Norepinephrine in Goal-Directed Fluid Therapy During General Anesthesia in Elderly Patients Undergoing Spinal Operation: Determining Effective Infusion Rate to Enhance Postoperative Functions

Abstract

Background and Objective

Intraoperative hypotension is a common complication in general anesthesia that could result in different serious complications particularly in elderly patients. This Randomized Clinical Trial (RCT) aims to determine effective continuous infusion rate of norepinephrine to prevent intraoperative hypotension during spinal surgery under general anesthesia in elderly patients.

Methods

This RCT was conducted on elderly patients (n= 108) undergoing general anesthesia for posterior lumbar spinal fusion. The patients were randomly divided into 0.030, 0.060, and 0.090 μg.kg-1.min-1 groups of norepinephrine infusion rates. The outcomes were assessed at entrance to operation room (T0), 15 mins after anesthesia induction (T1), 60 mins following surgery (T2), and immediately after surgery (T3). The intraoperative and postoperative complications and rehabilitation outcomes were comparatively assessed.

Results

All three groups significantly reduced the incidence of delayed wound healing (0.030 vs. 0.060 vs. 0.090 μg.kg^-1.min^-1; 33.3% vs. 10% vs. 10%, P=0.024) and wound infection (26.7% vs. 6.7% vs. 6.7%, P=0.031). Intraoperative total fluid volume and colloids volume in the 0.030 group were significantly higher than 0.060 and 0.090 groups (P=0.005, P=0.003, and P=0.01, respectively). The 0.060 and 0.090 groups significantly increased mean-arterial-pressure than the 0.030 group at T2 and T3. Both 0.060 and 0.090 infusion rates significantly reduced intraoperative hypotension than 0.030 dosage (P=0.01 and P=0.003, respectively). The bradycardia incidence in the 0.090 group was significantly higher than the 0.030 (P=0.026) and 0.060 groups (P=0.038). The 0.060 group decreased the first intake by 1.4 hours (P=0.008) and first flatus by 1.1 hours (P=0.004) and postoperative hospital stay by 1 day (P=0.066).

Conclusion

The 0.060 µg·kg^-1·min^-1 norepinephrine infusion combined with goal-directed fluid therapy exhibited adequate intraoperative management and postoperative outcomes.

Clinical Trial Registration

www.chictr.org.cn, identifier ChiCTR-1900021309.

1. INTRODUCTION

Spine degenerative disease affects a diverse population particularly older adult patients (age range: 65 to 80 years old) [1, 2]. Recent population-based cohort and longitudinal studies have demonstrated that those patients who present with three to four comorbid conditions have significantly improved symptoms and quality of life with low perioperative morbidity and hospital length of stays of 2 to 4 days on average [3-5]. The surgical intervention is a common treatment option to ameolirate symptoms and improve the quality of life [6-8]. General anesthesia is the common route of anesthesia in elderly patients for spinal surgery [9-12]. Intraoperative hypotension is a common complication after general anesthesia, which could result in different serious complications [13, 14]. Research is ongoing to develop effective method for the prevention and management of intraoperative hypotension particularly for elderly populations [15-18]. Findings on the efficacy and usefulness of fluid therapy or vasopressors for the management of intraoperative hypotension induced by general anesthesia in elderly are controversial and the ideal regimen has not been determined [13, 16, 19]. Long operative duration, increased intraoperative blood loss, and increased volumes of crystalloid fluid resuscitation have been reported to be not conducive to early rapid recovery of patients [20]. The goals of intraoperative fluid management are to maintain central euvolemia and to minimize excess salt and water [21]. Excessive fluid loading in elderly patients has been reported to disrupt glycocalyx. Glycocalyx is a carbohydrate-rich layer lining the endothelium that plays a crucial role in maintaining endothelial integrity. Destruction of endothelial glycocalyx can cause periorbital edema and affect prognosis [22]. Pulse pressure variation (PPV) is used as an accurate position indicator on the Frank–Starling curve. The arterial PPV induced by mechanical ventilation has been reported as a reliable and accurate predictor of fluid responsiveness in patients under anesthesia without cardiac arrhythmia. This indicator is a useful measure to predict the adverse hemodynamic effects of fluid depletion as well as the beneficial effects of fluid loading [23]. Norepinephrine is characterized by α-adrenergic agonistic activity in addition to a weak β-adrenergic agonistic activity [24]. This compound does not reduce the heart rate and cardiac output as much as phenylephrine. The prophylactic administration of norepinephrine to prevent and control hypotension during general anesthesia for spinal surgery in elderly patients is a new idea and few studies and data in the literature are scarce. Therefore, this study aims to investigate the effectiveness of prophylactic norepinephrine continuous infusion in preventing hypotension during general anesthesia for spinal surgery in elderly patients using a sequential allocation trial. The main objective is to determine the optimum continuous infusion rate of norepinephrine (0.030, 0.060, and 0.090 μg.kg^-1.min^-1) against intraoperative hypotension during spinal surgery in elderly patients.

2. MATERIALS AND METHODS

2.1. Research Design

This was a single center prospective double blind RCT with parallel group design conducted in the affiliated Hospital of Inner Mongolia Medical University (AHIMMU) (Hohhot, China) from September, 2018 to April, 2019. All experimental procedures of the study were approved by local ethics committee of IHIMMU, Hohhot, China (ethic code: KY2018022), which were in accordance with the ethical standards and regulations of human studies of Helsinki declaration (2014). The study was registered in the Chinese Clinical Trial Registry (website: www.chictr.org.cn, ChiCTR-1900021309) and adhered to CONSORT guidelines. After explaining the experimental procedures and objectives and possible risks and benefits of the study to them, all patients filled and signed written consent form for participation in the study.

2.2. Patients

Elderly patients with lumbar disk herniation or lumbar spondylolisthes candidates of elective lumber spinal fusion and with American Society of Anesthesiologists (ASA) physical status of I/II/III were included in the study. The experimental procedures of the study including surgeries, preoperative and postoperative assessments and follow ups were performed in the department of anesthesiology, AHIMMU, Hohhot, China. Patients with cardiac morbidities, hypertensive disorders, severe hepatic and renal dysfunction, hyperthyroidism, vascular diseases, and digestive ulcer were excluded from the study.

The surgery was posterior lumbar discectomy combined with pedicle screw fixation and intertransverse fusion. The inclusion criteria were the elderly patients with ASA grade less than III and aged 60 to 85 years old. The exclusion criteria were patients with bradycardia (heart rate < 50 beat per minute), cardiac morbidities, heart block greater than the first degree, abnormal liver or renal function, hyperthyroidism, vascular diseases and bowel disease (e.g. ulcerative colitis, Crohn’s disease, and irritable bowel syndrome). During the study at any time, patients were free to discontinue the study. Randomization was performed using an online random number generator. All surgeons, patients, attending anesthesiologists, nurses and follow-up anesthesiologists were blinded to the group assignments.

2.3. Interventions

At the holding area, an IV line was established with an18-gauge IV cannula in the forearm, and an infusion of lactated Ringer’s (LR) solution was started at a minimal rate to keep the vein open. A baseline mean arterial pressure (MAP) was measured in the supine position three times and then averaged. Readings were performed 1 minute apart using an automated device for noninvasive blood pressure assessment. Patients were divided into one of three groups:

Ninety patients were randomly divided into three groups (n=30). The 0.030 group (n = 30) who received 0.030 µg.kg^-1.min^-1 continuous norepinephrine infusion; the 0.060 group (n = 30) who received 0.060 µg.kg^-1.min^-1 continuous norepinephrine infusion; the 0.090 group (n = 30) who received 0.090 µg.kg^-1.min^-1 continuous norepinephrine infusion. All patients received e continuous norepinephrine infusion before the initiation of general anesthesia.

In the operating room, standard monitoring processes were performed for ECG, heart rate, noninvasive blood pressure, and pulse oximetry (SpO₂). 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 predefined dosage of norepinephrine infusion before the initiation of general anesthesia. Then, general anesthesia was induced with fentanyl (20 to 30 µg^-1.kg^-1 IV), lidocaine (1.5 mg^-1.kg^-1 IV), and etomidate (up to 0.3 mg^-1.kg^-1 IV) and maintained with propofol (1.5-3 mg.kg^-1.h^-1) and remifentanil (0.1-0.2 μg·kg^-1·min^-1). Neuromuscular blockade was achieved with rocuronium (0.1mg^-1.kg^-1, IV). Following endotracheal intubation, mechanical ventilation was performed without positive end-expiratory pressure using an inspired oxygen concentration of 50% and tidal volumes of 10 ml^-1.kg^-1 to maintain an end-expiratory P_ETCO₂ at 4~4.5 kPa. The patients’ lungs were ventilated with a tidal volume of 10 mg^-1.kg^-1 of ideal body weight and an inspiration and expiration ratio of 1:2.0 with positive-end expiratory pressure (PEEP) of 5-8cmH₂0. After the final measurement of the assessed variables, the tidal volume was reduced to 8 mL/kg of the ideal body weight. The anesthesia was maintained with continuous infusion of remifentanil (0.3-0.4 μg.kg^-1.min^-1) and propofol (4-6 kg^-1·h^-1) with bispectral index range between 50-60. The arterial pressure waveforms were monitored with Phillips Intellivue MP70 monitors (Intellivue MP70, Philips Medical Systems, Suresnes, France). The primary and secondary outcomes were monitored at four intervals of T₀, T₁, T₂, and T₃ corresponding to before induction, 15 min following anesthesia induction with the patient in a supine position, 60 min following surgery, and at the end of the surgery, respectively. At T₁,T₂,T₃ timepoints, PPV was measured and recorded. The MAP and HR were recorded at T₀,T₁,T₂ and T₃ timepoints.

All patients were continuouslly prophylacticly infused norepinephrine of the respective dosage before the initiation of general anesthesia. 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 fluid response to guide the individual fluid therapy. A PPV less than 13% was defined as the negative fluid responsiveness. If PPV was within the target range and MAP was below the baseline, the ephedrine 5~10mg 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 fluctuated 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 (1.5µg^-1.kg^-1) combined with ondansetron 8 mg. All patients received a basal dose of 0.015µg.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.

2.4. Data Collection

Demographic data, including age, gender, body mass index, duration of surgery, ASA grade, and perioperative complications were recorded. The mean blood pressure and heart rate were monitored and recorded at T₀,T₁,T₂ and T₃ timepoints. 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 fluid 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, first flatus, first ambulation, first intake timing were self-reported by patients and recorded by a follow-up anesthesiologist who was blinded to group assignments during follow-up.

The primary outcome was 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 delayed wound healing was defined 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 deficit 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 were the incidence of intraoperative nausea and vomiting, the frequency of hypertension, the frequency of hypotension, first intake, first flatus, 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 defined as a decrease and increase of >20% of the baseline level, respectively. The definition of bradycardia was set as a heart rate (HR) less than 55 beats per minute. If the HR was below 50 beats per minute, 0.3-0.5 mg atropine depending on patient's HR was injected intravenously. Further details of intraoperative fluid management protocol are presented in Fig. (1).

Fig. (1).

CONSORT flowdiagram of the study on experimental procedures and grouping of the study. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

2.5. Sample Size

The sample size was calculated with the Power Analysis and Sample Size (PASS Version 2019) Software with the incidence of postoperative complications as the primary outcome. The preliminary experimental results showed the incidence of postoperative complications about 40% of the elderly patients undergoing spinal surgery without norepinephrine infusion, while only 10% incidence of postoperative complications following prophylactic dose of 0.060 μg.kg^-1.min^-1 norepinephrine infusion. At the alpha error of 0.05, we calculated that eighty seven patients (n=29 each group) would give 80% power to detect a 20% absolute reduction in the incidence of postoperative complications in the treatment group. However, we defined a sample size of 108 (n=60 each group) to allow the comparisons between the control and each treatment group.

2.6. Statistical Analysis

Statistical Package for Social Science (SPSS) package (SPSS Inc., Chicago, IL, USA) was used for data analysis. Categorical data were expressed as frequency (%). Continuous data were tested for normality and presented as mean ( ± SD) using the Shapiro–Wilk test. The primary outcome (frequency of complications) was analyzed with Fisher’s exact test. Continuous data were analyzed with one-way ANOVA. For repeated measures, a two-way repeated-measures ANOVA was used to evaluate the dose (between-groups factor) and time (repeated measures). Post hoc pairwise comparison was performed with an LSD test. A P-value ≤0.05 was considered statistically significant.

3. RESULTS

A total of 108 patients were screened for eligibility, of which 18 subjects were excluded, 12 patients did not meet inclusion criteria, four patients declined to participate, two patients were excluded for other reasons. Finally, 90 patients were selected to undergo the randomization process (Fig. 2). Overall, there are homogeneity in age (P=0.173), body mass index (BMI) (P=0.085), gender (P=0.843), ASA grade classification (P=0.425), duration of surgery (P=0.563) and preoperative complications (Table 1).

Fig. (2).

Patients’ fluid management flowchart in three dosages of norepinephrine infusion groups (0.030 μg.kg^-1.min^-1 vs. 0.060 μg.kg^-1.min^-1 vs. 0.090 μg.kg^-1.min^-1). (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Table 1.

Demographic and clinical characteristics of the patients in the three dosages of norepinephrine infusion groups.

-	0.030 Group (n=30)	0.060 Group (n=30)	0.090 Group (n=30)	P-value
Age (years)	67.1 ± 2.7	68.0 ± 2.4	66.7 ± 2.8	0.173
BMI (kg/m2)	22.1 ± 2.1	21.1 ± 2.4	22.7 ± 2.1	0.085
Male/Female	8/22	7/23	9/21	0.843
ASA II/III	19/11	14/16	17/13	0.425
Time of surgery (min)	97.0 ± 17.1	99.8 ± 14.2	97.3 ± 11.0	0.563
Preoperative complications		-	-	-
Hypertension (%)	11 (36.7)	10 (33.3)	13 (43.3)	0.718
Diabetes (%)	7 (23.3)	6 (20)	7 (23.3)	0.938
Heart disease (%)	6 (20)	7 (23.3)	7 (23.3)	0.938
Cerebrovascular disease (%)	10 (33.3)	13 (43.3)	11 (36.7)	0.718

Data are expressed as mean (SD), n (%). BMI, body mass index; ASA, American Society of Anesthesiologist.

There was no significant difference in the incidence of total postoperative complications among the three groups (P>0.05). The incidence of delayed wound healing and wound infection were significantly reduced among three groups (P<0.05), especially in the 0.060 and 0.090 groups, compared to the 0.030 group (0.030 vs. 0.060 vs. 0.090: 33.3% vs. 10% vs. 10%, P=0.024; 26.7% vs. 6.7% vs. 6.7%, P=0.031) (Table 2).

Table 2.

The primary and secondary outcomes and incidence of complications in three dosages of norepinephrine infusion groups (0.030 vs. 0.060 vs. 0.090).

Parameter	Intervention			P-value
-	0.030 Group (n=30)	0.060 Group (n=30)	0.090 Group (n=30)	0.030 vs. 0.060	0.060 vs. 0.090	0.030 vs. 0.090	Overall
Total complications (%)	6 (20)	4 (13.3)	5 (16.7)	0.488	0.718	0.739	0.787
Cerebral complications (%)	1 (3.3)	0(0)	1 (3.3)	-	-	1	0.600
Renal complications (%)	0(0)	0(0)	0(0)	-	-	-	-
Pulmonary complications (%)	3 (10)	2 (6.7)	3 (10)	0.640	0.640	1	0.872
Cardiac complications (%)	2 (6.7)	2 (6.7)	1 (3.3)	1	0.554	0.554	0.809
Wound infection (%)	8 (26.7)	2 (6.7)	2 (6.7)	0.038	1	0.038	0.031
Fever (%)	5 (16.7)	3 (10)	2 (6.7)	0.448	0.640	0.228	0.690
Delayed wound healing (%)	10(33.3)	3 (10)	3 (10)	0.028	1	0.028	0.024

Data are expressed as mean ± SD. n (%).

The three groups showed different postoperative first intake and first flatus periods (P<0.01). The 0.060 group enhanced the postoperative first intake by 1.4 hours and first flatus by 1.1 hours, compared to the 0.030 dosage (P<0.01). Similarly, postoperative hospital stay was reduced by around 1 day in the 0.060 and 0.090 groups, compared to 0.030 group (0.030 vs. 0.060 vs. 0.090: 7.1 vs. 6.0 vs. 6.2, P=0.066). There was no significant difference in the incidence of nausea and vomiting among the three groups (Table 3).

Table 3.

Postoperative outcome in three dosages of norepinephrine infusion groups (0.030 vs. 0.060 vs. 0.090).

Parameter	Intervention			P-value
-	0.030 Group (n=30)	0.060 Group (n=30)	0.090 Group (n=30)	0.030 vs. 0.060	0.060 vs. 0.090	0.030 vs. 0.090	Overall
Nausea and vomiting (%)	8 (26.7)	6 (20)	7 (23.2)	0.761	1.000	0.761	0.830
Time of first flatus (h)	5.9 ± 0.8	4.8 ± 1.4	5.1 ± 1.5	0.003	0.562	0.053	0.004
Time of first ambulation (h)	50.5 ± 12.7	48.9 ± 8.9	48.6 ± 8.7	0.818	0.994	0.762	0.749
Time of first intake	6.8 ± 1.3	5.4 ± 1.9	5.8 ± 1.9	0.007	0.647	0.072	0.008
Postoperative hospital stays (d)	7.1 ± 2.3	6.0 ± 2.0	6.2 ± 1.3	0.073	0.914	0.17	0.066

Data are expressed as mean ± SD. n (%).

The patients in the 0.060 and 0.090 dosage groups had higher MAP compared to the 0.030 dosage group at the T₂ (P<0.05) and T₃ time points (P<0.01) (Table 4). The incidence of intraoperative hypotension in the 0.060 and 0.090 dosages of norepinephrine infusion groups were effectively decreased compared to the 0.030 dosage (P<0.01) at T₁, T₂, T₃ timepoints. Intraoperative infusion of crystalloids, colloids and total fluid volume in the 0.030 dosage group were higher than the 0.060 and 0.090 groups (P<0.01). The elderly patients in the 0.090 dosage group exhibited significantly lower HR than the 0.060 and 0.030 groups (P<0.05). The frequency of bradycardia in the patients of the 0.090 group was significantly greater than the 0.030 and 0.060 groups (P<0.05). The number of required atropine injection to the patients in the 0.090 dosage group was significantly higher than the 0.030 and 0.060 groups (P<0.01) (Tables 4 and 5).

Table 4.

Intraoperative hemodynamic parameters’ trend in three dosage of norepinephrine infusion groups (0.030 vs. 0.060 vs. 0.090).

Parameter	T	Intervention			P-value
-	-	0.030 Group (n=30)	0.060 Group (n=30)	0.090 Group (n=30)	0.030 vs. 0.060	0.060 vs. 0.090	0.030 vs. 0.090	overall
MAP	T0	98.3 ± 6.5	98.1 ± 8.1	100.6 ± 7.2	0.888	0.183	0.233	0.342
-	T1	71.8 ± 7.7	73.6 ± 7.8	72.4 ± 7.8	0.390	0.563	0.778	0.680
-	T2	56.9 ± 7.4*※	62.2 ± 7.9	63.3 ± 6.9	0.014	0.615	0.003	0.007
-	T3	75.2 ± 7.6*※	81.2 ± 8.1	81.5 ± 7.7	0.005	0.830	0.003	0.004
HR	T0	72.0 ± 8.0	74.3 ± 6.7	71.7 ± 6.9	0.228	0.178	0.887	0.334
-	T1	63.3 ± 4.8	62.7 ± 6.1	57.1 ± 3.1	0.629	0.001	0.001	0.001
-	T2	72.0 ± 8.6	68.8 ± 7.6	62.3 ± 7.3	0.114	0.002	0.001	0.001
-	T3	74.5 ± 9.5	73.7 ± 9.0	69.3 ± 7.0	0.740	0.048	0.022	0.045
PPV	T1	12.7 ± 1.7	12.5 ± 1.9	12.2 ± 1.1	0.740	0.508	0.322	0.599
-	T2	12.3 ± 1.7	11.5 ± 1.2	11.4 ± 1.3	0.233	0.927	0.199	0.357
-	T3	8.3 ± 0.8	8.0 ± 1.6	8.2 ± 0.9	0.296	0.513	0.695	0.571

Data are expressed as mean ± SD. n (%).

4. DISCUSSION

With advances in public health and continued medical progress, the elderly has been a fast-growing segment of the population [25]. 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 [26]. 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 [27]. It has been demonstrated that perioperative fluid management influences postoperative complication rates. However, the optimal intraoperative fluid regimen is still controversial. Especially in the use of vasopressors, or a goal-directed hemodynamic therapy [16]. To improve the quality of postoperative recovery and shorten hospital stays, significant efforts have been made to facilitate the early return to normal organ function.

Norepinephrine is a vasopressor with potent α-adrenergic agonistic activity in addition to some β-adrenergic 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 [28]. 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 first study to determine the optimal infusion rate of norepinephrine, which in any format manages hypotension and avoids fluid overload complications during general anesthesia for spinal surgery. However, there may be some concern regarding the administration of norepinephrine via peripheral veins. Significant 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 flexor veins. Minor complications (extravasation) occurred at a rate of 5.45% [29]. 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 [30, 31]. 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 [32]. 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.

Hasanin et al. reported both the 0.050 μg·kg^-1·min^-1 and 0.075 μg·kg^-1·min^-1 norepinephrine infusion rates effectively reduced the post-spinal hypotension during cesarean delivery as compared to the 0.025 μg·kg^-1·min^-1 infusion rate [33]. Kee et al. investigated the efficacy of manually titrated prophylactic norepinephrine infusion for maintaining the blood pressure during spinal anesthesia for elective cesarean 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 significant adverse events on the neonatal outcome [34]. The middle dose reported by the previously conducted studies (0.060 μg·kg^-1·min^-1) was used in the current study. Significant reductions in the heart rate were observed in all groups, compared to the baseline reading. However, in the higher doses, a few cases experienced marked bradycardia requiring atropine: 1(3%) case in the 0.030 group, 2 (6.7%) in the 0.060 group, and 8 (26%) in the 0.090 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 [35]. Furthermore, only a few cases of intraoperative hypertension were observed in the three study groups. These events were transient and resolved by stopping the fluid infusion. However, this side effect could not be evaluated in this study. Our primary outcomes were the incidence of complications (cerebral complications, renal complications, pulmonary complications, and cardiac complications). The two higher dose groups had fewer complications, but the differences were not statistically significant, which might be attributed to the anesthesiologists’ concern about the elderly patients with more complications, poor organ reserve function, and reduced tolerance to cyclic fluctuation; 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 beneficial [36]. Herein, we hypothesized that the prophylactic administration of norepinephrine could increase the peripheral vascular resistance, reduce the amount of fluid required to achieve goal-directed fluid therapy, and facilitate 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 fluid therapy in prone patients with minimal alterations in the optimal cutoff values to predict fluid responsiveness [37]. The PPV, contrary to the SVV, does not require additional kits and can reduce the patients’financial burden and the accuracy is similar [38]. 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 significant increase in PPV and SVV but does not alter their abilities to predict the responsiveness of the fluid [38]. 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. Moreover, the volume status of elderly patients suffering from lumbar disk herniation or lumbar spondylolisthesis was different. In future studies, more attention should be paid on perioperative endothelial function, especially 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 fluid therapy (PPV) is more suitable for elderly patients’ intraoperative management who had undergone lumbar spinal fusion during general anesthesia. It can improve the elderly patients’ postoperative outcome and facilitate their rehabilitation process by decreasing the incidence of intraoperative hypotentsion, bradycardia and fluid overloading risk.

Table 5.

Intraoperative basic materials and morbidity in three dosages of norepinephrine infusion groups (0.030 vs. 0.060 vs. 0.090).

Parameter	Intervention			P-value
-	0.030 Group (n=30)	0.060 Group (n=30)	0.090 Group (n=30)	0.030 vs. 0.060		0.060 vs. 0.090	0.030 vs. 0.090	Overall
Total fluid volume	1522.9 ± 138.2	1340.2 ± 240.2	1352.1 ± 298.1	0.001		0.076	0.001	0.005
Crystalloid	1035.1 ± 236.4	883.2 ± 208.1	838.3 ± 231.1	0.029		0.721	0.003	0.003
Colloid	610.2 ± 180.2	475.2 ± 206.7	467.8 ± 205.2	0.026		0.989	0.018	0.01
Autologous blood transfusion	104.2 ± 45.8	101.8 ± 44.4	83.6 ± 26.8	0.971		0.185	0.117	0.096
Blood loss	278.6 ± 128.7	241.3 ± 119.3	226.6 ± 71.6	0.387		0.862	0.163	0.171
Urine output	680.5 ± 253.1	651.1 ± 246.4	603.2 ± 262.9	0.895		0.797	0.980	0.805
Intraoperative hypotension (%)	10 (33.3)	2 (6.7)	1 (3.3)	0.01		0.554	0.003	0.001
Bradycardia (%)	1 (3.3)	2 (6.7)	8 (26.7)	0.554		0.038	0.026	0.012
Intraoperative hypertension (%)	0	0	1 (3.3)	-		1	1	0.364
Atropine requirements (mg)	0.1 ± 0.2	0.1 ± 0.1	0.3 ± 0.3	0.369		0.001	0.005	0.001

Data are expressed as mean ± SD. n (%).

AUTHORS' CONTRIBUTIONS

Conceptualization: TW and FW; methodology: TW ; software: TL; validation: TW, FW; formal analysis: TL; investigation: FW; resources: YM and JW; data curation: TL; writing-original draft preparation: LF and HF; writing-review and editing: FW; visualization: WX; supervision: FW; project administration: WX; funding acquisition: TW. The manuscript has been approved for publication by all listed authors.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

This study was approved by the Ethical Committee of Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia, P.R. China (Ethic code: NO. KY (2018022)).

HUMAN AND ANIMAL RIGHTS

No animals were used in this study. The study on humans was conducted in accordance with the Helsinki Declaration of 1975, as revised in 2013.

CONSENT FOR PUBLICATION

All patients filled and signed written consent form for participation in the study.

STANDARDS OF REPORTING

CONSORT guidelines were followed in this study.

AVAILABILITY OF DATA AND MATERIALS

All the data used in this study are available from the corresponding author [TW] on reasonable request.

FUNDING

This study was supported by the Natural Science foundation of Inner Mongolia autonomous region (2019MS08129), Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (ZYLX201813).

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.