Adequate Dosage of Norepinephrine Infusion Combined with Goal-Directed Fluid Therapy During General Anesthesia May Improve Elderly Patients’ Postoperative Outcome Undergoing Lumbar Spinal Fusion

Background: Norepinephrine is used to prevent anesthesia-related disorders in elderly patients. However, optimal dosage that improve the postoperative outcome undergone lumbar spinal fusion is unknown. Methods: A total of 108 elderly patients were randomized into three groups of norepinephrine infusion as 0.030 µg.kg − 1 .min − 1 , 0.060 µg.kg − 1 .min − 1 and 0.090 µg.kg − 1 .min − 1 . The hemodynamics and related parameters were monitored at the entrance to the operation room (T 0 ), 15 min following anesthesia induction (T 1 ), 60 min after surgical incision (T 2 ), and immediately after surgery (T 3 ), respectively. The primary outcome was set as the incidence of postoperative complications and wound infections. The secondary outcomes were recorded by the incidence of nausea and vomiting, the time of rst atus, rst ambulation, rst intake and postoperative hospital stay. Results: Finally, 90 patients were recruited into the clinical trial, with 30 in each group. The incidence of delayed wound healing and infection were increase with the dose of 0.030 µg.kg − 1 .min − 1 compared to others (0.030 µg.kg − 1 .min − 1 vs. 0.060 µg.kg − 1 .min − 1 vs. 0.090 µg.kg − 1 .min − 1 : 33.3% vs. 10% vs. 10%, P = 0.024; 26.7% vs. 6.7% vs. 6.7%, P = 0.031). Intraoperative total uid volume and crystalloids, colloids volume in 0.030 µg.kg − 1 .min − 1 group were signicantly higher than 0.060 and 0.090µg·kg − 1 ·min − 1 . The incidence of intraoperative hypotension effectively decreased in 0.060µg·kg − 1 ·min − 1 and 0.090µg·kg − 1 ·min − 1 compared to 0.030µg·kg − 1 ·min − 1 (6.7%vs33.3%,


Abstract
Background: Norepinephrine is used to prevent anesthesia-related disorders in elderly patients. However, optimal dosage that improve the postoperative outcome undergone lumbar spinal fusion is unknown.
Methods: A total of 108 elderly patients were randomized into three groups of norepinephrine infusion as 0.030 µg.kg − 1 .min − 1 , 0.060 µg.kg − 1 .min − 1 and 0.090 µg.kg − 1 .min − 1 . The hemodynamics and related parameters were monitored at the entrance to the operation room (T 0 ), 15 min following anesthesia induction (T 1 ), 60 min after surgical incision (T 2 ), and immediately after surgery (T 3 ), respectively. The primary outcome was set as the incidence of postoperative complications and wound infections. The secondary outcomes were recorded by the incidence of nausea and vomiting, the time of rst atus, rst ambulation, rst intake and postoperative hospital stay.

Background
Spine degenerative disease is very common in elderly patients. The surgical intervention is one of treatment option to ameolinate symptoms and improve the quality of life. General anesthesia is usually administered in elderly patients for lumbar spinal fusion surgery [1]. Intraoperative hypotension is a common complication, and inadequate treatment will result in higher incidence of complications during general anesthesia and adverse postoperative outcome. The ongoing research aims to develop an effective method for the prevention and management of intraoperative hypotension. Whether or not the uid therapy combined with vasopressors is the ideal approach has not yet been determined. Reportedly, prolonged surgery, intraoperative blood loss and volume of crystalloid uid resuscitation increased are harmful to the early rapid recovery of patients [2]. The goals of intraoperative uid management are to maintain central euvolemia and minimize excessive salt and water infusion [3]. Excessive uid loading in elderly patients will disrupt glycocalyx, which is a carbohydrate-rich layer lining the endothelium that plays a crucial role in maintaining endothelial integrity. Destruction of endothelial glycocalyx can result in tissue edema and adverse outcome [4].
Pulse pressure variation (PPV) is used as an accurate position indicator on the Frank-Starling curve. The arterial PPV induced by mechanical ventilation is a reliable and accurate predictor of uid responsiveness in the patients under general anesthesia. This indicator can predict the adverse hemodynamic effects of uid depletion, as well as the bene cial effects of uid loading [5]. Norepinephrine is characterized by αadrenergic agonistic activity in addition to a weak β-adrenergic agonistic activity [6]. After enrolment and before start of the experiments, the researchers clearly explained the experimental procedures, the objectives of the study, possible bene ts, and side effects of the study to all elderly patients and obtained the signed consent form for participation in the research. Verbal and written informed consents were obtained from all the included patients.

Patients
Elderly patients with lumbar disk herniation or lumbar spondylolisthes undergone elective lumber spinal fusion were recruited into the research. The type of surgery was selected as posterior lumbar discectomy combined with pedicle screw xation and intertransverse fusion. The inclusion criteria was the elderly patients with ASA grade less than III and aged 60 ~ 85 years. The exclusion criteria was con ned as patients refusal to participate in the research at any time. Patients with bradycardia (heart rate < 50 bpm), cardiac morbidities, heart block greater than the rst degree, abnormal liver or renal function, hyperthyroidism, vascular diseases and bowel disease (e.g, ulcerative colitis, Crohn's disease, and irritable bowel syndrome) were excluded.

Randomization and Blinding
Randomization was achieved by a statistician using an online random number generator. Patient codes were placed into sequentially numbered sealed opaque envelopes by a research assistant who was not involved in the research. An anesthesiologist resident not involved in the patient management was responsible for opening the envelope and preparing the research's drug according to the instructions in each envelope. All surgeons, patients, attending anesthesiologists, nurses and follow-up anesthesiologists were blinded to group assignments.

Interventions
At the holding area, an IV line was established with an18-gauge IV cannula in the forearm, and an infusion of Ringer's lactate (RL) solution was started at a minimal rate to keep the vein open. The baseline mean arterial pressure (MAP) was measured three times in the supine position and average computed. The readings were recorded 1 min apart for the assessment of the noninvasive blood pressure with an automated device. One hundred and eight patients were randomly divided into three groups by dosage of norepinephrine infusion: 0.030 µg.kg − 1 .min − 1 , 0.060 µg.kg − 1 .min − 1 ,and the 0.090 µg.kg − 1 .min − 1 group (n = 36). All patients was continuouslly infused norepinephrine by the dosage of 0.030 µg.kg − 1 .min − 1 , 0.060 µg.kg − 1 .min − 1 and 0.090 µg.kg − 1 .min − 1 , respectively before the initiation of general anesthesia.
In the operating room, standard monitoring were performed by ECG, Heart Rate, noninvasive blood pressure, and pulse oximetry (SpO 2 ). A radial artery cannula was inserted, and the pressure transducer was set to zero at the mid-axillary level to ambient pressure. The patients in three groups were given a Intellivue MP70 monitors (Intellivue MP70, Philips Medical Systems, Suresnes, France). The primary and secondary outcomes were monitored at four intervals of T 0 ,T 1 ,T 2 , and T 3 corresponding to before induction, 15 min following anesthesia induction with patient in a supine position, 60 min following surgery, and at the end of the surgery, respectively. At T 1 ,T 2 ,T 3 timepoints, PPV was measured and recorded. The MAP and HR were recorded at T 0 ,T 1 ,T 2 and T 3 timepoints.
The RL 5 ml − 1 .kg − 1 was infused as a bolus volume before general anesthesia induction. Then, the infusion rate was reduced to keep the vein open following endotracheal intubation. If PPV was less than 13%, the maintenance volume of RL was infused at a rate of 2 ml.kg − 1 .h − 1 . If PPV was more than 13%, the hydroxyethyl starch (HES, 130/0.4, Voluven) of 3 ml − 1 .kg − 1 (ideal body weight) was infused during 3 min to test the uid response to guide the individual uid therapy. A PPV less than 13% was de ned as the negative uid responsiveness. If PPV was within the target range and MAP was below the baseline, the ephedrine 5 ~ 10 mg was started and the case was excluded. If PPV was within the target range and MAP was > 20% of the baseline, 12.5 ~ 25 mg urapidil was administered. If PPV was within the target range and blood pressure uctuated within 20% of the base blood pressure, norepinephrine infusion was continued until 5 min after sewing.
The day before surgery, all patients were instructed on the use of a 10-point numeric rating scale to assess their pain intensity (0 = no pain, 10 = worst possible pain). Postoperative patient-controlled intravenous analgesia was performed with sufentanil (1.5 µg − 1 .kg − 1 ) combined with ondansetron 8 mg.
All patients received a basal dose of (0.015 µg.kg − 1 .h − 1 ) and PCA (0.030 µg − 1 .kg − 1 ). The interval time was set at 10 min, and patient-controlled intravenous analgesia was maintained up to 72 h following surgery to make sure all patient numeric rating scale scores were below 3.

Data Collection
Demographic data, including age, gender, body mass index, duration of surgery, American Society of Anesthesiologists grade and perioperative complications were recorded. The mean blood pressure and heart rate were monitored and recorded at baseline (before induction), 15 min following anesthesia induction with the patient in a supine position, 60 min following incision and at the end of the surgery.
The PPV was recorded at 15 min following anesthesia induction with the patient in a supine position, 60 min following surgery, and at the end of the surgery. The surgical indices, including blood loss, urine output, autologous blood transfusion and uid infusion volume (crystalloids and colloids) were recorded. The bradycardia, atropine requirements, intraoperative hypotension and hypertension, postoperative hospital stay were recorded. The incidence of nausea and vomiting, rst atus, rst ambulation, rst intake timing were self-reported by patients and recorded by a follow-up anesthesiologist who was blinded to group assignments during follow-up.
Our primary outcome was set as the incidence of complications, such as cerebral complications, renal complications, pulmonary complications, cardiac complications and other complications (the incidence of fever, wound infection and delayed wound healing). The de nition of delayed wound healing was set as the duration of wound healing more than fourteen days. The pulmonary infection, respiratory failure, pulmonary infarction and pulmonary embolism were recorded as pulmonary complications. Acute myocardial injury and acute myocardial infarction were included as cardiac complications. Progressive neurological de cit and acute cerebral infarction were a part of the cerebral complications, and oliguria and acute kidney injury (AKI) were included in the renal complications.
Secondary outcomes included the incidence of intraoperative nausea and vomiting, the frequency of hypertension, the frequency of hypotension, rst intake, rst atus, ambulation timing, postoperative hospital stay, the volume of autologous transfusion, the intraoperative blood loss volume, the urine output volume and postoperative hospital stay (days from admission).
The intraoperative hypotension and hypertension were de ned as a decrease and increase of > 20% of the baseline level, respectively. The de nition of bradycardia was set as an HR < 50 beats/minute (bpm). If the HR was < 45 bpm, atropine bolus 0.3 ~ 0.5 mg, depending on the patient's HR, was injected.

Sample Size Calculation
The sample size was calculated with PASS 2019 Software (Power Analysis and Sample Size). The primary outcome is de ned as the incidence of postoperative complications. The preliminary experimental results showed that the incidence of postoperative complications were found in about 40% of the elderly patients undergoing spinal surgery without norepinephrine infusion, while only 10% incidence of postoperative complications following prophylactic dosage of 0.060 µg.kg − 1 .min − 1 norepinephrine infusion. At the alpha error of 0.05, we calculated that eighty seven patients (twenty nine patients/group) would give 80% power to detect a 20% absolute reduction in the incidence of postoperative complications in the treatment group. However, to allow the comparisons between the control and each treatment group, the required sample size was assigned as one hundred and eight patients (thirty six patients for each group).

Statistical Analysis
Statistical Package for Social Science software, version 15 for Microsoft Windows (SPSS Inc., Chicago, IL, USA) was used for data analysis. Categorical data were expressed as frequency (%

Discussion
With advances in public health and continued medical progress, the elderly has been a fast-growing segment of the population [7]. This will lead to a proportional increase in age-related diseases such as lumbar disc herniation, stenosis and spondylolisthesis. However, the elderly population, especially those older than 80 years, are more likely to have a higher comorbidity and osteoporosis burden, often with multiple systems involved [8]. The complexity of the health status may increase the risks of complications, poor functional outcomes and mortality after surgery in patients aged 80 years and older [9].It is well established that perioperative uid management in uences postoperative complication rates. However, the optimal intraoperative uid regimen is still controversial.Especially in including use of vasopressors, or a goal-directed hemodynamic therapy [10]. In order to improve the quality of postoperative recovery and shorten hospital stays, many efforts are made to facilitate the early return to normal organ function.
Norepinephrine is a vasopressor with potent α-adrenergic agonistic activity in addition to some βadrenergic agonistic activity; thus, it has been suggested as an alternative to phenylephrine that would not compromise the cardiac function. This makes norepinephrine a possible choice for elderly patients with relative contraindications of phenylephrine, such as low baseline HR or poor cardiac function. We did not include such patients because of the monitoring indicators-PPV, which was not suitable for patients with arrhythmias [3]. Currently, studies are exploring the optimum single dose for use as a continuous infusion rate during other surgeries in elderly patients.
Norepinephrine is currently a novel option for the prevention and treatment of hypotension, and to the best of our knowledge, this is the rst study to determine the optimal infusion rate of norepinephrine, which in any format manages hypotension and avoids uid overload complications during general anesthesia for spinal surgery. However, there may be some concern about the administration of norepinephrine via peripheral veins. Signi cant morbidity was not demonstrated in a recent study wherein norepinephrine infusions were administered in hypotensive patients for an average of 32 h at a maximal rate of 30 µg.min − 1 via 18-gauge and 20-gauge cannulate in the antecubital fossa, dorsum of the hand, and forearm exor veins. Minor complications (extravasation) occurred at a rate of 5.45% [11]. Previous studies demonstrated that extravasation was observed in the veins distal to the antecubital fossa or in the feet, and recent reports suggested that placement within a large proximal vein might be preferred [12,13]. Moreover, the drug manufacturer does not specify that norepinephrine needs to be administered centrally, rather via a large vein, preferably antecubital and avoiding the lower extremities [14].
Furthermore, in this study, the small infusion rate of norepinephrine (8 µg/mL) was used. Therefore, the risk of any local tissue injury was minimal, and we did not observe any adverse effects. delivery. The study reported that for these patients, a manually titrated infusion of 5 µg.ml − 1 of norepinephrine is effective for maintaining blood pressure and decreasing the incidence of hypotension without signi cant adverse events on the neonatal outcome [16]. The middle dose reported by the previously conducted studies (0.060 µg·kg − 1 ·min − 1 ) was used in the current study.
Although a signi cant reduction in the heart rate was observed in all groups as compared to the baseline reading. Especially n the higher doses, a few cases experienced marked bradycardia requiring atropine: 1(3%) case in the 0.030 µg·kg − 1 ·min − 1 group, 2 (6.7%) in the 0.060 µg·kg − 1 ·min − 1 group, and 8 (26%) in the 0.090 µg·kg − 1 ·min − 1 group. Thus, we speculated that norepinephrine could be the appropriate vasopressor in elderly patients with low baseline HR. We did not measure the patients' cardiac output; however, it has been recently suggested that monitoring the HR could be used as a potential surrogate for cardiac output [17]. Furthermore, only a few cases of intraoperative hypertension were observed in the three study groups. These events were transient and resolved by stopping the uid infusion. However, this side effect could not be evaluated in this study.
Our primary outcome was the incidence of complications (cerebral complications, renal complications, pulmonary complications, and cardiac complications). The two higher dose groups had fewer complications but not statistically signi cant, which might be attributed to the anesthesiologists' concern about the elderly patients with more complications, poor organ reserve function, and reduced tolerance to cyclic uctuation; during anesthesia management, attention is paid to maintaining perfusion pressure to ensure the perfusion of critical organs. We used a continuous infusion rate of norepinephrine before starting the anesthesia. Our hypothesis was based on a previous study, which reported that the use of a prophylactic bolus of phenylephrine before starting infusion was bene cial [18]. Herein, we hypothesized that the prophylactic administration of norepinephrine could increase the peripheral vascular resistance, reduce the amount of uid required to achieve goal-directed uid therapy, and accelerate the rehabilitation process of elderly patients.
The prone position increases abdominal pressure, which results in reduced venous return and lung compliance. Yu et al. reported that high predictability of PPV, remained as useful indices for guiding uid therapy in prone patients with minimal alterations in the optimal cutoff values to predict uid responsiveness [19]. Compared to the SVV, PPV does not require additional kits and can reduce the patients' nancial burden and the accuracy is similar [20]. However,some researchers questioned the accuracy of the predicted volume of PPV in the prone position. Biais et al. reported that prone position induces a signi cant increase in PPV and SVV but does not alter their abilities to predict the responsiveness of the uid [21]. The 13% PPV threshold value was also based on previous studies. Nevertheless, There were several possible limitations to the present study. We did not use advanced hemodynamic monitors for cardiac output and peripheral vascular resistance .Also, The volume status of elderly patients suffering from lumbar disk herniation or lumbar spondylolisthesis were different.In future study,more attention should be paid on perioperative endothelial function,espcially the relationship between perioperative complications and syndecan-1.

Conclusion
In conclusion, the dosage 0.060 µg·kg − 1 ·min − 1 of norepinephrine infusion combined with goal-directed uid therapy (PPV) is more suitable for elderly patients' intraoperative management undergone lumbar spinal fusion during general anesthesia. It can improve the elderly patients' postoperative outcome and accelerate their rehabilitation process by decreasing the incidence of intraoperative hypotentsion, bradycardia and uid overloading risk. Abbreviations PPV: Pulse pressure variation; MAP: mean arterial pressure; ECG: Electro cardio graph; HES: hydroxyethyl starch; PEEP: positive-end expiratory pressure; BMI: Body Mass Index; ASA: American Society of Anesthesiologists. Figure 1 Schematic protocol of intraoperative management. Schematic chart showing the three dosages of norepinephrine infusion groups (0.030 μg.kg-1.min-1 vs. 0.060μg.kg-1.min-1 vs. 0.090μg.kg-1.min-1)