upper ureter or renal pelvis and fxed with tape to the indwelling Foley catheter, Excluded (n=0 ) patients were excluded from the study in case of age under 20, coagulopathy, urinary tract infection, skeletal deformities, BMI ≥ 30 kg/m2, systemic disease, mental illness, allergy to any drugs, history of peptic ulcer and antacid therapy, drug abuse, high-volume bleeding, blood transfusion, and the need to convert the spinal anesthesia method to general anesthesia. International Journal of Clinical Practice and patients were placed in the supine position. Te patient's supine position changed to the prone position, and renal access was conducted in the prone position under fuoroscopic guidance; superior and inferior bolsters were placed at the xiphoid process cartilage to support the lower rib cage, and at the symphysis pubis, vertical bolsters were put in the standard manner along the lateral sides of the chest.
All vital parameters, including HR and NIBP, were recorded perioperatively the time before spinal anesthesia performing (T0), immediately after spinal anesthesia induction (T1), after the lithotomy position (T2), when lithotomy position changed to the supine position (T3), and then when the patient was placed in the prone position (T4). Afterward, vital signs were documented every 3 minutes for 60 minutes (T5-T25) and fnally at the end of surgery time (Tf ).
If the systolic blood pressure was under 100 mmHg or less than 20% from the baseline, it was treated with 5 mg ephedrine and increased crystalloid speed. If the heart rate (HR) was under 50 beats/minute, it was treated with 0.75 mg of atropine. Te incidence of hypotension, bradycardia, nausea, vomiting, shivering, and other complications were recorded.
2.6. Primary Outcomes. Te blood pressure and heart rate (HR) variation between the two groups were measured and recorded in the checklist as the primary outcome.

Secondary
Outcomes. Te secondary outcome was the amount of prescribed ephedrine, nausea, and vomiting intraoperatively and postoperatively, which was recorded in a checklist.

Statistical
Analysis. Based on the Nada and Hegab' study in 2018 [13], considering the power (probability) test of 80%, confdence interval of 95% (α � 0.05 β � 20%), and a dropout risk of 20%, we enrolled 60 patients in each group. Tables, frequency charts, and descriptive statistics, including mean and standard deviation, were used to provide descriptive features. Te repeated measures test was used for normal data to compare the mean arterial pressure and heart rate at T0-T25 and Tf. Furthermore, the Friedman test was used for non-normal data. Tis study used the chi-square test to investigate qualitative variables such as gender. Moreover, for quantitative variables in two groups, an independent ttest was used for normal data. For non-normal data, the Mann-Whitney test was used. Te normality of data was tested using the Kolmogorov-Smirnov test. Te results were analyzed by SPSS software version 23, and a P value ≤0.05 was considered signifcant.

Results
Chi-square and t-tests did not show any signifcant diference between the patients' demographic information regarding age, gender, and stone characteristics. It confrmed the homogeneity of the patients in terms of demographic characteristics in the two groups and the generalizability of the results.
Te patients' demographic information in the two groups is presented in Table 1. According to the t-test and chi-square test, there was no statistically signifcant diference between the two groups' characterized data, including gender, BMI (body mass index), age, and location of the stone (P > 0.05).

Mean Arterial Pressure
Changes. Te mean arterial pressure changes during surgery between T3 and T9 in the intervention group were higher than in the control group, and this diference was statistically signifcant (P < 0.05). Also, at other times during the study (except for T0, T1, and T2), the mean arterial pressure was higher than the control group. However, it was not statistically signifcant (P > 0.05, Table 2 and Figure 2).

Heart Rate Variation.
Te mean heart rate (HR) variations at the onset of study T0 and T1-T2 were approximately equal in both groups; but in the intervention group, heart rate was higher than that in the control group in times of T3-T8, and this diference was statistically signifcant (P < 0.05). In other times (T10-Tf ), which evaluated during the study, the mean heart rate (HR) was higher than the control group. However, in the conducted independent ttest, it was not signifcant (P > 0.05, (Table 3 and Figure 3).
Te incidence of hypotension, bradycardia, nausea, and vomiting and the amount of prescribed ephedrine, atropine, and ondansetron in the control group were higher than in the intervention group, and the diference was statistically signifcant (P � 0.001). Tere was no blood transfusion required in both groups; in the conducted independent ttest, it was not signifcant (P � 1.00). Seven patients in the control group and four in the intervention group had shivering, but this diference was not statistically signifcant (P � 0.438) ( Table 4).

Discussion
Tere is no doubt about the low risk of the spinal anesthesia method over general anesthesia [15]. However, performing spinal anesthesia with at least hemodynamic variation and complications is always challenging for anesthesiologists. Tey always endeavor to crack this problem and provide excellent spinal anesthesia for patients, especially when patients should be placed in prone positions for surgery. PCNL (percutaneous nephrolithotomy) is one of the most common low-intervention surgeries for removing complex and large kidney calculi [16] performed under spinal anesthesia. Tis operation may be performed in various positions, but the prone position is the most common in percutaneous endourological surgery. In this clinical trial, we investigated the efect of ephedrine (5 mg) in maintaining hemodynamic stability in patients who were candidates for elective PCNL surgery in the prone position.
Our fndings demonstrated that the mean arterial pressure (MAP) during surgery between the time of lithotomy position changed to the supine position (T3) and when the patient was placed in the prone position (T4) up until T9 time in the intervention group were signifcantly higher than that in the control group. However, in the whole study period, except for T0-T2, the mean arterial pressure in the intervention group was higher than that in the control group, but it was not statistically signifcant. Also, the mean heart rate in the intervention group was higher than that in the control group, but it was statistically signifcant only in times T3-T8. Kamal et al. [17] compared 1298 PCNL operations, of which 1160 patients underwent PCNL under spinal anesthesia. Te results revealed that only in the frst 10 minutes of anesthesia, 148 (12.75%) patients developed hypotension, which was managed by ephedrine intravenously (IV); these fndings were compatible with our results. Movassaghi et al. [18] investigated spinal and general anesthesia for PCNL. Tere was no statistical diference between the two groups regarding trends of systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and heart rate (HR) (P � 0.990, P � 0.568, P � 0.710, and P � 0.934, respectively, from repeated measurements). However, in operation time-to-time analysis, SBP was signifcantly lower in general anesthesia group only in 120th minute, DBP in 60 th , 90 th , and 120 th minutes, and MAP in 90 th and 120 th minutes (P < 0.05) [18]. Nada and Hegab evaluated the efects of prophylactic ephedrine versus ondansetron on postspinal hemodynamic variation in percutaneous nephrolithotomy (PCNL). Teir trial illustrated that although mean arterial pressures (MAP) and heart rate (HR) were lower in the ondansetron group, there was no signifcant diference between the groups regarding the proportion of patients experiencing hypotension and ephedrine consumption [13]. Tese fndings were not consistent with our results; probably, this was due to the diferent positions of patients in the two trials. In the Nada and Hegab' study, patients were placed in a free-fank modifed supine position, but in our study, patients were placed in the prone position. Roodneshin et al. studied the efect of lateral versus prone position on hemodynamic stability and pain control in patients undergoing percutaneous nephrolithotomy (PCNL). Te results showed that the amount of ephedrine usage in the lateral group (3.6 ± 1.5 mg) was signifcantly lower than that in the prone group (16.4 ± 12 mg), suggesting more hemodynamic variations in the prone group during the operation [12]. However, a clinical trial conducted by Elnagar et al. assessed the efect of ondansetron on spinal-induced hypotension during PCNL; the trial demonstrated that ondansetron 4 mg intravenously 5 minutes before spinal anesthesia had no impact on reducing the incidence of hypotension and the required dose of ephedrine [19].
In our study, the incidence of hypotension, bradycardia, nausea, and vomiting, as well as the amount of prescribed ephedrine, atropine, and ondansetron in the control group, Values are presented as mean ± SD (standard deviation) or number. Tere were no signifcant diferences between the two groups (P > 0.05). International Journal of Clinical Practice 5 was higher than that in the intervention group. Tis difference was statistically signifcant (P � 0.001). Mehrabi and Shirazi analyzed the outcomes and complications of spinal anesthesia in percutaneous nephrolithotomy (PCNL) in 160 patients; during the frst phase after inducing spinal anesthesia, 18 patients developed hypotension, which was treated with 10 mg ephedrine intravenously. Ten patients required a blood transfusion (6.3%), and six experienced mild to moderate headache, dizziness, and mild low back pain for 2-4 days after the operation, which was treated with analgesics and bed rest [20]. Tis study had similar results regarding the incidence of hypotension to our clinical trial, but in our research, no blood transfusion was required in both groups. Tis was probably due to less stone bulk in our study than in Elnagar et al. [19] study, which was 34.2 ± 9.8 mm. It has been reported that the blood transfusion rate during PCNL is about 3.5%-9.29% [21,22]. Jain et al. investigated prophylactic phenylephrine and ephedrine infusion during spinal anesthesia for an emergency cesarean. Te study revealed a signifcant increase in heart rate from the baseline to 9 minutes after induction in the ephedrine group, and maternal bradycardia occurred in the phenylephrine group (P � 0.02). On the other hand, heart rate decreased signifcantly from baseline after the third minute in the phenylephrine group. As well as, the trial indicated that the incidence of maternal nausea and vomiting was higher in the ephedrine group than that in the phenylephrine group (22.2% vs. 4.4%; P � 0.02) [23]. In the study of Nada and Hegab [13], the incidence of nausea and vomiting in the ephedrine group was higher than that in the ondansetron group, and this diference was statistically signifcant (P � 0.019). In our investigation, the prescription of 5 mg ephedrine (1 ml) for two minutes before changing from lithotomy to supine position had a reasonable impact on the incidence of nausea and vomiting in the intervention group than that in the control group; and this diference was statistically signifcant. Tis diference between our study and with two trials mentioned above [13,23] is probably due to the kind of surgery; pregnancy afects many organs and viscera, especially the digestive system, such as the stomach, so in cesarean surgery, patients are considered full stomach and they are at the risk of vomiting. It has been proven that the patients' positions during surgery are related to the incidence of nausea and vomiting, whereas the incidence of nausea and vomiting in the supine and prone positions was higher than that in lateral and free-fank positions [24][25][26]. In our trial, seven patients in the control group and four in the intervention group had shivering. However, this diference was not statistically signifcant (P � 0.438). In  T0  T1  T2  T3  T4  T5  T6  T7  T8  T9  T10  T11  T12  T13  T14  T15  T16  T17  T18  T19  T20  T21  T22  T23  T24  T25  Tf  mean arterial [13] that compared the efect of ephedrine and ondansetron on the hemodynamics in the patients undergoing PCNL surgery, the results demonstrated that the ondansetron had an excellent antishivering efect than ephedrine (P � 0.002). El-Deeb and Barakat [27] attempted to answer whether ephedrine replaces meperidine to prevent shivering in women undergoing cesarean section under spinal anesthesia. Teir study illustrated that the incidence of shivering in meperidine and ephedrine groups in women undergoing cesarean section under spinal anesthesia was comparable (27% and 29%, respectively, P � 0.06). Also, the intensity of shivering was not diferent between the two groups. Ephedrine is a sympathomimetic agent with an antishivering efect and an antiemetic efect in the short term [27,28].

Conclusion
Tis study showed the efectiveness of the prescription of 5 mg ephedrine two minutes before changing from the lithotomy position to the supine in maintaining hemodynamic stability, reducing hypotension, bradycardia, nausea, and vomiting, and the amount of prescribed ephedrine, atropine, and ondansetron.

Study Limitation.
Our investigation restriction was generalizability because this clinical trial was conducted in a small area. Furthermore, due to the diferent doses of ephedrine used in other clinical trials, determining accurate doses needs more investigations in diferent geographical regions.

Suggestions.
Conducting more research in this feld and a combination of clinical knowledge and experience to generalize the results of evidence-based studies are suggested.

Data Availability
All relevant data are included within the article. Additional information is available from the corresponding author upon request.

Ethical Approval
Tis study was approved by Urmia University of Medical Sciences (IR.UMSU.REC.1401.182). Te trial was registered in the Iranian Registry of Clinical Trials (IRCTID: IRCT20160430027677N22).